[2.3] PART 2 SECTION 9

SECTION 9. QUALITY CONTROL

QUALITY CONTROL

is an essential part of Good Manufacturing Practices to provide assurance that the products will be consistently of a quality appropriate to their intended use. The involvement and commitment of all concerned at all stages are mandatory towards the achievement of this quality objective from the start of manufacturing to the distribution of the finished product. An independent quality control unit shall be established.

A quality control system shall be developed and designed so as to ensure that

finished products contain the correct materials of specified quality and quantity and are manufactured under proper conditions following standard procedures, thereby they will consistently meet the established specifications for identity, strength, purity, quality, and safety.

Quality control involves all analytical functions conducted in the laboratory, including sampling, inspecting and testing of starting materials, intermediate, bulk and finished products. It also includes

stability test, environmental monitoring program, validation tests, review of batch documentation, sample retention program and establishing and maintaining current specification of materials, products and their test methods.

Documentation and release procedures applied by the quality control unit shall ensure that the necessary tests are

carried out, and that the materials are not released for use, nor products released for distribution and sale until their quality has been determined to meet specifications.

The quality control unit shall have the following principal duties:

• to establish and revise control procedures and specification 

• to prepare detailed written instructions for carrying out each inspection, test and analysis

• to establish written sampling plans and sampling procedures 

• to maintain retained sample for future reference

• to release or reject each batch of starting material, intermediate, bulk or finished product

• to review all documentation relating to the batch processing, packaging and testing of each batch of finished product before authorizing release for distribution

• to evaluate the stability of all finished products on an on-going basis and raw materials where necessary, and to establish instructions for the storage of materials and products within the manufacturing plant on the basis of their stability data

• to establish expiration dates and shelf-life of raw materials and finished products based on their stability data and storage condition

• to evaluate and approve any reprocessing procedure for products

• to accredit those approved suppliers of raw and packaging materials capable of and reliable for supplying starting materials that meet the company’s established quality specifications

• to take part or assist in validation program

• to evaluate all complaints received or deficiencies noted about any batch, if necessary in co-operation with other units of the company, and to take appropriate corrective action

• to prepare secondary reference standards as specified in the current procedure for testing and to store these standards under proper conditions

• to maintain analytical records of the tests of all samples taken

• to evaluate returned drug products and determine whether such products could be released or reprocessed or shall be destroyed

• to participate in the self-inspection program with other units of the company and

• to recommend toll manufacturing operations after evaluating the toll manufacturer’s capability to produce products that meet the company’s specified quality standards.

Control laboratories

shall be designed, equipped and of sufficient space to suit relevant operations.

Provisions shall be made for the proper and safe storage of waste materials awaiting disposal.

Toxic substance and inflammable materials shall be stored in suitably designed and storage.

The laboratories shall be physically separated from the production rooms. Biological, microbiological and chemical laboratories .

shall be segregated from each other. Air handling facilities for biologicals and microbiologicals should be separate from process air handling facilities

A separate room shall be provided for

instruments to protect these against electrical interference, vibration, contact with excessive moisture and other external factors or where there is need to isolate the instrument.

The design of the laboratory shall take into account the

suitability of construction materials, fume prevention and ventilation. Separate air handling units shall be installed for biological, microbiological and radioisotope laboratories.

All service pipings/pipelines and devices shall be adequately marked and special attention paid to the

provision of non-interchangeable connections or adaptors for dangerous gases and liquids. 

A safety shower and eye bath shall be provided in close proximity

to the laboratory working area.

Each individual engaged in the supervision or conduct of a laboratory operation shall have

proper education, training and experience or combination thereof, to enable the individual to perform the assigned functions. Their duties and responsibilities shall be clearly defined in job descriptions or by other suitable means.

Personnel shall wear protective clothing and safety equipment such as

respirators or face masks, safety glasses and acid or alkali resistant gloves appropriate to the duties being performed

Control laboratory equipment and instruments shall be suitable to the

testing procedures undertaken.

Standard operating procedures

shall be available for each instrument and equipment

Equipment and instrument shall be serviced and calibrated at pre-specified intervals and their records shall be maintained. Pre-check of the instrument to

ensure its satisfactory functioning shall be conducted daily or prior to using the instrument for performing an analytical test

The date of calibration, servicing and due date of the next calibration shall be clearly displayed on the

equipment or by other appropriate means. Provisions shall be made to indicate failure of equipment or services to equipment. Defective equipment shall be withdrawn from use until the defect has been rectified

All reagents and culture media shall be

recorded upon receipt or preparation

Reagents made up in the laboratory shall be prepared following written procedures and appropriately labeled. The label shall indicate the

concentration, standardization factor, shelf-life, re-standardization due date and storage conditions. The label shall be signed and dated by the person preparing the reagent

Both positive and negative controls shall be applied to

verify the suitability of culture media. The size of the inoculum used in positive controls shall be appropriate to the sensitivity required.

Reference standards shall be under the

responsibility of a designated person

Official reference standards shall be used only for the purpose described in the appropriate monograph. Secondary or working standards may be established

by the application of appropriate tests and checks at regular intervals to correct deviations and to assure the accuracy of the result

All reference standards shall be stored and used in a manner which

will not adversely affect their quality. The label of reference standards shall indicate the concentration, date of manufacture, expiration date, date the closure is first opened and storage conditions where appropriate

Testing procedures shall be validated in the context of

available facilities and equipment before they are adopted for routine testing

Specifications and testing procedures established for each raw material, intermediate, bulk and finished product shall include

specifications and testing procedures for identity, purity, quality and strength

Testing procedures shall include

• amount of sample necessary for testing and retention for future analysis

• amount of each reagent, buffer solution, etc., necessary for the tests

• equations for computation

• target value and tolerance allowable for each test

Testing procedures shall include frequency for reassaying

each raw material determined by considering its stability

All tests shall follow the instructions given in the relevant test procedure for each material or product. The result,

especially where calculations are involved, shall be checked by the supervisor before the material or product is released or rejected.

A procedure should be available to describe the action taken when

an out of specification result is obtained.

RECORD OF ANALYSIS

• name and batch number of sample

• name of the individual who takes the sample

• methods of analysis

• all data, such as weight, buret readings, volumes and dilutions made

• calculation in units of measurement and the formula of calculation

• statement of permitted tolerance

• statement of compliance or non-compliance with specification

• date and signature of the person performing the test and the person verifying the calculations

• statement of approval or rejection and recommendation for its disposal, signed and dated by the authorized person

• the name of supplier, total quantity and the number of containers of material received

• total quantity and number of containers of raw material, packaging material, intermediate, bulk or finished product of each batch analyzed.

An appropriately identified retained sample representative of each batch

in each delivery of active raw material shall be retained for a specified period.

An appropriately identified retained sample representative of each batch of finished product in its complete packaging form

shall be retained for a specified period. These finished product samples shall be stored under conditions that simulate market conditions as indicated on the labels

Retained samples shall consist of

at least double the quantity necessary to perform all the required tests, except those for sterility.

The quality control unit shall conduct the following validation:

• validation of assay procedures

• calibration of instruments

VALIDATION OF ASSAY PROCEDURES

• The assay principle should be suitable for the prescribed application. The validation of the analytical method is intended to  

establish that performance characteristics such as accuracy, precision linearity of response are satisfactory. When the assay performance characteristics are not satisfactory, it will be necessary to subject the assay procedure to appropriate review, design study, revision or replacement.

CALIBRATION OF INSTRUMENTS specified in the testing procedure shall be

conducted on a regular basis to ensure that they are always performing satisfactorily.

Each specification shall be approved and maintained by the

quality control unit. Periodic revisions of the specifications are necessary to comply with the latest edition of the national pharmacopoeia or other official compendia.

Sampling

is an important operation in which only a small fraction of a batch is taken. Valid conclusions on the whole cannot be based on tests which have been carried out on non-representative samples. Correct sampling is thus an essential part of a system of quality assurance.

Personnel who take samples shall receive initial and on-going regular training in the disciplines relevant to correct sampling. This training shall include:

• sampling plans

• written sampling procedures

• the techniques and equipment for sampling

• the risks of cross-contamination

• the precautions to be taken with regard to unstable and/or sterile substances

• the importance of considering the visual appearance of materials, containers and labels

• the importance of recording any unexpected or unusual circumstances

Samples shall be representative of the batches of material from which

they are taken in accordance with the approved written procedures

The identity of a complete batch of raw materials can normally only be ensured if

individual samples are taken from all the containers and an identity test performed on each sample. 

The quality of a batch of raw materials may be assessed by taking and testing a representative sample. The samples taken for identity testing could be used for this purpose. The number of samples taken for the preparation of a representative sample should be determined statistically and specified in a sampling plan.

The number of individual samples which may be blended to form a composite sample should also be defined, taking into account the nature of the material, knowledge of the supplier, and the homogeneity of the composite sample.

The sampling plan for packaging materials shall take account of a least the following:

the quantity received, the quality required, the nature of the material (e.g. primary packaging materials and/or printed packaging materials), the production methods, and what is known of the quality assurance system of the packaging materials applied by the manufacturer based on audits. The number of samples taken shall be determined statistically and specified in a sampling plan.

Sampling shall be carried out so as

to avoid contamination or other adverse effects on quality. Containers from which sample has been taken shall be marked to show that sample has been removed from them.

Sampling instructions shall include:

• the method of sampling and the sampling plan

• the equipment to be used

• the amount of sample to be taken

• instructions for any required subdivision of the sample

• the type of sample container to be used i.e. whether it is for aseptic sampling or for normal sampling

• any special precautions to be observed, especially in regard to sampling of sterile or noxious materials

• the storage conditions

• instructions for the cleaning and storage of sampling equipment

Each sample container shall bear a label indicating:

• name of sampled material

• the batch or lot number reference

• the number of container from which the sample has been taken 

• signature of the person who takes the sample and 

• the date of sampling

Sampling equipment shall be

cleaned, if necessary sterilized, before and after each used and stored separately from other laboratory equipment

Care shall be taken during sampling to guard against contamination or mix-up of, or by, the material being sampled. All sampling equipment which comes in contact with the material

shall be cleaned. Some particularly hazardous or potent materials may require special precautions.

Sampling plans for starting materials shall differentiate:

• between accredited, approved and other suppliers, including new suppliers

• between starting materials that do not bear a manufacturer’s batch number and those that do

• etween materials that maybe expected to vary from container to container (for example by segregation or moisture uptake) and those that may not

Sampling plans for starting materials shall prescribe:

• the action to be taken where a delivery from an accredited or approved supplier has failed

• an increased sampling rate for damaged containers or where lots do not appear to be homogenous

Sampling plans for starting materials shall specify

the extent of pooling of samples destined for chemical tests

Sampling plans for starting materials shall require the sampling operator to

initially examine each sample for evidence of deterioration, lack of homogeneity or other visible defects

Sampling plans for in-process materials shall

• assure a representative sample of the batch is taken for in-process tests

• prescribe an increased sampling rate where in-process materials do not appear to be homogenous

• specify the extent of pooling of samples destined for chemical tests

• require sampling operator to initially examine each sample for evidence of lack of homogeneity or other visible defects

Each raw material shall be tested for conformity with specification for

identity, strength, purity and other quality parameters

Packaging materials shall conform to specifications, with emphasis placed on the compatibility of the material with the drug product it contains.

• The critical and major physical defects as well as the correctness of identity markings that may prejudice the quality of the product shall be examined.

INTERMEDIATE AND BULK PRODUCTS
To ensure batch uniformity and integrity,

in-process control shall be conducted by testing representative samples of intermediate and bulk product of each batch for identity, strength, purity and quality as appropriate

INTERMEDIATE AND BULK PRODUCTS
Written procedures describing sample taking, the controls and tests or examinations to be conducted on in- process product of each batch shall be established and followed. In-process controls are intended to

monitor the product yields and validate the performance of the production processes that may be responsible for causing variability in the characteristics of in-process products.

INTERMEDIATE AND BULK PRODUCTS
In-process specifications shall be consistent with the finished product specifications. They shall be derived from

previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical methods where appropriate.

INTERMEDIATE AND BULK PRODUCTS
Rejected intermediate and bulk products

shall be identified and controlled under a quarantine system designed to prevent their use in further processing unless such product is determined acceptable for reprocessing later on.

INTERMEDIATE AND BULK PRODUCTS
Quality control approval of the product is mandatory after

completion of critical steps of production or after the product has been stored for a long period

FINISHED PRODUCTS

For each batch of finished product (drugs, devices and other products),

there shall be appropriate laboratory determination of satisfactory conformance to its finished product specifications prior to release

FINISHED PRODUCTS failing to meet the established specifications and any other relevant quality criteria

shall be rejected. Reprocessing may be performed if feasible but the reprocessed product shall meet all specifications and other quality criteria prior to its acceptance and release

There shall be an appropriate time limit for storage of each starting material, intermediate, bulk and finished product. After this period

the material or product shall be re-tested by the quality control unit for identity, strength, purity and quality. Based on the results the materials/products are either re-approved for use or rejected

If a material is subject to unusual storage condition, it shall be

re-tested and approved for use by the quality control unit prior to processing

There shall be written procedures for environmental monitoring, for gowning, cleaning and disinfection within manufacturing areas. These procedures shall contain

“target”, “alert” and “action” limits for environmental contaminants. The procedure shall include the action/s to be taken in the event that the limit is exceeded or particular indicator organisms are isolated

Regular monitoring of the process water, including at the point of use, for chemical and microbiological quality. The sample size and test method employed shall be capable of

detecting the presence of low levels of indicator organisms, e.g. Pseudomonas.

Periodic microbiological monitoring of the production environment. There are varieties of sampling techniques that are available for monitoring of microbial contamination. Each technique has its own value and is

necessary to use a combination of techniques utilizing a formal sampling program to identify trends or highlight exceptional results within the manufacturing environment

Periodic microbiological monitoring of the production environment. There are varieties of sampling techniques that are available for monitoring of microbial contamination. Each technique has its own value and is necessary to use a combination of techniques utilizing a formal sampling program to identify trends or highlight exceptional results within the manufacturing environment. These techniques are:

• air sampling

• settle plates

• particle counting

• contact plates

• hand plates

• water sampling

Periodic testing of the environment around the

production areas for the presence of other drug product that will contaminate the product being processed.

Control of

airborne contaminants.

In-process quality control tests that may be performed for the following (where appropriate) by suitably trained process operators are:

• tablet granulation manufacture

• compression or encapsulation process

• tablet coating

• liquid processing

• creams, ointments, semi-solids, liniments

• filling/ packaging control

TABLET GRANULATION MANUFACTURE

moisture test

sieve (screen) analysis

COMPRESSION OR ENCAPSULATION PROCESS

individual weight determination

average unit weight determination

disintegration test

friability test (compressed tablets only)

hardness test (compressed tablets only)

maintenance of x & r charts

thickness (compressed tablets only)

TABLET COATING

average unit weight

individual weight

color and coating finish

LIQUID PROCESSING

clarity at final filtration

pH

specific gravity

final batch volume

CREAMS, OINTMENTS, SEMI-SOLIDS, LINIMENTS

active material dispersion/solubilization

pH (excluding ointments)

viscosity

FILLING/PACKAGING CONTROL

encoded batch number and expiry date

count or measures in finished pack

label appearance and adhesion

bulk material identification

cap torque

seal integrity of strip or blister pack

correctness of first and last packages

The quality control unit shall verify line clearance

before the packaging operation may proceed.

During the packaging run the in-process control inspector

will collect samples of packed unit at the beginning, middle and end of operation

Packed finished products shall be quarantined

until released by the quality control unit

Reprocessing shall not be performed

without prior review and approval of the quality control unit

The reprocessing of a batch of product shall be considered only after the

potential risks have been formally evaluated and complied with specifications.

The methods of reprocessing shall be specifically authorized and fully documented.

Documentation shall accurately record then reworking processes carried out

Additional testing of any finished product that has been reprocessed and added shall be

performed as required

Follow-up stability study of the reprocessed product

shall be conducted as necessary

Recovered material may be reprocessed by an

appropriate and authorized method, provided that the material was analyzed to be suitable for such reprocessing

The resultant product should meet its

specification and product quality.

Documentation should accurately record the

reworking processes carried out.

Residues that are not suitable for reprocessing which do not meet specifications

shall not be used in subsequent batches

The treatment of product residues and reprocessed material and the means of their inclusion in a subsequent batch shall be

specifically authorized and documented

Limits, approved by the quality control, shall be

established for the amount of any such material that may be added to a subsequent batch

Batches incorporating residues shall not be released until

the batches from which the residues originated have been evaluated and found suitable for use.

A finished product returned from the manufacturer’s own stores or warehouse (because, for example, of soiled or damaged labels or outer packaging) may be

relabeled or incorporated in subsequent batches, provided that there is no risk to product quality and the operation is specifically authorized and documented. If such products are re-labeled, extra care is necessary to avoid mix-up or mislabeling

Finished products returned from the market and which have left the control of the manufacturer shall be considered for re-sale, re-labeling or incorporation in a subsequent batch only after

the person responsible for quality control has critically assessed them. The nature of the product, any special storage condition required, its condition and history, and the time elapsed since it was issued shall all be taken into account in this assessment.

Where any doubt arises over the quality of the product,

it shall not be considered suitable for re-issue for re-use

The quality control unit shall participate in the

development of the master processing procedure and master packaging procedure for each batch size of a drug product to assure uniformity from batch to batch manufactured. Any changes and adjustments in the master processing procedure or master packaging procedure shall have quality control approval prior to execution in production.

The quality control unit shall approve the

production equipment cleaning and sanitation procedures.

All production and control records shall be reviewed and approved by the quality control unit to

determine the manufacturing compliance with the established procedures before a batch of finished product is released for distribution

Any discrepancy or failure of a batch to meet its specifications shall be thoroughly investigated. The investigation shall extend to other batches of the same product and other products that may have been associated with the specific failure or discrepancy

. A written record of the investigation shall be made and shall include the conclusion and follow-up action.