health products and food branch inspectorate - i.e.canada

Good Manufacturing Practices (GMP) for Active Pharmaceutical Ingredients (API) (GUI-0104) - draft for comment of 97

Health Santé 1 Canada Canada 2

3 Our Mandate: 4 To promote good nutrition and informed use of drugs, food, medical devices and natural health products, and to maximize the 5 safety and efficacy of drugs, food, natural health products, medical devices, biologics and related biotechnology products in the 6 Canadian marketplace and health system. 7 8 9 10 11

Health Products and Food Branch Inspectorate 12

13 14 15

Good Manufacturing Practices (GMP) Guidelines for 16

Active Pharmaceutical Ingredients (APIs) 17

18

19

GUI-0104 20

21 22 23

Supersedes: 24 New Document 25

26 Date issued: 27

October 19th, 2012 28 Date of Implementation: 29

Date of coming into force of the amended Food and Drug Regulations 30 31 32 33 34 35

Disclaimer 36 This document does not constitute part of the Food and Drugs Act (Act) or its associated Regulations and in 37 the event of any inconsistency or conflict between that Act or Regulations and this document, the Act or the 38 Regulations take precedence. This document is an administrative document that is intended to facilitate 39 compliance by the regulated party with the Act, the Regulations and the applicable administrative policies. 40 41

42

Health Canada / Health Products and Food Branch Inspectorate


43 Table of Contents 44

45 1. Introduction ................................................................................................................................................ 5 46 47 2. Purpose ........................................................................................................................................................ 5 48 49 3. Scope ............................................................................................................................................................ 5 50 51 4. Quality Management .................................................................................................................................. 8 52

53 4.1 Guiding Principle ................................................................................................................................... 8 54 55 4.2 Relationship among Quality Elements .................................................................................................. 9 56

4.2.1 Quality Assurance ....................................................................................................................... 9 57 4.2.2 Good Manufacturing Practices for APIs ................................................................................... 10 58 4.2.3 Quality Control ........................................................................................................................ 110 59

60 5. Interpretation of Regulations .................................................................................................................. 11 61

62 Regulation C.02.002 .................................................................................................................................. 11 63 Regulation C.02.002.1 ............................................................................................................................... 12 64 65 Sale ............................................................................................................................................................ 12 66 Regulation C.02.003 .................................................................................................................................. 12 67 Regulation C.02.003.1 ............................................................................................................................... 12 68 Regulation C.02.003.2 ............................................................................................................................... 12 69 70 Use in Fabrication .................................................................................................................................... 12 71 Regulation C.02.003.3 ............................................................................................................................... 12 72 73 Premises .................................................................................................................................................... 12 74 Regulation C.02.004 .................................................................................................................................. 12 75 76 Equipment ................................................................................................................................................ 15 77 Regulation C.02.005 .................................................................................................................................. 15 78 79 Personnel .................................................................................................................................................. 17 80 Regulation C.02.006 ................................................................................................................................ 165 81 82 Sanitation .................................................................................................................................................. 19 83 Regulation C.02.007 .................................................................................................................................. 65 84 Regulation C.02.008 .................................................................................................................................. 21 85 86 Raw Material Testing .............................................................................................................................. 23 87 Regulation C.02.009 .................................................................................................................................. 23 88 Regulation C.02.010 .................................................................................................................................. 24 89



90 Manufacturing Control ........................................................................................................................... 27 91 Regulation C.02.011 .................................................................................................................................. 27 92 Regulation C.02.012 .................................................................................................................................. 36 93 94 Quality Control Department .................................................................................................................. 40 95 Regulation C.02.013 .................................................................................................................................. 40 96 Regulation C.02.014 ................................................................................................................................ 419 97 Regulation C.02.015 .................................................................................................................................. 43 98 99 100 Packaging Material Testing .................................................................................................................... 49 101 Regulation C.02.016 .................................................................................................................................. 19 102 Regulation C.02.017 .................................................................................................................................. 19 103 104 Finished Product Testing ........................................................................................................................ 52 105 Regulation C.02.018 .................................................................................................................................. 52 106 Regulation C.02.019 .................................................................................................................................. 54 107

108 Records .......................................................................................................................................................... 55 109

Regulation C.02.020 .................................................................................................................................. 56 110 Regulation C.02.021 .................................................................................................................................. 56 111 Regulation C.02.022 .................................................................................................................................. 57 112 Regulation C.02.023 .................................................................................................................................. 57 113 Regulation C.02.024 .................................................................................................................................. 58 114 Regulation C.02.024.1 ............................................................................................................................... 58 115 116 Samples ..................................................................................................................................................... 64 117 Regulation C.02.025 .................................................................................................................................. 64 118 Regulation C.02.026 .................................................................................................................................. 65 119 120 Stability ..................................................................................................................................................... 65 121 Regulation C.02.027 .................................................................................................................................. 65 122 Regulation C.02.028 .................................................................................................................................. 65 123 124 Sterile Products ........................................................................................................................................ 68 125 Regulation C.02.029 .................................................................................................................................. 65 126 127 Medical Gases .......................................................................................................................................... 68 128 Regulation C.02.030 .................................................................................................................................. 65 129

130 Appendix A ................................................................................................................................................... 70 131

Acronyms ................................................................................................................................................... 70 132 133 Appendix B .................................................................................................................................................... 70 134

Glossary of Terms ..................................................................................................................................... 70 135 136 Appendix C ................................................................................................................................................... 78 137



ICH Q7 Guideline: Section 18 - Specific Guidance for APIs Manufactured by Cell Culture/Fermentation138 ................................................................................................................................................................... 78 139

140 Appendix D ................................................................................................................................................... 81 141

ICH Q7 Guideline: Section 19 – APIs for Use in Clinical Trials .............................................................. 81 142 143 Appendix E .................................................................................................................................................... 82 144

Annexes to the Current Edition of these API GMP Guidelines ................................................................ 83 145 References ................................................................................................................................................. 84 146

147 Appendix F .................................................................................................................................................... 86 148

Cross-walk between ICH Q7 and Guide 0001 documents ........................................................................ 86 149 150

151

152 153 154



1. Introduction 155

Activities relating to (1) dosage form drugs and (2) drugs that are active ingredients are regulated under 156 Divisions 1A and 2 to 4 of Part C of the Food and Drug Regulations. Division 1A specifies the activities for 157 which GMP compliance must be demonstrated prior to the issuance of an establishment licence (EL). Division 158 2 sets out the requirements for the Good Manufacturing Practices (GMP) requirements that apply to all dosage 159 form drugs and active ingredients. Division 3 and 4 set out GMP requirements that are specific to biologic and 160 radio-pharmaceuticals drugs and the Bulk Process Intermediates (BPIs) used to make them. 161

162 This guidance document, Guide 0104, applies only to the manufacture of Active Pharmaceutical Ingredients 163 (APIs). It does not apply to drugs in dosage form or active ingredients that are BPIs used in fabricating a 164 biologic or radiopharmaceutical drug. Further guidance on the fabrication, packaging/labelling, testing, 165 distribution, wholesaling, and importation of drugs in dosage form, and BPIs for radiopharmaceutical and 166 biological drugs is provided in the Good Manufacturing Practices Guidelines, 2009 Edition, Version 2 (GUI-167 0001). Guidance regarding the fabrication, packaging/labelling, testing, distribution, and importation of 168 medical gases is provided in the Good Manufacturing Practices for Medical Gases (GUI-0031). 169 170 This guidance is designed to facilitate compliance by the regulated industry and to enhance consistency in the 171 application of the regulatory requirements. It should be noted that these guidelines do not cover safety aspects 172 for the personnel engaged in the fabrication, packaging/labelling, and testing of APIs (including their 173 intermediates), or aspects of protection of the environment. These controls are inherent responsibilities of the 174 API fabricator, packager/labeller, and tester. 175 176 While the content of this guidance indicates the regulator’s views on how the above mentioned GMP and EL 177 Regulations apply to APIs this guidance does not cover every conceivable case; nor should it be interpreted as 178 specifying the only means of complying with these Regulations in a particular case. Alternative means of 179 complying with these Regulations can be considered with the appropriate scientific justification. Different 180 approaches may be called for as new technologies emerge. 181 182 This document has been written with a view to harmonize with GMP standards from other countries and with 183 those of the Pharmaceutical Inspection Cooperation/Scheme (PIC/S), and the International Conference on 184 Harmonisation (ICH). 185

2. Purpose 186

The purpose of this guide, Guide 0104, is to provide interpretive guidance for Part C, Division 2, of the Food 187 and Drug Regulations for the manufacture of APIs (including their intermediates). These guidelines are 188 designed to facilitate compliance by the regulated industry and to enhance consistency in the application of the 189 regulatory requirements. It is also intended to help ensure that APIs meet the requirements for quality and purity 190 that they purport or are represented to possess. 191

3. Scope 192

The focus of these guidelines is on the manufacture of APIs sold in their final labelled container and/or used in 193 the manufacture of finished dosage forms for human use. Any other further processing steps after the APIs are 194 in their final labelled container are subject to GUI-0001. More specifically, they apply to the fabrication, 195 packaging/labelling, testing, importation, distribution, wholesale, and re-packaging/re-labelling of APIs 196 (including their intermediates). Agents and brokers of APIs will be considered to be wholesalers if they sell 197 APIs as per the definition of "sell" in the Food and Drugs Act. Whether an agent or a broker is acting as a 198 wholesaler within the meaning of the regulatory scheme may require further review/examination. Those who 199

Health Canada / Health Products and Food Branch Inspectorate ____________________________________________________________________________________________________________


are in fact selling APIs shall comply with the requirements defined in Division 2, Part C of the Food and Drug 200 Regulations, as applicable to them. 201 202 Any regulatory requirements other than Division 2 requirements that applies or applied to a given activity or 203 product still applies. 204 205 This Guide does not apply to the following: 206 207

vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma 208

fractionation), and gene therapy APIs. However, it does include APIs that are produced using 209

blood or plasma as raw materials. 210

cell substrates (mammalian, plant, insect or microbial cells, tissue or animal sources including 211

transgenic animals) and early process steps (although they may be subject to GMP) 212

medical gases, 213

bulk-packaged drug (medicinal) products, and 214

manufacturing/control aspects specific to radiopharmaceuticals. 215

Although BPI are defined as active ingredients in subsection C.01A.001(1) of Division 1A in the Food and 216 Drug Regulations, the present guide does not apply to BPIs. For further guidance on the manufacture of BPIs, 217 please refer to the Annex 3 to the Current Edition of the Good Manufacturing Practices Guidelines - Schedule C 218 Drugs (Guide 0026) and Annex 2 to the Current Edition of the Good Manufacturing Practices Guidelines 219 Schedule D Drugs (Biological Drugs) (Guide 0027). 220 221 Health Canada considers fabrication, packaging/labeling, and testing of sterile APIs not terminally sterilized as 222 being finished dosage form manufacture and therefore, these guidelines only apply to the manufacture of sterile 223 APIs up to the point immediately prior to the APIs being rendered sterile. The sterilization and aseptic 224 processing of sterile APIs are not covered by this guidance, but should be performed in accordance with the 225 Good Manufacturing Practices Guidelines, Edition 2009, Version 2 (Guide 0001). 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240

241



242

Table 1: GMP Regulations (Division 2) Applicable to API Activities1 243

1. The following are licensable activities as per Division 1A, Part C of the Food and Drug Regulations: fabrication, 244 packaging/labelling, testing and importation of APIs. 245 2. F: Fabricator, P/L: Packager/Labeller, T: Tester, I: Importer, D: Distributor, W: Wholesaler 246 3. It should be noted that as per the new definition of wholesale as stated in Division 1A, Part C of the Food and Drug 247

Regulations, agents and brokers are considered wholesalers and thus should comply with Health Canada’s GMP regulatory 248 requirements. 249

* Where applicable depending on the nature of the activities. 250 251 252 The point at which production of the API begins and from which compliance to GMPs should be implemented 253 should be based on the application filed with Health Canada, where applicable, and/or other criteria including 254 the below Table 2. Whether or not all steps of a type of manufacturing as shown in Table 1 are completed, the 255 present guidelines apply to the steps shown in blue. The stringency of GMP in API manufacturing should 256 increase as the process proceeds from early API steps to final steps, purification, and packaging. 257

258 259 260 261

Section Regulation F2 P/L T I D W3

Premises C.02.004 √ √ √ √ √

Equipment C.02.005 √ √ √

Personnel C.02.006 √ √ √ √ √ √

Sanitation C.02.007 √ √

C.02.008 √ √

Raw Material Testing C.02.009 √ *

C.02.010 √ *

Manufacturing Control C.02.011 √ √ √

C.02.012 √ √ √ √ √

Quality Control C.02.013 √ √ √ √ √

C.02.014 √ √ √ √ √

C.02.015 √ √ √ √ √ √

Packaging Material Testing C.02.016 √ √

C.02.017 √ √

Finished Product Testing C.02.018 √ √ * √ √ √

C.02.019 √

Records

C.02.020 √ √ √ √

C.02.021 √ √ √ √ √ √

C.02.022 √ √ √

C.02.023 √ √ √ √ √

C.02.024 √ √ √ √ √

C.02.024.1 √ √ √ √ √

Samples C.02.025 √

C.02.026 √

Stability C.02.027 √ * √

C.02.028 √ * √



262 Table 24: Application of Guide 0104 to API Manufacturing 263

Type of manufacturing

Application of this Guide 0104 to steps (shown in blue) used in this type of manufacturing

Chemical Manufacturing

Production of the API Starting

Material

Introduction of the API Starting Material into

process

Production of Intermediate(s)

Isolation and purification

Physical processing, and

packaging

API derived from animal sources

Collection of organ, fluid, or

tissue

Cutting, mixing, and/or initial processing


process



packaging

API extracted from plant sources

Collection of plants

Cutting and initial extraction(s)


process



packaging

Herbal extracts used as API

Collection of plants

Cutting and initial extraction

Further

extraction


packaging

API consisting of comminuted or powdered herbs

Collection of plants and/or

cultivation and harvesting

Cutting/comminuting

Physical

processing, and packaging

Biotechnology: fermentation/cell culture

Establishment of master cell bank and working cell

bank

Maintenance of working cell bank

Cell culture and/or fermentation



packaging

“Classical” Fermentation to produce an API

Establishment of cell bank

Maintenance of the cell bank

Introduction of the cells into

fermentation



packaging

4. From International Conference on Harmonization Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients Q7, 264 November 2000 265

4. Quality Management 266

4.1 Guiding Principle 267

The holder of an establishment licence, or any operation to which the requirements of Division 2 Part C of the 268 Food and Drug Regulations are applicable, must ensure that the fabrication, packaging, testing, labelling, 269 importation, distribution, and wholesaling of APIs comply with these requirements and as per approved 270 specifications in the marketing authorization of the drug in dosage form, and do not place consumers at risk due 271 to inadequate safety and quality. 272 273 The attainment of this quality objective is the responsibility of senior management and requires the participation 274 and commitment of personnel in many different departments and at all levels within the establishment and its 275 suppliers. To ensure compliance, there must be a comprehensively designed and correctly implemented quality 276 management system that incorporates GMP and quality control such as the organisational structure, procedures, 277

Increasing GMP requirements



processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended 278 specifications for quality and purity. The quality management system including all quality related activities 279 should be defined and fully documented, and its effectiveness monitored. All parts of the quality management 280 system should be adequately resourced with qualified personnel, suitable premises, equipment, and facilities. 281

4.2 Relationship among Quality Elements 282

The basic concepts of quality assurance, GMP, and quality control are inter-related. They are described here in 283 order to emphasize their relationships and their fundamental importance to the production and control of APIs. 284

4.2.1 Quality Assurance 285

Quality assurance is a wide-ranging concept that covers all matters that individually or collectively 286 influence the quality of an API. It is the total of the organized arrangements made with the objective of 287 ensuring that APIs are of the quality required for their intended use. Quality assurance therefore 288 incorporates GMP, along with other factors that are outside the scope of these guidelines. 289

290 A system of quality assurance appropriate for the fabrication, packaging, labelling, testing, distribution, 291 importation, and wholesale of APIs should ensure that: 292

293

1. APIs are designed and developed in a way that takes into account the GMP requirements; 294

2. Each manufacturer should establish, document, and implement an effective system for managing 295 quality that involves the active participation of management and appropriate manufacturing 296 personnel. Managerial responsibilities should be clearly specified; 297

3. Systems, facilities and procedures are adequate and qualified, whether they are new or modified; 298

4. Production and control operations are clearly specified; 299

5. Analytical methods and critical processes are validated; 300

6. Arrangements are made for the supply and use of the correct raw and packaging materials; 301

7. All necessary control on APIs and any other in-process monitoring is carried out; 302

8. Outsourced activities are subject to appropriate controls and meet GMP requirements; 303

9. Fabrication, packaging/labelling, testing, distribution, importation, and wholesaling are 304 performed in accordance with established procedures; 305

10. APIs are not released for sale or for further fabrication before the authorized person from the 306 quality control department has approved that each lot has been produced and controlled in 307 accordance with the approved specifications in the marketing authorization of the drug in dosage 308 form and any other regulations relevant to the production, control and release of APIs; 309

11. Satisfactory arrangements exist for ensuring that the APIs are stored, distributed, and 310 subsequently handled in such a way that quality is maintained throughout their shelf life; 311

12. The quality risk management system should ensure that: 312

- the evaluation of the risk to quality is based on scientific knowledge, experience with the 313 process and ultimately links to the protection of the patient and 314

- the level of effort, formality and documentation of the quality risk management process is 315 commensurate with the level of risk. 316



13. The effectiveness, applicability, and continuous improvement of the quality management system 317 is ensured through regular management review and self-inspection; 318

14. An annual product quality review of all APIs should be conducted with the objective of verifying 319 the consistency of the existing process, the appropriateness of current specifications for both raw 320 materials and API to highlight any trends and to identify product and process improvements. 321

4.2.2 Good Manufacturing Practices for APIs 322

GMP are the part of quality assurance that ensures that APIs are consistently produced and controlled in 323 such a way to meet the quality standards appropriate to their intended use, as required by the approved 324 specifications in the market authorization of the drug in dosage form. 325

326 GMP basic requirements are as follows: 327 328

1. Manufacturing processes are clearly defined and controlled to ensure consistency and 329 compliance with approved specifications; 330

2. Critical steps of manufacturing processes and significant changes to the process are validated; 331

3. All necessary key elements for GMP are provided, including the following: 332

- qualified and trained personnel, 333

- adequate premises and space, 334

- suitable equipment and services, 335

- correct materials, containers and labels, 336

- approved procedures and instructions, and 337

- suitable storage and transport. 338

4. Instructions and procedures are written in clear and unambiguous language; 339

5. Operators are trained to carry out and document procedures; 340

6. Records are made during manufacture that demonstrate that all the steps required by the defined 341 procedures and instructions were in fact taken and that the quantity and quality of the API was as 342 expected. Deviations are investigated and documented; 343

7. Records of fabrication, packaging, labelling, testing, distribution, importation, and wholesaling 344 that enable the complete history of a lot to be traced are retained in a comprehensible and 345 accessible form; 346

8. Control of storage, handling, and transportation of the APIs minimizes any risk to their quality; 347

9. A system is available for recalling of APIs from sale; 348

10. Complaints about APIs are examined, the causes of quality defects are investigated, and 349 appropriate measures are taken with respect to the defective APIs and to prevent recurrence. 350

4.2.3 Quality Control 351

Quality control is the part of GMP that is concerned with sampling, specifications, testing, 352 documentation, and release procedures. Quality control ensures that the necessary and relevant tests are 353 carried out and that raw materials, packaging materials, and APIs are released for use or sale, only if 354



their quality is satisfactory. Quality control is not confined to laboratory operations but must be 355 incorporated into all activities and decisions concerning the quality of the API. 356

357 The basic requirements of quality control are as follows: 358

1. Adequate facilities, trained personnel, and approved procedures are available for sampling, 359 inspecting and testing of raw materials, packaging materials, APIs, and, where appropriate 360 monitoring environmental conditions for GMP purposes; 361

1.1 Samples of raw materials, packaging materials, and APIs are taken according to 362 procedures approved by the quality control department; 363

1.2 Test methods are validated; 364

1.3 Records demonstrate that all the required sampling, inspecting, and testing procedures 365 were carried out, and any deviations are recorded and investigated; 366

1.4 Records are made of the results of the self-inspection program; 367

1.5 The procedures for product release include a review and evaluation of relevant 368 production documentation and an assessment of deviations from specified procedures; 369

1.6 No API is released for sale or for further use prior to approval by the quality control 370 department; 371

1.7 Sufficient samples of raw material and final API forms are retained to permit future 372 examination if necessary. 373

5. Interpretation of Regulations 374

Regulation C.02.002 375

In this Division, 376

"medical gas" means any gas or mixture of gases manufactured, sold, or represented for use as a 377 drug; (gaz médical) 378

"packaging material" includes a label; (matériel d'emballage) 379

"specifications" means a detailed description of a drug, the raw material used in a drug, or the 380 packaging material for a drug and includes: 381

382 (a) a statement of all properties and qualities of the drug, raw material or packaging material that are 383

relevant to the manufacture, packaging, and use of the drug, including the identity, potency, and 384 purity of the drug, raw material, or packaging material, 385

386 (b) a detailed description of the methods used for testing and examining the drug, raw material, or 387

packaging material, and 388 389

(c) a statement of tolerances for the properties and qualities of the drug, raw material, or packaging 390 material. (spécifications) 391

392

Regulation C.02.002.1 393 This Division does not apply to fabricating, packaging/labelling, testing, storing and importing of antimicrobial 394 agents. 395



Sale 396


No distributor referred to in paragraph C.01A.003(b) and no importer shall sell a drug unless it has been 398 fabricated, packaged/labelled, tested and stored in accordance with the requirements of this Division. 399

Regulation C.02.003.1 400

No person shall sell a drug that they have fabricated, packaged/labelled, tested or stored unless they have 401 fabricated, packaged/labelled, tested or stored it in accordance with the requirements of this Division. 402


404 (1) No person shall import an active ingredient into Canada for the purpose of sale unless they have in Canada 405

a person who is responsible for its sale. 406 407

(2) No person who imports an active ingredient into Canada shall sell any lot or batch of it unless the name of 408 the person who imports it and the address of the principal place of business in Canada of the person 409 responsible for its sale appear on its label. 410

Use in Fabrication 411


No person shall use an active ingredient in the fabrication of a drug unless it is fabricated, packaged/labelled, 413 tested and stored in accordance with the requirements of this Division. 414

415 Rationale 416 417 The requirements described in these sections are intended to assure that APIs offered for sale at all levels of the 418 supply chain or used in the fabrication of drugs in dosage form are compliant to this Division. 419 420

Interpretation 421 422 1. APIs used in the fabrication of a drug in dosage form should be fabricated, packaged/labelled, tested and 423

stored in accordance with the requirements of this Division. 424 425 2. The distributor of a drug for which that distributor holds the drug identification number and importer of 426

a drug in dosage form should ensure that the API contained in the drug in dosage form meets the 427 requirements of this Division prior to selling the drug in dosage form. 428

Premises429


The premises in which a lot or batch of a drug is fabricated, packaged/labelled or stored shall be designed, 431 constructed and maintained in a manner that 432 433

(a) permits the operations therein to be performed under clean, sanitary and orderly conditions; 434 435



(b) permits the effective cleaning of all surfaces therein; and 436 437

(c) prevents the contamination of the drug and the addition of extraneous material to the drug. 438

439 Rationale 440 441 The design and construction of API establishments is influenced by various factors such as the nature of the API 442 and the location (climatic regions). API establishments should be designed and constructed in a manner that permits 443 cleanliness and orderliness while preventing contamination. The buildings and facilities should be regularly 444 maintained to prevent deterioration of the premises. Ultimately, the objective of all endeavours in the design 445 and construction of an API establishment is product quality. 446

447 Interpretation 448 449 1. Buildings and facilities used in the production of APIs should be located, designed, and constructed to 450

facilitate cleaning, maintenance, and operations as appropriate to the type and stage of production. 451 Facilities should also be designed to minimize potential contamination. Where microbiological 452 specifications have been established for the API, facilities should also be designed to limit exposure to 453 objectionable microbiological contaminants as appropriate. 454

455 2. Buildings used in the production of APIs should be properly maintained and repaired and kept in a clean 456

condition. 457 458 3. Buildings and facilities should have adequate space for the orderly placement of equipment and 459

materials to prevent mix-ups and contamination. 460 461 4. There should be defined areas or other control systems for the following activities: 462

Receipt, identification, sampling, and quarantine of incoming materials, pending release or 463 rejection; 464

Quarantine before release or rejection of APIs; 465

Sampling of APIs; 466

Holding rejected materials before further disposition (e.g., return, reprocessing or destruction); 467

Storage of released materials; 468

Production operations; 469

Packaging and labelling operations; and 470

Laboratory operations. 471

472 5. Laboratory areas/operations should normally be separated from production areas. Some laboratory areas, 473

in particular those used for in-process controls, can be located in production areas, provided the 474 operations of the production process do not adversely affect the accuracy of the laboratory 475 measurements, and the laboratory and its operations do not adversely affect the production process or 476 the APIs. 477

478



6. Drains should be of adequate size and should be provided with an air break or a suitable device to 479 prevent back-siphonage, when appropriate. 480

481 7. All utilities that could impact on product quality (e.g., water, steam, gases, compressed air, and heating, 482

ventilation and air conditioning) should be qualified and appropriately monitored and action should be 483 taken when limits are exceeded. Drawings for these utility systems should be available. 484

485 8. Adequate ventilation, air filtration and exhaust systems should be provided, where appropriate. These 486

systems should be designed and constructed to minimise risks of contamination and cross-contamination 487 and should include equipment for control of air pressure, microorganisms (if appropriate), dust, 488 humidity, and temperature, as appropriate to the stage of manufacture. Particular attention should be 489 given to areas where APIs are exposed to the environment. 490

491 8.1 If air is recirculated to production areas, appropriate measures should be taken to control risks of 492

contamination and cross-contamination. 493 494 9. Adequate, clean washing and toilet facilities should be provided for personnel. These washing facilities 495

should be equipped with hot and cold water as appropriate, soap or detergent, air driers or single service 496 towels. The washing and toilet facilities should be separate from, but easily accessible to, production 497 areas. Adequate facilities for showering and/or changing clothes should be provided, when appropriate. 498

499 10. The flow of materials and personnel through the building or facilities should be designed to prevent mix-500

ups or contamination. 501 502 11. Adequate lighting should be provided in all areas to facilitate cleaning, maintenance, and proper 503

operations. 504 505 12. Permanently installed pipework should be appropriately identified. This can be accomplished by 506

identifying individual lines, documentation, computer control systems, or alternative means. Pipework 507 should be located to avoid risks of contamination of the API. 508

509 13. Dedicated production areas, which can include facilities, air handling equipment and/or process 510

equipment, should be employed in the production of certain classes of highly sensitizing materials, such 511 as penicillins or cephalosporins. 512

513 14. Dedicated production areas should also be considered when material of an infectious nature or high 514

pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) 515 unless validated inactivation and/or cleaning procedures are established and maintained. 516

517 15. Any production activities (including weighing, milling, or packaging) of highly toxic non-518

pharmaceutical materials such as herbicides and pesticides should not be conducted using the buildings 519 and/or equipment being used for the production of APIs. Handling and storage of these highly toxic non-520 pharmaceutical materials should be separate from APIs. 521

522 16. Where water used in the process is treated by the manufacturer to achieve a defined quality, the 523

treatment process should be validated and monitored with appropriate action limits. 524



Equipment 525


The equipment with which a lot or batch of a drug is fabricated, packaged/labelled or tested shall be designed, 527 constructed, maintained, operated and arranged in a manner that 528 529

(a) permits the effective cleaning of its surfaces; 530 531 (b) prevents the contamination of the drug and the addition of extraneous material to the drug; and 532

533 (c) permits it to function in accordance with its intended use. 534

535 Rationale 536 537 The purpose of these requirements is to prevent the contamination of APIs by other APIs, by dust, and by 538 foreign materials such as rust, lubricant and particles coming from the equipment. Contamination problems may 539 arise from poor maintenance, the misuse of equipment, exceeding the capacity of the equipment and the use of 540 worn-out equipment. Equipment arranged in an orderly manner permits cleaning of adjacent areas and does not 541 interfere with other processing operations. It also minimizes the circulation of personnel and optimizes the flow 542 of materials. The fabrication of APIs of consistent quality requires that equipment perform in accordance with 543 its intended use. 544 545

Interpretation 546 547 1. Equipment used in the production of APIs should be of appropriate design and adequate size, and 548

suitably located for its intended use, cleaning, sanitization, where appropriate, and maintenance. 549 550

2. Equipment should be constructed so that surfaces that contact raw materials, intermediates or APIs do 551 not alter the quality of the APIs beyond the official or other established specifications. 552

553 3. Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to 554

prevent contamination or carry-over of a material that would alter the quality of the APIs beyond the 555 official or other established specifications. 556

557 4. Any substances associated with the operation of equipment, such as lubricants, heating fluids or 558

coolants, should not contact APIs so as to alter their quality beyond the official or other established 559 specifications. Any deviations from this should be evaluated to ensure that there are no detrimental 560 effects upon the fitness for purpose of the material. Wherever possible, food grade lubricants and oils 561 should be used. 562

563 5. Closed or contained equipment should be used whenever appropriate. Where open equipment is used, or 564

equipment is opened, appropriate precautions should be taken to minimize the risk of contamination. 565 566 5.1 Ovens, autoclaves and similar equipment contain only one API at a time unless precautions are taken 567

to prevent contamination and mix-ups. 568 569 6. Major equipment (e.g., reactors, storage containers) and permanently installed processing lines used 570

during the production of an API should be appropriately identified. 571



572 7. Schedules, procedures, and logs, including assignment of responsibility, should be established for the 573

preventative maintenance of equipment. 574 575 8. Equipment that is unsuitable for its intended use should be removed from production areas. When 576

removal is not feasible unsuitable equipment should be clearly labelled as such. 577 578 9. Control, weighing, measuring, monitoring and test equipment that is critical for assuring the quality of 579

APIs should be calibrated according to written procedures and an established schedule. Instruments that 580 do not meet calibration criteria should be clearly identified and not used. 581

582 9.1 Equipment calibrations should be performed using standards traceable to certified standards, if 583

existing and current calibration status of critical equipment should be known and verifiable. 584 585 9.2 Deviations from approved standards of calibration on critical instruments should be investigated 586

to determine if these could have had an impact on the quality of the APIs manufacture using this 587 equipment since the last successful calibration. 588

589 10. Weighing and measuring devices should be of suitable accuracy for the intended use. 590 591 11. Production equipment should only be used within its qualified operating range. 592 593 12. GMP related computerized systems should be validated. The depth and scope of validation depends on 594

the diversity, complexity and criticality of the computerized application. 595 596 13. Appropriate installation qualification (IQ) and operational qualification (OQ) should demonstrate the 597

suitability of computer hardware and software to perform assigned tasks. 598 599 14. Commercially available software that has been qualified does not require the same level of testing. If an 600

existing system was not validated at time of installation, a retrospective validation could be conducted if 601 appropriate documentation is available. 602

603 15. Computerized systems should have sufficient controls to prevent unauthorized access or changes to data. 604

There should be controls to prevent omissions in data (e.g. system turned off and data not captured). 605 There should be a record of any data change made that includes the previous entry, who made the 606 change, and when the change was made. 607

608 16. If computerized system breakdowns or failures would result in the permanent loss of records, a back-up 609

system should be provided. A means of ensuring data protection should be established for all 610 computerized systems. 611

612 17. Written procedures should be available for the operation and maintenance of computerized systems. 613 614 18. Qualification is usually carried out by conducting the following activities, individually or combined: 615

Design Qualification (DQ) 616

Installation Qualification (IQ) 617

Operational Qualification (OQ) 618

Performance Qualification (PQ) 619



Personnel 620

621

Regulation C.02.006 622 623 Every lot or batch of a drug shall be fabricated, packaged/labelled, tested and stored under the supervision of 624 personnel who, having regard to the duties and responsibilities involved, have had such technical, academic, 625 and other training as the Director considers satisfactory in the interests of the health of the consumer or 626 purchaser. 627 628

Rationale 629 630 It is essential that qualified and competent personnel be employed to supervise the production and control of 631 APIs. Personnel require education appropriate to the task performed. Education should be supplemented by 632 training and/or experience in the particular task performed. The education, training, competency and attitude of 633 all personnel directly impact’s the quality of the products. 634 635

Interpretation 636 637 1. There should be an adequate number of personnel qualified by appropriate education, training and 638

relevant experience to perform and supervise the fabrication, packaging/labeling, testing, importation, 639 distribution and storage of APIs. 640

641 2. The individual in charge of the quality control department of a fabricator, packager/labeller, tester, 642

importer, distributor, and wholesaler; and the individual in charge of the manufacturing department of a 643 fabricator and packager/labeller 644

645 2.1 should directly control and personally supervise on site, each working shift during which 646

activities under their control are being conducted. 647 648 2.2 may delegate duties and responsibility (e.g., to cover all shifts) to a person qualified by 649

appropriate education, training and relevant experience related to the work being carried out, 650 while remaining accountable for those duties and responsibility. 651

652 3. The responsibilities of all personnel engaged in the fabrication, packaging/labeling, testing, importation, 653

distribution and storage of APIs should be specified in writing and personnel should have authority to 654 carry out their responsibilities. 655

656 4. Training should be regularly conducted by qualified individuals in accordance with a written program. 657 658

4.1 The training should cover, at a minimum, the particular operations that the employee performs 659 and GMP as it relates to the employee's functions. 660

661 4.2 Records of training should be maintained. 662 663 4.3 Training should be periodically assessed and performance of personnel periodically reviewed. 664 665 4.4 Training should be provided prior to implementation of new or revised SOPs. 666

667



4.5 Personnel working in areas where highly active, toxic, infectious, or sensitizing materials are 668 handled should be given specific training. 669

670 5. Consultants and contractors advising on the manufacture and control of APIs should have appropriate 671

education, training, and relevant experience, or any combination thereof, to advise on the subject for 672 which they are retained. 673

674 6. The responsibility for production activities should be described in writing, and should include but not 675

necessarily be limited to: 676 677

6.1 Preparing, reviewing, approving and distributing the instructions for the production of APIs 678 according to written procedures; 679

680 6.2 Producing APIs and, when appropriate, intermediates according to pre-approved instructions; 681 682 6.3 Reviewing all production batch records and ensuring that these are completed and signed; 683 684 6.4 Ensuring that all production deviations are reported and evaluated and that critical deviations are 685

investigated and the conclusions are recorded; 686 687 6.5 Ensuring that production facilities are clean and when appropriate disinfected; 688 689 6.6 Ensuring that the necessary calibrations are performed and records kept; 690 691 6.7 Ensuring that the premises and equipment are maintained and records kept; 692 693 6.8 Ensuring that validation protocols and reports are reviewed and approved; 694 695 6.9 Evaluating proposed changes in product, process or equipment; and 696 697 6.10 Ensuring that new and, when appropriate, modified facilities and equipment are qualified. 698 699

7. The main responsibilities of the quality unit(s) in a manufacturing and packaging/labelling establishment 700 should not be delegated. These responsibilities should be described in writing and should include at a 701 minimum where applicable, 702

703 7.1 Releasing or rejecting all APIs; in some instances, the quality unit(s) can delegate to the 704

production unit the responsibility and authority for release of intermediates, except for those 705 shipped outside the control of the manufacturing company. 706

707 7.2 Establishing a system to release or reject raw materials, intermediates, packaging and labelling 708

materials; 709 710 7.3 Reviewing completed batch production and laboratory control records of critical process steps 711

before release of the API for distribution; 712 713 7.4 Ensuring that critical deviations are investigated and resolved; 714 715 7.5 Approving all specifications and master production documents; 716



717 7.6 Approving all procedures impacting the quality of APIs; 718 719 7.7 Ensuring that internal audits (self-inspections) are performed; 720 721 7.8 Approving API and intermediate contract manufacturers; 722 723 7.9 Approving changes that potentially impact APIs quality; 724 725 7.10 Reviewing and approving validation protocols and reports; 726 727 7.11 Ensuring that quality-related complaints are investigated and resolved; 728 729 7.12 Ensuring that effective systems are used for maintaining and calibrating critical equipment; 730 731 7.13 Ensuring that materials are appropriately tested and the results are reported; 732 733 7.14 Ensuring that there is stability data to support retest or expiry dates and storage conditions on 734

APIs, where appropriate; 735 736 7.15 Performing annual product quality reviews; and 737 738 7.16 Ensuring that quality control equipment is appropriate to testing activities undertaken. 739

740

Sanitation 741

742 Regulation C.02.007 743 744 (1) Every person who fabricates or packages/labels a drug shall have a written sanitation program that shall be 745

implemented under the supervision of qualified personnel. 746 747 (2) The sanitation program referred to in subsection (1) shall include: 748 749

(a) cleaning procedures for the premises where the drug is fabricated or packaged/labelled and for the 750 equipment used in the fabrication or packaging/labelling of the drug; and 751

752 (b) instructions on the sanitary fabrication and packaging/labelling of drugs and the handling of 753

materials used in the fabrication and packaging/labelling of drugs. 754 755

Rationale 756 757 Sanitation in an API plant, as well as employee attitude, influences the quality of drug products. The quality 758 requirement for drug products demand that such products be fabricated and packaged in areas that are free from 759 environmental contamination and free from contamination by another drug. 760 761 There is a significant difference between a finished product production environment (physical process) and an 762 API production environment (chemical process), where aggressive and corrosive reagents may be used. The 763



level of cleanliness required for an API production environment may vary depending on whether it is an open or 764 closed production system and the stage of production. Open production systems (e.g., vessel with no lid) or 765 processes closer to the end of production (e.g., purification) would require a higher level of environmental 766 controls to prevent and/or minimise contamination. Overall, the sanitation program implemented at a site should 767 be effective in preventing unsanitary conditions. 768 769

Interpretation 770 771 1. Written procedures should be established assigning responsibility for sanitation and describing the 772

cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and facilities. 773 774

1.1 There should be an environmental monitoring program with alert and action limits in areas where 775 susceptible products are fabricated or packaged, when applicable. 776

777 1.2 The description of the responsibilities of any outside contractors should be available in writing. 778 779

2. Non-dedicated equipment should be cleaned between productions of different materials to prevent cross-780 contamination. 781

782 3. Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be 783

defined and justified. 784 785 4. Sewage, refuse, and other waste (e.g., solids, liquids, or gaseous by-products from manufacturing) in 786

and from buildings and the immediate surrounding area should be disposed of in a safe, timely, and 787 sanitary manner. Containers and/or pipes for waste material should be clearly identified. 788

789 5. Cleaning procedures should normally be validated. In general, cleaning validation should be directed to 790

situations or process steps where contamination or carryover of materials poses the greatest risk to the 791 API quality. For example, in early production it may be unnecessary to validate equipment cleaning 792 procedures where residues are removed by subsequent purification steps. 793

794 6. Validated analytical methods having sensitivity to detect residues or contaminants should be used. The 795

detection limit for each analytical method should be sufficiently sensitive to detect the established 796 acceptable level of the residue or contaminant. The method’s attainable recovery level should be 797 established. Residue limits should be practical, achievable, and verifiable and based on the most 798 deleterious residue. Limits can be established based on the minimum known pharmacological, 799 toxicological, or physiological activity of the API or its most deleterious component. Further guidance is 800 detailed in Health Canada’s document entitled Cleaning Validation Guidelines (Guide 0028). 801

802 7. Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination 803

for those processes where there is a need to reduce total microbiological count or endotoxins in the API, 804 or other processes where such contamination could be of concern (e.g., non-sterile APIs used to 805 manufacture sterile products). 806

807 8. When necessary, written procedures should also be established for the use of suitable rodenticides, 808

insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the 809 contamination of equipment, raw materials, packaging/labelling materials, intermediates, and APIs. 810

811



9. Written procedures should be established for cleaning of equipment and its subsequent release for use in 812 the manufacture of APIs. Cleaning procedures should contain sufficient details to enable operators to 813 clean each type of equipment in a reproducible and effective manner. These procedures should include: 814

815

Assignment of responsibility for cleaning of equipment; 816

Cleaning schedules, including, where appropriate, sanitizing schedules; 817

A complete description of the methods and materials, including dilution of cleaning agents used 818 to clean equipment; 819

When appropriate, instructions for disassembling and reassembling each article of equipment to 820 ensure proper cleaning; 821

Instructions for the removal or obliteration of previous batch identification; 822

Instructions for the protection of clean equipment from contamination prior to use; 823

Inspection of equipment for cleanliness immediately before use, if practical; and 824

Establishing the maximum time that may elapse between the completion of processing and 825 equipment cleaning, when appropriate. 826

827 10. Where equipment is assigned to continuous production or campaign production of successive batches of 828

the same API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-over 829 of contaminants (e.g. degradants or objectionable levels of micro-organisms). 830

831 11. Records of major equipment use, cleaning, sanitization and/or sterilization and maintenance should 832

show the date, time, if appropriate, product, and batch number of each batch processed in the equipment, 833 and the person who performed the cleaning and maintenance. 834

835 12. Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these 836

proceedings are effective when used during routine production. Equipment cleanliness can be monitored 837 by analytical testing and visual examination, where feasible. Visual inspection can allow detection of 838 gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or 839 analysis. 840

841 13. Dusty operations should be contained. The use of unit or portable dust collectors should be avoided in 842

fabrication areas especially in dispensing, unless the effectiveness of their exhaust filtration is 843 demonstrated and the units are regulatory maintained in accordance with written approved procedures. 844

845 846 Regulation C.02.008 847 848 (1) Every person who fabricates or packages/labels a drug shall have, in writing, minimum requirements for 849

the health and the hygienic behaviour and clothing of personnel to ensure the clean and sanitary 850 fabrication and packaging/labelling of the drug. 851

852 (2) No person shall have access to any area where a drug is exposed during its fabrication or 853

packaging/labelling if the person 854 855

(a) is affected with or is a carrier of a disease in a communicable form; or 856 857

(b) has an open lesion on any exposed surface of the body. 858 859



Rationale 860 861 Employee’s health, behaviour, and clothing may contribute to the contamination of the product. Poor personal 862 hygiene will nullify the best sanitation program and greatly increase the risk of product contamination. 863

864 Interpretation 865 866 1. Personnel and visitors should practice good sanitation and health habits. 867 868 1.1 Requirements concerning cosmetics and jewellery worn by employees should be outlined and 869

observed by employees. 870 871 2. Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body 872

should not engage in activities that could result in compromising the quality of APIs. Any person shown 873 at any time (either by medical examination or supervisory observation) to have an apparent illness or 874 open lesions should be excluded from activities where the health condition could adversely affect the 875 quality of the APIs until the condition is corrected or qualified medical personnel determine that the 876 person's inclusion would not jeopardize the safety or quality of the APIs. 877

878 2.1 Employees should be instructed to report to their supervisor any health conditions they have that 879

could adversely affect APIs. 880 881 2.2 A procedure should be in place to describe the actions to be taken in the event that a person with 882

a communicable disease has been identified as having handled exposed materials. 883 884 3. Personnel should wear clean clothing suitable for the manufacturing activity with which they are 885

involved and this clothing should be changed when appropriate. Additional protective apparel, such as 886 head, face, hand, and arm coverings, should be worn when necessary, to protect APIs from 887 contamination. 888

889 3.1 Soiled protective garments, if reusable, should be stored in separate containers until properly 890

laundered and, if necessary, disinfected or sterilized, according to a written procedure. Washing 891 garments in a domestic setting is unacceptable. 892

893 4. Personnel should avoid direct contact with APIs. 894 895 5. Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated 896

areas separate from the manufacturing areas. 897 898

Raw Material Testing 899

900 Regulation C.02.009 901 902 (1) Each lot or batch of raw material shall be tested against the specifications for that raw material prior to its 903

use in the fabrication of a drug. 904 905



(2) No lot or batch of raw material shall be used in the fabrication of a drug unless that lot or batch of raw 906 material complies with the specifications for that raw material. 907

908 (3) Notwithstanding subsection (1), water may, prior to the completion of its tests under that subsection, be 909

used in the fabrication of a drug. 910 911 (4) Where any property of a raw material is subject to change on storage, no lot or batch of that raw material 912

shall be used in the fabrication of a drug after its storage unless the raw material is retested after an 913 appropriate interval and complies with its specifications for that property. 914

915 (5) Where the specifications referred to in subsections (1), (2) and (4) are not prescribed, they shall 916 917

(a) be in writing; 918 919 (b) be acceptable to the Director who shall take into account the specifications contained in any 920

publication mentioned in Schedule B to the Act; and 921 922

(c) be approved by the person in charge of the quality control department. 923 924 925

Rationale 926 927 The testing of raw materials before their use has three objectives: to confirm the identity of the raw materials, to 928 provide assurance that the quality of APIs will not be altered by raw material defects, and to obtain assurance 929 that the raw materials have the characteristics that will provide the desired quantity or yield in a given 930 manufacturing process. 931

932 Interpretation 933 934 1. Specifications should be established and documented for raw materials, intermediates and where 935

necessary, APIs. In addition, specifications may be appropriate for certain other materials, such as 936 process aids or other materials used during the production of APIs that could critically impact on 937 quality. Acceptance criteria should be established and documented for in-process controls. 938 Specifications are approved and dated by the person in charge of the quality control department or by a 939 designated alternate who meets the requirements described under Regulation C.02.006, Interpretation 1. 940

941 2. Specifications should be of pharmacopoeial or equivalent status and should be in compliance with the 942

current approved specifications in the marketing authorization of the drug in dosage form, where 943 applicable. Additional critical properties or qualities not included in the pharmacopoeia should be 944 included in the specifications, where appropriate. 945

946 3. Raw materials should be purchased against an agreed specification, from suppliers approved by the 947

quality unit(s). 948

949 4. Water used in the manufacture of APIs should be demonstrated to be suitable for its intended use. 950

951 5. Unless otherwise justified, process water should, at a minimum, meet World Health Organization 952

(WHO) guidelines for drinking (potable) water quality. 953

954



6. If drinking (potable) water is insufficient to assure API quality, and tighter chemical and/or 955 microbiological water quality specifications are called for, appropriate specifications for 956 physical/chemical attributes, total microbial counts, objectionable organisms and/or endotoxins should 957 be established. 958

959 7. Where the manufacturer of a non-sterile API either intends or claims that it is suitable for use in further 960

processing to produce a sterile drug, water used in the final isolation and purification steps should be 961 monitored and controlled for total microbial counts, objectionable organisms, and endotoxins. 962

963 8. Analytical methods should be validated unless the method employed is included in the relevant 964

pharmacopoeia or other recognised standard reference. The suitability of all analytical methods used 965 should nonetheless be verified under actual conditions of use and documented. 966

967 9. Methods should be validated to include consideration of characteristics included within the ICH 968

guidelines on validation of analytical methods. The degree of analytical validation performed should 969 reflect the purpose of the analysis and the stage of the API production process. 970

971 Note: Guidance for the validation of particular types of methods can be obtained in publications such 972 as the ICH document entitled ICH Q2 (R1): Validation of Analytical Procedures: Text and Methodology 973 or in any standard listed in Schedule B to the Food and Drugs Act. 974

975 10. Raw materials should be re-evaluated as appropriate to determine their suitability for use (e.g., after 976

prolonged storage or exposure to heat or humidity). 977

978 979 Regulation C.02.010 980 981 (1) The testing referred to in section C.02.009 shall be performed on a sample taken 982

983 (a) after receipt of each lot or batch of raw material on the premises of the fabricator; or 984 985 (b) subject to subsection (2), before receipt of each lot or batch of raw material on the premises of the 986

fabricator, if 987 988

(i) the fabricator 989 990

(A) has evidence satisfactory to the Director to demonstrate that raw materials sold to him by 991 the vendor of that lot or batch of raw material are consistently manufactured in 992 accordance with and consistently comply with the specifications for those raw materials, 993 and 994

995 (B) undertakes periodic complete confirmatory testing with a frequency satisfactory to the 996

Director, and 997 998

(ii) the raw material has not been transported or stored under conditions that may affect its 999 compliance with the specifications for that raw material. 1000

1001 (2) After a lot or batch of raw material is received on the premises of the fabricator, the lot or batch of raw 1002

material shall be tested for identity. 1003



1004

Rationale 1005 1006 Section C.02.010 outlines options as to when the testing prescribed by Section C.02.009 is carried out. The 1007 purchase of raw materials is an important operation that requires a particular and thorough knowledge of the 1008 raw materials and their suppliers. To maintain consistency in the fabrication of APIs, raw materials should 1009 originate from reliable suppliers. 1010

1011 Interpretation 1012 1013 1. Manufacturers of APIs should have a written system for evaluating the suppliers of critical materials. 1014 1015 2. Specific identity testing of each batch of material received on the premises of the API fabricator should 1016

be conducted, with the exception of the materials described below in 4. A supplier's Certificate of 1017 Analysis (CoA) can be used in place of performing other tests, provided that the manufacturer has a 1018 system in place to evaluate suppliers. 1019

1020 2.1 Provided that the identity test referred to in interpretation 2 is performed, the lot of raw material 1021

selected for confirmatory testing may be used in fabrication prior to completion of all tests with 1022 the approval of the quality control department. 1023

1024 3. Vendor approval should include a written evaluation that provides adequate evidence (e.g., past quality 1025

history) that the manufacturer can consistently provide material meeting specifications. Complete 1026 confirmatory testing should be conducted on at least three batches before reducing in-house testing and 1027 after significant change to the manufacturing process. However, as a minimum, complete confirmatory 1028 testing should be performed at appropriate intervals and compared with the CoA. Reliability of CoAs 1029 should be checked at regular intervals. 1030

1031 3.1 A document is issued verifying that the supplier meets the criteria for certification. The document is 1032

approved by the quality control department and is updated at an appropriate frequency. 1033 1034

3.2 A written system should be in place to address re-testing failures and any subsequent re-qualification 1035 of the supplier. 1036

1037 4. Processing aids, hazardous or highly toxic raw materials, other special materials, or materials transferred 1038

to another unit within the company’s control do not need to be tested if the manufacturer’s CoA is 1039 obtained, showing that these raw materials conform to established specifications. Visual examination of 1040 containers, labels, and recording of batch numbers should help in establishing the identity of these 1041 materials. The lack of on-site testing for these materials should be justified and documented. 1042

1043 5. Samples should be representative of the batch of material from which they are taken. Sampling methods 1044

should specify the number of containers to be sampled, which part of the container to sample, and the 1045 amount of material to be taken from each container. The number of containers to sample and the sample 1046 size should be based upon a sampling plan that takes into consideration the criticality of the material, 1047 material variability, past quality history of the supplier, and the quantity needed for analysis. 1048

1049 6. There should be written procedures describing the identification, and testing of materials. 1050 1051



6.1 If any raw material is held in storage after the established re-test date, that raw material is quarantined, 1052 evaluated, and tested prior to use. The re-test date or expiry date is based on acceptable stability data 1053 developed under predefined storage conditions or on any other acceptable evidence. A batch of raw material 1054 can be re-tested and used immediately (i.e., within 30 days) after the re-test as long as it continues to comply 1055 with the specifications and has not exceeded its expiry date. A raw material held in storage after the 1056 established expiry date should not be used in fabrication. 1057

1058 7. If the supplier of a critical material is not the manufacturer of that material, the name and address of that 1059

manufacturer should be known by the API manufacturer. 1060 1061 8. Changing the source of supply of critical raw materials should be treated according to 1062

Section C.02.015, Change Control. 1063 1064 9. Where appropriate, a copy of the residual solvent profile should be obtained. Additionally, for APIs, a 1065

copy of the impurity profile should be obtained. 1066 1067 10. Generally, due to the nature of its operations, a broker or wholesaler of raw materials cannot be directly 1068

certified. However, when a broker or wholesaler supplies materials received from the original vendor 1069 without changing the existing labels, packaging, certificate of analysis, and general information, then 1070 certification of the original source is still acceptable. 1071

1072 11. Conditions of transportation and storage should be such that they prevent alterations to the potency, 1073

purity, or physical characteristics of the raw material. In order to demonstrate that these conditions have 1074 been met, standard operating procedures (SOP) and records for shipping and receiving should be 1075 available and contain: 1076

1077 11.1 the type of immediate packaging for the raw material; 1078 1079 11.2 the labelling requirements including storage conditions and special precautions or warnings, for 1080

the packaged raw material; 1081 1082 11.3 the mode(s) of transportation approved for shipping the packaged raw material; 1083 1084 11.4 a description of how the packaged raw material is sealed; 1085 1086 11.5 the verification required to ensure that each package has not been tampered with and that there 1087

are no damaged containers; and 1088 1089 11.6 evidence that special shipping requirements (e.g., refrigeration) have been met if required. 1090

1091 12. If a delivery or shipment of raw material is made up of different batches, each batch should be 1092

considered as separate for the purposes of sampling, testing, and release. 1093 1094 13. If the same batch of raw material is subsequently received, this batch should also be considered as 1095

separate for the purpose of sampling, testing, and release. However, full testing to specifications may not 1096 be necessary on such a batch provided that all the following conditions are met: 1097

1098 13.1 a specifically discriminating identity test is conducted; 1099

1100



13.2 the raw material has not been repackaged or re-labelled; 1101 1102 13.3 the raw material is within the re-test date assigned by its vendor; and 1103 1104 13.4 evidence is available to demonstrate that all pre-established transportation and storage conditions 1105

have been maintained. 1106

Manufacturing Control 1107

1108 Regulation C.02.011 1109 1110 (1) Every fabricator, packager/labeller, distributor referred to in paragraph C.01A.003(b) and importer of a 1111

drug shall have written procedures prepared by qualified personnel in respect of the drug to ensure that the 1112 drug meets the specifications for that drug. 1113

1114 (2) Every person required to have written procedures referred to in subsection (1) shall ensure that each lot or 1115

batch of the drug is fabricated, packaged/labelled and tested in compliance with those procedures. 1116 1117

Rationale 1118 1119 This Regulation requires that measures be taken to maintain the integrity of an API from the moment the 1120 various raw materials enter the plant to the time the API is released for sale or for further fabrication. These 1121 measures ensure that all manufacturing processes are clearly defined, systematically reviewed in light of 1122 experience, and demonstrated to be capable of consistently manufacturing APIs of the required quality that 1123 comply with their established specifications. Refer to Table 2 for the point at which production of the API 1124 begins and from which compliance to GMPs should be implemented. 1125

1126 Interpretation 1127 1128 1. Access to production areas is restricted to designated personnel. 1129

1130 2. All handling of raw materials, products, and packaging materials such as receipt, identification, 1131

quarantine, storage, sampling, testing, approval or rejection of materials, tracking, labeling, packaging, 1132 dispensing, processing, and distribution should be done in accordance with written procedures or 1133 instructions and recorded. 1134

1135 3. Validation should extend to those operations determined to be critical to the quality and purity of the 1136

API. 1137 1138

3.1 Changes to production processes, systems, equipment, or materials that may affect product 1139 quality and/or process reproducibility should be validated prior to implementation. The potential 1140 impact of the proposed change on the quality of the API should be evaluated. A classification 1141 procedure may help in determining the level of testing, validation, and documentation needed to 1142 justify changes to a validated process. Changes can be classified (e.g., as minor or major) 1143 depending on the nature and extent of the changes, and the effects these changes may impart on 1144 the process. Scientific judgement should determine what additional testing and validation studies 1145 are appropriate to justify a change in a validated process. 1146

1147



Where no significant changes have been made to the system or process, and a quality review 1148 confirms that the system or process is consistently producing material meeting its specifications, 1149 there is normally no need for revalidation. 1150

1151 4. A written validation protocol should be established that specifies how validation of a particular process 1152

will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other 1153 designated units. For more information on this matter, refer to Section 12 Validation of the ICH Q7 1154 Guidelines. 1155

1156 4.1 The validation protocol should specify critical process steps and acceptance criteria as well as the 1157

type of validation to be conducted (e.g. retrospective, prospective, concurrent) and the number of 1158 process runs. 1159

1160 4.2 A validation report that cross-references the validation protocol should be prepared, summarising 1161

the results obtained, commenting on any deviations observed, and drawing the appropriate 1162 conclusions, including recommending changes to correct deficiencies. 1163

1164 4.3 Any variations from the validation protocol should be documented with appropriate justification. 1165

1166 5. Before starting process validation activities, appropriate qualification of critical equipment and ancillary 1167

systems should be completed. 1168 1169 6. Any deviation should be documented and explained. Any critical deviation (i.e. one which could affect 1170

the quality and/or purity of the API) should be investigated. 1171 1172 7. Actual yields should be compared with expected yields at designated steps in the production process. 1173

Expected yields with appropriate ranges should be established based on previous laboratory, pilot scale, 1174 or manufacturing data. Deviations in yield associated with critical process steps should be investigated 1175 to determine their impact or potential impact on the resulting quality of affected batches. 1176

1177 8. Residual materials can be carried over into successive batches of the same API as long as there is 1178

adequate control. Examples include residue adhering to the wall of a micronizer, residual layer of damp 1179 crystals remaining in a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals 1180 from a processing vessel upon transfer of the material to the next step in the process. Such carryover 1181 should not result in the carryover of degradants or microbial contamination that may adversely alter the 1182 established API impurity profile. 1183

1184 9. Provided that validated changeover procedures are implemented, non-medicinal products may be 1185

fabricated or packaged/labelled in areas or with equipment that is also used for the production of APIs. 1186

1187 10. Facilities where APIs are fabricated, packaged and labelled should be inspected immediately before use 1188

to ensure that all materials not needed for the next operation have been removed. This examination 1189 should be documented in the batch production records, the facility log, or other documentation system. 1190

1191 11. Production operations should be conducted in a manner that will prevent contamination of APIs by other 1192

materials. 1193 1194



12. In-process sampling should be conducted using procedures designed to prevent contamination of the 1195 sampled material and other APIs. Procedures should be established to ensure the integrity of samples 1196 after collection. 1197

1198 13. Written procedures should be established to monitor the progress and control the performance of 1199

processing steps that cause variability in the quality characteristics of APIs. In-process controls and their 1200 acceptance criteria should be defined based on the information gained during the development stage or 1201 historical data. 1202

1203 14. The acceptance criteria and type and extent of testing can depend on the nature of the API being 1204

manufactured, the reaction or process step being conducted, and the degree to which the process 1205 introduces variability in the product’s quality. Less stringent in-process controls may be appropriate in 1206 early processing steps, whereas tighter controls may be appropriate for later processing steps (e.g., 1207 isolation and purification steps). 1208

1209 15. Critical in-process controls (and critical process monitoring), including the control points and methods, 1210

should be stated in writing and approved by the quality unit(s). 1211 1212 16. In-process controls can be performed by qualified production department personnel and the process 1213

adjusted without prior quality unit(s) approval if the adjustments are made within pre-established limits 1214 approved by the quality unit(s). All tests and results should be fully documented as part of the batch 1215 record. 1216

1217 17. Written procedures should describe the sampling methods for in-process materials, intermediates, and 1218

APIs. Sampling plans and procedures should be based on scientifically sound sampling practices. 1219 1220 18. Precautions to avoid contamination should be taken when APIs are handled after purification. 1221 1222 19. Production operations on different products should not be carried out simultaneously or consecutively in 1223

the same room unless there is no risk of mix-up or cross-contamination. 1224 1225

19.1 Appropriate measures should be established and implemented to prevent cross-contamination from 1226 personnel, materials, etc. moving from one dedicated area to another. 1227 1228 19.2 Where applicable, checks should be carried out to ensure that removable and interchangeable 1229 transfer lines and other pieces of equipment used for the transfer of materials from one area to another 1230 are correctly connected. 1231

1232 20. Equipment should be identified as to its contents, including name of product and batch number, and its 1233

cleanliness status by appropriate means. 1234 1235 21. The processing status of major units of equipment should be indicated either on the individual units of 1236

equipment or by appropriate documentation, computer control systems, or alternative means. 1237 1238 22. Rejected materials should be identified and controlled under a quarantine system designed to prevent 1239

their unauthorized use in manufacturing. 1240 1241 23. Materials to be reprocessed or reworked should be appropriately controlled to prevent unauthorized use. 1242 1243



24. Upon receipt and before acceptance, each container or grouping of containers of materials should be 1244 examined visually for correct labelling (including correlation between the name used by the supplier and 1245 the in-house name, if these are different), container damage, broken seals and evidence of tampering or 1246 contamination. All containers are verified to ensure that the information on the order, the delivery note and 1247 the vendor's labels is in agreement. 1248

1249 24.1Materials should be held under quarantine until they have been sampled, examined or tested as 1250 appropriate, and released for use. 1251

1252 25. Before incoming materials are mixed with existing stocks (e.g., solvents or stocks in silos), they should 1253

be identified as correct, tested, if appropriate, and released. Procedures should be available to prevent 1254 discharging incoming materials wrongly into the existing stock. 1255

1256 26. If bulk deliveries are made in non-dedicated tankers, there should be assurance of no cross-1257

contamination from the tanker. Means of providing this assurance could include one or more of the 1258 following: 1259

certificate of cleaning, 1260

testing for trace impurities, and 1261

audit of the supplier. 1262 1263 27. Intermediates held for further processing should be stored under appropriate conditions to ensure their 1264

suitability for use. 1265 1266 28. Materials should be transported in a manner that does not adversely affect their quality. 1267 1268 29. Special transport or storage conditions for an API should be stated on the label. 1269 1270 30. Sampling should be conducted at defined locations and by procedures designed to prevent 1271

contamination of the material sampled and contamination of other materials. 1272 1273 31. Containers from which samples are withdrawn should be opened carefully and subsequently reclosed. 1274

They should be marked to indicate that a sample has been taken. 1275 1276 32. Large storage containers, and their attendant manifolds, filling and discharge lines should be 1277

appropriately identified. 1278 1279 33. Each container or grouping of containers (batches) of materials should be assigned and identified with a 1280

distinctive code, batch, or receipt number. The identification number should be used in recording the 1281 disposition of each batch. A system should be in place to identify the status of each batch. All materials 1282 should be labeled with an expiry date or re-test date, when applicable. 1283

1284 34. Materials should be handled and stored in a manner to prevent degradation, contamination, and cross-1285

contamination. 1286 1287 35. Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, 1288

suitably spaced to permit cleaning and inspection. 1289 1290 36. Materials should be stored under conditions and for a period that have no adverse effect on their quality, 1291

and should normally be controlled so that the oldest stock is used first. 1292



1293 37. Certain materials in suitable containers can be stored outdoors, provided identifying labels remain 1294

legible and containers are appropriately cleaned before opening and use. 1295 1296 38. Raw materials for API manufacturing should be weighed or measured under appropriate conditions that 1297

do not affect their suitability for use. 1298 1299 39. Critical weighing, measuring, or subdividing operations should be witnessed or subjected to an 1300

equivalent control. Prior to use, production personnel should verify that the materials are those specified 1301 in the batch record for the intended API. 1302

1303 40. Other critical activities should be witnessed or subjected to an equivalent control. 1304 1305 41. All quality related activities should be recorded at the time they are performed. 1306 1307 42. When entries are made in records, these should be made indelibly in spaces provided for such entries, 1308

directly after performing the activities, and should identify the person making the entry. Corrections to 1309 entries should be dated and signed and leave the original entry still readable. 1310

1311 43. All documents related to the manufacture of APIs should be prepared, reviewed, approved and 1312

distributed according to written procedures. 1313 1314 43.1 To ensure uniformity from batch to batch, master production instructions for each API should be 1315

prepared, dated, and signed by one person and independently checked, dated, and signed by a person in 1316 the quality unit(s). 1317

1318

Manufacturing Operations 1319 1320 44. Master production documents should include: 1321 1322

The name of the API being manufactured, batch size, and an identifying document reference 1323 code, if applicable; 1324

A complete list of raw materials and intermediates designated by names or codes sufficiently 1325 specific to identify any special quality characteristics; 1326

An accurate statement of the quantity or ratio of each raw material or intermediate to be used, 1327 including the unit of measure. Where the quantity is not fixed, the calculation for each batch size 1328 or rate of production should be included. Variations to quantities should be included where they 1329 are justified; 1330

The production location and major production equipment to be used; 1331

The procedures, or reference to the procedures, to be used in production; 1332

Detailed production instructions, including the: 1333

sequences to be followed, 1334

ranges of process parameters to be used, 1335

sampling instructions and in-process controls with their acceptance criteria, where 1336 appropriate, 1337



time limits for completion of individual processing steps and/or the total process, where 1338 appropriate; and 1339

expected yield ranges at appropriate phases of processing or time; 1340

Where appropriate, special notations and precautions to be followed, or cross-references to 1341 these; and 1342

The instructions for storage of the intermediate or API to assure its suitability for use, including 1343 the labelling and packaging materials and special storage conditions with time limits, where 1344 appropriate. 1345

1346 45. Batch production records should be prepared for each API and should include complete information 1347

relating to the production and control of each batch. The batch production record should be checked 1348 before issuance to assure that it is the correct version and a legible accurate reproduction of the 1349 appropriate master production instruction. If the batch production record is produced from a separate 1350 part of the master document, that document should include a reference to the current master production 1351 instruction being used. 1352

1353 46. The batch production records should be numbered with a unique batch or identification number, dated 1354

and signed when issued. In continuous production, the product code together with the date and time can 1355 serve as the unique identifier until the final number is allocated. 1356

1357 47. Documentation of completion of each significant step in the batch production records (batch production 1358

and control records) should include: 1359 1360

Dates and, when appropriate, times of commencement and completion of significant intermediate 1361 stages (blending, heating, etc.) and of production; 1362

Identity of major equipment (e.g., reactors, driers, mills, etc.) used; 1363

Specific identification of each batch, including weights, measures, and batch numbers of raw 1364 materials, intermediates, or any reprocessed materials used during manufacturing; 1365

Actual results recorded for critical process parameters; 1366

Any sampling performed; 1367

Signatures of the persons performing and directly supervising or checking each critical step in 1368 the operation; 1369

In-process and laboratory test results 1370

Actual yield at appropriate phases or times; 1371

Any deviation noted, its evaluation, investigation conducted (if appropriate) or reference to that 1372 investigation if stored separately; and 1373

Results of release testing. 1374

Upon completion, the signature of the person responsible for the processing operations. 1375

1376 48. If a material is subdivided for later use in production operations, the container receiving the material 1377

should be suitable and should be so identified that the following information is available: 1378 1379



Material name and/or item code; 1380

Receiving or control number or distinctive code; 1381

Weight or measure of material in the new container; and 1382

Re-evaluation or retest date if appropriate. 1383 1384

Blending 1385 1386 49. For the purpose of this document, blending is defined as the process of combining materials within the 1387

same specification to produce a homogeneous API. In-process mixing of fractions from single batches 1388 (e.g., collecting several centrifuge loads from a single crystallization batch) or combining fractions from 1389 several batches for further processing is considered to be part of the production process and is not 1390 considered to be blending. 1391

1392 50. Out-of-Specification batches should not be blended with other batches for the purpose of meeting 1393

specifications. Each batch incorporated into the blend should have been manufactured using an 1394 established process and should have been individually tested and found to meet appropriate 1395 specifications prior to blending. 1396

1397 51. Acceptable blending operations include but are not limited to: 1398 1399

Blending of small batches to increase batch size 1400

Blending of tailings (i.e., relatively small quantities of isolated material) from batches of the same 1401 API to form a single batch. 1402

1403 52. Blending processes should be adequately controlled and documented and the blended batch should be 1404

tested for conformance to established specifications where appropriate. 1405 1406 53. The batch record of the blending process should allow traceability back to the individual batches that 1407

make up the blend. 1408 1409 54. Where physical attributes of the API are critical (e.g., APIs intended for use in solid oral dosage forms 1410

or suspensions), blending operations should be validated to show homogeneity of the combined batch. 1411 Validation should include testing of critical attributes (e.g., particle size distribution, bulk density, and 1412 tap density) that may be affected by the blending process. 1413

1414 55. If the blending could adversely affect stability, stability testing of the final blended batches should be 1415

performed. 1416 1417 56. The expiry or retest date of the blended batch should be based on the manufacturing date of the oldest 1418

tailings or batch in the blend. 1419 1420

1421 1422 Recovery 1423 1424



57. Recovery (e.g., from mother liquor or filtrates) of reactants, s, or the API is considered acceptable, 1425 provided that approved procedures exist for the recovery and the recovered materials meet specifications 1426 suitable for their intended use. 1427

1428 58. Solvents can be recovered and reused in the same processes or in different processes, provided that the 1429

recovery procedures are controlled and monitored to ensure that solvents meet appropriate standards 1430 before reuse or co-mingling with other approved materials. 1431

1432 59. Fresh and recovered solvents and reagents can be combined if adequate testing has shown their 1433

suitability for all manufacturing processes in which they may be used. 1434 1435 60. The use of recovered solvents, mother liquors, and other recovered materials should be adequately 1436

documented. 1437

1438 Packaging Operations 1439 1440 61. Packaging operations should be performed according to comprehensive and detailed written operating 1441

procedures or specifications, which include identification of equipment and packaging lines used to 1442 package the API or intermediate, the dedication of packaging lines, if necessary, and disposal 1443 procedures for the unused printed packaging materials. Packaging orders should be individually 1444 numbered. 1445

1446 62. Labelling operations should be designed to prevent mix-ups. There should be physical or spatial 1447

separation from operations involving other APIs. 1448 1449 63. Access to the label storage areas should be limited to authorised personnel. 1450 1451 64. Packaging and labelling facilities should be inspected immediately before use to ensure that all materials 1452

not needed for the next packaging operation have been removed. This examination should be 1453 documented in the batch production records, the facility log, or other documentation system. 1454

1455 65. There should be documented procedures designed to ensure that correct packaging materials and labels 1456

are used. 1457 1458 66. Printing devices used to print labels for packaging operations should be controlled to ensure that all 1459

imprinting conforms to the print specified in the batch production record. 1460 1461 67. Printed labels issued for a batch should be carefully examined for proper identity and conformity to 1462

specifications in the master production record. The results of this examination should be documented. 1463 1464 68. Containers should be clean and, where indicated by the nature of the API, sanitized to ensure that they 1465

are suitable for their intended use. These containers should not be reactive, additive, or absorptive so as 1466 to alter the quality of the API beyond the specified limits. 1467

1468 69. If containers are re-used, they should be cleaned in accordance with documented procedures and all 1469

previous labels should be removed or defaced. 1470 1471 70. Labels used on containers of APIs should indicate the name or identifying code, the batch number of the 1472

product, and storage conditions, when such information is critical to assure the quality of APIs. 1473



1474 71. If the API is intended to be transferred outside the control of the manufacturer’s material management 1475

system the name and address of the manufacturer, quantity of contents, and special transport conditions 1476 and any special legal requirements should also be included on the label. For APIs with an expiry date, 1477 the expiry date should be indicated on the label and CoA. For APIs with a retest date, the retest date 1478 should be indicated on the label and/or the CoA. 1479

1480 72. API containers that are transported outside of the manufacturer's control should be sealed in a manner 1481

such that, if the seal is breached or missing, the recipient will be alerted to the possibility that the 1482 contents may have been altered. 1483

1484 73. Packaged and labelled APIs should be examined to ensure that containers and packages in the batch 1485

have the correct label. This examination should be part of the packaging operation. Results of these 1486 examinations should be recorded in the batch production or control records. 1487

1488 74. Procedures should be used to reconcile the quantities of labels issued, used, destroyed and returned. All 1489

discrepancies found between the number of containers labelled and the number of labels issued should 1490 be investigated, and the investigation should be approved by the quality unit(s). 1491

1492 75. Upon completion of the labelling operation, all excess labels bearing batch numbers or other batch-1493

related printing should be destroyed and their destruction recorded. Returned labels should be stored in a 1494 manner that prevents mix-ups and provides proper identification. 1495

1496 76. Obsolete and out-dated labels should be destroyed. 1497 1498 77. All APIs that have been packaged and labelled should be held in quarantine and be so identified until 1499

released by the quality controlled department. 1500 1501 78. Packaging orders should include the following information (recorded at the time each action is taken): 1502

1503 78.1 The date(s) and time(s) of the packaging operations; 1504 1505 78.2 The identification of the personnel who are supervising packaging operations and the withdrawal 1506

of bulks; 1507 1508 78.3 The identification of the operators of the different significant steps; 1509 1510 78.4 Whether the correct products and packaging materials are used; 1511 1512 78.5 Whether any on-line printing is correct; 1513 1514 78.6 Whenever possible, samples of the printed packaging materials used, including specimens 1515

bearing the batch number, expiry date, and any additional overprinting, are attached to packaging 1516 orders. 1517

1518 78.7 The correct functioning of line monitors; 1519 1520 78.8 Handling precautions applied to a partly packaged product; and 1521 1522



78.9 Notes on any special problems, including details of any deviation from the packaging 1523 instructions with written approval by qualified personnel. 1524

1525 Product Quality Review 1526 1527 79. Regular quality reviews of APIs should be conducted by the fabricator with the objective of verifying 1528

the consistency of the process. Such reviews should normally be conducted and documented annually 1529 and should include at least: 1530

1531 79.1 A review of critical in-process control and critical API test results; 1532 1533 79.2 A review of all batches that failed to meet established specification(s); 1534 1535 79.3 A review of all critical deviations or non-conformances or related investigations; 1536 1537 79.4 A review of results of the stability monitoring program; 1538 1539 79.5 A review of all quality-related returns, complaints and recalls; and 1540 1541 79.6 A review of adequacy of corrective actions. 1542

1543 80. The results of this review should be evaluated and an assessment made of whether corrective action or 1544

any revalidation should be undertaken. Reasons for such corrective action should be documented. 1545 Agreed corrective actions should be completed in a timely manner. 1546

1547 1548

Regulation C.02.012 1549 (1) Every fabricator, packager/labeller, distributor referred to in section C.01A.003, importer and wholesaler 1550

of a drug shall maintain 1551 1552

(a) a system of control that permits complete and rapid recall of any lot or batch of the drug that is on 1553 the market; and 1554

1555 (b) a program of self-inspection. 1556

1557 (2) Every fabricator and packager/labeller and, subject to subsections (3) and (4), every distributor referred to 1558

in paragraph C.01A.003(b) and importer of a drug shall maintain a system to ensure that any lot or batch 1559 of the drug fabricated and packaged/labelled on premises other than their own is fabricated and 1560 packaged/labelled in accordance with the requirements of this Division. 1561

1562 (3) Subsection (2) does not apply to a distributor if the drug is fabricated, packaged/labelled and tested in 1563

Canada by a person who holds an establishment licence that authorizes those activities in respect of that 1564 drug. 1565

1566 (4) Subsection (2) does not apply to a distributor or importer if the drug is fabricated or packaged/labelled in 1567

an MRA country of a recognized building and both of the following requirements are met: 1568 1569

(a) the address of the building is set out in their establishment licence; and 1570 1571



(b) they retain a copy of the batch certificate for each lot or batch of the drug that they receive. 1572 1573

Rationale 1574 1575 The purpose of a recall is to remove from the market, an API that represents an undue health risk. 1576 1577 APIs that have left the premises of a fabricator, packager/labeller, distributor, and importer of APIs can be 1578 found in a variety of locations. Depending on the severity of the health risk, it may be necessary to recall a 1579 product to one level or another. Fabricators, packagers/labellers, distributors, and importers of APIs are 1580 expected to be able to recall to the consumer level if necessary. Additional guidance recalls can be found in 1581 Health Canada’s document entitled Recall Policy (POL-0016). 1582 1583 This Regulation also requires fabricators, packagers/labellers, distributors, and importer to maintain a program 1584 of self-inspection. The purpose of self-inspection is to evaluate the compliance with GMP in all aspects of 1585 production and quality control. The self-inspection program is designed to detect any shortcomings in the 1586 implementation of GMP and to recommend the necessary corrective/preventative actions. 1587 1588 APIs offered for sale in Canada, regardless of whether they are domestically produced or imported, must meet 1589 the requirements of Part C, Division 2 of the Food and Drug Regulations. Contract production and analysis 1590 must be correctly defined, agreed on, and controlled in order to avoid misunderstandings that could result in a 1591 product, work or analysis of unsatisfactory quality. Normally, a written agreement exists between the parties 1592 involved, and that document clearly establishes the duties of each party. 1593

1594 Interpretation 1595

1. Procedures should exist for notifying responsible management in a timely manner of regulatory 1596 inspections, serious GMP deficiencies, product defects and related actions (e.g., quality related 1597 complaints, recalls, regulatory actions, etc.). 1598

1599 2. There should be a written procedure that defines the circumstances under which a recall of an API 1600

should be considered. 1601 1602 3. The recall procedure should designate who should be involved in evaluating the information, how a 1603

recall should be initiated, who should be informed about the recall and how the recalled material should 1604 be treated), specifically: 1605

1606 3.1 Health Canada should be notified of the recall. 1607 1608

3.2 The recall procedure should be capable of being put into operation at any time, during and 1609 outside normal working hours. 1610

1611 3.3 The progress and efficacy of the recall should be assessed and recorded at intervals, and a final 1612

report should be issued (including a final reconciliation). 1613 1614 4. In the event of a serious or potentially life-threatening situation, local, national, and/or international 1615

authorities should be informed and their advice sought. 1616 1617



5. A system should be in place by which the distribution of each batch of API can be readily determined to 1618 permit its recall. This should include any products in transit, any samples removed by the quality control 1619 department and any professional samples that have been distributed. 1620

1621 5.1 A written agreement should clearly describe respective responsibilities of all parties involved with 1622 respect to recalls. 1623

1624 6. Unless there is an alternative system to prevent the unintentional or unauthorized use of quarantined, 1625

rejected, returned, or recalled materials, separate storage areas should be assigned for their temporary 1626 storage until the decision as to their future use has been taken. 1627

1628 7. All Canadian and foreign establishments involved in the production, distribution and importation, 1629

including agents, brokers, re-packagers and re-labellers of the recalled API should be notified and 1630 maintain records of all complaints and recalls that come to their attention. 1631

1632 8. In order to verify compliance with Division 2, Part C of the Food and Drug Regulations, regular self-1633

inspections appropriate to the type of operations of the company should be performed in accordance 1634 with an approved schedule. 1635

1636 8.1 The self-inspection team should include personnel who are suitably trained and qualified in 1637

GMP. 1638 1639

9. A comprehensive written procedure that describes the function of the self-inspection program should be 1640 available. Self-inspection findings and corrective/preventive actions should be documented and brought 1641 to the attention of responsible management of the firm. Agreed corrective/preventive actions should be 1642 completed in a timely and effective manner. 1643

1644 10. All Canadian and foreign establishments involved in the production, distribution and importation, 1645

including agents, brokers, re-packagers and re-labellers should comply with GMP as defined in this 1646 Guide. 1647

1648 11. Contract manufacturers (including laboratories) should be evaluated by the contract giver to ensure 1649

GMP compliance of the specific operations occurring at the contract sites. 1650 1651 12. To ensure compliance of contractors performing fabrication or packaging/labelling: 1652 1653

12.1 All arrangements for contract fabrication or packaging/labelling should be in accordance with the 1654 current regulatory filing for the API concerned. 1655

1656 12.2 There should be a written agreement covering the fabrication or packaging/labelling arranged 1657

among the parties involved. The agreement should specify their respective GMP responsibilities 1658 relating to the fabrication or packaging/labelling and quality control of the API. 1659

1660 12.2.1 Technical aspects of the agreement should be drawn up by qualified personnel suitably 1661

knowledgeable in pharmaceutical technology, and GMP. 1662 1663

12.2.2 The agreement should permit the contract giver to audit the facilities of the contractor for 1664 compliance with GMP. 1665

1666



12.2.3 The agreement should clearly describe as a minimum who is responsible for: 1667 1668

12.2.3.1 purchasing, sampling, testing and releasing materials; 1669 1670

12.2.3.2 undertaking production, quality, and in-process controls; and 1671 1672

12.2.3.3 process validation. 1673 1674

12.2.4 No subcontracting of any work should occur without written authorization by the contract 1675 giver and approval of the arrangements. 1676

1677 12.2.5 The agreement should specify the way in which the quality control department of the 1678

distributor or importer releasing the lot or batch for sale, ensuring that each lot or batch 1679 has been fabricated and packaged/labelled in compliance with the current regulatory 1680 filing for the API concerned, if applicable. 1681

1682 12.2.6 The agreement should describe the handling of raw materials, packaging materials, 1683

intermediates, and APIs if they are rejected. 1684 1685

12.3 The contractor’s complaint/recall procedures should specify that any records relevant to 1686 assessing the quality of a drug product in the event of complaints or a suspected defect are 1687 accessible to the distributor or importer. 1688

1689 12.4 The fabricator, packager/labeller, distributor, or importer should provide the contractor with all 1690

the information necessary to carry out the contracted operations correctly in accordance with the 1691 current regulatory filing associated to the API concerned, if applicable, and any other legal 1692 requirements. The fabricator, packager/labeller, distributor, or importer should ensure that the 1693 contractor is fully aware of any problems associated with the product, work or tests that might 1694 pose a hazard to premises, equipment, personnel, other materials or other products. 1695

1696 12.4.1 Changes in the process, equipment, test methods, specifications, or other contractual 1697 requirements should not be made unless the contract giver is informed and approves the changes. 1698

1699 12.5 The fabricator, packager/labeller, distributor, or importer should be responsible for assessing the 1700

contractor’s continuing competence to carry out the work or tests required in accordance with the 1701 principles of GMP described in these guidelines. 1702

1703 12.5.1 Distributors of APIs fabricated, packaged/labelled and tested at Canadian sites should be 1704

required only to have a copy of the relevant valid Canadian establishment licence held by 1705 the Canadian fabricator or packager/labeller or tester. 1706

1707 12.5.2 Importers of APIs fabricated, packaged/labelled, or tested at a foreign site should meet 1708

the requirements described in Health Canada’s document entitled Guidance on Evidence 1709 to Demonstrate Drug GMP Compliance of Foreign Sites (GUI-0080) and hold a copy of 1710 the Drug Master File or have a letter of authorization if submitted to Health Canada. 1711

1712



Quality Control Department 1713

1714 Regulation C.02.013 1715 1716 (1) Every fabricator, packager/labeller, wholesaler, distributor referred to in section C.01A.003 and importer 1717

of a drug shall have on their premises in Canada a quality control department that is supervised by 1718 personnel described in section C.02.006. 1719

1720 (2) Except in the case of a wholesaler or a distributor referred to in paragraph C.01A.003(a), the quality 1721

control department shall be a distinct organizational unit that functions and reports to management 1722 independently of any other functional unit, including the manufacturing, processing, packaging or sales 1723 unit. 1724

1725

Rationale 1726 1727 Quality control is the part of GMP concerned with sampling, specifications, and testing and with the 1728 organization, documentation, and release procedures. This Regulation ensures that the necessary and relevant 1729 tests are actually carried out and that raw materials and packaging materials are not released for use and APIs 1730 are not released for sale or further used in fabrication, until their quality has been judged to be satisfactory. 1731 Quality control is not confined to laboratory operations but must be incorporated into all activities and decisions 1732 concerning the quality of the API. 1733 1734 The rationale for the requirement that the quality control department be supervised by qualified personnel is 1735 outlined under Regulation C.02.006. 1736

1737 Interpretation 1738 1739 1. The quality unit(s) should be involved in all quality-related matters. 1740

2. The quality unit should review and approve all quality-related documents. Approved written procedures 1741 should be available for the receipt, identification, quarantine, storage, handling, sampling, label, 1742 dispensing, processing, distribution, inspecting, testing, and approval or rejection of raw materials, 1743 packaging materials, in-process APIs, APIs, and for the recording and storage of laboratory data. 1744

3. The quality unit of the fabricator and packager/labeller should be independent of production and fulfill 1745 both quality assurance (QA) and quality control (QC) responsibilities. This can be in the form of 1746 separate QA and QC units or a single individual or group, depending upon the size and structure of the 1747 organization. 1748

4. The quality unit should have access to facilities, including a laboratory, trained personnel, and 1749 equipment in order to fulfill its duties and responsibilities. 1750

Regulation C.02.014 1751 1752 (1) Except in the case of a wholesaler or a distributor referred to in paragraph C.01A.003(a), no lot or batch of 1753

a drug may be made available for further use in fabrication or for sale or unless the person in charge of the 1754 quality control department approves the further use or the sale. 1755

1756



(2) A drug that is returned to its fabricator, packager/labeller, wholesaler, distributor referred to in section 1757 C.01A.003 or importer shall not be made available for further use in fabrication or for further sale unless 1758 the person in charge of the quality control department approves the further use or further sale. 1759

1760 (3) No lot or batch of a raw material or packaging/labelling material shall be used in the fabrication or 1761

packaging/labelling of a drug unless the person in charge of the quality control department approves the 1762 use. 1763

1764 (4) No lot or batch of a drug shall be reprocessed unless the person in charge of the quality control department 1765

approves the reprocessing. 1766 1767

Rationale 1768 1769 The responsibility for the approval of all raw materials, packaging materials and APIs is vested in the quality 1770 control department. It is very important that adequate controls be exercised by this department in order to 1771 guarantee the quality of the end product. 1772 1773 To maintain this level of quality, it is also important to examine all returned APIs and to give special attention 1774 to reprocessed APIs. 1775

1776 Interpretation 1777 1778 1. All decisions made by the quality control department pursuant to Regulation C.02.014 should be signed 1779

and dated by the person in charge of the quality control department or by a designated alternate meeting 1780 the requirements described under Section C.02.006. The names of such persons should be specified. 1781

1782 2. No materials should be released or used before the satisfactory completion of evaluation by the quality 1783

unit(s) unless there are appropriate systems in place to allow for such use (e.g. release under quarantine 1784 or the use of raw materials or intermediates pending completion of evaluation). 1785

1786 3. The assessment for the release of APIs should embrace all relevant factors, including the production 1787

conditions, the results of in-process testing, the fabrication and packaging documentation, compliance 1788 with the APIs specifications, an examination of the finished package, and if applicable, a review of the 1789 storage and transportation conditions. 1790

1791 4. APIs should only be released for distribution to third parties after they have been released by the quality 1792

unit(s). APIs can be transferred under quarantine to another unit under the company’s control when 1793 authorized by the quality unit(s) and if appropriate controls and documentation are in place. 1794

1795 5. The quality control department should ensure that raw materials and packaging materials are 1796

quarantined, sampled, tested, and released prior to their use in the fabrication or packaging/labelling of a 1797 drug. 1798

1799 6. Any deviations, non-conformances, and malfunctions or errors including those pertaining to premises, 1800

equipment, sanitation, and testing, such as deviations from written procedures, that may have an impact 1801 on the quality and safety of batches pending release or released, should be assessed, investigated, if 1802 needed, and the rationale and decisions documented. 1803

1804



7. Rejected materials, such as APIs, failing to meet established specifications, should be identified as such 1805 and quarantined. These materials should be returned to the vendors, reprocessed, reworked, or 1806 destroyed. Actions taken should be recorded. 1807

1808 8. APIs returned from the market should be destroyed unless it has been ascertained that their quality is 1809

satisfactory. Returned goods may be considered for resale only after they have been assessed in 1810 accordance with a written procedure. The reason for the return, the nature of the product, the storage and 1811 transportation conditions, the API’s condition and history, and the time elapsed since it was originally 1812 sold should be taken into consideration in this assessment. If the conditions under which returned APIs 1813 have been stored or shipped before or during their return or the condition of their containers casts doubt 1814 on their quality, the returned APIs should be reprocessed, reworked, or destroyed, as appropriate. 1815 Records of any action taken should be maintained. 1816

1817 8.1 Documentation should be available to support the rationale to place returned goods into 1818

inventory for further resale. 1819 1820

Reworking 1821 9. Approval by the quality control department should be required prior to reworking of any lot or batch of 1822

API. An investigation into the reason for non-conformance should be performed. Documented scientific 1823 data of the reworked batch must show that the reworked product is of equivalent quality to that produced 1824 by the original process. These data may include validation, such as concurrent validation, testing, and 1825 stability testing, if warranted. 1826

1827 9.1 Concurrent validation is often the appropriate validation approach for rework procedures. This 1828

allows a protocol to define the rework procedure, how it will be carried out, and the expected 1829 results. If there is only one batch to be reworked, then a report should be written and the batch 1830 released once it is found to be acceptable. 1831

1832 10. Procedures should provide for comparing the impurity profile of each reworked batch against batches 1833

manufactured by the established process. Where routine analytical methods are inadequate to 1834 characterize the reworked batch, additional methods should be used and records maintained. 1835

1836 Reprocessing 1837 11. The reprocessing of any lot or batch of an API should be given prior approval by the quality control 1838

department. Approval of a reprocessed lot or batch of an API by the quality control department should 1839 be based on documented scientific data, which may include validation. The reprocessing of products by 1840 repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., 1841 distillation, filtration, chromatography, milling) that fail to meet their specifications should be 1842 undertaken only in exceptional cases. 1843

1844 11.1 Reprocessing should be permitted only when the following conditions are met: 1845

1846 11.1.1 The quality of the API is not affected; 1847 1848 11.1.2 The reprocessed lot meets specifications; 1849 1850 11.1.3 The reprocessing is done in accordance with a defined procedure approved by the quality 1851

control department; 1852 1853



11.1.4 All risks have been evaluated; 1854 1855 11.1.5 Complete records of the reprocessing are kept; 1856 1857 11.1.6 A new batch number is assigned; and 1858 1859 11.1.7 Validation demonstrates that the quality of the API is not affected. 1860

1861 11.2 If such reprocessing is used for a majority of batches, such reprocessing should be included as 1862

part of the standard manufacturing process. 1863 1864 12. Introducing un-reacted material back into a process and repeating a chemical reaction is considered to be 1865

reprocessing unless it is part of the established process. Such reprocessing should be preceded by careful 1866 evaluation to ensure that the quality of the API is not adversely impacted due to the potential formation 1867 of by-products and over-reacted materials. 1868

1869 Regulation C.02.015 1870 (1) All fabrication, packaging/labelling, testing, storage, and transportation methods and procedures that may 1871

affect the quality of a drug shall be examined and approved by the person in charge of the quality control 1872 department before their implementation. 1873

1874 (2) The person in charge of the quality control department shall cause to be investigated any complaint or 1875

information that is received respecting the quality of a drug or its deficiencies or hazards and cause any 1876 necessary corrective action to be taken, in the case where the complaint or information relates to an 1877 activity over which the department exercises quality control. 1878

1879 (2.1) In the case where the complaint or information that is received does not relate to an activity over 1880

which the quality control department exercises quality control, the person in charge of the 1881 department shall forward the complaint or information to the person in charge of the quality control 1882 department that exercises quality control over that activity. 1883

1884 (3) The person in charge of the quality control department shall cause all tests or examinations required 1885

pursuant to this Division to be performed by a competent laboratory. 1886 1887

Rationale 1888 1889 Pharmaceutical processes and products must be designed and developed taking GMP requirements into account. 1890 Production procedures and other control operations are independently examined by the quality control 1891 department. Proper storage, transportation, and distribution of materials and products minimize any risk to their 1892 quality. Complaints may indicate problems related to quality. By tracing their causes, one can determine which 1893 corrective measures should be taken to prevent recurrence. Having tests carried out by a competent laboratory 1894 provides assurance that test results are genuine and accurate. 1895 1896 Written agreements for consultants and contract laboratories should describe the education, training, and 1897 experience of their personnel and the type of services provided, and should be available for examination and 1898 inspection. Records of the activities contracted should be maintained. 1899

1900 1901 1902



Interpretation 1903 1904 1. Procedures should exist for notifying responsible management in a timely manner of regulatory 1905

inspections, serious GMP deficiencies, product defects and related actions (e.g., quality related 1906 complaints, recalls, regulatory actions, etc.). 1907

1908 2. A formal change control system should be established to evaluate all changes that may affect the 1909

production and control of the API. 1910 1911 3. Written procedures should provide for the identification, documentation, appropriate review, and 1912

approval of changes in raw materials, specifications, analytical methods, facilities, support systems, 1913 equipment (including computer hardware), processing steps, labelling and packaging materials, and 1914 computer software. 1915

1916 4. Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate 1917

organisational units, and reviewed and approved by the quality unit(s). 1918 1919 5. The potential impact of the proposed change on the quality of the API should be evaluated. A risk 1920

assessment may help in determining the level of testing, validation, and documentation needed to justify 1921 changes to a validated process. Changes can be classified (e.g., as minor or major) depending on the 1922 nature and extent of the changes, and the effects these changes may impart on the process. Scientific 1923 judgement should determine what additional testing and validation studies are appropriate to justify a 1924 change in a validated process. 1925

1926 5.1 The potential for critical changes to affect established retest or expiry dates should be evaluated. 1927

If necessary, samples of the API produced by the modified process can be placed on an 1928 accelerated stability program and/or can be added to the stability monitoring program. 1929

1930 5.2 After the change has been implemented, there should be an evaluation of the first batches 1931

produced or tested under the change. 1932 1933

5.3 When implementing approved changes, measures should be taken to ensure that all documents 1934 affected by the changes are revised. 1935

1936 6. Current dosage form manufacturers should be notified of changes from established production and 1937

process control procedures that can impact the quality of the API. 1938 1939 7. All establishments involved in the production, distribution and importation, including agents, brokers, 1940

re-packagers and re-labellers should have a system in place to record and investigate all quality related 1941 complaint, whether received orally or in writing, in accordance with written procedures. 1942

1943 7.1 If the situation warrants, the agents, brokers, traders, distributors, re-packagers, or re-labellers 1944

should review the complaint with the original API manufacturer in order to determine whether 1945 any further action, either with other customers who may have received this API or with the 1946 regulatory authority, or both, should be initiated. The investigation into the cause for the 1947 complaint or recall should be conducted and documented by the appropriate party. 1948

1949



7.2 Where a complaint is referred to the original API manufacturer, the record maintained by the 1950 agents, brokers, traders, distributors, re-packagers, or re-labellers should include any response 1951 received from the original API manufacturer (including date and information provided). 1952

1953 8. Records of complaints should be retained in order to evaluate trends, product-related frequencies, and 1954

severity with a view to taking additional, and if appropriate, immediate corrective actions. All decisions 1955 and measures taken as a result of a complaint are recorded. 1956

1957 9. All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to 1958

ensure that raw materials, APIs, and labels and packaging materials conform to established standards of 1959 quality and/or purity. Specifications and test procedures should be consistent with those included in the 1960 registration/filing. There can be specifications in addition to those in the registration/filing. 1961 Specifications, sampling plans, and test procedures, including changes to them, should be drafted by the 1962 appropriate organizational unit and reviewed and approved by the quality unit(s). 1963

1964 10. Laboratory controls should be followed and documented at the time of performance. Any departures 1965

from the above described procedures should be documented and explained. 1966 1967 11. Laboratory control records should include complete data derived from all tests conducted to ensure 1968

compliance with established specifications and standards, including examinations and assays, as 1969 follows: 1970

1971 11.1 A description of samples received for testing, including the material name or source, batch 1972

number or other distinctive code, date sample was taken, and, where appropriate, the quantity 1973 and date the sample was received for testing; 1974

1975 11.2 A statement of or reference to each test method used; 1976 1977 11.3 A statement of the weight or measure of sample used for each test as described by the method; 1978

data on or cross-reference to the preparation and testing of reference standards, reagents and 1979 standard solutions; 1980

1981 11.4 A complete record of all raw data generated during each test, in addition to graphs, charts, and 1982

spectra from laboratory instrumentation, properly identified to show the specific material and 1983 batch tested; 1984

1985 11.5 A record of all calculations performed in connection with the test, including, for example, units 1986

of measure, conversion factors, and equivalency factors; 1987 1988 11.6 A statement of the test results and how they compare with established acceptance criteria; 1989 1990 11.7 The signature of the person who performed each test and the date(s) the tests were performed; 1991

and 1992 1993 11.8 The date and signature of a second person showing that the original records have been reviewed 1994

for accuracy, completeness, and compliance with established standards. 1995 1996



12. Reagents and standard solutions should be prepared and labelled following written procedures. “Use by” 1997 dates should be applied as appropriate for analytical reagents or standard solutions and data should be 1998 available to support these expiry or retest dates. 1999

2000 13. The tests should be performed by a laboratory that meets all relevant GMP requirements. 2001 2002 13.1 Laboratory facilities are designed, equipped, and maintained to conduct the required testing. 2003 2004

13.1.1 In the microbiology laboratory, environmental monitoring should be performed 2005 periodically. Microbiological cultures and sample testing are handled in an environment that 2006 minimizes contamination. 2007 2008 13.1.2 The facility used to perform the sterility testing should comply with the microbial limits 2009 of an aseptic production facility which should conform to Grade A within a Grade B background 2010 or in an isolator of a Grade A within and appropriate background and limited access to non-2011 essential personnel. 2012 2013

13.2 The individual in charge of the laboratory should meet personnel requirements as set forth in 2014 C.02.006 and report to a person who has these qualifications. 2015 2016 13.3 Laboratory personnel should be sufficient in number and be qualified to carry out the work they 2017 undertake. 2018 2019 13.4 Laboratory control equipment and instruments should be suited to the testing procedures 2020 undertaken. Equipment and records should be maintained as per the interpretations under C.02.005. 2021

13.5 Computerized systems are validated, and spreadsheets are qualified. 2022

13.6 Water used for microbial and analytical tests meets the requirements of the test or assay in which it 2023 is used. 2024

13.7 All reagents and culture media are recorded upon receipt or preparation. Reagents made up in the 2025 laboratory are prepared according to written procedures and are properly labelled. 2026

13.7.1 Prepared media are sterilized using validated procedures and stored under controlled 2027 temperatures. 2028

13.7.2 Prepared media are properly labelled with the lot numbers, expiration date and media 2029 identification. The expiration date of media is supported by growth-promotion testing results that 2030 show the performance of the media still meets acceptance criteria up to the expiration date. 2031

13.7.3 Sterility and growth-promotion testing are performed to verify the suitability of culture 2032 media. 2033

13.7.4 All purchased ready to use media received are accompanied by a certificate of analysis 2034 with expiry date and recommended storage conditions as well as the quality control organisms 2035 used in growth-promotion and selectivity testing of that media. 2036



13.7.4.1 Procedures are in place to ensure that media are transported under conditions 2037 that minimize the loss of moisture and control the temperature. 2038

13.7.4.2 Media are stored according to the vendor's instructions. 2039

13.7.4.3 Sterility and growth-promotion testing are performed on lots received, unless the 2040 vendor is certified. Periodic confirmatory testing is performed for ready to use media 2041 received from each certified vendor. 2042

13.7.4.4 Records are maintained. 2043

13.8 Reference standards are available in the form of the current reference standards listed in Schedule 2044 B to the Food and Drugs Act. When such standards have not been established or are unavailable, 2045 primary standards can be used. Secondary standards are verified against a Schedule B reference standard 2046 or against the primary standard and are subject to complete confirmatory testing at predetermined 2047 intervals. All reference standards are stored and used in a manner that will not adversely affect their 2048 quality. Records relating to their testing, storage, and use are maintained. 2049

13.9 Out of Specification (OOS) test results are investigated to determine the cause of the OOS. 2050

13.9.1 Procedures are in place to describe the steps to be taken as part of the investigation. 2051

13.9.2 In the case of a clearly identified laboratory or statistical error, the original results may be 2052 invalidated, and the test repeated. The original results should be retained and an explanation 2053 recorded. 2054

13.9.3 When there is no clearly identified laboratory or statistical error and retesting is 2055 performed, the number of retests to be performed on the original sample and/or a new sample, 2056 and the statistical treatment of the resultant data, are specified in advance in the procedure. 2057

13.9.4 All valid test results, both passing and suspect, should be reported and considered in 2058 batch release decisions. 2059

13.9.5 If the original OOS result is found to be valid, a deviation is raised against the batch and 2060 a complete investigation is conducted. The investigation is performed in accordance to written 2061 procedures and should include an assessment of root cause, description of corrective actions and 2062 preventive actions carried out and conclusions. 2063

13.9.6 Out-of-specification investigations are not normally needed for in-process tests that are 2064 performed for the purpose of monitoring and/or adjusting the process. 2065 2066

14. Primary reference standards should be obtained as appropriate for the manufacture of APIs. The source 2067 of each primary reference standard should be documented. Records should be maintained of each 2068 primary reference standard’s storage and use in accordance with the supplier’s recommendations. 2069 Primary reference standards obtained from an officially recognised source are normally used without 2070 testing if stored under conditions consistent with the supplier’s recommendations. 2071

2072 15. Where a primary reference standard is not available from an officially recognized source, an “in-house 2073

primary standard” should be established. Appropriate testing should be performed to establish fully the 2074



identity and purity of the primary reference standard. Appropriate documentation of this testing should 2075 be maintained. 2076

2077 16. Secondary reference standards should be appropriately prepared, identified, tested, approved, and stored. 2078

The suitability of each batch of secondary reference standard should be determined prior to first use by 2079 comparing against a primary reference standard. Each batch of secondary reference standard should be 2080 periodically re-qualified in accordance with a written protocol. 2081

2082 17. Complete records should also be maintained for: 2083 2084

17.1 Any modifications to an established analytical method; 2085 2086 17.2 Periodic calibration of laboratory instruments, apparatus, gauges, and recording devices; 2087 2088 17.3 All stability testing performed on APIs; and 2089 2090 17.4 Out-of-specification investigations. 2091 2092

18. Where critical data are entered into a computerized system manually, there should be an additional 2093 check on the accuracy of the entry. This can be done by a second operator or by the system itself. 2094

2095 19. Incidents related to computerized systems that could affect the quality of APIs or the reliability of 2096

records or test results should be recorded and investigated. 2097 2098 20. Changes to the computerized system should be made according to a change procedure and should be 2099

formally authorized, documented and tested. Records should be kept of all changes, including 2100 modifications and enhancements made to the hardware, software and any other critical component of the 2101 system. These records should demonstrate that the system is maintained in a validated state. 2102

2103 21. All deviation, investigation, and OOS reports should be reviewed as part of the batch record review 2104

before the batch is released. 2105 2106 22. To ensure compliance of contractors conducting testing required under Part C, Division 2 of the Food 2107

and Drug Regulations: 2108 2109

22.1 A Canadian contract laboratory must have a relevant valid current establishment licence. A foreign 2110 testing site must be listed on a Canadian establishment licence, as described in Health Canada’s policy 2111 document entitled Guidance on Evidence to Demonstrate Drug GMP Compliance of Foreign Sites 2112 (Guide 0080), 2113

2114 22.2 All arrangements for external testing are in accordance with the current regulatory filing for the 2115 API concerned if applicable, including the testing of intermediates, raw materials, packaging materials 2116 and all other necessary testing required by Part C, Division 2 of the Food and Drug Regulations, and 2117

2118 22.3 There is a written agreement covering all activities of testing between the contract laboratory and 2119 the parties involved. The agreement specifies their respective responsibilities relating to all aspects of 2120 testing. 2121

2122



22.3.1 Technical aspects of the agreement are drawn up by qualified personnel suitably 2123 knowledgeable in analysis and GMP, 2124

2125 22.3.2 The agreement permits audit of the facilities and operations of the external laboratory, 2126 2127 22.3.3 The agreement clearly describes, as a minimum, who is responsible for: 2128 2129

22.3.3.1 collection, transportation and storage conditions of samples before testing, 2130 2131 22.3.3.2 keeping stability samples at predetermined temperatures and humidity, if 2132 applicable, 2133

2134 22.3.3.3 testing methods to be used, limits and test method validation, and 2135 2136 22.3.3.4 retention of analytical results and supporting documentation (additional guidance 2137 under interpretations of C.02.021). 2138 2139

22.3.4 No subcontracting of any work should occur without written authorization. 2140 2141 23. The manufacturer should ensure that the contract acceptor (contractor) for transportation of the API 2142

knows and follows the appropriate transport and storage conditions. 2143

Packaging Material Testing 2144

2145

Regulation C.02.016 2146 2147 (1) Each lot or batch of packaging material shall, prior to its use in the packaging of a drug, be examined or 2148

tested against the specifications for that packaging material. 2149 2150 (2) No lot or batch of packaging material shall be used in the packaging of a drug unless the lot or batch of 2151

packaging material complies with the specifications for that packaging material. 2152 2153 (3) The specifications referred to in subsections (1) and (2) shall 2154 2155

(a) be in writing; 2156 2157 (b) be acceptable to the Director who shall take into account the specifications contained in any 2158

publication mentioned in Schedule B to the Act; and 2159 2160

(c) be approved by the person in charge of the quality control department. 2161 2162

Regulation C.02.017 2163 2164 (1) The examination or testing referred to in section C.02.016 shall be performed on a sample taken 2165 2166

(a) after receipt of each lot or batch of packaging material on the premises of the person who packages a 2167 drug; or 2168

2169



(b) subject to subsection (2), before receipt of each lot or batch of packaging material on the premises of 2170 the person who packages a drug, if 2171

2172 (i) that person 2173

2174 (A) has evidence satisfactory to the Director to demonstrate that packaging materials sold to 2175

him by the vendor of that lot or batch of packaging material are consistently 2176 manufactured in accordance with and consistently comply with the specifications for 2177 those packaging materials; and 2178

2179 (B) undertakes periodic complete confirmatory examination or testing with a frequency 2180

satisfactory to the Director, 2181 2182

(ii) the packaging material has not been transported or stored under conditions that may affect its 2183 compliance with the specifications for that packaging material. 2184 2185

(2) After a lot or batch of packaging material is received on the premises of the person who packages a drug, 2186 2187

(a) the lot or batch of the packaging material shall be examined or tested for identity; and 2188 2189 (b) the labels shall be examined or tested in order to ensure that they comply with the specifications for 2190

those labels. 2191 2192

Rationale 2193 2194 The suitability of APIs for their subsequent use depends not only on the production process but also on the 2195 protection of the API from contamination or degradation before use. Care should be taken in the choice of 2196 container, and, as the filling of solid APIs is often a dusty operation, how this is filled and closed will affect the 2197 quality. Packaging materials are required to be tested or examined prior to their use in a packaging operation to 2198 ensure that materials of acceptable quality are used in the packaging of APIs. 2199 2200 The inner packaging should be controlled by the establishment with respect to identity and traceability. 2201 Labelling, storage, and distribution contribute materially to final suitability for use in the manufacture of 2202 medicinal products. 2203 2204 Regulation C.02.017 outlines options as to when the testing or examination prescribed by Regulation C.02.016 2205 is carried out. As with raw materials, the purchase of packaging materials is an important operation that 2206 involves personnel who have thorough knowledge of the packaging materials and supplier. 2207 2208 Packaging materials originate only from supplier named in the relevant specifications. It is of benefit that all 2209 aspects of the production and control of packaging materials be discussed between the manufacturer and the 2210 supplier. Particular attention is paid to printed packaging materials; labels are examined or tested after receipt 2211 on the premises of the person who packages an API. 2212

2213 Interpretation 2214 2215 1. There should be written procedures describing the receipt, identification, quarantine, sampling, 2216

examination and/or testing and release, and handling of packaging and labelling materials. 2217 2218



2. Each packaging material used in the packaging/labelling of an API should be covered by specifications 2219 (as defined under C.02.002) that are approved and dated by the person in charge of the quality control 2220 department or by a designated alternate who meets the requirements described under Regulation 2221 C.02.006, interpretation 1.4. 2222

2223 2.1 Where applicable, specifications should be of pharmacopeial or equivalent status, and should be in 2224 compliance with the approved specifications in the marketing authorization for the drug in dosage form. 2225

2226 2.2 The adequacy of test or examination methods that are not of pharmacopeial or equivalent status 2227

should be established and documented. 2228 2229 2.3 The use of recycled or reprocessed primary packaging components should be permitted only after a 2230

full evaluation of the risks involved, including any possible deleterious effects on product integrity. 2231 Specific provision should be made for such a situation in the specifications. 2232

2233 2.4 These containers should not be reactive, additive, or absorptive so as to alter the quality of the API 2234

beyond the specified limits. 2235 2236 2.5 Any packaging material in direct contact with the API should be at minimum of food grade quality. 2237 2238 3. Sampling should take place in an appropriate environment and with precautions to prevent 2239

contamination, where necessary. 2240 2241 4. Positive identification of all packaging materials, along with examination of all labels and other printed 2242

packaging materials should be conducted following their receipt on the premises of the person who 2243 packages the API. 2244

2245 4.1 Master labels should be maintained for comparison to issued labels. 2246 2247 5. Packaging and labelling materials should conform to established specifications. Those that do not 2248

comply with such specifications should be rejected to prevent their use in operations for which they are 2249 unsuitable. 2250

2251 6. Only packaging materials released by the quality control department should be used in 2252

packaging/labelling. 2253 2254 7. Containers should provide adequate protection against deterioration or contamination of the API that 2255

may occur during transportation and recommended storage. 2256 2257 8. Containers should be clean and, where indicated by the nature of the API, sanitized to ensure that they 2258

are suitable for their intended use. 2259 2260 9. Outdated or obsolete packaging material should be adequately identified and segregated until its 2261

disposition. 2262

2263 10. The testing or examination of the packaging material should be performed on a sample taken after their 2264

receipt on the premises of the person that packages the drug unless the vendor is certified. A packaging 2265 material vendor certification program, if employed, should be documented in a standard operating 2266 procedure. 2267



2268 10.1 Vendor approval should include an evaluation that provides adequate evidence (e.g., past quality 2269 history) that the manufacturer can consistently provide material meeting specifications. Confirmatory 2270 testing should be conducted on at least three batches before reducing in-house testing. However, as a 2271 minimum, confirmatory testing should be performed at appropriate intervals, at least one lot per year, 2272 and compared with the Certificates of Analysis. Reliability of Certificates of Analysis should be checked 2273 at regular intervals. 2274

2275

Finished Product Testing 2276

2277 Regulation C.02.018 2278 2279 (1) Each lot or batch of a drug shall, before it is made available for further use in fabrication or for sale, be 2280

tested against the specifications for that drug. 2281 2282 (2) No lot or batch of a drug may be made available for further use in fabrication or for sale unless it complies 2283

with the specifications for that drug. 2284 2285 (3) The specifications referred to in subsections (1) and (2) shall 2286 2287

(a) be in writing; 2288 2289 (b) be approved by the person in charge of the quality control department; and 2290

2291 (c) comply with the Act and these Regulations. 2292

2293

Rationale 2294 2295 Tests on the API complement the controls employed during the manufacturing process. It is the responsibility of 2296 each fabricator, packager/labeller, distributor and importer to have adequate specifications, test methods and/or 2297 evidence that will help ensure that each drug sold is safe and meets the standard under which it is represented. 2298

2299 Interpretation 2300 2301 1. For each batch of API, appropriate laboratory tests should be conducted to determine conformance to 2302

specifications. 2303 2304 2. All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to 2305

ensure that APIs conform to established standards of quality and/or purity. Specifications and test 2306 procedures should be consistent with those included in the registration/filing. There can be specifications 2307 in addition to those in the registration/filing. Specifications, sampling plans, and test procedures, 2308 including changes to them, should be documented and approved by the appropriate organizational unit 2309 and reviewed and approved by the quality unit(s). 2310

2311 2.1Specifications should be equal to or exceed a recognized standard as listed in Schedule B to the Food 2312 and Drugs Act and should be in compliance with the approved specifications in the marketing 2313 authorization for the drug in dosage form to which the API is associated to. 2314



2315 2.2 Where a recognized pharmacopoeia (Schedule B to the Food and Drugs Act) contains a specification for 2316 microbial content, that requirement is included. 2317

2318 3. Appropriate specifications should be established for APIs in accordance with accepted standards and 2319

consistent with the manufacturing process. The specifications should include a control of the impurities 2320 (e.g. organic impurities, inorganic impurities, and residual solvents). If the API has a specification for 2321 microbiological purity, appropriate action limits for total microbial counts and objectionable organisms 2322 should be established and met. If the API has a specification for endotoxins, appropriate action limits 2323 should be established and met. 2324 2325

4. Analytical methods should be validated unless the method employed is included in the relevant 2326 pharmacopoeia or other recognized standard reference. The suitability of all testing methods used should 2327 nonetheless be verified under actual conditions of use and documented. 2328

2329 5. Methods should be validated to include consideration of characteristics included within publications 2330

such as the ICH document entitled ICH Q3(R1): Validation of Analytical Procedures: Text and 2331 Methodology. The degree of analytical validation performed should reflect the purpose of the analysis 2332 and the stage of the API production process. 2333

2334 6. All tests are performed according to the approved specifications. These tests may be carried out by the 2335

fabricator or by their contracted testing laboratory when a written contract specifies the responsibilities 2336 of each party. 2337

2338 7. An impurity profile describing the identified and unidentified impurities present in a typical batch 2339

produced by a specific controlled production process should normally be established for each API. The 2340 impurity profile should include the identity or some qualitative analytical designation (e.g. retention 2341 time), the range of each impurity observed, and classification of each identified impurity (e.g. inorganic, 2342 organic, solvent). The impurity profile is normally dependent upon the production process and origin of 2343 the API. Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin. 2344 Biotechnology considerations are covered in ICH Guideline Q6B. 2345

2346 8. The impurity profile should be compared at appropriate intervals against the impurity profile in the 2347

regulatory submission or compared against historical data in order to detect changes to the API resulting 2348 from modifications in raw materials, equipment operating parameters, or the production process. 2349

2350 9. Information on the name of the API including where appropriate its grade, the batch number, and the 2351

date of release should be provided on the Certificate of Analysis. For APIs with an expiry date, the 2352 expiry date should be provided on the label and CoA. For APIs with a retest date, the retest date should 2353 be indicated on the label and/or CoA. 2354

2355 10. Authentic CoAs should be issued for each batch of API. 2356 2357 11. The CoA should list each test performed in accordance with compendial or customer requirements, 2358

including the acceptance limits, and the numerical results obtained (if test results are numerical). 2359 2360 12. Certificates of Analysis should be dated and signed by authorised personnel of the quality unit(s) and 2361

should show the name, address and telephone number of the original manufacturer. Where the analysis 2362 has been carried out by a repackager or reprocessor, the CoA should show the name, address and 2363



telephone number of the repackager/reprocessor and a reference to the name of the original 2364 manufacturer. 2365

2366 13. If new Certificates are issued by or on behalf of repackagers/reprocessors, agents or brokers, these 2367

Certificates should show the name, address and telephone number of the laboratory that performed the 2368 analysis. They should also contain a reference to the name and address of the original manufacturer and 2369 to the original batch Certificate, a copy of which should be attached. 2370

2371 14. Any lot or batch of an API that does not comply with specifications should be quarantined pending final 2372

disposition, investigated and documented according to a procedure, and is not made available for sale. 2373

2374 Regulation C.02.019 2375 (1) A packager/labeller of a drug, a distributor referred to in paragraph C.01A.003(b) and an importer of a 2376

drug other than an active ingredient shall perform the finished product testing on a sample of the drug that 2377 is taken either 2378

2379 (a) after receipt of each lot or batch of the drug on their premises in Canada; or 2380 2381 (b) before receipt of each lot or batch of the drug on their premises in Canada if the following conditions 2382

are met: 2383 2384

(i) the packager/labeller, distributor or importer 2385 2386

(A) has evidence satisfactory to the Director to demonstrate that drugs sold to them by the 2387 vendor of that lot or batch are consistently manufactured in accordance with and 2388 consistently comply with the specifications for those drugs, and 2389

2390 (B) undertakes periodic complete confirmatory testing, with a frequency satisfactory to the 2391

Director, to confirm that those drugs comply with those specifications, and 2392 2393

(ii) the drug has not been transported or stored under conditions that may affect its compliance with 2394 the specifications for that drug. 2395

2396 (2) If the packager/labeller, distributor or importer receives a lot or batch of a drug on their premises in 2397

Canada the useful life of which is more than 30 days, the lot or batch shall be tested for identity and the 2398 packager/labeller shall confirm the identity after the lot or batch is packaged/labelled. 2399

2400 (3) Subsections (1) and (2) do not apply to a distributor if the drug is fabricated, packaged/labelled and tested 2401

in Canada by a person who holds an establishment licence that authorizes that activity. 2402 2403 (4) Subsections (1) and (2) do not apply to a distributor or importer if the drug is fabricated, 2404

packaged/labelled and tested in an MRA country at a recognized building and both of the following 2405 requirements are met: 2406

2407 (a) the address of the building is set out in their establishment licence; and 2408 2409 (b) they retain a copy of the batch certificate for each lot or batch of the drug that they receive. 2410

2411

2412



Rationale 2413 2414 C.02.019 outlines conditions and exemptions as to when the finished product (API) testing is to be performed. 2415 Paragraph C.02.019(1)(b) outlines requirements that are to be met if the finished product testing is done before 2416 receipt on the premises of the packager/labeller of the drug. 2417

2418 Interpretation 2419 2420 1. Identity of the API should be confirmed by the packager/labeller at least after the lot or batch is 2421

packaged. In order for the packager/labeller to rely on the CoA of the API supplier, the following 2422 conditions apply: 2423

2424 1.1 Evidence of ongoing GMP compliance should be provided according to Guide 0080. 2425

2426 1.2 Each lot should be accompanied by an authentic CoA or by a copy thereof (an electronic copy 2427

with an electronic signature is acceptable). The CoA should exhibit actual numerical results and 2428 make reference to the product specifications and validated test methods used; 2429

2430 1.3 Evidence should be available to demonstrate that each lot or batch received has been transported 2431

and stored in a manner that maintains the quality of the API. Further requirements are described 2432 in Guide 0069. 2433

2434 2. Where an API has an expiry date greater than 30 days upon receipt on the premises of the 2435

packager/labeller, positive identification of each lot or batch in a shipment of that API using a specific 2436 analytical method should be carried out on a sample taken after receipt on the premises of the 2437 packager/labeller and after packaging. 2438

2439

Records 2440

2441 Regulation C.02.020 2442 (1) Every fabricator, packager/labeller, distributor referred to in paragraph C.01A.003(b) and importer shall 2443

maintain all of the following records on their premises in Canada for each drug that they fabricate, 2444 package/label, distribute or import: 2445

2446 (a) subject to subsection (1.1), master production documents for the drug; 2447

2448 (b) evidence that each lot or batch of the drug has been fabricated, packaged/labelled, tested and stored 2449

in accordance with the procedures described in the master production documents; 2450 2451

(c) evidence that the conditions under which the drug was fabricated, packaged/labelled, tested and 2452 stored are in compliance with the requirements of this Division; 2453

2454 (d) evidence that establishes the period during which the drug in the container in which it is sold or 2455

made available for further use in fabrication will meet the specifications for that drug; and 2456 2457

(e) evidence that the finished product testing referred to in section C.02.018 was carried out, including 2458 the results. 2459



2460 (1.1) An importer need not maintain master production documents on their premises in Canada if the documents 2461

are maintained in a way that the importer can retrieve them in a timely manner when an inspector requests 2462 them. 2463

2464 (2) Every distributor referred to in paragraph C.01A.003(b) and importer shall make available to the Director, 2465

on request, the results of testing performed on raw materials and packaging/labelling materials for each lot 2466 or batch of drug that it distributes or imports. 2467

2468 (3) Every fabricator shall maintain on their premises written specifications for all raw materials and adequate 2469

evidence of the testing of those raw materials referred to in section C.02.009 and of the test results. 2470 2471 (4) Every person who packages a drug shall maintain on their premises written specifications for all 2472

packaging materials and adequate evidence of the examination or testing of those materials referred to in 2473 section C.02.016 and of any test results. 2474

2475 (5) Every fabricator, packager/labeller and tester shall maintain on their premises in Canada detailed plans 2476

and specifications of each building in Canada where they fabricate package/label or test drugs and a 2477 description of the design and construction of those buildings. 2478

2479 (6) Every fabricator, packager/labeller and tester shall maintain on their premises in Canada personnel records 2480

in respect of each person who is employed to supervise the fabrication, packaging/labelling and testing of 2481 drugs, including the person’s title, responsibilities, qualifications, experience and training. 2482 2483


2485 (1) All records and evidence on the fabrication, packaging/labelling, finished product testing and storage of a 2486

drug in dosage form that are required to be maintained under this Division shall be retained for one year 2487 after the expiration date of the drug unless the person's establishment licence specifies some other period. 2488

2489 (2) Subject to subsection (4), all records and evidence of the fabrication, packaging/labelling, finished product 2490

testing referred to in section C.02.018 and storage of an active ingredient that are required to be 2491 maintained under this Division shall be retained in respect of each lot or batch of the active ingredient for 2492 the following period unless the person holds an establishment licence that specifies some other period: 2493 2494 (a) in the case of an active ingredient that has a retest date, three years after the lot or batch has been 2495

completely distributed; and 2496 2497 (b) in any other case, one year after the expiration date of the lot or batch. 2498

2499 (3) Subject to subsection (4), all records and evidence of the raw material testing referred to in section 2500

C.02.009 and of the testing of packaging/labelling materials that are required to be maintained under this 2501 Division shall be retained for five years after the raw materials and packaging/labelling materials were last 2502 used in the fabrication or packaging/labelling of a drug unless the person's establishment licence specifies 2503 some other period. 2504

2505 (4) If a fabricator is required to maintain records and evidence in respect of the same active ingredient under 2506

subsections (2) and (3), they shall maintain them for the longest period that is applicable. 2507




2509 (1) Every wholesaler, distributor referred to in C.01A.003 and importer of a drug in dosage form shall retain 2510

records of sale of each lot or batch of the drug, which enable them to recall the lot or batch from the 2511 market, for one year after the expiration date of that lot or batch, unless their establishment licence 2512 specifies some other period. 2513

2514 (2) Every distributor of an active ingredient referred to in paragraph C.01A.003(a) and every wholesaler and 2515

importer of an active ingredient shall retain records of sale of each lot or batch of the active ingredient, 2516 which enable them to recall the lot or batch from the market, for the following period unless the person 2517 holds and establishment licence that specifies some other period: 2518

2519 (a) in the case an active ingredient that has a retest date, three years after the lot or batch has been 2520

completely distributed; or 2521 2522 (b) in any other case, one year after the expiration date of the lot or batch. 2523

2524


2526 (1) On receipt of a complaint or any information respecting the quality of a drug or its deficiencies or hazards, 2527

every fabricator, packager/labeller, wholesaler, distributor referred to in paragraph C.01A.003 and 2528 importer of the drug shall make a record of the complaint or information that contains the following: 2529

2530 (a) the results of any investigation carried out under subsection C.02.015(2) and, if applicable, any 2531

corrective action taken; or 2532 2533 (b) the name and business address of the person in charge of the quality control department to whom the 2534

complaint or information was forwarded under subsection C.02.015(2.1) and the date on which it 2535 was forwarded. 2536

2537 (2) Records referred to in subsection (1) shall be retained for the following period unless the person holds an 2538

establishment licence that specifies some other period: 2539 2540

(a) in the case of a drug in dosage form, one year after the expiration date of the lot or batch of the drug; 2541 and 2542

2543 (b) in the case of an active ingredient, 2544 2545

(i) if the active ingredient has a retest date, three years after the lot or batch has been completely 2546 distributed, or 2547

2548 (ii) in any other case, one year after the expiration date of the lot or batch of the active ingredient. 2549

2550



2551


2553 (1) Every fabricator, packager/labeller, distributor referred to in section C.01A.003, importer and wholesaler 2554

shall 2555 2556

(a) maintain records of the results of the self-inspection program required by section C.02.012 and of 2557 any action taken in connection with that program; and 2558

2559 (b) retain those records for a period of at least three years. 2560

2561 (2) Every person who fabricates or packages/labels a drug shall 2562 2563

(a) maintain records on the operation of the sanitation program required to be implemented under 2564 section C.02.007; and 2565

2566 (b) retain those records for a period of at least three years. 2567

2568


2570 Every distributor of an active ingredient referred to in paragraph C.01A.003(a) and every fabricator, 2571 packager/labeller, wholesaler and importer of an active ingredient shall add all of the following information to 2572 the documentation that accompanies the active ingredient, immediately after any like information that has been 2573 added by another person: 2574 2575

(a) their establishment licence number, or if there is none, their name, address, telephone number, fax 2576 number and email address; 2577

2578 (b) an indication whether they have fabricated, packaged/labelled, wholesaled, distributed or imported 2579

the active ingredient and the date on which that activity was carried out; 2580 2581

(c) the expiration date; and 2582 2583

(d) the lot number. 2584 2585

Rationale 2586 2587 Good documentation is an essential part of the quality assurance system and should therefore be applied to all 2588 aspects of GMP. Its aims are to define the specifications for all materials and methods of fabrication, 2589 packaging/labelling, and control; to ensure that the quality control department has all the information necessary 2590 to make a decision as to whether or not a batch of an API should be released for sale; and to provide an audit 2591 trail that will allow for thorough investigation of the history of any batch that is suspected to be defective. 2592 2593 Evidence that APIs have been fabricated, packaged/labelled, testing, and stored under prescribed conditions can 2594 be maintained only after developing adequate record systems. This evidence and related information should 2595 provide assurance that imported APIs are fabricated and packaged/labelled in a like manner to those produced 2596 in Canada. 2597



2598

Interpretation 2599 2600 1. Any documentation requested for evaluation by Health Canada should be provided in one of the official 2601

languages. 2602 2603 2. For all sections of these Good Manufacturing Practices guidelines for APIs, standard operating 2604

procedures (SOPs) should be established and retained for reference and inspection. These SOPs should 2605 be regularly reviewed and kept up to date by qualified personnel. The reasons for any revisions should 2606 be documented and a system should be in place to ensure that only current SOPs are in use. 2607

2608 2.1 The issuance, revision, superseding and withdrawal of all documents should be controlled with 2609

maintenance of revision histories. 2610 2611 2.2 SOPs should be reviewed, approved, signed, and dated by the quality control department. 2612 2613 2.3 SOPs should not be altered without the approval of the quality control department. 2614 2615 2.4 The retention period of documents should be specified in applicable SOPs. For example, the type of 2616

documents that need to be retained are development history reports, scale-up reports, technical transfer 2617 reports, process validation reports, training records, production records, control records, and distribution 2618 records). 2619

2620 3. Specifications, instructions, procedures, and records can be retained either as originals or as true copies 2621

such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. The 2622 above may also be maintained in electronic format provided that backup copies are also maintained and 2623 that the electronic records are readily retrievable in a printed format. During the retention period, such 2624 records should be secured and readily available by the fabricator, packager/labeller, distributor, or 2625 importer within 48 hours of the Inspector’s request. Records that can be promptly retrieved from another 2626 location by electronic or other means are acceptable. 2627

2628 3.1 Manufacturing and laboratory records should be kept at the site where the activity occurs and be 2629

readily available. 2630 2631 4. Where an electronic system is used to create, modify or store records required to be maintained under 2632

these Regulations, the system should be qualified and tested for security, validity, and reliability, and 2633 records of those qualifications and tests should be maintained. 2634

2635 4.1 An electronic signature is an acceptable alternative to a handwritten signature as long as it is 2636 authenticated and secure. The validation of electronic signature identification systems should be 2637 documented. 2638

2639 5. An alteration made to a document should be signed and dated; the alteration should permit the reading 2640

of the original information. Where appropriate, the reason for the change should be recorded. 2641 2642 6. Fabricators and packagers/labellers of APIs should maintain evidence that the conditions under which 2643

the API was fabricated, packaged/labelled, tested, and stored should be in compliance with the 2644 requirements of Part C, Division 2 of the Food and Drug Regulations. All of these records should be 2645



retained for (a) in the case of an API that has a retest date, three years after the lot or batch has been 2646 completely distributed; and (b) in any other case, one year after the expiration date of the lot or batch. 2647

2648 6.1 Detailed plans and specifications of each building in Canada where fabrication, packaging/labelling 2649 or testing occurred, including a description of the design and construction of those buildings, should be 2650 maintained in the premises of the establishment where the API activity occurred. These records should 2651 be retained for a period of at least one year past the expiration date of the API to which the records 2652 apply. 2653

2654 6.2 This evidence includes records generated under subsection C.02.012(2) and evidence that 2655 manufacturing and packaging processes and analytical methods are validated. 2656 2657 6.3 In cases where dedicated equipment is employed, the records of cleaning, calibration, maintenance, 2658 and use can be part of the batch record or maintained separately. 2659 2660 6.4 Records of equipment calibrations should be maintained on the premises. 2661

6.5 Records in respect of each person who is employed to supervise the fabrication, packaging/labelling, 2662 and testing of APIs, including organization charts; each person's title, job description, responsibilities, 2663 qualifications, experience, and training; and the name(s) of each person's designated alternate(s). 2664

6.6 Records should be maintained detailing the name, address, qualifications/experience of any 2665 consultant employed for GMP purposes, along with the services that each consultant provides. 2666

6.7 Records on the operation of the sanitation program. 2667

6.8 Batch production and laboratory control records of critical process steps should be reviewed and 2668 approved by the quality unit(s) before an API batch is released or distributed. Production and laboratory 2669 control records of non-critical process steps can be reviewed by qualified production personnel or other 2670 units following procedures approved by the quality unit(s). 2671

6.9 Records of the self-inspection program including the evaluation, conclusions, and corrective 2672 measures implemented. 2673

2674 6.10 Evidence establishing the period of time during which the API in the container in which it is sold or 2675 made available for further use in fabrication should meet the specifications for that API. 2676

2677 6.10.1 The documentation to be maintained should include the written stability program, the 2678

data generated in accordance with that program, and the conclusions leading to the 2679 establishment of the period of time during which each API in the package in which it is 2680 sold complies with the specifications for that API. 2681

2682 6.11 Records of storage conditions for materials (e.g. controlled temperature and humidity when 2683 necessary). 2684 2685

7. Evidence that each lot or batch of the API has been fabricated, packaged/ labelled, tested, and stored in 2686 accordance with the procedures described in the master production documents. This evidence should include the 2687 following: 2688 2689



7.1 Written procedures followed for the review and approval of batch production and laboratory control 2690 records, including packaging and labelling, to determine compliance of the API with established 2691 specifications before a batch is released or distributed. (F, P/L,T) 2692

2693 7.2 Manufacturing orders, packaging orders, test methods, and test results for raw materials, packaging 2694 materials, and APIs. When the API is fabricated or packaged outside Canada/premises of the importer, 2695 test results for raw materials and packaging materials need only be made available on request. (F, P/L,T) 2696 2697

8. The following documents should be maintained by the fabricator, packager/labeller, wholesaler (agents, 2698 brokers, traders and any other party providing services), distributor referred to in paragraph C.01A.003(a) and 2699 importer of an API as they relate to all operations in Canada. These records should be retained for a period, in 2700 the case of an API that has a retest date, three years after the lot or batch has been completely distributed or in 2701 any other case, one year after the expiration date of the lot or batch. 2702 2703

8.1 Distribution records of all sales of an API. 2704 2705

8.1.1 Records of all sales of each lot or batch of the API should be retained or kept readily 2706 accessible in a manner that will permit a complete and rapid recall of any lot or batch of 2707 the API. 2708

2709 8.1.2 Records to indicate that all customers who have received a recalled API have been 2710

notified. 2711 2712

8.1.3 Records of returned APIs should be maintained. For each return, documentation should 2713 include: 2714

2715

the name and address of the consignee; 2716

the API, lot or batch number, and quantity returned; 2717

the reason for return; and 2718

the use or disposal of the returned API. 2719

2720 8.2 Records of complaints or any information received orally or in writing respecting the quality of an 2721 API or its deficiencies or hazards, and of subsequent investigations of complaints, including corrective 2722 actions taken. 2723

2724 8.2.1 Complaint records should include the following information: 2725

2726

the name and address of the complainant (if available); 2727

the name and phone number of the person submitting the complaint (if available); 2728

the nature of the complaint (including the name and batch number of the API); 2729

the date on which the complaint was received; 2730

the action initially taken (including the dates and identity of the person taking the 2731 action); 2732

the actions taken, if any; 2733



the response provided to the complainant, where possible (including the date on which 2734 the response was sent); and 2735

the final decision on the API batch or lot. 2736 2737

8.2.2 Fabricator, packagers/labellers, testers, importers, distributors, and wholesalers are 2738 responsible for obtaining all quality or regulatory information, as applicable, related to the 2739 production of APIs from any party that provides services such as, but not limited to, agents, 2740 brokers, distributors, repackagers, or relabellers. 2741

2742 9. The following documents should be maintained by the fabricator and the packager/labeller on their 2743

premises and retained for a period of at least five years after the materials were last used in the 2744

fabrication or packaging/labelling of the API, unless the person=s establishment licence specifies some 2745 other period. 2746

2747 9.1 The written specifications for the materials. 2748

2749 9.2 Adequate evidence of the receipt and sources of each shipment of materials for the manufacture of 2750 APIs. The following information should be included: 2751

2752

the name of the manufacturer, 2753

the date of receipt and the number allocated on receipt; 2754

the identity and quantity of each shipment of each batch; 2755

the name of the supplier; and 2756

the supplier's control number(s), if known, or other identification number. 2757

2758 9.3 Adequate evidence of the testing, or examination of those materials as per section C.02.009 and 2759 C.02.016 and of the results of this testing. The following information should be included: 2760

2761

documentation of the examination and/or tests of materials for conformity with established 2762 specifications and conclusions derived from this; 2763

the final decision as to whether the batches were accepted or rejected; and 2764

records tracing the use of the materials. 2765

2766 9.3.1 Laboratory records should be maintained. 2767

2768 10. The following documents should be maintained by the fabricator, packager/labeller, and/or importer of an 2769 API. All of these records should be retained for (a) in the case of an API that has a retest date, three years after 2770 the lot or batch has been completely distributed; and (b) in any other case, one year after the expiration date of 2771 the lot or batch. 2772

2773

10.1 Master production documents for each API. 2774 2775



The master production documents should be signed and dated by a qualified person and then 2776 independently checked, dated, and signed by a person in the quality unit. These documents should 2777 include the following information: 2778

2779

The name of the API manufactured and an identifying document reference code, if 2780 applicable; 2781

The list of raw materials used and designated by names or codes sufficiently specific to 2782 identify any special quality characteristics; 2783

The accurate quantity with a unit of measure or ratio of each raw material used. Where the 2784 quantity is not fixed, the calculation for each batch size or rate of production should be 2785 included. Variations to quantities should be included where they are justified; 2786

The location of production and major production equipment used; 2787

The detailed production instructions, including the sequences to follow, ranges of process 2788 parameters to use, sampling instructions and in-process controls with their acceptance 2789 criteria, where appropriate, time limits for completion of individual processing steps and/or 2790 the total process, where appropriate, and expected yield ranges at appropriate phases of 2791 processing or time; 2792

Where appropriate, any special notations and precautions to follow, or cross-references to 2793 these, and 2794

The instructions for storage of the API to assure its suitability for use, including the labelling 2795 and packaging materials and special storage conditions with time limits, where appropriate. 2796

2797 10.2 When the fabricator is located outside Canada, specific parts of a master production document 2798 considered to be a trade secret or confidential may be held on behalf of the importer by an independent 2799 party in Canada provided the importer ensures that Health Canada has access to the data in a timely 2800 manner. 2801

2802 10.3 Regardless of whether the fabricator is Canadian or foreign, the master production documents 2803

retained by the importer should describe in general terms whatever information has been deleted as a 2804 trade secret or confidential. 2805

2806 11. Importers, agents, brokers, traders, distributors, repackagers, or relabellers should maintain complete 2807 traceability APIs that they distribute. Documents that should be retained and available include: 2808 2809

11.1 name identity of original manufacturer fabricator and packager/labeller; 2810 2811

11.2 address of original manufacturer fabricator and packager/labeller; 2812 2813

11.3 purchase orders; 2814 2815

11.4 bills of lading (transportation documentation); 2816 2817

11.5 receipt documents; 2818 2819

11.6 name or designation of the API; 2820



2821

11.7 Manufacturer fabricator=s or packager/labeller=s batch number; 2822 2823

11.8 transportation and distribution records; 2824 2825

all authentic CoA, including those of the original manufacturer 2826

fabricator; and retest or expiry date. 2827

2828 12. The fabricator, packager/labeller, wholesaler, distributor referred to in paragraph C.01A.003(a), 2829

importer of an API (including any party other than the original manufacturer who may trade and/or take 2830 possession, repackage, re-label, manipulate, or store an API, should add the following information to the 2831 documentation that accompanies the API: 2832 2833 12.1 the establishment licence number; if the establishment does not have an establishment licence, they 2834 should add their name, address, telephone number, fax number and email address; 2835 2836 12.2 the activity including fabrication, packaging/labelling, wholesale, distribution or importation and 2837 the date on which the activity was conducted; 2838 2839 12.3 the expiration date and/or retest date; and 2840

2841 12.4 the lot number of the API. 2842

Samples 2843

2844


2846 (1) Every distributor referred to in paragraph C.01A.003(b) and importer of a drug in dosage form shall retain in 2847 Canada a sample of each lot or batch of the packaged/labelled drug for one year after the expiration date of the 2848 drug unless their establishment licence specifies some other period. 2849 2850 (2) Subject to subsection (4), the fabricator of a drug in dosage form shall retain a sample of each lot or batch of 2851 raw materials used in the fabrication for two years after the materials were last used in the unless their 2852 establishment licence specifies some other period. 2853 2854 (3) Subject to subsection (4), the fabricator of an active ingredient shall retain a sample of each lot or batch of it 2855 for the following period, unless their establishment licence specifies some other period: 2856 2857

(a) in the case of an active ingredient that has a retest date, three years after the lot or batch has 2858 been completely distributed; or 2859

2860 (b) in any other case, one year after the expiration date of the lot or batch. 2861

2862 (4) If a fabricator is required to maintain samples in respect of the same active ingredient under subsections (2) 2863 and (3), they shall maintain them for the longest period that is applicable. 2864




2866 The samples referred to in section C.02.025 shall be in an amount that is sufficient to determine whether the 2867 drug or raw material complies with the specifications for that drug or raw material. 2868 2869 Rationale 2870 2871 These requirements help ensure that responsible officials at fabricating, establishments and at Health Canada 2872 have ready access to those samples that are essential for re-examination should a product quality concern arise. 2873 2874

Interpretation 2875 2876 1. A representative sample should be taken for the purpose of performing a retest. 2877 2878 2. The packaging and holding of retained samples is for the purpose of potential future evaluation of the 2879

quality of batches of APIs and not for future stability testing purposes. 2880 2881

3. Appropriately identified retained samples of each API batch should be retained by the fabricator of an 2882 API for one year after the expiry date of the batch, or for three years after distribution of the batch, 2883 whichever is the longer. For APIs with retest dates, similar retained samples should be retained for three 2884 years after the batch is completely distributed by the fabricator. 2885

2886 3.1 Retention samples may be stored at another site pursuant to a written agreement clearly describing the 2887 respective responsibilities of each party. 2888 2889

4. The retained sample should be stored in the same packaging system in which the API is stored or in one 2890 that is equivalent to or more protective than the marketed packaging system. Sufficient quantities should 2891 be retained to conduct at least two full compendial analyses or, when there is no pharmacopoeial 2892 monograph, two full specification analyses. 2893

2894 5. The sample should be stored under the conditions indicated on the label. 2895 2896 6. Retention samples should be maintained in accordance with a written procedure. 2897 2898 Retention samples may be stored at another site pursuant to a written agreement clearly describing the respective 2899 responsibilities of each party. 2900 2901 2902

Stability 2903

2904 Regulation C.02.027 2905 (1) Every distributor referred to in paragraph C.01A.003(b) and importer of a drug in dosage form shall 2906

establish the period during which each drug in the package in which it is sold will comply with the 2907 specifications for that drug. 2908

2909 (2) Every fabricator and importer of an active ingredient shall establish the period during which each drug in 2910

the package in which it is sold will comply with the specifications for that drug. 2911



2912

Rationale 2913 2914 The purpose of the written stability program is to ascertain the expiry or retest date of an API, therefore to 2915 determine how long the APIs can be expected to remain within specifications under recommended storage 2916 conditions. The expiry or retest date for an API should be based on well-designed stability studies. The 2917 requirements for the stability studies are outlined in the various Health Canada, and ICH Guidelines. 2918

2919 Interpretation 2920 2921 1. When an intermediate is intended to be transferred outside the control of the manufacturer’s material 2922

management system and an expiry or retest date is assigned, supporting stability information should be 2923 available (e.g. published data, test results). 2924

2925 2. An API expiry or retest date should be based on an evaluation of data derived from stability studies. 2926

Common practice is to use a retest date, not an expiration date. 2927

2928 3. Preliminary API expiry or retest dates can be based on pilot scale batches if (1) the pilot batches employ 2929

a method of manufacture and procedure that simulates the final process to be used on a commercial 2930 manufacturing scale; and (2) the quality of the API represents the material to be made on a commercial 2931 scale. 2932

2933 3.1 Accelerated stability data are considered to be preliminary information only. The accelerated data 2934 are supported by long term testing. When the shelf-life is assigned based on accelerated data and 2935 extrapolated long-term data, it should be verified by additional long term stability data as these data 2936 become available. 2937

2938 4. Stability samples should be stored in containers that simulate the market container. For example, if the 2939

API is marketed in bags within fiber drums, stability samples can be packaged in bags of the same 2940 material and in smaller-scale drums of similar or identical material composition to the market drums. 2941

2942 4.1 Stability studies to justify assigned expiration or retest dates should be conducted if the API is 2943 repackaged in a different type of container than that used by the API manufacturer. 2944

2945 5. Normally the first three commercial production batches should be placed on the stability monitoring 2946

program to confirm the retest or expiry date. However, where data from previous studies show that the 2947 API is expected to remain stable for at least two years, fewer than three batches can be used. 2948

2949 6. For imported products, stability studies originating from foreign sites are acceptable provided that the 2950

data meet the requirements of the various Health Canada and ICH guidelines regarding stability and that 2951 the site can demonstrate GMP compliance. 2952

2953 7. Where appropriate, the stability storage conditions should be consistent with the ICH guidelines on 2954

stability. 2955 2956 8. Analytical test procedures used in stability evaluation are validated in accordance with the ICH 2957

document entitled, ICH Q2(R1): Validation of Analytical Procedures: Text and Methodology. Assays 2958 are to be stability-indicating, (e.g., sufficiently specific to detect and quantify degradation products and 2959



to distinguish between degraded and non-degraded materials). Limits for individual specified, 2960 unspecified, and total degradation products are included. 2961

2962 Regulation C.02.028 2963 (1) Every distributor referred to in paragraph C.01A.003(b) and importer of a drug in dosage form shall 2964

monitor, by means of a continuing program, the stability of the drug in the package in which it is sold. 2965 2966 (2) Every fabricator and importer of an active ingredient shall monitor, by means of a continuing program, the 2967

stability of the drug in the package in which it is sold. 2968 2969 2970

Rationale 2971 2972 The purpose of the written continuing stability program is to monitor the validity of the API expiry or retest 2973 date on an on-going basis. 2974

2975 Interpretation 2976 2977 1. A documented, on-going testing program should be designed to monitor the stability characteristics of 2978

APIs, and the results should be used to confirm appropriate storage conditions and retest or expiry dates. 2979 2980 2. At least one batch per year of API manufactured (unless none is produced that year) should be added to 2981

the stability monitoring program and tested at least annually to confirm the stability. 2982

2983 3. For APIs with short shelf-lives, testing should be done more frequently. For example, for those APIs 2984

with shelf-lives of one year or less, stability samples should be obtained and should be tested monthly 2985 for the first three months and at three month intervals after that. When data exist that confirm that the 2986 stability of the API is not compromised, elimination of specific test intervals (e.g. 9 month testing) can 2987 be considered.) 2988

2989 4. Where appropriate, the stability storage conditions should be consistent with the ICH guidelines on 2990

stability. 2991 2992 5. Any differences in the protocol for the continuing stability program and the protocol for the formal 2993

stability studies should be scientifically justified. 2994 2995 6. Worst case situations should be addressed by the continuing stability program (e.g., inclusion of 2996

reworked or reprocessed lots). 2997 2998 7. Any confirmed out of specification result or significant negative trend that may have an impact on the 2999

quality of the API should be assessed and may require further stability studies. 3000 3001 8. For imported APIs, stability studies originating from foreign sites are acceptable, provided that the data 3002

meet the requirements of the various Health Canada and ICH guidelines regarding stability and that the 3003 site can demonstrate GMP compliance. It should be the importer’s responsibility to obtain and maintain 3004 up to date records associated with the ongoing stability program. 3005

3006



Sterile Products 3007

3008 Regulation C.02.029 3009 3010 In addition to the other requirements of this Division, a drug that is intended to be sterile shall be fabricated and 3011 packaged/labelled 3012 3013

(a) in separate and enclosed areas; 3014 3015 (b) under the supervision of personnel trained in microbiology; and 3016

3017 (c) by a method scientifically proven to ensure sterility. 3018

3019 This guideline applies to the manufacture of sterile APIs only up to the point immediately prior to the API being 3020 rendered sterile. The sterilization and aseptic processing of sterile APIs are not covered by this guidance, but 3021 should be performed in accordance with the Good Manufacturing Practices Guidelines, Edition 2009, Version 2 3022 (Guide 0001). 3023

3024

Medical Gases 3025

3026 Regulation C.02.030 3027 3028 This guideline does not apply to medical gases. The guidance regarding the fabrication, packaging, labelling, 3029 testing, distribution, and importation of medical gases is described in the guideline Good Manufacturing 3030 Practices for Medical Gases (Guide 0031). 3031 3032

3033



Appendix A 3034

Acronyms 3035

AI: Active Ingredient 3036 API: Active Pharmaceutical Ingredient 3037 DIN: Drug Identification Number 3038 GMP: Good Manufacturing Practices 3039 HPFB: Health Products and Food Branch 3040 ICH: International Conference on Harmonisation 3041 ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients Q7 3042 MPD: Master Production Documents 3043 NOC: Notice of Compliance 3044 OOS: Out of specification 3045 PIC/S: Pharmaceutical Inspection Cooperation/Scheme 3046 WHO: World Health Organization 3047

3048

Appendix B 3049

Glossary of Terms 3050

The following definitions apply to the terms used in these guidelines; they also apply to the terms used in the 3051 annexes unless otherwise specified therein. Definitions quoted from other documents are identified in brackets 3052 at the end of the definition. 3053 3054 Acceptance Criteria (critère d’acceptation) - Numerical limits, ranges, or other suitable measures for 3055 acceptance of test results. (ICH Q7) 3056 3057 Active Ingredient (ingrédient actif) - Means a drug that, when used as a raw material in the fabrication of a 3058 drug in dosage form, provides its intended effect. (Division 1A, Part C, Food and Drug Regulations) 3059 3060 Active Pharmaceutical Ingredient (ingrédient pharmaceutique actif) - Means an active ingredient that is used 3061 in the fabrication of a pharmaceutical. (Division 1A, Part C, Food and Drug Regulations) 3062 3063 API Establishment Licence (licence d’etablissement pour les IPA) – A licence issued to a person in Canada to 3064 conduct licensable activities in a building which has been inspected and assessed as being in compliance with 3065 the requirement of Division 2 of the Food and Drug Regulations. (Guide 0001) 3066 3067 Alternate Sample Retention (ASR) Site (site alternatif pour la rétention des échantillons) - An alternate site 3068 specified on a Drug Establishment Licence for the storage of samples pursuant to section C.02.025 (1) of the 3069 Food and Drug Regulations. (Guide 0001) 3070 3071 Batch (or Lot) (lot de fabrication) - A specific quantity of material produced in a process or series of processes 3072 so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch 3073 may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity 3074 or by the amount produced in a fixed time interval. (ICH Q7) 3075 3076



Batch Number (or Lot Number) (numéro de lot de fabrication) - A unique combination of numbers, letters, 3077 and/or symbols that identifies a batch (or lot) and from which the production and distribution history can be 3078 determined. (ICH Q7) 3079 3080 Bioburden (xxx) - The level and type (e.g. objectionable or not) of micro-organisms that can be present in raw 3081 materials, API starting materials, intermediates or APIs. Bioburden should not be considered contamination 3082 unless the levels have been exceeded or defined objectionable organisms have been detected. (ICH Q7) 3083 3084 Biological Drug (drogue biologique) - A drug that is listed in Schedule D to the Food and Drugs Act. 3085 3086 Bulk APIs (IPA en vrac) – An API that is not in its final shipping package configuration. 3087 3088 Bulk Process Intermediate (produit intermédiaire en vrac) - Means an active ingredient that is used in the 3089 fabrication of a drug of biological origin that is listed in Schedule C or a drug that is listed in Schedule D to the 3090 Act. (Division 1A, Part C, Food and Drug Regulations) 3091 3092 Calibration (étalonnage) - The demonstration that a particular instrument or device produces results within 3093 specified limits by comparison with those produced by a reference or traceable standard over an appropriate 3094 range of measurements. (ICH Q7) 3095 3096 Campaign Production (production consecutive) – Sequential processing of material, either more than one 3097 product in a multi-product facility or more than one lot of the same product in a dedicated facility, over a 3098 defined period of time. Campaign production could occur at any point in a production process where common 3099 rooms/suites and/or equipment are reused for multiple products/lots. (Guide 0001) 3100 3101 Certificate of Analysis (COA) (certificat d’analyse) - A document containing the name and address of the 3102 laboratory performing the test(s), name and specifications of the material(s), test(s) performed, test method(s) 3103 used, actual numerical results, approval date(s), signature of approver, and any other technical information 3104 deemed necessary for its proper use. (Guide 0001) 3105 3106 Certificate of Manufacture (certificat de fabrication) - A document issued by a vendor to a distributor or 3107 importer that attests that a specific lot or batch of drug has been produced in accordance with its master 3108 production documents. Such certificates include a detailed summary of current batch documentation, with 3109 reference to respective dates of revision, manufacture, and packaging, and are signed and dated by the vendor’s 3110 quality control department. (Guide 0001) 3111 3112 Change control (contrôle des changements) - A written procedure that describes the action to be taken if a 3113 change is proposed (a) to facilities, materials, equipment, and/or processes used in the fabrication, packaging, 3114 and testing of drugs, or (b) that may affect the operation of the quality or support system. (Guide 0001) 3115 3116 Changeover Procedure (procédure de conversion) - A logical series of validated steps that ensures the proper 3117 cleaning of suites and equipment before the processing of a different product begins. (Guide 0001) 3118 3119 Computerized System (système informatisé) - Consists of all components, including but not limited to 3120 hardware, software, personnel, and documentation, necessary to capture, process, transfer, store, display, and 3121 manage information. (Guide 0001) 3122 3123 Concurrent validation (validation concomitante): A process where current production batches are used to 3124 monitor processing parameters. It gives assurance of the present batch being studied, and offers limited 3125



assurance regarding consistency of quality from batch to batch. (Guide 0029) 3126 3127 Containment (confinement) - Total isolation of one or more steps of a manufacturing process to prevent cross-3128 contamination of the product, or staff, from all other steps of the process. (Guide 0001) 3129 3130 Contamination (contamination) - The undesired introduction of impurities of a chemical or microbiological 3131 nature, or of foreign matter, into or onto a raw material, intermediate, or API during production, sampling, 3132 packaging or repackaging, storage or transport. (ICH Q7) 3133 3134 Contractor (entrepreneur) - Legal entity carrying out activities on behalf of a company pursuant to a written 3135 agreement. This includes other sites within the same corporate structure. (Guide 0001) 3136 3137 Critical (critique) - Describes a process step, process condition, test requirement, or other relevant parameter or 3138 item that must be controlled within predetermined criteria to ensure that the API meets its specification. (ICH 3139 Q7) 3140 3141 Cross-Contamination (contamination croisée) - Contamination of a material or product with another material 3142 or product. (ICH Q7) 3143 3144 Design Qualification (DQ) - Documented verification that the proposed design of the facilities, equipment, or 3145 systems is suitable for the intended purpose. (ICH Q7) 3146 3147 Deviation (déviation) - Departure from an approved instruction or established standard. (ICH Q7) 3148 3149 Director (directeur) - “The Assistant Deputy Minister, Health Products and Food Branch, of the Department of 3150 Health.” (A.01.010) 3151 3152 Distributor (distributeur) or Manufacturer (fabricant) - “A person, including an association or partnership, 3153 who under their own name, or under a trade, design or word mark, trade name or other name, word, or mark 3154 controlled by them, sells a food or drug.” (A.01.010) 3155 3156 Divisions 1A and 2 to 4 apply to the following distributors (C.01A.003): 3157 3158

(a) a distributor of an active ingredient or of a drug in dosage form that is listed in Schedule C to the Act; 3159 and 3160 3161 (b) a distributor of a drug for which the distributor holds the drug identification number. 3162

3163 Dosage Form (forme posologique) - A drug product that has been processed to the point where it is now in a 3164 form in which it may be administered in individual doses. (Guide 0001) 3165 3166 Drug (drogue) - “Any substance or mixture of substances manufactured, sold, or represented for use in (a) the 3167 diagnosis, treatment, mitigation, or prevention of a disease, a disorder, an abnormal physical state, or the 3168 symptoms thereof, in humans or animals, (b) restoring, correcting, or modifying organic functions in humans or 3169 animals, or (c) "disinfection" in premises in which food is manufactured, prepared, or kept.” (Section 2 of the 3170 Food and Drugs Act) 3171 3172 In Division 1A and Division 2 of the Food and Drug Regulations, "drug" does not include a dilute drug premix, 3173 a medicated feed as defined in subsection 2(1) of the Feeds Regulations, 1983, an active ingredient that is for 3174



veterinary use, or a drug that is used only for the purposes of an experimental study in accordance with a 3175 certificate issued under Section C.08.015. (C.01A.001(2)) 3176 3177 Drug Establishment Licence (licence d’établissement pour les produits pharmaceutiques) - A licence issued 3178 to a drug establishment in Canada which has been inspected and assessed as being in compliance with the 3179 applicable requirements of Divisions 2 to 4 of the Food and Drug Regulations. 3180 3181 Drug Identification Number (drogue: identification numérique) - A number assigned to each drug in dosage 3182 form under the Food and Drug Regulations with the exception of blood and blood components and 3183 radiopharmaceuticals. 3184 3185 Expiry Date (or Expiration Date) – (date limite d’utilisation) The date placed on the container/labels of an 3186 API designating the time during which the API is expected to remain within established shelf life specifications 3187 if stored under defined conditions, and after which it should not be used. (ICH Q7) 3188 3189 Fabricate (manufacturer) - “To prepare and preserve a drug for the purpose of sale.” (C.01A.001) 3190 3191 Filling (remplissage) – Transferring a bulk drug into its final container and enclosing it in the container. (Guide 3192 0001) 3193 3194 Import (importer) - “Means to import into Canada a drug for the purpose of sale” (C.01A.001) 3195

3196 Impurity (impureté) - Any component present in the intermediate or API that is not the desired entity. (ICH 3197 Q7) 3198 3199 Impurity Profile (profil d’impureté) - A description of the identified and unidentified impurities present in an 3200 API. (ICH Q7) 3201 3202 In-Process Control or Process Control (contrôle en cours de fabrication) - Checks performed during 3203 production in order to monitor and, if appropriate, to adjust the process and/or to ensure that the intermediate or 3204 API conforms to its specifications. (ICH Q7) 3205 3206 In-Process Testing (analyse en cours de fabrication) - The examination or testing of any material or mixture of 3207 materials during the manufacturing process. (Guide 0001) 3208 3209 Installation Qualification (IQ) (qualification d’installation) - Documented verification that the equipment or 3210 systems, as installed or modified, comply with the approved design, the manufacturer’s recommendations 3211 and/or user requirements. (ICH Q7) 3212 3213 Intermediate (intermédiaire) - A material produced during steps of the processing of an API that undergoes 3214 further molecular change or purification before it becomes an API. Intermediates may or may not be isolated. 3215 (ICH Q7) 3216 3217 Label (étiquette) - “Includes any legend, word, or mark attached to, included in, belonging to, or accompanying 3218 any food, drug, cosmetic, device, or package (Section 2 of the Act). As described in package/label, the action 3219 of labelling refers to affixing the inner or outer label to the drug.” (C.01A.001) 3220 3221 Lot (lot) – Refer to the definition of Batch. 3222 3223



Lot Number (numéro de lot) – Refer to the definition of Batch Number. 3224 3225 Manufacture (manufacture) - All operations of receipt of materials, production, packaging, repackaging, 3226 labelling, relabelling, quality control, release, storage, and distribution of APIs and related controls. (ICH Q7) 3227

3228 Manufacturer (fabricant) or Distributor (distributeur) – Refer to definition of distributor. 3229 3230 Marketing Authorization (autorisation de mise en marché) - A legal document issued by Health Canada, 3231 authorizing the sale of a drug in dosage form or a device based on the health and safety requirements of the 3232 Food and Drug Act and its associated Regulations. The marketing authorization may be in the form of a Notice 3233 of Compliance (NOC), Drug Identification Number (DIN), a device licence for classes II, III and IV medical 3234 devices, or a natural product number (NPN) or homeopathic DIN (DIN-HM). (Guide 0001) 3235 3236 Master Formula (formule-type) - A document or set of documents specifying the raw materials with their 3237 quantities and the packaging materials, together with detailed processing instructions, including in-process 3238 controls and precautions required to produce a specified quantity of an API. (Guide 0001) 3239 3240 Master Production Documents (MPD) (document-type de production) - Documents that include 3241 specifications for raw material, and for packaging material; master formula (including composition and 3242 instructions as described in the definition above), sampling procedures, and other processing related SOPs, 3243 whether or not these SOPs are specifically referenced in the master formula. (Guide 0001) 3244 3245 Material (matière) - A general term used to denote raw materials (starting materials, reagents, solvents), 3246 process aids, intermediates, APIs and packaging and labelling materials. (ICH Q7) 3247 3248 Medicinal Ingredient (ingrédient médicinal) - Refer to the definition of active pharmaceutical ingredient. 3249 3250 Mother Liquor (liquide-mère) - The residual liquid which remains after the crystallization or isolation 3251 processes. The mother liquor may contain unreacted materials, intermediates, levels of the API and/or 3252 impurities. It may be used for further processing. (ICH Q7) 3253 3254 MRA Country (pays participant à un ARM) - “A country that is a participant to a mutual recognition 3255 agreement with Canada.” (C.01A.001) 3256 3257 Mutual Recognition Agreement (MRA) (accord de reconnaissance mutuelle (ARM)) – “An international 3258 agreement that provides for the mutual recognition of compliance certification for Good Manufacturing 3259 Practices for drugs.” (C.01A.001) 3260 3261 Operational Qualification (OQ) (qualification des opérationelle) - Documented verification that the 3262 equipment or systems, as installed or modified, perform as intended throughout the anticipated operating 3263 ranges. (ICH Q7) 3264 3265 Package (emballer) - “As described in package/label, the action of packaging refers to putting a drug in its 3266 immediate container.” (C.01A.001) 3267 3268 Package/Label (emballer/étiqueter) - “To put a drug in its immediate container or to affix the inner or outer 3269 label to the drug.” (C.01A.001) This includes the repackaging and relabelling of previously packaged and 3270 labelled drugs. 3271 3272



Packaging Batch Record (fiche d'emballage de lot de fabrication) - Records demonstrating that the batch of a 3273 drug was packaged in accordance with the approved master production documents. (Guide 0001) 3274

3275 Packaging Material (matériel d'emballage) - Labels, printed packaging materials, any material intended to 3276 protect the intermediate or API during storage and transport and those components in direct contact with the 3277 final API. (Guide 0001 modified) 3278 3279 Performance Qualification (PQ) - Documented verification that the equipment and ancillary systems, as 3280 connected together, can perform effectively and reproducibly based on the approved process method and 3281 specifications. (ICH Q7) 3282 3283 Pharmaceutical (produit pharmaceutique) - “A drug other than a drug listed in Schedule C or D to the Act.” 3284 (C.01A.001). 3285 3286 Potency (teneur) - The activity or amount of active moiety, or any form thereof, indicated by label claim to be 3287 present. (Guide 0001) 3288 3289 Procedure (procédure) – A documented description of the operations to be performed, the precautions to be 3290 taken and measures to be applied directly or indirectly related to the manufacture of an intermediate or API. 3291 (ICH Q7) 3292 3293 Process Aids (aide à la transformation) - Materials, excluding solvents, used as an aid in the manufacture of an 3294 intermediate or API that do not themselves participate in a chemical or biological reaction (e.g. filter aid, 3295 activated carbon, etc). (ICH Q7) 3296 3297 Process Validation (PV) (validation du procédé) - Documented evidence that the process, operated within 3298 established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its 3299 predetermined specifications and quality attributes. (ICH Q7) 3300 3301 Production (production) - All operations involved in the preparation of an API, from receipt of materials, 3302 through processing and packaging, to completion of the final API, including storage. (Guide 0001) 3303 3304 Production Batch Record (fiche de lot de fabrication) - Records demonstrating that the batch of a final API 3305 was fabricated in accordance with the approved master production documents. (Guide 0001) 3306 3307 Purified Water (eau purifiée) - As defined in any standard listed in Schedule B to the Food and Drugs Act. 3308 (Guide 0001) 3309 3310 Purity (pureté) - The extent to which a raw material or a final API is free from undesirable or adulterating 3311 chemical, biological, or physical entities as defined by specifications. (Guide 0001) 3312 3313 Qualification (qualification) - Action of proving and documenting that equipment or ancillary systems are 3314 properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, 3315 but the individual qualification steps alone do not constitute process validation. (ICH Q7) 3316 3317 Quality Assurance (QA) (assurance qualité) - The sum total of the organised arrangements made with the 3318 object of ensuring that all APIs are of the quality required for their intended use and that quality systems are 3319 maintained. (ICH Q7) 3320 3321



Quality Control (QC) (contrôle de qualité) - Checking or testing that specifications are met. (ICH Q7) 3322 3323 Quality Risk Management (gestion des risques à la qualité) - A systematic process for the assessment, 3324 control, communication and review of risks to the quality of the medicinal product. It can be applied both 3325 proactively and retrospectively (ICH Q9). 3326 3327 Quality Unit (unité de qualité) - An organizational unit independent of production which fulfills both Quality 3328 Assurance and Quality Control responsibilities. This can be in the form of separate QA and QC units or a single 3329 individual or group, depending upon the size and structure of the organization. (ICH Q7) 3330 3331 Quarantine (quarantaine) - The status of materials isolated physically or by other effective means pending a 3332 decision on their subsequent approval or rejection. (ICH Q7) 3333

3334 Raw Material (matière première) - A general term used to denote starting materials, reagents, and solvents 3335 intended for use in the production of intermediates or APIs. (ICH Q7) 3336

3337 Reconciliation (bilan comparatif) - A comparison, making due allowance for normal variation, between the 3338 amount of product or materials theoretically produced or used and the amount actually produced or used. 3339 (Guide 0001) 3340 3341 Recovery (récupération) - The introduction of all or part of previous batches of the required quality into 3342 another batch at a defined stage of manufacture. (Guide 0001) 3343 3344 Reference Standard, Primary (étalon standard primaire) - A substance that has been shown by an extensive 3345 set of analytical tests to be authentic material that should be of high purity. This standard can be: (1) obtained 3346 from an officially recognised source, or (2) prepared by independent synthesis, or (3) obtained from existing 3347 production material of high purity, or (4) prepared by further purification of existing production material. (ICH 3348 Q7) 3349 3350 Reference Standard, Secondary (étalon standard secondaire) - A substance of established quality and purity, 3351 as shown by comparison to a primary reference standard, used as a reference standard for routine laboratory 3352 analysis. (ICH Q7) 3353 3354 Repackaging/Relabelling (réemballer/réétiqueter) - Replacement of packaging or labelling of previously 3355 packaged and labelled products. (Guide 0001) 3356 3357 Reprocessing (retraitement) - Introducing an intermediate or API, including one that does not conform to 3358 standards or specifications, back into the process and repeating a crystallization step or other appropriate 3359 chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of 3360 the established manufacturing process. Continuation of a process step after an in-process control test has shown 3361 that the step is incomplete is considered to be part of the normal process, and not reprocessing. (ICH Q7) 3362 3363 Retest Date (date de ré-analyse) - “The date when a material should be re-examined to ensure that it is still 3364 suitable for use.” (ICH Q7) 3365 3366 Reworking (reprise) - Subjecting an intermediate or API that does not conform to standards or specifications 3367 to one or more processing steps that are different from the established manufacturing process to obtain 3368 acceptable quality intermediate or API (e.g., recrystallizing with a different solvent). (ICH Q7) 3369 3370



Sell (vendre) - “Offer for sale, expose for sale, have in possession for sale, and distribute, regardless of whether 3371 the distribution is made for consideration.” (Section 2 of the Food and Drugs Act) 3372 3373 Shelf Life (durée de conservation) - The time interval during which a drug is expected to remain within the 3374 approved specification provided that it is stored under the conditions defined on the label and in the proposed 3375 containers and closure. (Guide 0001) 3376 3377 Signed (signé) - The record of the individual who performed a particular action or review. This record can be 3378 initials, full handwritten signature, personal seal, or authenticated, and secure electronic signature. (ICH Q7) 3379 3380 Solvent (solvent) - An inorganic or organic liquid used as a vehicle for the preparation of solutions or 3381 suspensions in the manufacture of an intermediate or API. (ICH Q7) 3382 3383 Specifications (spécifications) - “Means a detailed description of a drug, the raw material used in a drug, or the 3384 packaging material for a drug and includes: 3385 3386

(a) a statement of all properties and qualities of the drug, raw material or packaging material that are 3387 relevant to the manufacture, packaging, and use of the drug, including the identity, potency, and 3388 purity of the drug, raw material, or packaging material, 3389

3390 (b) a detailed description of the methods used for testing and examining the drug, raw material, or 3391

packaging material, and 3392 3393

(c) a statement of tolerances for the properties and qualities of the drug, raw material, or packaging 3394 material.” (C.02.002) 3395

3396 Standard Operating Procedure (SOP) - (procédure opératoire normalisée (PON)) - A written procedure 3397 giving instructions for performing operations not necessarily specific to a given product or material but of a 3398 more general nature (e.g., equipment operation, maintenance and cleaning; validation; cleaning of premises and 3399 environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific 3400 master and batch production documents. (Guide 0001) 3401 3402 Starting Material (Matériel de départ) – Raw material, intermediate, or an API that is used in the production 3403 of an API and that is incorporated as a significant structural fragment into the structure of the API. It can be an 3404 article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, 3405 or produced in-house. Starting Materials normally have defined chemical properties and structure. (ICH Q7) 3406

3407 System (système) - A regulated pattern of interacting activities and techniques that are united to form an 3408 organized whole. (Guide 0001) 3409 3410 Test (analyser) - To perform the tests, including any examinations, evaluations, and assessments, as specified in 3411 the Division 2 of the Food and Drug Regulations. (Guide 0001) 3412 3413 Validation (validation) - A documented program that provides a high degree of assurance that a specific 3414 process, method, or system will consistently produce a result meeting pre-determined acceptance criteria. (ICH 3415 Q7) 3416 3417 Vendor/Supplier (fournisseur) - Any person or company that sells or supplies goods or services to another 3418 company. Also called supplier. 3419



3420 Veterinary Drugs (médicaments vétérinaires) - Drugs that are administered to food-producing and companion 3421 animals. (Guide 0001) 3422

3423 Wholesaler (grossiste) - “Means a person who is not a distributor described in section C.01A.003 and who sells 3424 any of the following drugs other than at retail sale: 3425 3426 (a) a drug in dosage form that is listed in Schedule C or D to the Act or in Schedule F to these Regulations 3427

or a controlled drug as defined in subsection G.01.001(1); or 3428 3429 (b) an active ingredient; or 3430 3431 (c) a narcotic as defined in the Narcotic Control Regulations.” (C.01A.001(1)) 3432 3433 As per the new definition of wholesaler in Division 1A, Part C of the Food and Drug Regulations, agents, 3434 brokers, traders are considered wholesalers. 3435 3436 Yield, Expected (rendement prévu) - The quantity of material or the percentage of theoretical yield anticipated 3437 at any appropriate phase of production based on previous laboratory, pilot scale, or manufacturing data. (ICH 3438 Q7) 3439 3440 Yield, Theoratical (rendement théorique) - The quantity that would be produced at any appropriate phase of 3441 production, based upon the quantity of material to be used, in the absence of any loss or error in actual 3442 production. (ICH Q7) 3443 3444 3445

3446 3447 3448 3449 3450 3451 3452 3453 3454 3455 3456 3457

3458



Appendix C 3459

ICH Q7 Guideline: Section 18 - Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 3460

3461

18.1 General 3462

18.10 Section 18 is intended to address specific controls for APIs or intermediates manufactured by cell culture 3463 or fermentation using natural or recombinant organisms and that have not been covered adequately in the 3464 previous sections. It is not intended to be a stand-alone Section. In general, the GMP principles in the 3465 other sections of this document apply. Note that the principles of fermentation for “classical” processes 3466 for production of small molecules and for processes using recombinant and non-recombinant organisms 3467 for production of proteins and/or polypeptides are the same, although the degree of control will differ. 3468 Where practical, this section will address these differences. In general, the degree of control for 3469 biotechnological processes used to produce proteins and polypeptides is greater than that for classical 3470 fermentation processes. 3471

18.11 The term “biotechnological process” (biotech) refers to the use of cells or organisms that have been 3472 generated or modified by recombinant DNA, hybridoma or other technology to produce APIs. The APIs 3473 produced by biotechnological processes normally consist of high molecular weight substances, such as 3474 proteins and polypeptides, for which specific guidance is given in this Section. Certain APIs of low 3475 molecular weight, such as antibiotics, amino acids, vitamins, and carbohydrates, can also be produced by 3476 recombinant DNA technology. The level of control for these types of APIs is similar to that employed 3477 for classical fermentation. 3478

18.12 The term “classical fermentation” refers to processes that use microorganisms existing in nature and/or 3479 modified by conventional methods (e.g. irradiation or chemical mutagenesis) to produce APIs. APIs 3480 produced by “classical fermentation” are normally low molecular weight products such as antibiotics, 3481 amino acids, vitamins, and carbohydrates. 3482

18.13 Production of APIs or intermediates from cell culture or fermentation involves biological processes such 3483 as cultivation of cells or extraction and purification of material from living organisms. Note that there 3484 may be additional process steps, such as physicochemical modification, that are part of the 3485 manufacturing process. The raw materials used (media, buffer components) may provide the potential 3486 for growth of microbiological contaminants. Depending on the source, method of preparation, and the 3487 intended use of the API or intermediate, control of bioburden, viral contamination, and/or endotoxins 3488 during manufacturing and monitoring of the process at appropriate stages may be necessary. 3489

18.14 Appropriate controls should be established at all stages of manufacturing to assure intermediate and/or 3490 API quality. While this Guide starts at the cell culture/fermentation step, prior steps (e.g. cell banking) 3491 should be performed under appropriate process controls. This Guide covers cell culture/fermentation 3492 from the point at which a vial of the cell bank is retrieved for use in manufacturing. 3493

18.15 Appropriate equipment and environmental controls should be used to minimize the risk of 3494 contamination. The acceptance criteria for quality of the environment and the frequency of monitoring 3495 should depend on the step in production and the production conditions (open, closed, or contained 3496 systems). 3497

18.16 In general, process controls should take into account: 3498

− Maintenance of the Working Cell Bank (where appropriate); 3499

− Proper inoculation and expansion of the culture; 3500



− Control of the critical operating parameters during fermentation/cell culture; 3501

− Monitoring of the process for cell growth, viability (for most cell culture processes) and productivity 3502 where appropriate; 3503

− Harvest and purification procedures that remove cells, cellular debris and media components while 3504 protecting the intermediate or API from contamination (particularly of a microbiological nature) and 3505 from loss of quality; 3506

− Monitoring of bioburden and, where needed, endotoxin levels at appropriate stages of production; and 3507

− Viral safety concerns as described in ICH Guideline Q5A Quality of Biotechnological Products: Viral 3508 Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. 3509

18.17 Where appropriate, the removal of media components, host cell proteins, other process-related 3510 impurities, product-related impurities and contaminants should be demonstrated. 3511

3512

18.2 Cell Bank Maintenance and Record Keeping 3513

18.20 Access to cell banks should be limited to authorized personnel. 3514

18.21 Cell banks should be maintained under storage conditions designed to maintain viability and prevent 3515 contamination. 3516

18.22 Records of the use of the vials from the cell banks and storage conditions should be maintained. 3517

18.23 Where appropriate, cell banks should be periodically monitored to determine suitability for use. 3518

18.24 See ICH Guideline Q5D Quality of Biotechnological Products: Derivation and Characterization of Cell 3519 Substrates Used for Production of Biotechnological/Biological Products for a more complete discussion 3520 of cell banking. 3521

3522

18.3 Cell Culture/Fermentation 3523

18.30 Where aseptic addition of cell substrates, media, buffers, and gases is needed, closed or contained 3524 systems should be used where possible. If the inoculation of the initial vessel or subsequent transfers or 3525 additions (media, buffers) are performed in open vessels, there should be controls and procedures in 3526 place to minimize the risk of contamination. 3527

18.31 Where the quality of the API can be affected by microbial contamination, manipulations using open 3528 vessels should be performed in a biosafety cabinet or similarly controlled environment. 3529

18.32 Personnel should be appropriately gowned and take special precautions handling the cultures. 3530

18.33 Critical operating parameters (for example temperature, pH, agitation rates, addition of gases, pressure) 3531 should be monitored to ensure consistency with the established process. Cell growth, viability (for most 3532 cell culture processes), and, where appropriate, productivity should also be monitored. Critical 3533 parameters will vary from one process to another, and for classical fermentation, certain parameters (cell 3534 viability, for example) may not need to be monitored. 3535

18.34 Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation 3536 equipment should be cleaned, and sanitized or sterilized. 3537

18.35 Culture media should be sterilized before use when appropriate to protect the quality of the API. 3538

18.36 There should be appropriate procedures in place to detect contamination and determine the course of 3539 action to be taken. This should include procedures to determine the impact of the contamination on the 3540



product and those to decontaminate the equipment and return it to a condition to be used in subsequent 3541 batches. Foreign organisms observed during fermentation processes should be identified as appropriate 3542 and the effect of their presence on product quality should be assessed, if necessary. The results of such 3543 assessments should be taken into consideration in the disposition of the material produced. 3544

18.37 Records of contamination events should be maintained. 3545

18.38 Shared (multi-product) equipment may warrant additional testing after cleaning between product 3546 campaigns, as appropriate, to minimize the risk of cross-contamination. 3547

3548

18.4 Harvesting, Isolation and Purification 3549

18.40 Harvesting steps, either to remove cells or cellular components or to collect cellular components after 3550 disruption, should be performed in equipment and areas designed to minimize the risk of contamination. 3551

18.41 Harvest and purification procedures that remove or inactivate the producing organism, cellular debris 3552 and media components (while minimizing degradation, contamination, and loss of quality) should be 3553 adequate to ensure that the intermediate or API is recovered with consistent quality. 3554

18.42 All equipment should be properly cleaned and, as appropriate, sanitized after use. Multiple successive 3555 batching without cleaning can be used if intermediate or API quality is not compromised. 3556

18.43 If open systems are used, purification should be performed under environmental conditions appropriate 3557 for the preservation of product quality. 3558

18.44 Additional controls, such as the use of dedicated chromatography resins or additional testing, may be 3559 appropriate if equipment is to be used for multiple products. 3560

3561

18.5 Viral Removal/Inactivation steps 3562

18.50 See the ICH Guideline Q5A Quality of Biotechnological Products: Viral Safety Evaluation of 3563 Biotechnology Products Derived from Cell Lines of Human or Animal Origin for more specific 3564 information. 3565

18.51 Viral removal and viral inactivation steps are critical processing steps for some processes and should be 3566 performed within their validated parameters. 3567

18.52 Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-3568 viral removal/inactivation steps. Therefore, open processing should be performed in areas that are 3569 separate from other processing activities and have separate air handling units. 3570

18.53 The same equipment is not normally used for different purification steps. However, if the same 3571 equipment is to be used, the equipment should be appropriately cleaned and sanitized before reuse. 3572 Appropriate precautions should be taken to prevent potential virus carry-over (e.g. through equipment or 3573 environment) from previous steps. 3574

3575



Appendix D 3576

ICH Q7 Guideline: Section 19 – APIs for Use in Clinical Trials 3577

3578

19.1 General 3579

19.10 Not all the controls in the previous sections of this Guide are appropriate for the manufacture of a new 3580 API for investigational use during its development. Section 19 provides specific guidance unique to 3581 these circumstances. 3582

19.11 The controls used in the manufacture of APIs for use in clinical trials should be consistent with the stage 3583 of development of the drug product incorporating the API. Process and test procedures should be 3584 flexible to provide for changes as knowledge of the process increases and clinical testing of a drug 3585 product progresses from pre-clinical stages through clinical stages. Once drug development reaches the 3586 stage where the API is produced for use in drug products intended for clinical trials, manufacturers 3587 should ensure that APIs are manufactured in suitable facilities using appropriate production and control 3588 procedures to ensure the quality of the API. 3589

3590

19.2 Quality 3591

19.20 Appropriate GMP concepts should be applied in the production of APIs for use in clinical trials with a 3592 suitable mechanism of approval of each batch. 3593

19.21 A quality unit(s) independent from production should be established for the approval or rejection of each 3594 batch of API for use in clinical trials. 3595

19.22 Some of the testing functions commonly performed by the quality unit(s) can be performed within other 3596 organizational units. 3597

19.23 Quality measures should include a system for testing of raw materials, packaging materials, 3598 intermediates, and APIs. 3599

19.24 Process and quality problems should be evaluated. 3600

19.25 Labelling for APIs intended for use in clinical trials should be appropriately controlled and should 3601 identify the material as being for investigational use. 3602

3603

19.3 Equipment and Facilities 3604

19.30 During all phases of clinical development, including the use of small-scale facilities or laboratories to 3605 manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that 3606 equipment is calibrated, clean and suitable for its intended use. 3607

19.31 Procedures for the use of facilities should ensure that materials are handled in a manner that minimizes 3608 the risk of contamination and cross-contamination. 3609

3610

19.4 Control of Raw Materials 3611

19.40 Raw materials used in production of APIs for use in clinical trials should be evaluated by testing, or 3612 received with a supplier’s analysis and subjected to identity testing. When a material is considered 3613 hazardous, a supplier's analysis should suffice. 3614



19.41 In some instances, the suitability of a raw material can be determined before use based on acceptability 3615 in small-scale reactions (i.e., use testing) rather than on analytical testing alone. 3616

3617

19.5 Production 3618

19.50 The production of APIs for use in clinical trials should be documented in laboratory notebooks, batch 3619 records, or by other appropriate means. These documents should include information on the use of 3620 production materials, equipment, processing, and scientific observations. 3621

19.51 Expected yields can be more variable and less defined than the expected yields used in commercial 3622 processes. Investigations into yield variations are not expected. 3623

3624

19.6 Validation 3625

19.60 Process validation for the production of APIs for use in clinical trials is normally inappropriate, where a 3626 single API batch is produced or where process changes during API development make batch replication 3627 difficult or inexact. The combination of controls, calibration, and, where appropriate, equipment 3628 qualification assures API quality during this development phase. 3629

19.61 Process validation should be conducted in accordance with Section 12 when batches are produced for 3630 commercial use, even when such batches are produced on a pilot or small scale. 3631

3632

19.7 Changes 3633

19.70 Changes are expected during development, as knowledge is gained and the production is scaled up. 3634 Every change in the production, specifications, or test procedures should be adequately recorded. 3635

3636

19.8 Laboratory Controls 3637

19.80 While analytical methods performed to evaluate a batch of API for clinical trials may not yet be 3638 validated, they should be scientifically sound. 3639

19.81 A system for retaining reserve samples of all batches should be in place. This system should ensure that 3640 a sufficient quantity of each reserve sample is retained for an appropriate length of time after approval, 3641 termination, or discontinuation of an application. 3642

19.82 Expiry and retest dating as defined in Section 11.6 applies to existing APIs used in clinical trials. For 3643 new APIs, Section 11.6 does not normally apply in early stages of clinical trials. 3644

3645

19.9 Documentation 3646

19.90 A system should be in place to ensure that information gained during the development and the 3647 manufacture of APIs for use in clinical trials is documented and available. 3648

19.91 The development and implementation of the analytical methods used to support the release of a batch of 3649 API for use in clinical trials should be appropriately documented. 3650

19.92 A system for retaining production and control records and documents should be used. This system 3651 should ensure that records and documents are retained for an appropriate length of time after the 3652

approval, termination, or discontinuation of an application.3653



Appendix E 3654

Annexes to the Current Edition of these API GMP Guidelines 3655

3656 Annexes are available on Health Canada’s website at the following address: http://www.hc-sc.gc.ca/dhp-3657 mps/compli-conform/gmp-bpf/docs/index-eng.php. 3658 3659 1. Annex 1 to the Current Edition of the Good Manufacturing Practices Guidelines - Selected Category IV 3660

Monograph Drugs (GUI-0066) 3661 3662 2. Annex 2 to the Current Edition of the Good Manufacturing Practices Guidelines - Schedule D Drugs, 3663

Biological Drugs (GUI-0027) 3664 3665 3. Annex 3 to the Current Edition of the Good Manufacturing Practices Guidelines - Schedule C Drugs (GUI-3666

0026) 3667 3668 4. Annex 4 to the Current Edition of the Good Manufacturing Practices Guidelines - Veterinary Drugs (GUI-3669

0012) 3670 3671 5. Annex 5 to the Current Edition of the Good Manufacturing Practices Guidelines - Positron Emitting 3672

Radiopharmaceuticals (PERs) (GUI-0071) 3673 3674 6. PIC/S Annex 11: Computerised Systems 3675 3676 7. Annex 13 to the Current Edition of the Good Manufacturing Practices Guidelines - Drugs Used in Clinical 3677

Trials (GUI-0036) 3678 3679 8. Annex 14 to the Current Edition of the Good Manufacturing Practices Guidelines - Schedule D Drugs, 3680

Human Blood and Blood Components (GUI-0032) 3681 3682 9. Annex 17 to the Current Edition of the Good Manufacturing Practices Guidelines - Guidance on Parametric 3683

Release (GUI-0046) 3684 3685

3686

3687



References 3688

3689

Justice Canada 3690 3691

Acts and regulations of Canada are available on Justice Laws website. 3692 3693 1. Food and Drugs Act 3694 3695 2. Food and Drug Regulations 3696 3697 3698

Health Canada 3699 3700

Guidance documents and Questions and Answers that relate to GMPs are available on Health Canada’s 3701 website 3702 3703 3. Good Manufacturing Practices (GMP) Guidelines, Edition 2009, Version 2 (GUI-0001) 3704 3705 4. Guidance on Evidence to Demonstrate Drug GMP Compliance of Foreign Sites (GUI-0080) 3706 3707 5. Annex 3 to the Current Edition of the Good Manufacturing Practices Guidelines - Schedule C Drugs 3708

(Guide 0026) 3709 3710 6. Annex 2 to the Current Edition of the Good Manufacturing Practices Guidelines Schedule D Drugs 3711

(Biological Drugs) (Guide 0027) 3712 3713 7. Good Manufacturing Practices Questions and Answers 3714 3715 8. Active Pharmaceutical Ingredients Questions and Answers 3716 3717 9. Risk Classification of GMP Observations (GUI–0023) 3718 3719 10. Guidelines for Temperature Control of Drug Products during Storage and Transportation (GUI-0069) 3720 3721 11. Product Recall Procedures 3722 3723 12. Cleaning Validation Guidelines (GUI-0028) 3724 3725 13. Validation Documentation Requirements and Responsibilities for Drug Fabricators, 3726

Packagers/Labellers, Distributors and Importers (GUI-0042) 3727 3728 14. Process Validation Guidelines: 3729 3730

Moist Heat Sterilization for Pharmaceuticals (GUI-0010) 3731 3732 Irradiation Sterilization for Pharmaceuticals (GUI-0009) 3733 3734



Gaseous Sterilization for Pharmaceuticals (GUI-0007) 3735 3736 Aseptic Processes for Pharmaceuticals (GUI-0006) 3737

3738 15. Importation and Exportation Questions and Answers 3739 3740 16. Alternate Sample Retention Site Guidelines (GUI-0014) 3741 3742

Documents that relate to stability are available on Health Canada’s website in the Drug Products section 3743 under Application and Submissions. 3744 3745 17. Stability Testing of Existing Drug Substances and Products (TPD) 3746 3747

Guidance documents developed by the International Conference on Harmonisation (ICH) and adopted 3748 by Health Canada are available on the web in the Drug Products section under ICH (International 3749 Conference on Harmonisation). 3750 3751 18. ICH Q1A(R2): Stability Testing of New Drug Substances and Products 3752 3753 19. ICH Q1B: Stability Testing: Photostability Testing of New Drug Substances and Products 3754 3755 20. ICH Q2(R1): Validation of Analytical Procedures: Text and Methodology 3756 3757 21. ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients 3758 3759 22. ICH Q8: Pharmaceutical Development 3760 3761 23. ICH Q9: Quality Risk Management 3762 3763 24. ICH Q10: Pharmaceutical Quality System 3764

3765



Appendix F 3766

Cross-walk between ICH Q7 and Guide 0001 documents 3767

Interpretations of the API Guide

Section of ICH Q7 Section of GUI-0001

Quality Management 4.1 2.10, 2.12 4.1 4.2 n/a 4.2

4.2.1 n/a 4.2.1 4.2.1.1 n/a 4.2.1.1 4.2.1.2 2.11 4.2.1.2 4.2.1.3 2.3.10 4.2.1.3 4.2.1.4 n/a 4.2.1.4 4.2.1.5 n/a 4.2.1.5 4.2.1.6 2.17 4.2.1.6 4.2.1.7 n/a 4.2.1.7 4.2.1.8 n/a 4.2.1.8 4.2.1.9 n/a 4.2.1.9

4.2.1.10 2.17, partial 2.14 4.2.1.10 4.2.1.11 n/a 4.2.1.11 4.2.1.12 n/a 4.2.1.12 4.2.1.13 n/a 4.2.1.13 4.2.1.14 n/a 4.2.1.14

4.2.2 n/a 4.2.2 4.2.2.1 n/a 4.2.2.1 4.2.2.2 n/a 4.2.2.2 4.2.2.3 n/a 4.2.2.3 4.2.2.4 n/a 4.2.2.4 4.2.2.5 n/a 4.2.2.5 4.2.2.6 2.16 4.2.2.6 4.2.2.7 n/a 4.2.2.7 4.2.2.8 n/a 4.2.2.8 4.2.2.9 n/a 4.2.2.9

4.2.2.10 n/a 4.2.2.10 4.2.3 n/a 4.2.3

4.2.3.1 n/a 4.2.3.1 4.2.3.1.1 n/a 4.2.3.1.1 4.2.3.1.2 n/a 4.2.3.1.2 4.2.3.1.3 n/a 4.2.3.1.3 4.2.3.1.4 2.41 4.2.3.1.4 4.2.3.1.5 n/a 4.2.3.1.5 4.2.3.1.6 n/a 4.2.3.1.6 4.2.3.1.7 n/a 4.2.3.1.7

C.02.003 – Sale and Use in Fabrication 1. n/a n/a 2. n/a n/a

C.02.004 – Premises1. 4.10 C.02.004: 1, 11, Partial 3, Partial 3.1, C.02.007: 2.9, Records: 5.4 2. 4.70 C.02.004: 1, 2.1-2.4, 9, Partial 3.1, Records: 5.4 3. 4.11 C.02.004: 2, 2.5, 6.1, 6.2, 11, C.02.005: 3.3, 3.4 4. 4.14 C.02.004: Partial 2.2, 2.3, 6.1-6.4, C.02.011: 48, 49 5. 4.16 C.02.004: Partial 2.3, 10, C.02.011: 12



6. 4.24 C.02.004: 3.5 7. 4.20 C.02.004: 3.6, 7, C.02.007: 2.9 8. 4.21 C.02.004: 3.6, 4

8.1 4.22 n/a 9. 4.15 C.02.004:5

10. 4.13 C.02.004: 6, 11, C.02.005: 3.3 11. 4.50 C.02.004: 6.5 12. 4.23 C.02.004: 8 13. 4.40 C.02.004: 11, 11.2.1, C.02.005: 3.6 14. 4.41 C.02.004: 11, 11.1, 11.2.2, C.02.005: 3.6 15. 4.43 C.02.004: 11.2.2, 11.4, C.02.011: Partial 9 16. 4.33 C.02.005: 3.7

C.02.005 - Equipment

1. 5.10 C.02.005: 1, 1.1, 1.3, 3.3, 5, Partial 1.2, Partial 1.5, Partial 4.2, Partial 4.3, Partial 4.4

2. 5.11 C.02.005: 1, Partial 1.2, 2, 2.1, 2.3, 4.1, 4.4 3. 5.22 C.02.005: 1.1, 1.2, 1.3, 1.4, 2.4 4. 5.14 C.02.005: 2.2, 3.2 5. 5.15 C.02.005: 2.4, 2.5, 3.2

5.1 n/a C.02.005: 3.1 6. 5.13 C.02.005: 3.5 7. 5.16, 5.20 C.02.005: 4, Partial 4.2 8. N/A C.02.005: 5.2 9. 5.30, 5.34 C.02.005: 5.1, 5.3, 5.4, C.02.011: 13

9.1 5.31 n/a 9.2 5.33, 5.35 n/a 10. Partial 8.10 C.02.005: 5.1, C.02.011: 22 11. 5.12 C.02.005: 5.2, 5.3, C.02.011: 35.10 12. 5.40 C.02.005: 5.3, C.02.015: Partial 7.5 13. 5.41 C.02.005: 5.3 14. 5.42 n/a 15. 5.43 n/a 16. 5.44, 5.48 n/a 17. 5.49 n/a 18. 12.30 C.02.005: 5.3

C.02.006 - Personnel 1. 3.10 C.02.006: 1, 1.1, 1.2, 1.3, 1.4, 3, 3.1, 3.2, 4, 4.1, 4.2, 5, 5.1, 5.3 2. n/a C.02.006: 1 2.1 n/a C.02.006:1.3 2.2 n/a C.02.006: 1.4 3. 3.11 C.02.006: 5.2 4. Partial 3.12 C.02.006: 6, 6.1

4.1 Partial 3.12 C.02.006: 6 4.2 Partial 3.12 C.02.006: 6.4 4.3 Partial 3.12 C.02.006: 6.2, 6.6 4.4 n/a C.02.006: 6.3 4.5 n/a C.02.006: 6.5 5. 3.30 C.02.006: 7 6. 2.3 C.02.011: Partial 1

6.1 2.3.1 C.02.011: Partial 1 6.2 2.3.2 C.02.011: Partial 23 6.3 2.3.3 C.02.011: 27.10 6.4 2.3.4 C.02.011: 5

6.5 2.3.5 C.02.004: 1, 2, 3, 9, 11 C.02.005: 1, 3, 4



6.6 2.3.6 C.02.005: 5.1 Records: 2.3

6.7 2.3.7 C.02.004: 2 C.02.005: 4, 5 Records: 2.3, 5.4, 6.4

6.8 2.3.8 C.02.011: Partial 3 6.9 2.3.9 C.02.011: 4

6.10 2.3.10 C.02.004: Partial 7 C.02.005: Partial 5.3

7 2.22 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2 C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.1 2.22.1 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2 C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.2 2.22.2 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.3 2.22.3 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.4 2.22.4 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.5 2.22.5 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.6 2.22.6 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.7 2.22.7 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.8 2.22.8 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.9 2.22.9 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.10 2.22.10 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.11 2.22.11 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.12 2.22.12 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.13 2.22.13 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.14 2.22.14 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.15 2.22.15 C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

7.16 n/a C.02.009: Partial 1, 7, C.02.011: 3, 4, 5, 19, C.02.012: 3.2

C.02.014: 2, 2.1, 3, C.02.015: 4, 6, C.02.016: 1, C.02.018: Partial 1

C.02.007 - Sanitation Rationale 4.70 C.02.007: 3

1. 4.71 C.02.007: 1, 2, 2.1, 2.4, 2.10

1.1 n/a C.02.007: 2.9

1.2 n/a C.02.007: 2.5 2. 5.24 C.02.007: 2.3 3. 5.25 C.02.007: 2.4, 3.2 4. 4.60 C.02.007: 2.6 5. 12.70 C.02.007: 3.1 6. 12.74 C.02.007: 3.2, 3.4 7. 12.75 C.02.007: 3.3

8. 4.72 C.02.004: 2 C.02.007: 2.7, 2.8



9. 5.21 C.02.005: 1, 1.1, 1.3, 1.4, 1.6, C.02.007: 1, 2.2, 2.3, 2.4, 2.10, 3.2, Partial 1.2

10. 5.23 C.02.007: 2.3, 2.8, 3.5, Partial 2.7 11. 6.20 C.02.005: 5.5 12. 12.76 n/a 13. n/a C.02.007: 5

C.02.008 - Sanitation 1. 3.20 C.02.008: 2.1, Partial 1, Partial 2, Partial 2.4, Records: Partial 5.4, 6.4

1.1 n/a C.02.008: 2.5 2. 3.24 C.02.008: 1.3, 1.4

2.1 n/a C.02.008: 1.2 2.2 n/a C.02.008: 1.5 3. 3.21 C.02.008: 2.1, 2.7

3.1 n/a C.02.008: 2.6 4. 3.22 C.02.008: 2.2 5. 3.23 C.02.008: 2.3

C.02.009 – Raw Materials Testing 1. 6.17 C.02.009: 1, C.02.018: 1, Records: 5.1 2. n/a C.02.009: 2 3. 7.12 C.02.009 : Partial 1 4. 4.30 C.02.005: Partial 3.7 5. 4.31 C.02.009: Partial 4 6. 4.32 C.02.009: Partial 4, Partial 4.1, Partial 4.2 7. 4.34 C.02.005: Partial 3.7 8. 12.80 C.02.009: Partial 5, C.02.018: 2 9. 12.81 C.02.009: Partial 5, C.02.018: 2

10. 7.50 n/a

C.02.010 – Raw Materials Testing 1. 7.11 C.02.010: Partial 1 2. 7.30 C.02.010: Partial 1, C.02.017: Partial 1

2.1 n/a C.02.010: 3 3. 7.31 C.02.010: Partial 1, Partial 1.3, C.02.017: Partial 1

3.1 n/a C.02.010 : 1.7 3.2 n/a C.02.010 : 1.4 4. 7.32 n/a 5. 7.33 C.02.009 : Partial 6, C.02.013 : Partial 3, C.02.015: 4 6. Partial 7.10 C.02.011: Partial 1, Partial 17 7. 7.13 Records: 5.3, 6.3 8. 7.14 n/a 9. n/a C.02.010: 1.3

10. n/a C.02.010: 1.8 11. n/a C.02.010: 4

11.1 n/a C.02.010: 4.1 11.2 n/a C.02.010: 4.2 11.3 n/a C.02.010: 4.3 11.4 n/a C.02.010: 4.4 11.5 n/a C.02.010: 4.5 11.6 n/a C.02.010: 4.6 12. n/a C.02.010: 5 13. n/a C.02.010: 6

13.1 n/a C.02.010: 6.1 13.2 n/a C.02.010: 6.2 13.3 n/a C.02.010: 6.3 13.4 n/a C.02.010: 6.4

C.02.011 – Manufacturing Control



1. n/a C.02.011: 8 2. Partial 7.10 C.02.011: 1, 17 3. 12.12 C.02.011: 2

3.1 12.60, 13.13 C.02.011: 4, C.02.015: 6 4. 12.20 C.02.011: 3

4.1 12.21 C.02.011 : Partial 3 4.2 12.22 n/a 4.3 12.23 n/a 5. Partial 12.30 C.02.005: 5.3 6. 8.15, 8.20 C.02.011: 5, 19, 35.12, Partial 41 7. 8.14 C.02.011: 6, 7 8. 8.50 C.02.005: 2, 3, C.02.011: Partial 9 9. n/a C.02.011: 9

10. 9.44 C.02.011: 10 11. 8.51 C.02.004: 3.2, 3.3, 3.4, C.02.011: 11, 20, Partial 9, Records: 5.4, 6.4 12. 8.35 C.02.011: 12 13. 8.30 N/A 14. 8.31 N/A 15. 8.32 N/A 16. 8.33 N/A 17. 8.34 N/A 18. 8.52 C.02.004: 3.2, 3.3, 3.4, C.02.011: Partial 9 19. 4.42 C.02.004: 1, 2 20. 5.26 C.02.005: 3.5, C.02.011: 14 21. 8.16 C.02.005: 3.5, C.02.011: 14, 34 22. 7.44 C.02.011: 15 23. 8.17 C.02.011: 15 24. 7.20 C.02.011: 16, 17, 19

24.1 7.20 C.02.011: 16 25. 7.21 C.02.011: 16, 17, 19 26. 7.22 C.02.011: 16, 17, 19 27. 8.21 C.02.011: 48

28. 10.21 C.02.011: 48 C.02.015: 3

29. 10.22 C.02.015 : 3.2 30. 7.34 C.02.004: 6.4, C.02.011: 20 31. 7.35 C.02.011: 17 32. 7.23 C.02.011: 14

33. 7.24 C.02.010: 5, 6, 6.1. 6.2, 6.3, 6.4 C.02.011: 14, 21.5 C.02.017: 5

34. 7.40 C.02.004: 4 C.02.011: 48 C.02.017: Partial 3, 3.1, 3.2, 3.4, 3.5

35. 7.41 n/a 36. 7.42 n/a 37. 7.43 n/a 38. Partial 8.10 C.02.005: 5.1, C.02.011: 22 39. 8.12 C.02.011: 22 40. 8.13 n/a 41. 2.15 C.02.011: 35.4

42. 6.14 C.02.011: 35.4 Records: Interpretation paragraph

43. 6.10 C.02.011: 1 43.1 6.40 C.02.011: 23 44. 6.41, 8.20 C.02.011: 24, 24.1, 24.3, 24.4, 24.5, 24.7, 24.8, 24.9, 25, 25.1, 25.2, 27,



27.1, 27.3, 27.4, 35.7, Partial 24.6 45. 6.50 C.02.011: 26, Records: 2.2 46. 6.51 C.02.011: 26, 27.2, Records: 2.2 47. 6.52 C.02.011: 27.3 to 27.10, 35, 35.1 to 35.4, Records: 2.2 48. 8.11 C.02.011: Partial 21, Partial 21.4 49. 8.40 n/a 50. 8.41 n/a 51. 8.42 n/a 52. 8.43 C.02.011: 28 53. 8.44 n/a 54. 8.45 n/a 55. 8.46 n/a 56. 8.47 C.02.027: Partial 1.5 57. 14.40 C.02.011: 28.1 58 14.41 n/a 59. 14.42 n/a 60. 14.43 n/a 61. n/a C.02.011: 29 62. 9.41 C.02.011: 29, 38 63. 9.30 C.02.011: Partial 43, 43.1 64. 9.44 C.02.011: 25.4, 31

65. 9.40 C.02.011: 25.1, 25.5, 29, 35.8, 35.13, 38, 45, 46 C.02.017: Partial 3, Partial 3.1, Partial 3.2, Partial 3.4, Partial 3.5

66. 9.34 n/a 67. 9.35 C.02.011: 43, 47 68. 9.21 C.02.011: 33 69. 9.22 n/a 70. 9.42 C.02.011: 21, 21.1, 21.2, 21.3, 50 71. 9.43 C.02.011: 21, 21.1 to 21.4, Partial 35.7 72. 9.46 n/a 73. 9.45 C.02.011: 25.6, 35.5, 35.6, 35.8 74. 9.31 C.02.011: 35.14, 42 75. 9.32 C.02.011: 39 76. 9.33 C.02.011: 40 77. n/a C.02.011: 49 78. n/a C.02.011 : 35

78.1 n/a C.02.011 : 35.1 78.2 n/a C.02.011 : 35.3 78.3 n/a C.02.011 : 35.4 78.4 n/a C.02.011 : 35.8 78.5 n/a C.02.011 : 35.9 78.6 n/a C.02.011 : 35.10 78.7 n/a C.02.011 : 35.11 78.8 n/a C.02.011 : 35.12 78.9 n/a C.02.011 : 37

79. 2.50 C.02.011: 51, 51.2, 51.3, 51.5, 51.6, 51.7 C.02.015: 4, C.02.028: 1

80. 2.51 C.02.011: 55 81. n/a C.02.011: 53 82. n/a C.02.011: 54

C.02.012 – Manufacturing Control Rationale 17.40 C.02.012 : Interpretation paragraph

1. 2.18 C.02.012 :1.4

2. 15.13 C.02.012: Partial 1, Partial 1.10, Partial 1.11, 1.2 Records: 3.2

3. 15.14 C.02.012: 1.3, 1.5, 1.9, Partial 1



Records: 3.2 3.1 n/a C.02.012: 1.1 3.2 n/a C.02.012: 1.4 3.3 n/a C.02.012: 1.10

4. 15.15 C.02.012: Partial 1.1 Records: 3.2

5. 10.24 C.02.012: 1.6 Records: 2.1, 2.1.1, 2.1.2

6. 10.11 C.02.012: 1.9

7. 17.70 C.02.012: 1.11 Records: 3.1

8. 2.40 C.02.012: 2, 2.1, 2.2, 2.4 8.1 n/a C.02.012: 2.3 9. 2.41 C.02.012: 2.1, 2.5, Records: 2.2

10. Partial 16.10, 17.11 C.02.012: 3.2.2 11. 16.11 n/a 12. n/a C.02.012: 3.

12.1 n/a C.02.012: 3.1 12.2 16.12 C.02.012: 3.2

12.2.1 n/a C.02.012: 3.2.1 12.2.2 16.13 C.02.012: 3.2.2 12.2.3 n/a C.02.012: 3.2.3

12.2.3.1 n/a C.02.012: 3.2.3.1 12.2.3.2 n/a C.02.012: 3.2.3.2 12.2.3.3 n/a C.02.012: 3.2.3.3 12.2.4 16.14 C.02.012: 3.2.4 12.2.5 n/a C.02.012: 3.2.5 12.2.6 n/a C.02.012: 3.2.6 12.3 n/a C.02.012: 3.3 12.4 n/a C.02.012: 3.4

12.4.1 16.16 n/a 12.5 n/a C.02.012: 3.5

12.5.1 n/a C.02.012: 3.5.1 12.5.2 n/a C.02.012: 3.5.2

C.02.013 – Quality Control Department 1. 2.20 C.02.015: 4

2. 2.21, Partial 7.10,

Partial 11.11

C.02.011: 1, 17 C.02.013: 3 C.02.014: 3 C.02.015: 3

3. 2.13 n/a

4. 11.10 C.02.013: 2 C.02.015: 7, 7.1

C.02.014 – Quality Control Department

1. Partial 2.14, Partial

2.22 C.02.014: 1

2. 2.17 n/a 3. 2.22 C.02.014: 2 4. 10.20 n/a 5. n/a C.02.014: 3 6. 2.16, 6.53 C.02.014: 2.1, 2.2

7. 14.10, 14.50 C.02.011: 15 C.02.014: 5 C.02.018: 4

8. 14.51 C.02.014: 4 8.1 n/a C.02.014: 4.1



9. 14.30, 14.31 C.02.014: 6 9.1 14.31 C.02.014: 6, 6.1 to 6.7 10. 14.32 C.02.014: 9 11. 14.20 C.02.014: 7, 7.1 to 7.7

11.1 14.20 C.02.014: 7, 7.1 to 7.7 11.1.1 14.20 C.02.014: 7, 7.1 to 7.7 11.1.2 14.20 C.02.014: 7, 7.1 to 7.7 11.1.3 14.20 C.02.014: 7, 7.1 to 7.7 11.1.4 14.20 C.02.014: 7, 7.1 to 7.7 11.1.5 14.20 C.02.014: 7, 7.1 to 7.7 11.1.6 14.20 C.02.014: 7, 7.1 to 7.7 11.1.7 14.20 C.02.014: 7, 7.1 to 7.7 11.2 14.20 C.02.014: 7, 7.1 to 7.7 12. 14.22 C.02.014: 7, 7.1-7.5, 7.7

C.02.015 – Quality Control Department 1. 2.18 C.02.012 : 1.4 2. 13.10 C.02.015 : 5

3. 13.11 C.02.014 :4 C.02.015 : 5

4. 13.12 C.02.015 : 5

5. 13.13 C.02.011 : 4 C.02.015 : 5

5.1 13.16 C.02.015 : Partial 6 5.2 13.15 C.02.015 : Partial 6 5.3 13.14 C.02.015 : Partial 6 6. 13.17 n/a

7. 15.10 C.02.015 : 4 Records : 3.1, 3.2

7.1 17.71 n/a 7.2 17.72 n/a

8. 15.12 C.02.015 : 5 Records : 3.2

9. 11.12 C.02.009 : Partial 2, C.02.015 : Partial 3, C.02.016 : Partial 2, 3, C.02.018 : 1.2

10. 11.14 C.02.015 : 6 11. 6.60 C.02.014 : 1, C.02.015 : 1, Records : 4.2

11.1 6.60 C.02.014 : 1, C.02.015 : 1, Records : 4.2 11.2 6.60 C.02.014 : 1, C.02.015 : 1, Records : 4.2 11.3 6.60 C.02.014 : 1, C.02.015 : 1, Records : 4.2 11.4 6.60 C.02.014 : 1, C.02.015 : 1, Records : 4.2 11.5 6.60 C.02.014 : 1, C.02.015 : 1, Records : 4.2 11.6 6.60 C.02.014 : 1, C.02.015 : 1, Records : 4.2 11.7 6.60 C.02.014 : 1, C.02.015 : 1, Records : 4.2 11.8 6.60 C.02.014 : 1, C.02.015 : 1, Records : 4.2 12. 11.16 n/a 13. n/a C.02.015 :7

13.1 n/a C.02.015 :7.1 13.1.1 n/a C.02.015 :7.1.1 13.1.2 n/a C.02.015 :7.1.2 13.2 n/a C.02.015 :7.2 13.3 n/a C.02.015 :7.3 13.4 n/a C.02.015 :7.4 13.5 n/a C.02.015 :7.5 13.6 n/a C.02.015 :7.6 13.7 n/a C.02.015 :7.7

13.7.1 n/a C.02.015 :7.7.1



13.7.2 n/a C.02.015 :7.7.2 13.7.3 n/a C.02.015 :7.7.3 13.7.4 n/a C.02.015 :7.7.4

13.7.4.1 n/a C.02.015 :7.7.4.1 13.7.4.2 n/a C.02.015 :7.7.4.2 13.7.4.3 n/a C.02.015 :7.7.4.3 13.7.4.4 n/a C.02.015 :7.7.4.4

13.8 n/a C.02.015 :7.8 13.9 2.16, 11.15 C.02.015 : 7.9

13.9.1 n/a C.02.015 : 7.9.1 13.9.2 n/a C.02.015 : 7.9.2 13.9.3 n/a C.02.015 : 7.9.3 13.9.4 n/a C.02.015 : 7.9.4 13.9.5 n/a C.02.015 : 7.9.5 13.9.6 8.36 n/a

14. 11.17 C.02.015 : Partial 7.8 15. 11.18 C.02.015 : Partial 7.8 16. 11.19 C.02.015 : Partial 7.8 17. 6.61 Records : 2.3

17.1 6.61 C.02.015 : 6

17.2 6.61 C.02.005 : 5.1 C.02.015 : Partial 7.4

17.3 6.61 Records : Partial 2.4, 2.4.1

17.4 6.61 C.02.015: Partial 7.9 Records: 2.3

18. 5.45 n/a 19. 5.46 n/a 20. 5.47 n/a 21. 6.72 C.02.015 : 7.9.4 22. n/a C.02.015 : 7.10

22.1 n/a C.02.015 : 7.10.1 22.2 n/a C.02.015 : 7.10.2 22.3 n/a C.02.015 : 7.10.3

22.3.1 n/a C.02.015 : 7.10.3.1 22.3.2 n/a C.02.015 : 7.10.3.2 22.3.3 n/a C.02.015 : 7.10.3.3

22.3.3.1 n/a C.02.015 : 7.10.3.3.1 22.3.3.2 n/a C.02.015 : 7.10.3.3.2 22.3.3.3 n/a C.02.015 : 7.10.3.3.3 22.3.3.4 n/a C.02.015 : 7.10.3.3.4 22.3.4 n/a C.02.015 : 7.10.3.4

23. 10.23 C.02.015 : Partial 3.6

C.02.016 – Packaging Material Testing and C.02.017 – Packaging Material Testing 1. 9.10 n/a 2. n/a C.02.016: Partial 1

2.1 n/a C.02.016 : 2 2.2 n/a C.02.016 : 3 2.3 n/a C.02.016 : Partial 1 2.4 9.21 n/a 2.5. n/a n/a 3. n/a C.02.016: 7 4. N/A C.02.017: 4

4.1 6.31, 9.36 C.02.011 : 25.3, Partial 37 5. 9.11 C.02.016 : Partial 4 6. n/a C.02.016 : 4 7. 9.20 n/a



8. 9.21 n/a 9. n/a C.02.016: 5

10. n/a C.02.017: 1

10.1 7.31 C.02.010: 1 C.02.017: Partial 1

C.02.018 – Finished Products Testing 1. 11.20 n/a 2. 11.12, Partial 6.17 C.02.018: 1

2.1 n/a C.02.018: 1.2

3. 11.13, 11.23 C.02.015: 6 C.02.018: 1.1

4. 12.80 C.02.018: 2 5. Partial 12.81 C.02.018: Partial 2 6. n/a C.02.018: 3 7. 11.21 n/a 8. 11.22 n/a 9. 11.41 C.02.011: Partial 21.4

10. 11.40 n/a 11. 11.42 n/a 12. 11.43 n/a 13. 11.44 n/a

14. Partial 11.15 C.02.018: 4 C.02.019: Partial 5

C.02.019 – Finished Products Testing 1. n/a C.02.019: 1 2. n/a C.02.019: 2 3. n/a C.02.019: 4

3.1 n/a C.02.019: 4.1 3.2 n/a C.02.019: 4.2 3.3 n/a C.02.019: 4.3 4. n/a C.02.019: 6

C.02.020 to C.02.024 – Records 1. n/a Partial Records Interpretation Paragraph 2. n/a Partial Records Interpretation Paragraph

2.1 6.11 n/a 2.2 Partial 6.10 Partial Records Interpretation Paragraph 2.3 n/a Partial Records Interpretation Paragraph 2.4 6.12 n/a 3. 6.15, 6.16 Partial Records Interpretation Paragraph

3.1 16.15 n/a 4. n/a Records: 1

4.1 6.18 Partial Records Interpretation Paragraph 5. 6.14 Partial Records Interpretation Paragraph 6. n/a Records: Partial 2.3, 8

6.1 6.13 Records: 5.5 6.2 n/a Records: 2.3.1 6.3 6.21 n/a 6.4 5.32 C.02.005: 5.1 6.5 n/a Records: 7, 7.1 6.6 3.31 Records: Partial 2.3.2 6.7 n/a Records: 5.4 6.8 6.71 n/a 6.9 n/a Records: 3.2

6.10 n/a Records: 2.4 6.10.1 n/a Records: 2.4.1



6.11 10.10 C.02.004: 4, C.02.015: 2, C.02.025/C.02.026: 2.2 7. n/a Records: 2.2

7.1 6.70 n/a 7.2 n/a Records: 2.2.1 7.3 n/a Records: 2.2.2 7.4 n/a Records: 2.2.3 7.5 n/a Records: 2.2.4 7.6 n/a Records: equivalent to 2.5 8. n/a Records: 3, 4, 8

8.1 n/a Records: 3.1 8.1.1 n/a Records: 3.1.1 8.1.2 n/a Records: 3.1.2 8.1.3 14.52 n/a 8.2 Partial 15.10 Records: 4.1, 4.2

8.2.1 15.11 n/a 8.2.2 17.60 n/a

9. n/a Records: 5, 6 9.1 6.17 Records: 5.1, 6.1 9.2 6.30, 9.12 Records: 2.2.1, 5.3, 6.3 9.3 6.30 Records: 6.2

9.3.1 Partial 11.11 Records: 2.2.1, 5.2, 6.2 10. 6.13 Records: 2, 10

10.1 6.40, 6.41 Records: 2.1 10.2 n/a Records: 2.1.1 10.3 n/a Records: 2.1.2 11. 17.20 n/a 12. n/a n/a

12.1 n/a n/a 12.2 n/a n/a 12.3 n/a n/a 12.4 n/a n/a

C.02.025 and C.02.026 – Samples 1. 11.63 n/a 2. 11.70 n/a 3. 11.71 n/a 4. 11.72 C.02.025: 2.1, 3 5. n/a C.02.025: 1.2 6. n/a C.02.025: 1.3

C.02.027 – Stability1. 11.60 C.02.027: 1 2. 11.61 Records: 2.4, 2.4.1, C.02.027: Partial 1.1 3. 11.62 C.02.027: Partial 1

3.1 n/a C.02.027:1.1 4. 11.52 C.02.027: 1.2

4.1 n/a n/a 5. 11.53 C.02.027: Partial 1.3 6. n/a C.02.027: 1.4 7. 11.56 C.02.027: Partial 1.4 8. Partial 11.51 C.02.027: 1.7

C.02.028 – Stability

1. 11.50 Records: 2.4, 2.4.1 C.02.028: 1

2. 11.54 C.02.028: 1.2 3. 11.55 n/a 4. 11.56 Rationale Paragraph



5. n/a C.02.028: 1.1 6. n/a C.02.028: 1.3 7. n/a C.02.028: 1.4 8. n/a C.02.028: 1.5

3768 3769