2 the regulations
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TRANSCRIPT
GMP - The Regulations
Objectives
Have an understanding of the regulations governing GMP
Have an understanding of application of regulations
Discuss interpretation of regulations
Goal
You will have a basic understanding of the regulation governing GMPs and be able to apply this understanding when presented with examples.
Characteristics of GMP regulations and interpretations
Benefit: Manufacturers and researchers are able to
interpret and apply the regulations in ways that may work best for their unique situations
Risk: The flexibility may lead to confusion during the
interpretation of the regulation and misapplied control mechanisms
GMP regulations are largely general and open for interpretation
GMP – Characteristics
The Regulations
21 CFR Parts 210 and 211 (Drug Industry)21 CFR Part 820 (Medical Device Industry)21 CFR Part 110 (Food Industry)21 CFR Part 606 (Blood Industry
Part 210
CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL
Remember “current”
In the US, the phrase "current good manufacturing practice" appears in 501(B) of the 1938 Food, Drug, and Cosmetic Act (21USC351). US courts may theoretically hold that a drug product is adulterated even if there is no specific regulatory requirement that was violated as long as the process was not performed according to industry standards.
Part 211
Subpart A – General ProvisionSubpart B – Organization and personnelSubpart C – Buildings and FacilitiesSubpart D – EquipmentSubpart E - Control of Components and
Drug Products Containers and ClosuresSubpart F – Production and process
controls
Part 211 cont.
Subpart G – Packaging and Labeling Control
Subpart H – Holding and distributionSubpart I – Laboratory ControlsSubpart J – Records and ReportsSubpart K – Returned and Salvaged
Drug Products
Organization and Personnel
Buildings and Facilities
Equipment
Control of components and Drug Product Containers and Closures
Production and Process Controls
Packaging and Labeling Control
Holding and Distribution
Laboratory controlsGMP
Subpart A – General Provisions
Scope - The regulations in this part contain the minimum current good manufacturing practice for preparation of drug products for administration to humans or animals.
Subpart B- Organizations and Personnel
Subpart B
211.22 Responsibility of QC211.25 Personnel Qualifications211.28 Personnel Responsibilities211.34 Consultants.
Quality Control Unit
The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.
211.22 Responsibility of Quality Control Unit
Authorities and ResponsibilityApprove or Reject all:
o Componentso Drug Product Containero Closureso in-process Materialso Packaging Materialso Labelingo Drug Products
Review Production records to assure no erros have occurred
If errors have occurred the responsibility to assure that they have been fully investigated
Subpart B – Organization and Personnel
Personnel qualifications. Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions.
Personnel responsibilities- Personnel engaged in the manufacture, processing, packing, or holding of a drug product shall wear clean clothing appropriate for the duties they perform.
Consultants advising on the manufacture, processing, packing, or holding of drug products shall have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained
Quality Assurance Manual
Should indicate that have a well-documented Quality Assurance (QA) program in place.
The QA program should provide a systematic approach for evaluation, inspection, testing, calibration or whatever is needed to monitor and assure the quality of your product.
Qualifications of Personnel (training)
All personnel in manufacturing or management must have education training and experience or a combination thereof to perform assigned duties
Training in the GMPs and operations performed by the employees
Training conducted on a continuing basis by qualified individuals
Adequate number of personnel to perform functions. Clean clothing and protective apparel worn as
necessary to protect drug products from contamination Good sanitation and health habits should be followed.
Consultants
Consultants advising on GMP areas and operations must be qualified by education, training or experience.
Maintain records of their qualification, work and address
Summary
The quality unit must have the authority to make independent quality related decisions.
Personnel must have documented adequate training & experience.
Training for staff and contractors
Subpart C-Buildings and Facilities
Subpart C
211.42 Design and Construction211.44 Lighting211.46 Ventilation, HVAC211.48 Plumbing211.50 Sewage and Refuse211.52 Washing and Toilet Facilities211.56 Sanitation211.58 Maintenance
Design
First principle: Quality by Design
GMP requirements for Process Design211.42 Design of Facility211.63 Design of Equipment211.100 Design of Production and
Control Procedures211.160 Design of Laboratory Controls
Buildings and Facilities
The temperature and relative humidity should be controlled, monitored in accordance with an SOP, and the results recorded. The limits should be appropriate according to the materials stored and product processed
Premises
Sanitation
Sanitation
Building maintained in a clean and sanitary condition
Written procedures assigning responsibility for sanitation methods.
Written procedures for use of suitable elimination of pests and environmental contaminants
All agents used must be in accordance with EPA standards
Sanitation
Buildings maintained in a clean and sanitary condition Written procedures assigning responsibility for
sanitation methods, equipment, materials & schedules Written procedures for the use of suitable:
Insecticides Rodenticides Fungicides Fumigating agents Cleaning and sanitizing agents
All pest control products must be registered and used in accordance with EPA standards.
Buildings and Facilities
Separate receiving and dispatch bays
Materials and products protected from weather
Area to clean incoming materials provided
Summary
Data must exist to show suitability or fitness for use of major instruments., equipment, and systems.
Control, cleaning and maintenance prevents contamination
Subpart D Equipment
Subpart D – Equipment
§ 211.63 Equipment design, size, and location. § 211.65 - Equipment construction. § 211.67 - Equipment cleaning and maintenance. § 211.68 - Automatic, mechanical, and electronic equipment. § 211.72 - Filters.
Equipment
Adequate space to facilitate cleaning and maintenance of equipment
To prevent contamination there should be separate or defined areas or other control systems for the receipt identification, storage and withholding of all materials.
Orderly placement of equipment.
Equipment Design of areas for
weighing of materials Proper air supply Dust control measures
(including extraction of dust and air)
Easily cleanable surfaces
No areas for dust accumulation
Protection of material, product and operator
Equipment
All aspects including Design, installation,
operation, performance, specifications, logs, maintenance, use, cleaning, qualification, calibration etc…
Maintenance Procedures (MP)
Periodic proceduresTo minimize the risk of losing raw data and
analytical results Inspection/replacement of normal wear and
maintenance itemsFile back-up and recoveryData archival and retrievalSecurityLan administration
Equipment design size and location
Must be suitable for intended useEasily cleaned and maintainedMust be non reactiveLubricants coolants etc. required for
operation should not contact any component.
Equipment Design, Size, and Location
Must be suitable for intend use: Appropriate design Adequate size Suitably located
Facilitate its use, cleaning and maintenance
Equipment Construction Cannot be
Additive Absorptive Reactive
Lubricants, coolants etc. required for operations should not contact any component
Equipment Cleaning and Maintenance
Equipment and utensils Must be cleanedMaintained at suitable intervals
Written ProceduresAssign responsibility for cleaning Include schedules for maintenance
Materials
Equipment Cleaning and Maintenance
Equipment and utensils must be cleaned and maintained at suitable intervals
Written procedures assign responsibility for cleaning and schedules for maintenance.
State methods, materials and equipment for cleaning
State disassembly reassembly procedures Obliteration of previous batch information Inspection of equipment before use.
Written Procedures
State methods, materials and equipment for cleaning
State disassembly/reassembly methodsObliteration of pervious batch
informationProtection of equipment prior to use Inspection of equipment immediately
before use
Subpart E- Control of components and drug Product containers and Closures
Subpart E- Control of Components
General requirements. § 211.82 - Receipt and storage of untested components, drug product containers, and closures. § 211.84 - Testing and approval or rejection of components, drug product containers, and closures. § 211.86 - Use of approved components, drug product containers, and closures. § 211.87 - Retesting of approved components, drug product containers, and closures. § 211.89 - Rejected components, drug product containers, and closures. § 211.94 - Drug product containers and closures.
General Requirements
Written Procedures describing: Receipt Identification Storage Handling Sampling Testing Approval or Rejection
Handled and stored in a manner to prevent contamination Bagged or boxed component of containers or closure stored off
floor and suitably spaced to permit cleaning and inspection Identified with a distinctive code for each lot in each shipment
received Each lot identified as to its status: quarantined, approved,
rejected.
Component Tests
At least one test must be conducted to verify the identity of each component of a drug product
Specific identity tests, if they exist, should be used Each component must be tested for conformity with all
appropriate written specification for purity, strength, and quality. A certificate of analysis may be accepted from the supplier provided that: At least one specific identity test is conducted The manufacturer has established the reliability of the
supplier’s analyses through appropriate validation of the supplier's test results at appropriate intervals
Containers and Closures
Should not be reactive, additive, or adsorptive Provide adequate protection against
foreseeable external factors in storage and use
Clean, and if appropriate, sterilized and processed to remove pyrogenic properties
Written procedures for: standards or specifications, methods of testing, and where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties
Summary
Material must always be released by QC before they are used.
No provisional releases
Vender CoA must be verified.
Subpart F- Production &Process Controls
Subpart F- Production and Process Controls
Written procedures; deviations. § 211.101 - Charge-in of components. § 211.103 - Calculation of yield. § 211.105 - Equipment identification. § 211.110 - Sampling and testing of in-process materials and drug products. § 211.111 - Time limitations on production. § 211.113 - Control of microbiological contamination. § 211.115 - Reprocessing.
Validation Requirement
Process Validation is an Enforceable Requirement Finished Dosage Form Products
21 CFR 211.100 21 CFR 211.11021 CFR 211.11321 CFR 211.4221 CFR 211.6321 CFR 211.16521 CFR 211.180
Validation Requirement
Process Validation is an Enforceable RequirementActive Pharmaceutical Ingredients
Statutory CGMP provisions of 501(a)(2)(b) of the Food Drug and Cosmetic Act
No regulations GMP guidance available - ICH Q7A
Goal of Process Validation
Drug product meeting the needs of the patient, i.e., safe and effective; and has the identity, strength, purity, and quality characteristics it is represented to possess.
Achieved through proper product development and proper process validation.
Process Validation Lifecycle
Validation
Principle
Documented evidence: Process is capable of reliably and repeatedly rendering a product of the required quality
Planning, organizing and performing process validation
Process validation protocols Data collected and reviewed against predetermined
acceptance criteria – recorded in validation report
Qualification
Installation Qualification (IQ)Operational Qualification (OQ)Performance Qualification (PQ)Maintenance Procedures (MP)
Production and process control
Pertains to processing steps- Dispensing to Bulk dose
Written Procedures: DeviationsChange ControlCharge-in of componentsCalculation of yieldEquipment IDSamplingProduction time limits
In-process testing
Rejected Product
Action Limits
Acceptable Range
Action Limits
Rejected Product
Target value
In-process testing
Rejected Product
Release Specifications
Action Limits
Acceptable Range
Action Limits
Release Specifications
Rejected Product
Target value
Summary
Use only valid processes and systems.Keep adequate records to allow
deviations to be recorded and investigated.
Make drug products right, first time, every time.
Subpart G Packaging and Labeling Control
Subpart G – Packaging and Labeling Control
Materials examination and usage criteria. § 211.125 - Labeling issuance. § 211.130 - Packaging and labeling operations. § 211.132 - Tamper-evident packaging requirements for over-the-counter (OTC) human drug products. § 211.134 - Drug product inspection. § 211.137 - Expiration dating.
Labeling Issuance
Labeling issued for each batch shall be examined for identity and conformity with labeling in master or batch records
Reconciliation between labeling issued, used and returned and product produced
Discrepancies outside of narrow preset limits, based on historical data, require an investigation
Packaging and Labeling Operations
Written procedures Procedures should incorporate the following
features:• Prevention of mix-ups and cross-contamination• Identification and handling of filled drug containers • Examination of labels for correctness• Line inspection before packaging to assure that
lines have been cleared• Documentation of all activities in the batch record
Drug Product Inspection
Examine packaged and labeled products during finishing operations to assure the correct label has been used
Collect a representative sample of units at the completion of finishing and examined for correct labeling
Record results of the examination of the batch record
Subpart H- Holding and Distribution
Subpart H- Holding and Distribution
§ 211.142 - Warehousing procedures.
§ 211.150 - Distribution procedures.
Warehouse Procedures
Written procedures forQuarantine prior to QC release Storage under appropriate conditions of
temperature, humidity and light
Subpart I lab controls: Instrument Controls, Training, Standards/Reagents, Testing and Release, OOS
Subpart I- Laboratory Controls
§ 211.160 - General requirements. § 211.165 - Testing and release for distribution. § 211.166 - Stability testing. § 211.167 - Special testing requirements. § 211.170 - Reserve samples. § 211.173 - Laboratory animals. § 211.176 - Penicillin contamination.
Out of Specification (OOS)
What does the cGMP Regulation say about Handling OOS Results?
Averaging
Assay results should never be averaged because averaging hides individual variability: e.g. 89, 89, 92 (x=90)
Individual content uniformity tests should not be averaged to obtain passing value
Microbiology averaging is acceptable due to biological variability
Make sure each technician understands the calculations
General Requirements
Scientifically sound specifications, standards, sampling plans, test procedures and other laboratory controls procedures and any changes should be drafted by the appropriate organization and approved by QC
Documented at the time of performanceDeviations recorded and justified
Testing and Release
Appropriate laboratory determination of each lot for conformance to final specifications
Appropriate laboratory testing of each lot of drug required to be free of objectionable microorganisms
Stability Defined
Definition (ICH/FDA)The capacity of a drug substance or drug
product to remain within specifications established to ensure its identity, strength, quality and purity throughout a retest or expirations dating period.
Stability Testing
Written testing program designed to assess stability of drug and determine expiration dates Sample size & test interval based on statistical
criteria for each attribute examined. Storage conditions Reliable, meaningful and specific test methods. Utilization of same container/closure system as
marketed drug Test products for reconstitution at time of
dispensing and after reconstitution
Stability Testing
An adequate number of batches need to be tested to determine the expiration date.
Accelerated studies, combined with data from long-term stability studies support tentative expiration dates.
Expiration dates assigned from accelerated study data much be verified by ongoing shelf-life studies
Reserve Samples
2X quantity for tests (except sterility &pyrogen)
Representative samples, selected statistically, examined visually at least annually for deterioration
Any evidence of deterioration shall be investigated and results maintained with other stability data
Subpart J- Records and Reports
Subpart J- Records and Reports
§ 211.180 - General requirements. § 211.182 - Equipment cleaning and use log.
§ 211.184 - Component, drug product container, closure, and labeling records. § 211.186 - Master production and control records. § 211.188 - Batch production and control records. § 211.192 - Production record review. § 211.194 - Laboratory records. § 211.196 - Distribution records. § 211.198 - Complaint files.
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If it was not documented, it was not done!
Great Mounds of Paper?
Some may think that GMP stands for Great Mounds of Paper!
There’s some truth to that.
Records and Reports
QUALITY MANUAL
Testing Method
Note :• Blue : WI (standard, specification & procedure) • Red : record
Product Destruction Record
Return Product Handling RecordRecall Record
Product Complaint Record
Batch Production Record
Distribution Record
Master productiondocument
Master Formula
Master Prod. Procedure
Master Pack. Procedure
TYPE OF GMP DOCUMENTS
Specification/ Standard
S.O.P.
Validation Protocol Report
Work Protocol(WP)
Raw & packaging material
Bulk
Finished productTesting result record and report
Stability test record
Sampling record
Microbial and particle monitoring record
Equipment StatusMaterial Status Product Status
Identity/Label
Can we ship this batch?
QC
Not untilthe
paperwork is released!
Lot no. XYZ
The GMP Paperwork is a Product
The paperwork produced is of equal importance to the products produced.
Product = Paperwork
General Requirements
Retain all records at least 1 year after expiration date of the batch
OTC drugs lacking expiration dates retain all records for at least 3 years after distribution of the batch
Records for components, containers, closures, and labeling follow the same rules.
cGMP Part 211.192
The failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated…
The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure of discrepancy…
cGMP Part 211.194
A written record of the investigation shall include the conclusions and follow-up…
A complete record of all data secured in the course of each test…
Complete records shall be maintained of all stability testing performed…
Packaging and Labeling
Holding and Distribution
General Requirements
Written Procedures describingo Receipto Identificationo Storage o Handlingo Stamping o Testingo Approval or
rejection
Handled and stored in a manner to handle contamination
Stored off the floorIdentified with a
distinctive codeEach lot identified
as to its status quarantined, approved or rejected
Subpart K- Returned and Salvaged Drugs
Subpart K – Returned and Salvaged Drug Products
§ 211.204 - Returned drug products.
§ 211.208 - Drug product salvaging.
Returned and Salvaged Drugs
Returned Drug ProductsShall be identified and held If the condition of the drug, packaging or
labeling casts doubt on its safety, identity, strength, quality or purity, it must be destroyed unless examination, testing, or investigation proves the drug meets its specifications.
Returned Products- Maintained in a separate defined area
Organization and Personnel
Buildings and Facilities
Equipment
Control of components and Drug Product Containers and Closures
Production and Process Controls
Packaging and Labeling Control
Holding and Distribution
Laboratory controlsGMP
This is for your family…
Raw Materials
Manufacture
Dispense
A word about Drug Master File…
http://wwwbdp.ncifcrf.gov/pdf1/GuidetoRegSubsR1.pdf
Questions