quality control

Quality Control

Quality Control

Pharmaceutical and cosmetic manufacturing is recognized as a major industry which requires a clearly defined organization. Each segment of this organization is expected to fine-tune its functions and responsibilities. An effective coordination is called for among its personnel, equipment, building and inventory of materials. All these activities are performed towards the production of a drug or cosmetic of the highest standard and at the lowest cost.

In a manufacturing firm, it is common to have the following divisions under a general manager:

1. Finance

2. Production

3. Quality Assurance (Quality Control)

4. Marketing (optional in a third party contract manufacturer)

All manufacturing must be done in compliance with Current Good Manufacturing Practice (CGMP). All production personnel should know and understand the CGMP applicable to their area of responsibility.

In enforcing CGMP to achieve the desired goal of delivering a safe, pure and effective product at the lowest cost to the consumer, a specific group must be organized to be the core of the companys quality audit program. Thus, the quality control department is organized to maintain the quality of products to a prescribed level.

Quality is the combination of attributes or characteristics of a product which, when compared to a standard, serves as a basis for measuring the uniformity of the product and determines its degree of acceptability.

Quality control is a tool which gives the assurance that a product conforms to standards and specifications through a system of inspection, analysis, and action.

Quality is everybodys business. It cannot be inspected into a product; but rather it must be built in. It must be produced. With this responsibility, a quality control system is established at the conception of a new product, during production of the batch, and during distribution of the commercial package. This system is a combination of those administrative and technical procedures which must be used to produce and deliver a safe, pure, and effective product to the end user.The potential benefits derived from a quality control system are as follows:

1. The system minimizes or eliminates the risk of marketing unsafe products.

2. It guarantees conformance to regulatory requirements.

3. It guarantees product efficacy.

4. It reduces operating costs.

5. It reduces operating losses.

6. It produces higher employee morale.

7. It motivates the pharmaceutical/medical profession to sell or prescribe the product.

ORGANIZATION OF QUALITY CONTROL

Each pharmaceutical or cosmetic company has an organizational structure which differs somewhat from those of other companies in scope and responsibilities.

Materials Inspection Section

Inspectors are alert individuals who had experience and who are familiar with the physical characteristics of the materials they sample and are well versed in sampling techniques. The functions of this section are:

1. To sample and examine all raw materials received.

2. To sample and conduct physical tests on:

i. All shipments of packaging materials

ii. All manufacturing, filling and packaging operations

3. To maintain periodic examination on the quality of inventories throughout all phases of storage, shipping and distribution.

4. To perform an audit which is independent of the work done by production personnel.

Inspection stations are placed in the area of operation, viz., warehouse, manufacturing and packaging areas.

Analytical Laboratory

The analytical laboratory should be in an accessible area and protected from noise and vibration common to manufacturing operations.

In order to perform physical and chemical analysis, the analysts should know the usual gravimetric and volumetric analysis. Furthermore, they should be skilful in handling instruments for ultraviolet and infrared spectrophotometry, non-aqueous titrimetry, autoanalysis, polarography, x-ray diffraction, x-ray fluorescence, spectrophotofluorimetry, radioactive tracer techniques and chromatography, viz.: column, gas, paper, thin layer and high performance liquid chromatography.

Biological Testing Laboratory

The staff in a biological testing laboratory should be well trained and experienced in both simple and complex microbiological procedures and biological interactions. They should possess a high degree of skill and judgment in order to perform the job. A veterinarian is recommended to supervise the care and maintenance of the various species of animals used in the tests. The functions of this laboratory are:

1. To perform and evaluate microbiological and pharmacological assays, sterility, pyrogen and bacteriological tests, irritation, safety or acute toxicity tests.

2. To conduct environmental monitoring.

Sterile conditions should be provided for areas where biological tests are conducted. Noise should be precluded from areas where animals are used. An animal house should be maintained as a separate unit from the main laboratory, if necessary.

Specifications and Analytical Development

This sections should have firm background not only in the principles of quality control and analytical procedures but also in manufacturing, research, product development and in statistics in order to perform the following functions:

1. To coordinate with research, product development, production, sales and management towards improvement of a product.

2. To establish specifications for raw and packaging materials.

3. To validate existing and tentative procedures of testing.

4. To establish specifications based on validated procedures.

5. To develop new assay methods for in-house use.

6. To develop and improve specifications for quality characteristics of the final product being manufactured.

Quality Coordination Office

This section should be accessible to all manufacturing and packaging operations since documentation is its main responsibility. The functions of this section are:

1. To maintain and store records that represent the history of the batch from start to finish. These records include the batch and master formula records, raw material analytical records, printed and packaging material inspection reports and retention files.

2. To be able to furnish data that will aid in analyzing product performance in the market. These documents are the stability studies and returned goods reports.

3. To investigate customer complaints or inquiries on product quality and to forward the results of the investigations in the form of technical reports to the sales organization.

4. To call the attention of the appropriate development group any aspect that provides a basis for improvement of a product for consideration and action

5. To provide data that give scientific and legal status, i.e., data generated from the use of recognized standard compendia. This is essentially a function of the distribution section or warehouse.

6. To maintain and develop SOPs

STANDARDS AND SPECIFICATIONSQuality characteristics are interpreted by descriptive words and measurements. Characteristics are subject to variation. Quality variation which is not confined within a specific range, tolerance or limit, will grow to uncontrolled magnitude and will encourage the proliferation of errors; thus producing a defective product. Errors may be due to chance or assignable causes such as: materials, machines, methods and men. To avoid producing a defective product, standards and specifications are developed to serve as a basis for accepting or rejecting a product. In a product, these must cover the following points:

1. Formula: This is concise and precise statement of the ingredients that comprise the product, together with the percentage and/or weight of each.2. Raw material specification: This should enumerate the characteristics of all the materials that go into the product and the permissible range of purity of each ingredient. Deviation beyond this range may be expected to cause failure of the product to function as planned or, at least, result in an undesirable lack of uniformity. Standard compendia like the USP, NF, BP, BPC, Merck Index, etc., provide this valuable information.

3. Standard operating procedure: This is a step by step method on how to go about a job. It must spell out all information and instructions that assure that variations in production from day to day and week to week will be held to within acceptable established ranges.

4. Finished product specification: This should cover all characteristics that affect the proper performance, purity, safety and stability of the product. Tolerances may be minimum, maximum, or both, depending on the nature of the situation.

5. Packaging material standard: This should be set for everything that goes around the product, i.e., bottles, cans, aluminium foil, cellophane, jars, caps, cap liners, labels, printed inserts, cartons, wrapping papers, and shipping cases. Packaging must be considered with the following points in mind:i. The units may have to run on a high-speed line.

ii. They may involve a complicated assembly.

iii. The package may be functional.

iv. The package must be completely compatible with the product.

v. The package must protect the product and assure its stability.

vi. The package must ship well

6. Testing Methods: These are indispensable in assuring conformity to standards. Since they play such a vital role, testing procedures must be standardized so that they yield results of comparable precision and accuracy in the hands of different operators and laboratories. The tests must be validated to ensure precision and accuracy on application.

DEFECTS

In a broad sense, a defect is an undesirable characteristic of a product. It is defined as a failure to conform to specifications. A unit of a product which contains one or more defects is called a defective. Defects can be classified as follows:

1. According to measurability:

i. Variable defect a defect which can be measured directly by instruments giving dimensions of length, weight, height, thickness, concentration, volume, viscosity, pH or size particles

ii. Attribute defect a defect which cannot be measured directly by instruments. It shows mainly the conformance or non-conformance of the material to specifications. This applies to many things that can be judged only by odor or visual examination like color, clarity, sheen, cleanliness, smoothness, taste and presence or absence of a characteristic.

2. According to seriousness or gravity:

i. Critical defect a defect which may endanger life or property and may render the product non-functional. Absence of warning in a label for a potent drug or disintegration time of one hour for an analgesic are considered critical defects.

ii. Major defect a defect which may affect the function of the object and therefore, may render the product useless. The presence of a crack in a bottle is a major defect.iii. Minor defect a defect which does not endanger life or property nor will it affect the function but nevertheless remains a defect since it is outside the prescribed limits. An example of a minor defect is the slight deviation of the color of the label from the color standards

3. According to nature:

i. Ocular defect a defect that is visible, e.g., foreign particular contamination

ii. Internal defect a defect which is not seen although present, e.g., a subpotent drug product.

iii. Performance defect a defect in function, e.g., a suppository that does not melt at body temperature.

SOURCES AND CONTROL OF QUALITY VARIATION

The manufacture of a cosmetic or drug product frequently involves a series of simple to complex steps. The risk of errors increases as the number of materials used in the formulation becomes larger, and the manufacturing processes become more complex. The errors, which are the sources of quality variation of a product, are given below.

Sources of VariationExample

1. Materialsa. Variation between suppliers of same substance

b. Variation between batches from same supplier

c. Variation within a batch

2. Machinesa. Variation of equipment for the same process

b. Difference in adjustment of equipment

c. Aging and improper care

3. Methodsa. Inexact procedures

b. Inadequate procedures

c. Negligence by chance

4. Mena. Improper working conditions

b. Inadequate training, and understanding

c. Dishonesty, fatigue and carelessness

To minimize and eliminate the sources of variation which can cause product quality variation, approaches such as material control, good manufacturing practice, packaging control, automation and statistical sampling plans are employed.CONTROL FUNCTIONS

Control functions may appear varied and never quite identical in any two companies but basically, these functions can be classified into four categories: analysis, monitor, record review and release, and audit function.Analysis Function

To assure the acceptability of a product, it is essential that all materials are within specifications. Tests are made not only on the raw materials and packaging components but also on the bulk product during processing and after packaging prior to its release to the market. The analytical function continues even after distribution to the end user when selected lots are subjected to shelf life studies to confirm the expiration period of the finished product. Product against which a complaint is registered may also be analyzed to determine its validity and the cause of the reported deficiency. Appropriate steps may then be taken to prevent recurrence of a similar problem.

Monitor Function

It is the responsibility of quality control to sample and examine materials while they are being processed. This is to assure that even though production personnel have the primary responsibility for control over their processes, these processes are maintained and that any deviation from specified requirements are reported.

Another monitor function, usually performed on a time basis, rather than on a lot or batch basis, is environmental monitoring. This is to control the microbial and particulate matter content of environmental air in areas where pharmaceuticals such as parenterals are processed. The environmental monitoring function is also responsible for periodically checking equipment and personnel burden. The objective of environmental monitoring is to assure that microbial and particulate matter levels are within acceptable tolerances, and when not, to report to appropriate supervision for corrective action.

Record Review and Release Function

All records generated during the course of producing a quality controlled product is known collectively as a batch record. Prior to the release of each lot of finished product to the market, the record-review function is responsible for carefully reviewing the batch record for that lot and assuring that all necessary records are present, complete and where feasible to determine, accurate. A detailed checklist is frequently employed by the reviewer. Only after there is full assurance of the completeness and accuracy may the lot of a finished pharmaceutical or cosmetic product be released for distribution to the market.

Audit Function

The production and quality control of quality products are governed by standard operating procedures (SOPs) which embrace the legal requirements set forth by the Current Good Manufacturing Practice (CGMP) regulations as well as additional standards of operation established by the manufacturing firm. It is the responsibility of supervisors to train their employees to comply with the SOPs and to understand why and how these SOPs are to be followed. The quality audit is designed to detect areas where the established SOPs are not being followed and to report these findings to the supervisor for appropriate action.

Sampling and Sampling Plan

A basic quality function is that of deciding whether the product conforms to specifications. This function is generally called acceptance. To arrive at a decision, the primary step is inspection. Inspection is the comparison of certain attributes and dimensions of a product against specifications to find out if the product is within the prescribed limits.

Acceptance inspection is a necessary part of manufacturing and may be applied to incoming materials, to partially finished product at various intermediate stages of manufacturing process (in-process inspection), and to the final product. Acceptance may also be carried out by the purchaser of the manufactured product. Inspection consists of several steps:

1. Interpretation of the specification;

2. Measurement of the product;

3. Comparison of the product with specification;

4. Judgment as to conformance;

5. Disposition of the product; and

6. Recording of the data obtained.

Acceptance Sampling

Much of acceptance inspection is by sampling. Sampling may be defined as the process of removing an appropriate number of items from a population in order to make inferences to the entire population.

Population is the totalling of all actual or conceivable items of a certain class under consideration.

A sample is a finite number of objects selected from a population. In other words, instead of inspecting the entire batch of 300,000 tablets (population), one examines a small part of the batch (sample). A random sample is a sample chosen in such a manner that one object has a good chance of being selected as another.

Representatives of materials to be sampled are:

1. Raw materials;

2. Packaging and printed materials;

3. Intermediate products; and

4. Final products: before, during and after manufacturing, and packaging operations.

It is an accepted knowledge that no two ampules, capsules or tubes will contain exactly the same amount of ingredient. However, one does not have to rely on examination performed on every unit of a batch in order to avoid sampling errors or to make a conclusion concerning the entire batch, 100% inspection often turns out to be impracticable or clearly uneconomical. Moreover, the quality of the product accepted may actually be better with modern statistical procedures that would be the case if the same product were subjected to 100% inspection. Sampling inspection has also a psychological advantage over 100% inspection.Sampling inspection is therefore used in lieu of 100% inspection for several reasons:

1. The cost of 100% inspection is prohibitive.

2. 100% inspection is tiring and the probability that the inspector will commit errors is high.

3. The inspection operation may involve destructive testing.

4. A statistical sampling plan well applied may give better quality assurance than 100% inspection.

It is common knowledge that on many types of inspection, even several 100% inspections will not eliminate all of the defective product from a stream of product, a portion of which is defective. The best protection is, of course having the product made right in the first place.

Inspection Methods

The most common and distinct methods of inspection are the single and double sampling methods. In single sampling, a decision is reached after only one sampling. In double sampling, a decision is obtained after the result of the second sampling is known.

Sampling Plan

In sampling, one must consider the laws of probability. There are certain risks involved; namely, the risk of error. A producers risk is the probability of rejecting a good batch, whereas a consumers risk is the probability of accepting a bad batch. Sampling plans can be designed and applied in such a manner as to reduce these risks to a minimum and over a period of time to give assurance of quality products.

A sampling plan is a definite working rule regarding size and frequency of a sample and the basis for acceptance or rejection. It is therefore a specification of sampling.

It requires that three numbers be specified. One is the number of items (N) in the lot or batch from which the sample is drawn. The second is the number of items (n) in the random sample drawn from the lot. The third is the acceptance number (c). For example, if N=50, n=5, c=0; these three numbers may be interpreted as saying: Take a random sample of 5 from a lot of 50. If the sample contains more than 0 defects, reject the lot; otherwise, accept the lot.

There are several sampling plans on hand. One simple sampling plan is the square root system which uses the formula: n = N + 1. The acceptance number is specified by the AQL (acceptance quality level).

Material Control

As each batch of incoming material is received, it is given a receiving number by which it will be identified in subsequent operations. A receiving number should have distinguishing characteristics which will prevent possible confusion with any number previously placed on the container by the supplier.A receiving tally report (reception of materials, incoming cargo report, receiving report or receiving report or receiving ticket) should be prepared for every shipment. Information indicated therein are as follows:

I. Pre-printed data1. Name of report

2. Name of drug/cosmetic company

3. Address

4. Receiving number

5. Name of the department receiving a copy

II. Information to be supplied by:

a. Warehouse

1. Name of the material

2. Item code number

3. Label clain

4. Purchase order number

5. Invoice number

6. Vendor (supplier/distributor)

7. Unit of measure

8. Number of containers received

9. Weight/volume/pieces contained in each container

10. Date the report was prepared

11. Date the shipment was received

12. Name of the warehouse personnel receiving the shipment

b. Quality Control

1. Inspectors report

a. Quantity of sample

b. Comments, if any

c. Name of inspector

d. Date inspected

2. Analysis

a. Analytical reference number

b. Name of analyst

c. Date of analysis

3. Disposition

a. Reason if rejected

b. If approved

b-1) Reassay date

b-2) Release number

4. Name of the person responsible for receiving the report

5. Date of the review

If the shipment consists of more than one manufacturing lot number, a separate receiving number is assigned to each lot. The receiving tally report (RTR) should be distributed to all groups concerned with the purchase, inventory, use, and control of the materials. Thus a copy of the RTR is given to quality control, warehouse, purchasing, and accounting departments. Manufacturing firms may have different entries but the basic information is quite similar.

The RTR is prepared in the warehouse by the warehouse personnel who is responsible for assigning a receiving number to the material. The shipment is held in quarantine pending quality control approval.

Raw materials

Raw materials are the ingredients intended for use in the manufacture of drugs and cosmetics, including those that may not appear in the final product.

The control of raw materials at different stage is handled in the following manner:

Reception

1. The RTR is checked by a QC inspector for accuracy.

2. Each container of raw materials is examined visually for damage or contamination in transit, including breakage of seals when indicated.

3. Adequate number of samples are taken from a representative number of containers.

i. Sampling plan is used to determine the number of raw material container to be sample.

ii. Calculate for the total quantity of material required for a complete test to determine the amount of sample to be taken from each container.

iii. The composite sample should not be less than three times the amount required for one complete test.

Quarantine

1. The inspector checks that the raw material container has a Hold or a quarantine sticker pasted by the receiving warehouse personnel to indicate that a decision to accept or reject is yet to be made by quality control.2. Samples are submitted to the laboratory for testing.

3. The sample is subjected to tests such as:

4. If the test results indicate that the raw material meets monograph specifications, the material is approved for use; otherwise, it is rejected. Decision stickers are then issued by quality control.

5. The decision stickers are either placed on top of the quarantine sticker or the quarantine sticker is first removed before the decision sticker is pasted. No two stickers of different dispositions must be present on the same container. At this stage, the raw material is transferred to either the rejected or approved materials area.

RejectedThe material so marked is checked that it is held at a rejected materials area to prevent the possibility of use in any manufacturing or processing procedure.

Approved1. The material marked as approved is checked that it is brought to the approved materials area.

2. Approved materials are tested when reassay date is due to assure that they conform to appropriate specifications of identity, strength and purity at time of use.

3. Approved raw materials are audited to assure that they are rotated in such a manner that the oldest stock is used first. This is known as the FIFO (first in, first out) policy.Stickers

In order to avoid mix-ups, a material warehouse is subdivided into several sections. Accordingly, the materials are segregated and properly identified by the stickers attached on the individual containers, cage or pallet of materials. On reception of the materials, a quarantine sticker is pasted on the container of the material. The materials are held in a quarantine area while waiting for its release by quality control. After disposition is given, the appropriate sticker is pasted on top of the quarantine sticker; or it is more convenient, the quarantine sticker is defaced or removed prior to attaching the approved or rejected sticker. Under no circumstances should two different stickers be present or prominently displayed on a material container at the same time.

To distinguish the sticker, different color codes may be assigned such as yellow for quarantine, green for approved and red for rejected. A sticker may have any other color but it would be wise to use a color easily associated with what it means.

Printed and Packaging Materials

Product containers, closures and other components parts of product package should not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality and purity of the product. These should be tested for suitability for its intended use. Storage and handling are audited to prevent them from contamination and deterioration and to avoid mix-ups.

Packaging materials are two types, namely:

1. Primary packaging components packaging materials which come in direct contact with the product itself; like bottles, tubes, ampules, vials, carpules, caps, stoppers, plungers, stripping materials jars, fillers, and seals.

2. Secondary packaging components packaging materials which do not come in direct contact with the product and serve as accessory to the primary packaging component. Most of these are labels, inserts, unit cartoons, brochures, packer boxes and shippers.

Printed Materials

By official definition, labelling includes all written, printed or graphic materials accompanying a product. As such, they are subjected to inspections by an experienced proofreader for graphical errors, for compliance with specifications as to type and grade of stock printing quality and dimensional tolerance.

Minimum criteria for acceptance of printed materials consists of:

1. Text2. Color

3. Size

4. Thickness

5. Grain direction

6. Sealability

7. Cleanliness

8. Surface finish

9. Adequate paste

10. Shape

Labeling Control

Below is a summary of labelling requirements for drugs and cosmetics.

Labels

1. Name of drug or cosmetic

2. The strength or quantity of the substance contained per unit dosage form

3. Lot or batch number

4. Expiration date

5. Registration date

6. Storage condition

7. Name of manufacturer, packer or distributor

8. Business address

9. Quantity of contents of package

10. Names and quantities of components in the preparation

11. Rx symbol (if necessary)

12. Warning or precaution

13. Adequate direction for use

Package Insert

1. Product name

2. Strength or quantity of the active substance contained per unit dosage form

3. Description

4. Action

5. Indication

6. Contraindications

7. Warnings

8. Precautions

9. Adverse reactions

10. Dosage and Administration

11. Overdosage

12. How supplied

13. Manufacturer/packer/distributor

14. Business Address

To prevent mix-ups of inventories of printed labelling materials of similar color and shape, bar codes placed on edge have been found useful.

Containers

Physical and chemical evaluation of containers like those made of glass, plastic, and metal have been extensive.

Physical inspections generally include the following criteria:

1. Shape

2. Volume

3. Finish

4. Opening

5. Diameter

6. Height

7. Shape

8. Thickness

9. Color

10. Clarity

11. Leak

12. Torque

13. Print

14. Peeling

15. Cleanliness

16. Light Transmission

17. Stress crack resistance

The physico-chemical tests for containers include:

1. Identification

2. Infra-red properties

3. Thermal analysis

4. Extractable substance

5. Non-volatile residue

6. Water vapour permeation/transmission

7. Moisture

8. Resistance to water attack

It should be noted that plastic containers for parenteral use is tested further using biological test procedures: e.g. implantation, systemic and intracutaneous injections.

Container and Closure Control

The integrity of the seal between the closure and container depends on the geometry of the two, the materials used in their construction, the composition of the cap liner and the tightness with which the cap has been applied.

Geometry can be controlled by the mold of the packaging components. A mold number is assigned which is used as its identification number.

Closures should fit the tread of the container. It should sit on a container without tilting, produce no leaks, should not rotate continuously, be reasonably tight and look elegant.

Those familiar with bottling problems recognize the necessity for control of cap tightness and the difficulties that can result from the failure of such control. The following considerations are very important in this connection:

1. A minimum tightness is essential to avoid evaporation or leakage of the product.

2. Excessive torque may break the moulded closures.

3. Caps applied too tightly may be difficult to remove.

Experience has proven the desirability of regular testing of packages from each bottling line to make sure that tightness is maintained at all times. To check tightness, a torque tester is used. Torque is a measure of circular force required to loosen the cap; an application torque is the amount of force used to tighten the cap. The unit of force is in terms of inch pound. Sample size is 10 bottles.

Reassay Dates

The finished product can only be good as the raw materials used in its manufacture. To assure product excellence, the monitoring of the quality of the raw materials during storage is therefore an important step after such materials are released by quality control. Periodic testing is done to revalidate the material. The date of retest is known as reassay date. This is also given in terms of month and year, determined from the last assay date.

Based on the stability of raw materials, the reassay dates assigned are:

Monthly or prior to use highly unstable materials

6 months vitamins, flavors

12 months active ingredients, dyes

24 months active ingredients, excipients

Not all tests are performed during a retest. The tests given below serve as a general guide since manufacturing companies provide a listing of tests which must be performed to satisfy the reassay requirements for the raw materials.

Retest requirements:

1. Appearance2. Identification

3. Melting range

4. Specific gravity

5. Refractive index

6. pH

7. Loss on drying, moisture content/water

8. Alkalinity

9. Acidity

10. Alcohol content

11. Degradation limits

12. Assay

13. Microbial tests

Manufacturing ControlWritten procedures are extremely vital to the manufacture of drugs and cosmetics. These procedures are embodied in four important documents designed to explain why and how the products are made. These are:

1. Manufacturing monographs

2. Quality control monographs

3. Batch records

4. Standard operating procedures

The manufacturing monograph is the basic document from where the master formula and batch production records are based. The quality of each and every component used in the manufacture of the product is assured by testing these components in accordance with the specifications and methods provided by the quality control monographs. Standard operating procedures are generated to explain in detail the reason behind a procedure and proper sequence of steps to be done, and how equipment are to be operated for maximum performance.

During processing, the quality of the product at various stages of production is audited by quality control. In-process quality control (IPQC) tests are performed to determine if the product meets specifications throughout the entire processing period and particularly during critical stages of manufacturing. Any out of range measurement can thus be corrected before further processing is continued. The audit also fulfils the primary objective of the IPQC which is to monitor all features of a product.

Master Formula Record

A master formula record is the original document used as key in the production of products. Being the prototype, it is kept in a secured documentation room, duplicated or photocopied only whenever a job order is issued. It assures identical reproduction of the product document.

Batch Reproduction Record

A batch reproduction record is an accurate reproduction of the master formula record. After being used as the guide to production and actual data of what has been done are recorded therein, the completed document permits reconstruction of the history of the product formula, manufacturing procedures, production record (processing batch records, processing control records, packaging records), raw material records, packaging materials records and product experience reports.

Batch, Lot or Control Codes

The batch means a specific amount produced in a unit time or according to a single manufacturing order during the same cycle of manufacture. The term lot means a batch, a portion of a batch, or a combination of batches. The term batch number, lot number, or control number mean any distinctive combination of markings, letters, or numbers by which the history of the manufacture and control of a batch or lot of a product can be determined. Control codes should be identified as such on the label.

Differences in format and content of batch production records from product to product are to be expected. However the basic information remains similar. These are given below:

Product Formula1. The product name and/or unique identification such as:a. Batch size

b. Dosage form and strength

c. Formula code number and date

d. Batch or lot number

2. An authorizing signature and date by a competent and responsible individual.

3. A complete list of raw materials designated by whole names and codes sufficiently specific to indicate any special characteristics.

4. The theoretical weight, measure, or percent of each raw material regardless of whether it appears in the finished product or not.

5. The standards or specifications of each ingredient used in the product.

6. An appropriate statement concerning any calculated excess of an ingredient, reasonable variations, and adjustments.

7. A statement of total weight, measure or percent.

8. Appropriate statements of theoretical yield at various stages and the termination of the product.

9. The actual weight, measure or percent of each raw material allocated or dispensed for the batch.

10. The receiving number of the raw material dispensed.

11. The signature of competent individuals responsible for measuring and dispensing the raw materials, duly endorsed by another competent and responsible individual. Signatures should be dated.

Manufacturing Process

1. Product name and/or unique identification

2. An authorizing signature and date by a competent and responsible individual duly endorsed by another competent and responsible individual.

3. A step by step description of all significant aspects of the process including, where necessary:

a. Means of raw material measurement

b. Order of addition and point of addition of raw materials

c. List of major equipment

d. Temperature

e. Mixing speeds

f. Mixing times

4. Signature of the individual performing and endorsement of the individual supervising each step. Both should be dated.

5. Intermediate and finished product specifications, test methods and sampling instructions

6. Special notations and precautions including, where necessary:

a. Cleaning procedures

b. Storage conditions

c. Filling temperatures

d. Remedial measures

e. Special safety and health measures

Product Specifications

1. The finished product name/or unique identification

2. Physical, chemical and microbiological specifications, where necessary, for the acceptance of each lot in-process samples and finished products and a description of the sampling and test procedures used

3. The result of control tests

4. Samples retained

5. Endorsement and date of the authorized individual performing the test

6. Disposition of the batch or lot endorsed by an authorized individual

Control Tests

In order to satisfy product identity, purity, safety, quality and strength, products must be subjected to certain specific tests. The specifications and test methods will not be given. Individual company monographs and published compendia provide these. Minimum attributes common to general categories of products are enumerated below. Where necessary, some of the tests are performed during processing (IPQC) of the product and repeated in the final product.Solid Preparation

The most common solid preparations are tablets, capsules, powders, cakes, and sticks. Minimum test requirements are as follows:

1. Assay for the active ingredient(s)

2. Assay for degradation product(s)

3. Disintegration

4. Dissolution/bioavailability

5. Content uniformity

6. Weight variation

7. Identification tests for the active ingredient(s) and possible contaminants

8. Visual appearance

9. Odor

10. Taste

11. Texture

12. Hardness

13. Friability

14. Powder fineness

15. Moisture content

16. Humidity effect

17. Color stability


19. Microbiological burden

20. Thickness

Liquid Preparation





5. Color

6. Odor

7. Taste

8. Redispersibility

9. Suspendability

10. Pourability

11. Viscosity

12. Isotonicity

13. Particle size agglomeration and particle distribution

14. Clarity

15. Crystallization and precipitation

16. Gas evolution

17. Specific gravity

18. pH

19. Refractive index

20. Surface tension

21. Pyrogen testing

22. Sterility testing

23. Toxicity testing


25. Fill volume

26. Leak test

Semi-solid Preparations

The following tests are applicable to ointments, creams, jellies and suppositories:





5. Color

6. Odor

7. Viscosity

8. Softening range

9. Loss of water

10. Consistency

11. Homogeneity

12. Particle size distribution

13. pH

14. Release rate of active ingredient from dosage form

15. Sterility testing


Lyophilized Preparations and Products for Reconstitution Before Use




4. Visual appearance (original and reconstituted)

5. Color of cake

6. Odor of cake

7. Odor of solution

8. Color of solution

9. pH (original and reconstituted)

10. Moisture content of cake

11. Clarity of solution

12. Rate of solution (lyophilized)

13. Container pressure


Aerosols1. Assay for active ingredient(s)2. Assay for degradation product(s)


4. Net content

5. Spray test

6. Leak test

7. Pressure measurement

8. Moisture determination

9. Propellant

10. Valve delivery accuracy

11. Particle size distribution


Packaging Control

The burden of auditing the quality of the product during the packaging and labelling operations falls on the inspector. These operations are controlled for the following reasons:

1. To assure that only those products that have met the standards and specifications established in the master formula records shall be distributed to the market.

2. To prevent mix-ups and errors.

3. To assure that correct labels and labelling materials are employed for the product

4. To assure that the finished product is properly indentified with a control code that permits construction of the history of the product.

At this stage, the inspector should see to it that mix-ups and errors are prevented by the following measures:

1. Prior to use, facilities are cleared out of packaged finished products and packaging materials of the previous run.

2. Products which are similar in appearance, containers or labelling are not processed simultaneously on adjacent or nearby lines unless these operations are separated by a physical barrier.

3. Proper reconciliation is done after the packaging operation is completed. Discrepancies between the theoretical yield and the actual yield should be adequately explained before final release of the product.

At regular intervals, the inspector checks the packaging operation with the aid of a checklist. The important points considered are:

Products

1. Product mixed with another product2. Wrong product or strength

3. Homogeneity

4. Appearance/color/odor

5. Contamination with foreign matter

6. Fill/weight/volume

7. Heat marks on product

8. Freedom from capping, chips, cracks

Containers

1. Freedom from cracks, chips

2. Freedom from dents, distortions

3. Contamination with foreign matter

4. Leakage


Strips/Pouches

1. Product name/strength

2. Control code

3. Expiration date

4. Rx symbol

5. Leakers in vacuum test

6. Weak seal

7. Empty of wrong count

8. Torn strip of pouch

9. Freedom from dust or smears

10. Correct cutting

11. Powder in pouches and seals

12. Perforations of tear notches non-functional


Closures

1. Sealing tightness

2. Freedom from dust/smears

3. Crimping

4. Correct design/color

Labels

1. Product name/strength

2. Control code

3. Expiration date

4. Rx symbol

5. Registration number

6. Incorrect

7. Glueing

8. Alignment

9. Torn/soiled

10. Freedom from dust/smears

11. Missing

Package insert

1. Incorrect

2. Missing

3. Freedom from dirt/smears

4. Torn/soiled

5. Poorly folded or inserted

Printing: Control Code/ Expiration Date

1. Incorrect

2. Missing

3. Illegible

4. Smeared by legible

5. Mislocation

6. Printing skips

7. Misaligned

Accessories

1. Missing

2. Mislocated

3. Freedom from dust and smears

4. Defective

Product Unit

1. Incorrect packaging

2. Empty package

3. Incomplete package content

4. Incorrect count per unit

5. Incorrect count per display unit

6. Contamination with foreign material

7. Wrong size

8. Improper assembly of printed materials

9. Improper position of liquid containers

10. Torn packaging component

11. Soiled packaging component

12. Incorrect count per packer/shipper

13. Ragged cuts

Distribution Control

Finished products pending disposition should be separately stored from finished goods which have been approved by quality control for distribution.

Certificate antibiotics and insulin are withheld from distribution until batch certification certificate from the Food and Drug Administration (FDA) is actually received.

Finished goods warehouse control and distribution records should include an adequate perpetual inventory control system or other suitable system so that distribution of each lot of product, identified by its control code, can be readily determined to facilitate recall, if necessary, from all consignees of the manufacturer or repacker.

A stock card indicates a beginning and an ending inventory within a certain period. If the stock goes from the manufacturer to a single distributor, the stock card need not indicate the name of the recipient. However, it is good inventory practice to write the name of the distributor if there are several involved. A stock transfer number or its equivalent is posted on the card. Other details such as receiving report number of stock by the distributor, actual date of receipt by the distributor, etc., are included in the card depending on the actual warehouse practice of the manufacturing company. Below is an example of a simple stock card.

Stock Card No._______

Product ____________________________ Pack size ___________________

Lot No. ____________________________ Expiration Date ______________

Date received _______________________ Quantity received ____________

DateInvoice No.Quantity IssuedBalanceIssued by

At the distribution level, it is necessary to indicate the name of the customer. This information is of great value in recalls. Below is an example of a typical distribution card.

Stock Card No._______

Product __________________ Pack size _______________ Lot No.______________

Quantity received __________ Date received____________ Expiry Date __________

DateInvoice No.Customer/AddressQuantity IssuedIssued by

When the stock is not handled by a professional distributor, the stock card and the distribution card can be made into only one document.

In both cases separate cards are prepared per lot, and arranged in such a way wherein the card bearing the nearest expiration date is filled up. This will ensure that the oldest approved stock is distributed first, whenever possible.

Statistical Quality Control

The quality of a manufactured product is defined as its conformity to given standards or specifications. When measured, quality is always subject to a certain amount of variation as a result of chance, which is inevitable. However, as soon as the variation is due to assignable factors, the product departs from conformity to standard and quality is no longer in control.

To maintain quality at optimum level with a minimum of non-uniformity, quality control is faced with the problem of evaluating the magnitude of chance variation and detecting the existence of assignable causes of variation which can be corrected. Statistical methodology, which is now an integral part of many quality control systems, has been shown to be applicable in solving this problem.

Statistical quality control is monitoring the quality by the application of statistical methods in all stages of production. It consists of proper sampling, determining quality variation of the sample, and making inferences to the entire batch under investigation. It makes use of control charts, a tool which may influence decisions related to the functions of specification, production or inspection.

Quality Control Charts

There are two basic quality control charts which are based on the measurability of the quality characteristics, namely:

1. Attribute chart this is a chart which makes use of discrete data classifying the number of items conforming and the number of items failing to conform to any specified requirements. An example of an attribute chart is the control chart for fraction defective known as P chart.

2. Variable chart this is a chart using actual records of numerical measurement on a full continuous scale such as meter, grams, liter. A control chart consists of a solid and two horizontally parallel lines on either side of the solid line. The control solid line is the target value of the historical process average and/or range. The two dotted parallel lines indicate the limits within which practically all observed results should fall as long as the process is under normal variation (statistically controlled). The upper dotted line is the upper control limit (UCL), which is normally three standard deviations above the center line. Likewise, the lower line is the lower control limit (LCL) and is also three standard deviations below the center line.

If the process is in control the six standard deviations spread between the upper and lower control limits will encompass 99.7 percent of the values in a normal distribution with its mean at the center line.

The control limits on the chart are so placed as to disclose the presence or absence of assignable causes. Although their actual elimination is usually an engineering job, the control chart tells when and, in some instances, suggests where to look.

Statistical Control of Quality Characteristics

The principle of the control chart technique is that quality measurements obtained from samples from production will vary due to chance causes or assignable causes. When all observations are found within the limits, the process is in control. If an observation is found outside the limit lines, this variation is due to an assignable cause.

General Method:

1. Select the sample of size n at random from production.

2. Compute an average for each set of sample measurements.

3. Compute the appropriate standard deviation of the average used.

4. Prepare a graphic control chart (see Figure below, by drawing a solid horizontal line extending from the vertical quality scale at the average value. A pair of dotted lines or broken lines (control limits) are drawn on either side of this central line at a distance x times the standard deviation.5. Plot the averages obtained from the sample average values. If any of the plotted points fall outside of the established control limits, the process is out of control.

Stability

Stability of a drug or cosmetic can be defined as the ability of a particular formulation in a specific container to remain within its physical, chemical, therapeutic and toxicological specifications.

Assurances that the product in its container will be suitably stable for an anticipated shelf life must come from an accumulation of data on the package preparation. These stability data involve several parameters which, when taken together, form the stability profile.

The period of stability of a preparation is the time from the date of manufacture of the formulation until its chemical or biological activity is not less than 90% of the labelled potency. This in a sense, is the shelf life of the product; the duration of time during which a preparation will remain physically, chemically and biologically stable.

A good quality assurance program provides for a comprehensive stability testing plan. In accordance with GMP, stability studies should be conducted on products in its intended packaging container and determined by reliable, meaningful and specific test methods. Monograph assays may be used if they are stability-indicating, i.e., if they accurately differentiate between intact drug molecules and their degradation products. These tests are performed at certain intervals of time for the packages stored at specific temperature, humidity, air and light exposure and other storage conditions. Stability considerations should include not only the specific compendial requirements, but also changes in physical appearance of the product that should warn users of the product that its continued integrity is questionable. Important parameters for drug products are loss of activity or potency of the active ingredient and amount of degradation product. For cosmetics, retention of the physical qualities of a freshly manufactured product is of prime importance. Instability is gauged by its loss of elegance.

Accelerated stability testing is used to predict product stability. Factors that accelerate instability are:

1. Temperature

2. Light

3. Moisture

4. Gravity

5. Agitation

6. Inversion

7. Method of Manufacture

Accelerating stress conditions are often used to intensify the degradation loss with time. This enables the researcher to predict the shelf life of a product within a short period of time. A suggestion that has been made by the US FDA that shows wide acceptance of this method is as follows:

1. Three months acceptable data at 37-40 degrees C/75% R.H. can be extrapolated to a two-year expiry date.

2. If two-year controlled room temperature (R.T.) samples are available, up to two more years could be added to the expiry daye (i.e., four years total) by storing the two-year R.T. samples at 37 degrees C/75% R.H. for three months.

Assessment of product stability by using accelerated stress conditions can prove beneficial provided careful consideration is given to the interpretation of results. In all cases accelerated stress conditions should be validated with regard to the correctness of their predictions at normal storage conditions.

Shelf life is calculated by using the Arrhenius equation, if applicable, or by the regression line analysis by the method of least squares.The expiration date is a direct application and interpretation of the knowledge gained from stability testing. It limits the period during which a preparation may be expected to have its labelled potency, provided it has been stored as directed in the labelling. The storage requirements must be observed throughout the distribution of the product, i.e., beyond the time it leaves the manufacturer up to and including the time it is handled by the consumer. Although proper storage conditions are indicated in the labelling, it is recognized that control beyond the dispenser or seller is difficult. When the expiration date appears on the product labelling as month and year, it is understood that if refers to the last day of the indicated month.

Physical and Chemical StabilityProduct stability evaluations have been separated into a study of the physical and chemical stability of a formulation.

Physical stability is of importance to formulators for three primary reasons:

1. Appearance a pharmaceutical product, most specially a cosmetic, is expected to look fresh, elegant and professional no matter how long it stands on the shelf. A product that undergoes physical deterioration can easily cause a loss of confidence in the formulation.2. Uniformity since most products are sold in multiple dose containers, the manufacturer must insure that the patient will receive the proper amount of the ingredient in each dose. A cloudy solution or a broken emulsion can lead to a non-uniform dosage pattern.

3. Availability the active ingredient must be available to the patient throughout the expected shelf life of the preparation. A breakdown in the physical system can lead to non-availability of the medicament to the patient.

The chemical causes of product deterioration have been classified into incompatibility oxidation, reduction, hydrolysis, racemisation and others. In the latter category, decarboxylation, deterioration of hydrogen peroxide and hypochlorites and the formation of precipitates have been included.

Overages

The problem of declining potency in an unstable preparation can be ameliorated by the addition of an excess or overage of the active ingredient. This can be calculated mathematically or by drawing a line parallel to the slope of loss of potency.

The use of overages to extend shelf life is a particularly tempting solution, except perhaps in the case of extremely expensive substances. With some drugs, overage can mean overdosage since there is no guarantee that administration will occur at the appropriate period of declining potency. However, there is a need for the use of overage in some pharmaceutical preparations under some conditions.The General Assembly of the International Pharmaceutical Federation (FIP) at their September 1964 meeting in Amsterdam defined overage as the voluntary introduction of a specific excess during the manufacture of pharmaceutical forms of medicaments that are unstable by nature and difficult to stability, in order to maintain during their period of use an active content within the limits compatible with therapeutic requirements.

It was noted that overages are justifiable when:

1. The labile (unstable) active ingredients cannot possibly be standardized.

2. The overage allows an even equilibrium of the content of the active ingredient within the acceptable limits.

3. The overage would not present a possibility of a therapeutic overdosage if the preparation were used during the early part of the products shelf life.

4. The clinical studies show that overage is safe therapeutically.

5. The lower limit proposed for the decrease in strength applies only at the end of the period of validity of unstable preparations.

The proposed rules on overages for vitamins are:

1. A loss of not more than 10% of the labelled potency potency is considered normal at the end of the term of validity of the product.

2. Different galenical dosage forms is considered separately with a distinction made between simple and complex preparations, including a separate study of preparations containing higher doses.

3. The added overage is limited to no more than 30% of the labelled potency of the particular ingredient.

A 15% decrease in potency of antibiotic products is considered admissible for unstable antibiotics, but the following overages normally should not be exceeded: dry dosage forms, 15%; fluids, 20%; ointment, suppositories, aerosols, creams and foams, 25%.

Overage added to a preparation to compensate loss during manufacturing of the preparation is called a manufacturing overage. A stability overage is the excess added to a preparation to extend its shelf life.

3. Regulatory Aspects of Drug and Cosmetics Quality ControlTo ensure the safety and purity of drugs and cosmetics made available to the public, the Food, Drug and Cosmetic Act, otherwise known as Republic Act No. 3720 was finally passed by the Congress in 1963. This act declared that it is the policy of the state to ensure safe and good quality supply of food, drug and cosmetics, and to regulate the production, sale and traffic of the same to protect the health of the people. To carry out the provisions of this act, The Food and Drug Administration in the Department of Health was created.

Several terms are defined under this act. They are:

Drugs

1. Articles recognized in the United States Pharmacopeia, official Homeopathic Pharmacopeia of the United States, of official National Formulary, or any supplement to any of them.

2. Articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or animals.

3. Articles (other than food) intended to affect the structure or any function of the body of man or animals.

4. Articles intended for use of component of any articles specified in clause (1), (2) and (3) but does not include devices or their components, parts or accessories.Devices

Instrument, apparatus or contrivances, including their components, parts and accessories, intended:

1. For use in the diagnosis, cure, mitigation, treatment or prevention of disease in man or animals or;

2. To affect the structure or any function of the body of man or animals.

Cosmetics1. Articles intended to be rubbed, poured, sprinkled or sprayed on, introduced into or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness or altering the appearance.

2. Articles intended for use as a component of any such articles.

To enforce the Food, Drug and Cosmetics Act, the BFAD upon presenting appropriate credentials to the owner, operator or agent in-charge, is authorized:

1. To enter at reasonable hours, any factory, warehouse or establishment in which drugs or cosmetics are manufactured, processed, packed, or held before and after introduction into the market; or to enter any vehicle being used transport or hold any drug or cosmetic for commercial use.

2. To inspect in a reasonable manner, such factory, warehouse, establishment or vehicle and all pertinent equipment, finished or unfinished materials, containers and labelling therein.

Current Good Manufacturing Practice

Among the regulatory guidelines promulgated by the FDA, Administrative Order No. 220, s. 1974 on current good manufacturing practice (CGMP) made the strongest impact on the drug and cosmetic industry. This administrative order was patterned after the guidelines developed in 1963 by the US FDA with the participation of the drug companies. As the word implies, current means dynamic, changing as the occasion arises, viz., the need for technical improvement and for the greater protection of the consumer.

It should be emphasized at this point that good manufacturing practices is not the sole responsibility of quality control, but also of the production group. The quality control function is to audit or inspect periodically the procedures, equipment and facilities employed by the various disciplines within the firm engaged in research, development, production, control, purchasing, distribution and sale of the product to detect non-compliance to CGMP and to correct the said deviations.

CGMP also permits the use of precision automatic, mechanical or electronic equipment in the production and control of drugs when adequate inspection and checking procedures are used to assure proper performance.

Contamination

Non-compliance to CGMP could result in quality variation and worse, in contamination, mix-ups and errors. In extreme cases where the product is already in the market, a recall is made.A recall can involve millions of units of one product. Every hospital, pharmacists or doctor who has received a shipment may have to be notified since every unit must be sent back to the plant. Recalls have the following disadvantages:1. It causes a lot of money lost.

2. Bad publicity damages the good reputation of the company.

3. Harmful publicity can hurt sales.

4. Recalls have an adverse effect on the employees.

The main objective of CGMP is to produce a product that is safe, pure and effective. To understand the objective better, the following terms are defined:

Safe:unable to cause damage, free from dangerPure:free from contaminationEffective:producing the desired effect

There are three types of contamination: Particulate, cross and microbial contamination. The sources and prevention of each type of contamination is tabulated below.

ContaminationSourcesPrevention

ParticulateUnclean clothingAlways wear clean clothing and uniform

Clothing that sheds lint or particlesAvoid wearing clothes that shed lint or particles

Wear head coverings, gloves, masks, facial hair covering and protective gear

Objects falling out of ones pocketDo not use breast pocket

Not following SOPsFollows SOPs that relate to proper cleaning of equipment

Cross-contaminationAirborne particles within the storage area and through the ventilation systemKeep containers tightly closed and in separate rooms

Packaging machines not cleared out prior to a new packaging runFollow specific SOPs on cleaning equipments and proper labelling and packaging procedures

Improper dispensing of componentsFollow SOPs on correct dispensing of components

Inaccuracies and mix-ups in record keepingFollow SOPs on record keeping

MicrobialPeopleGood personal hygiene

Report all injuries and illnesses

SOPs not being followedFollow SOPs on handling, storage, cleaning and sterilization

Conduct quality control tests

EnvironmentMonitor microbial level of environment

It is clear that contamination, mix-ups and error come from people and environment. CGMP provides specific guidelines to ensure production of quality products.

It should be noted that firms manufacturing both penicillin (including certifiable antibiotics) and non-penicillin products on the same premises or use the same equipment create a condition or environment conducive to cross-contamination. Non-penicillin products are therefore tested for cross-contamination. Such products should not be marketed for human consumption if found to contain an amount of penicillin equivalent to 0.05 unit or more of penicillin G per maximum single dose recommended in the labelling of a drug intended for parenteral and oral use.

PersonnelThe qualified personnel are those with the proper education, training and experience to execute technological assignments.

Personnel having direct contact with drugs and cosmetics should have periodic health checks, and should be free from communicable disease and open lesions on the exposed surface of the body. They should have an awareness of the importance of good personal hygiene, wear clean outer garments, and maintain a high degree of personal cleanliness and conform to hygienic practices.

No personnel should store personal belongings, eat food, drink beverages, or use tobacco in any but prescribed areas.

Buildings

Buildings must be planned for easy cleaning, maintenance and freedom from congestion and traffic. Buildings should provide for:1. Adequate space for proper operation of manufacturing, processing, packaging, control and storage of products and their components.

2. Adequate lighting, ventilation and when necessary for the intended production and control purposes, facilities for adequate air-pressure, microbiological, dust screening, filtering, humidity and temperature controls to minimize contamination of products and dissemination of microorganisms from one area to another.

3. Adequate locker facilities and hot and cold washing facilities, including soap or detergent, air drier or single serve towels, and clean toilet facilities near working areas.

4. Adequate supply of potable water under continuous positive pressure in a plumbing system free of defects that could cause or contribute to contamination. Drains should be of adequate size and, where connected directly to a sewer, should be equipped with traps to prevent backsiphonage.5. Suitable housing and space for the care of all laboratory animals.

6. Safe and sanitary disposal of sewage, trash and other refuse within and from the buildings and immediate premises.

Equipment

Equipment used for the manufacture, processing, packaging, holding, testing, or control of drugs and cosmetics should be maintained in a clean and an orderly manner. They should be of suitable design, size, construction and location in relation to surroundings to facilitate maintenance, and operation for its intended purposes. The equipment should have the following properties:

1. Its surface should not be reactive, additive or absorptive so as to alter the properties of the drug or cosmetic.2. It should prevent any substance required for its operation, such as lubricants or coolants, to come in contact with the product.

3. It should facilitate adjustment, disassembly, cleaning and maintenance as necessary to assure the reliability of control procedures, uniformity of production, and exclusion of the product from contaminants from previous and current operations.

4. It should be of suitable type, size and accuracy for any intended testing, measuring, mixing, weighing or other processing or storage operations.

Each piece of equipment should have its own logbook and identification number. Entries in the equipment logbook must cover:

1. Date when equipment was used

2. Name of product where equipment was used

3. Date when it was cleaned

4. Person responsible for cleaning it

5. Date when equipment was validated

6. Result of validation

Complain RecordsIt is the consumer who performs the final test on the product. A dissatisfied consumer may write or phone his complain and such complaint must be received by the company. A decision is made whether or not an investigation is necessary. Complaint records must contain the following.

1. Name and address of the person complaining

2. Product name, strength and control number

3. Nature of the complaint

4. Reply to the person complaining

5. Result of the investigation and follow-up action that was required

6. If no investigation took place, the record must indicate:

i. Why it was considered unnecessary

ii. The name of the person responsible for that decision

Preservation: Samples and Records

A reserve sample of components and finished products consisting of at least twice the quantity necessary for all required test of identity, quality, purity and strength is set aside for preservation. Complete records related to the control, use, production, distribution and complaint are maintained to permit reconstruction of the history of the product. In general, records and samples are retained for a period of five years. However, local BFAD recommends the following retention periods:

Components

1. At least two years after the distribution of the last lot of product incorporating the component has been completed, or

2. One year after the expiration date of this last lot incorporating the components

Finished Products

1. At least two years after lot distribution is completed, or

2. One year after the expiration date of the product

Records

1. Drugs: as above

2. Cosmetics: at least three years after manufacture is completed.

SpectrometrySpectrometry may be defined as methods of analysis which deals with the measurement of spectra. In pharmaceutical analysis the more common measurements which are made of spectra and which are aspects of spectrometry are measurements of the position (wavelength) in the electromagnetic spectrum where radiant energy has interacted with a chemical species and measurement of transmitted, fluorescent reflected or emitted energy.

Spectrophotometry is a branch of spectrometry which embraces the measurement of the absorption by chemical species of radiant energy of definite and narrow wavelength approximating monochromatic radiation. Monochromatic radiation is radiation of a single wavelength. In actual practice, monochromatic radiation is obtained by using prism or diffraction grating and consists of more than a single wavelength. The length of a complete wave or cycle from peak of the wave to the peak of the next is called wavelength. The units of wavelength measurement generally used are the micrometer (um) which is equal to 10-4cm, the nanometer (nm) which is equal to 10-7cm and less frequently is the angstrom (A) which is equal to 10-8cm. The ranges of the wavelength of radiant energy of importance in the practice of spectrophotometry are: UV (220-380nm), Visible (380-780nm), near IR (780-3000nm), medium IR (3.0-15um) and far IR (15-300um).Spectrophotometer is a term used to designate the instruments which have a radiant energy dispersing device such as prism or grating and the associated electronics which permit the measurement of wavelength and radiant power. These instruments may either by manually operated or automatic recording instruments. Both type of instruments have (1) a radiant power source, (2) a radiant energy dispersing device, (3) a sample compartment and (4) the associated electronics which permit the measurement of radiant power transmitted by the sample. Manually operated instruments are either direct reading or null-balance instruments. An example of null-balance manually operated instrument is the Beckman DU-2 spectrophotometer. This instrument which covers the UV, visible and near IR regions has continuous range from 190-1000nm isolating spectra region from 0.5-1.5nm. An example of a direct-reading manully operated spectrophotometer is the Bausch and Lomb Spectronic 20. This instrument has an operating range of 240-950nm.Fundamental Laws of Spectrophotometry

Beers Law states that the power of a transmitted radiant beam decreases exponentially as the concentration of the solution containing the absorbing chemical species increases arithmetically. Lamberts or Bouguers Law states that the power of a transmitted radiant beam decreases exponentially as the thickness of the solution containing the absorbing chemical species increases arithmetically.

Beer-Lamber or Beer-Bouguers Law is a combination of the above law and relates the power of the incident and the transmitted radiant beam to the thickness and concentration of the solution containing the absorbing chemical species.

Official Identification Tests using Spectrometric Absorption Methods

Spectrometric absorption methods are frequently used as identification tests for pharmaceutical substances. Although all three regions of the electromagnetic spectrum are used, the UV and IR regions are used most frequently. Of the three regions the medium region (3-15um) is most often applied for identification purposes. The region from 3-8 um is referred to as the group frequency region because the absorption peaks which appear in this region are due to functional groups (carbonyl, amine, hydroxyl, etc.) formed in the organic compound. The 8-15 um region is known as the fingerprint region because this region gives a spectrum of the molecule as a whole.

1. Flame Spectroscopy

Flame Spectroscopy or Flame photometry is used in the assay of lithium carbonate. This technique is also used for the assay of other elements or metals such as potassium, sodium and calcium in blood and other biological samples. The flame spectroscopic methods most frequently used for analysis are flame emission spectrophotometry and atomic absorption spectrophotometry. This method deals with the emission of energy of a particular wavelength when a diluted solution of a metallic ion is sprayed into a colorless flame. The intensity of the emitted radiation is determined by a suitable spectrophotometer and compared to a standard.

2. FluorometryIn Fluorometric Analysis the test solution absorbs some of the incident light photons and observations is made of light emerging from the test solution at right angles to the beam of incident light. Some of the energy of the incident light photons absorbed by the test solution is re-emitted as light photons of a longer wavelength. A substance capable of performing this function is called a fluorescent substance and may be quantitatively determined by the fluorometric method.This method has found most applications in the analysis of vitamins in particular in the analysis of thiamine and riboflavin.

3. Turbidimetry and 4. Nephelometry

Turbidimetry and Nephelometry may be considered as branches of Spectrometry in which transmitted or reflected light respectively is measured after radiant energy passes through a turbid solution or suspension. Since light transmittance is used as a measure of turbidity, instruments such as colorimetric and spectrophotometric may be employed in turbidimetric measurements. Nephelometry is based on the measurement of the brightness of light reflected by a cloud of finely divided particles suspended in a liquid. Colorimeters may also be used. Turbidimetric methods are used in the official assay of the majority of antibiotics, calcium panthothenate, vitamin B12 and other medicinal agents. In these methods the activity of the biological agent is determined by measuring the turbidity produced in a series of antibiotics dilutions containing microbiological culture. The greater the turbidity (due to microbial growth) the less is the activity of the antibiotic. Turbidimetric tests are also applied to certain official chemicals to ensure the absence of excessive amounts of chloride and sulfate.

5. Nuclear Magnetic ResonanceIn Nuclear Magnetic Resonance (NMR) transitions between energy levels may be generated by radiant energy if the molecules are first placed in a magnetic field. Nuclear transitions of the protons H for example can be made to occur in the radiofrequency region when an organic compound is placed in a magnetic field of about 14000 grams. Under these conditions protons absorb radiant energy and peaks characteristic of the organic groups associated with the protons are observed. The spectral data obtained provide useful information in qualitative and quantitative studies of medicinal agents and other organic compounds. The basic instrumentation needed to measure NMR spectra includes (1) a magnet with strong, stable homogenous field, (2) a stable radiofrequency transmitter, (3) a radio receiver and detector, (4) a coil of wire surrounding the sample which serves as a sensor, (5) a cell containing the sample, (6) a method of sweeping through the spectrum and (7) a recorder to display absorption peaks.

ChromatographyChromatography is a process in which a solution of a mixture containing inert materials, drug principles and impurities is separated into its components while moving through a bed of fixed porous solid having different and reversible affinities for the substance being separated. The separation of substances comes about because each component of the mixture possesses a different mobility by reason of differences in adsorption, partition solubility, vapor pressure, molecular size or ionic charge. The drug principles so separated on a porous solid may be removed from the solid by means of a flowing solvent (elution) or by simple solvent extraction and assayed by any suitable analytical method appropriate for the specific drug.

Chromatography is particularly useful as a means of separating and purifying complex and closely related chemical substances which are difficult if not impossible to separate by chemical methods based on differences in solubility and volatility. Chromatographic techniques are more applicable in instances where small quantities are involved in the assay or identification test.

The principal objectives obtainable through the use of chromatography are:

1. Resolution of mixtures into constituent parts

2. Determination of homogeneity

3. Comparison of substances suspected to be identical

4. Purification

5. Concentration of substance from dilute solutions

6. Identification and control of technical products

7. Quantitative separation from complex mixtures

8. Indication of molecular structure

The basic principles upon which chromatographic separation depends on: (1) adsorption, (2) partition, (3) ion-exchange and (4) molecular exclusion. Based on the techniques employed in holding the porous solid, the procedure is called column chromatography, paper chromatography and thin layer chromatography.

Column Chromatography

The simplest type of chromatographic column consists of a suction flask and a cylindrical glass tube constricted to one end. The material placed in the column to absorb the drug is referred to as the adsorbent. Purified siliceous earth, activated alumina, silica gel and calcium carbonate are examples of adsorbents commonly used. The adsorbent is uniformly and firmly packed into the tube so that the solvents called mobile phase will pass through it. The column adsorbent is treated with fresh portions of components as each drug progresses down the column at a characteristic rate resulting in a chromatogram. When the separated column are colored or fluorescent under UV light, the adsorbent column is forced intact from the tube and the fractions are easily divided into segments with a knife. The segments are then extracted with a suitable solvent to obtain the pure compounds which may be analyzed by any appropriate method applicable to the drug in question. When the compounds are colorless they may be visualized by spraying the column with a color-forming agent and proceed as described above.

Another procedure commonly used to develop chromatograms is known as elution chromatography. The column is washed with suitable solvents referred to as eluants until each compound is successively obtained in the effluent liquid known as the eluate. The separated drug in different fractions of the eluate may then be determined by any appropriate method selected.Adsorption Chromatography

Adsorption Chromatography brings about the separation of a mixture through a competitive process in which the molecules of the mobile phase compete with the analyte molecules for polar adsorption site on the adsorbent. The chromatographic process is known as liquid-solid chromatography (LSC). The mobile phase is a liquid.

Partition Chromatography

Partition Chromatography in which the molecule and stationary phases are liquids referred to as liquid-liquid chromatography (LLC).

Paper-Partition Chromatography

The basic principle of separation in the partition chromatography is that of difference in partition coefficients of substances between two immiscible liquids. One of which is a stationary phase supported on a solid adsorbent with the other mobile liquid phase flowing through it. If the solid adsorbent is filter paper (cellulose) the process is referred to as paper-partition chromatography. In this process, the mobile phase, an organic solvent moves slowly over the stationary phase, usually water, is held in place by the fibers of the filter paper. Different substances move over the paper at different rates depending upon the relative solubilities in the immiscible solvents resulting in a separation by partition. The ratio of the distance travelled over the paper sheets by a given compound to the distance travelled by the front of the mobile phase from the point of application of the test substance is designated as the Rf value of the compound.

Retention factor (Rf) = distance solute moves/distance solvent movesThe ratio between the distance travelled by a given compound and reference substance constitutes the Rr value.

There are three main methods for the preparation of paper-partition chromatograms. These are: (1) descending chromatography, which is accomplished by allowing the mobile phase to flow downward on the paper strip, (2) ascending chromatography, in which the mobile phase is allowed to rise upward on the paper by capillary attraction and (3) radial chromatography, in which the mobile phase moves out in concentric circles from the center of a circular piece of paper.

Reversed-Phased Chromatography

Reversed-Phase Chromatography is based on partition phenomenon but the non-polar solvent is fixed to the paper or solid column materials and acts as the stationary phase and a polar solvent is used as a mobile phase. This method is especially useful in the separation of water-insoluble substances such as steroids.

Ion-Exchange Chromatography

Materials used to pack column for use in ion-exchange chromatography are either cat-ionic or an-ionic exchange resins. These substances are insoluble in water and exchange cations or anions in solutions in the mobile phase which comes in contact with the active sites of exchange resins.Molecular Exclusion ChromatographyThis is also known as gel filtration or gel permeation chromatography and maybe defined as a separation procedure in which differential migration of solute molecules is based on molecular size.

Thin-Layer Chromatography

Thin-layer Chromatography (TLC) involves the spotting of a sample of a mixture of components at one end of an adsorbent-coated glass plate or other suitable support followed by passage of solvent through the adsorbent for the purpose of separating components of the sample. It offers the advantages over column and paper chromatography of (1) achieving separations in a relatively short time of about 30 minutes or less, (2) accomplishing a complete analysis with as little as 20 mg of material, (3) providing a complete separation of components in complex mixtures. The method is rapid, sensitive and provides a high degree of resolution. Silica gel G and alumina are the best widely used adsorbents. For colored components such as dyes, it is not necessary to spray a special color producing reagent in order to detect the location of the spot. One general reagent used when components are colorless for the purpose of detecting organic is concentrated sulfuric acid. The organic components char after chromatogram has been sprayed with sulfuric acid and heated. Another method is the placing of the chromatogram in a close container holding a few iodine crystals. The organic component reacts with iodine and form brown spots. A third method is the use of UV radiation for organic compounds, the fluorescence. Rf and Rr values are determined as in that of paper chromatography. For quantitative analysis, spots may be scraped from the TLC plate into a suitable solvent and arranged by an appropriate method.

Gas Chromatography

Gas Chromatography (GC) uses as mobile phases an inert gas commonly known as carrier gas. The stationary phase referred to as the liquid substrate consists of a high boiling liquid which is used to coat granular particles made of siliceous earth or fire trick. The coated particles are placed in a tube made up of copper, glass or stainless steel. The tube containing the coated particles is called a column. This is mounted in a constant temperature heating chamber of GC apparatus. The temperature of the column is elevated to a constant value with the carrier gas passing through the column at a constant rate. A small quantity of the liquid sample is injected into a heated injection port using a needle and syringe. The components of the sample will volatilize and are carried to the column by the carrier gas. The substances then partition between the liquid substrate and gas phase and are transported at different rates down the column. When a component of the sample finally reaches the end of the column it passes through a differential detector connected to a strip chart recoder. A peak is then recorded on the chart pape