PRINCIPLE
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. Quality Control is not confined to
laboratory operations, but must be involved in all decisions which may concern
the quality of the product. The independence of Quality Control from Production
is considered fundamental to the satisfactory operation of Quality Control.
GENERAL
Each holder of a manufacturing authorization
should have a Quality Control Department. This department should be independent
from other departments, and under the authority of a person with appropriate
qualifications and experience, who has one or several control laboratories at
his disposal. Adequate resources must be available to ensure that all the
Quality Control arrangements are effectively and reliably carried out.
Quality Control should involve 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, sample retention program and establishing and maintaining current
specification of materials and products and their test methods.
Documentations and approval procedures applied
by the quality control unit should ensure that the necessary tests are carried
out before the materials are used for production and products are approved for
distribution.
The quality control unit should have the
following principal duties:
to establish and revise control procedures and
specifications;
to prepare detailed written instructions for
carrying out each inspection, test and analysis;
to establish written sampling plans and sampling
procedures;
to ensure the correct labelling of containers of
materials and products;
to maintain retained sample for future
reference;
to release or reject each batch of starting
material, intermediate, bulk or finished product;
to evaluate the stability of all finished
products on an on-going basis and starting materials where necessary, and
to establish instructions for the storage of
materials and products on the basis of their stability data;
to establish shelf-life of starting materials
and finished products based on their stability data and storage condition;
to take part or assist in validation program;
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 pharma-ceutical products
and determine whether such products could be released or reprocessed or should
be destroyed;
to participate in the self-inspection program
with other units of the company; and
to recommend contract manufacturing operations
after evaluating the contractor's capability to produce products that meet the
company's specified quality standards.
Quality Control personnel should have access to
production areas for sampling and investigation as appropriate.
GOOD QUALITY CONTROL
LABORATORY PRACTICES
Premises
Control laboratories should be designed,
equipped and of sufficient space to suit the relevant operations.
Provisions should be made for the proper and
safe storage of waste materials awaiting disposal. Toxic substances and
inflammable materials should be stored in suitably designed and separated
enclosed cupboards.
The laboratories should be physically separated
from the production rooms.
Biological, microbiological and chemical
laboratories should be segregated from each other.
A separate room may be needed 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 should take into
account the suitability of construction materials, fume prevention and
ventilation. Separate air handling units should be installed for biological,
microbiological and radioisotope laboratories.
All service piping and devices should be
adequately marked and special attention paid to the provision of non-interchangeable
connections or adaptors for dangerous gases and liquids.
Personnel
Each individual engaged in the supervision or
conduct of a laboratory operation should have proper education, training and
experience or combination thereof, to enable the individual to perform the
assigned functions. Their duties and responsibilities should be clearly defined
in job descriptions or by other suitable means.
Personnel should 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.
Equipment
Control laboratory equipment and instruments
should be suitable to the testing procedures undertaken.
Standard operating procedures should be
available for each instrument and equipment; the forms should be
placed in close proximity to the equipment.
Equipment, instrument and related soft ware
should be qualified / validated, maintained and calibrated at pre-specified
intervals and their records maintained. Pre-check of the instrument to ensure
its satisfactory functioning should be conducted daily or prior to using the
instrument for performing analytical tests.
The date of calibration, maintenance and
recalibration due date should be clearly displayed on the equipment or by other
appropriate means.
Provisions should be made to indicate failure of
equipment or maintenance to equipment. Defective equipment should be withdrawn
from use until the defect has been rectified.
A safety shower and eye-bath should be provided
in close proximity to the laboratory working area.
The personnel, premises, and equipment in the
laboratories should be appropriate to the tasks imposed by the nature and the
scale of the manufacturing operations. The use of outside laboratories, in
conformity with the principles detailed in Chapter 11, Contract Manufacture and
Analysis, can be accepted for particular reasons.
Reagents and Culture Media
All reagents and culture media should be
recorded upon receipt or preparation.
Reagents and culture media made up in the
laboratory should be prepared following written procedures and appropriately
labelled. The label should indicate the concentration, standardization factor,
shelf-life, re-standardization due date and storage conditions. The label
should be signed and dated by the person preparing the reagent.
Both positive and negative controls should be
applied to verify the suitability of culture media. The size of the inoculum
used in positive controls should be appropriate to the sensitivity required.
Reference Standards
Reference standards should be under the
responsibility of a designated person.
Reference standards should 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 should be stored and
used in a manner which will not adversely affect their quality.
The label of reference standards should indicate
the concentration, date of manufacture, expiration date, date the closure is
first opened and storage conditions where appropriate.
Where necessary, the date of receipt of any
substance used for testing operations (e.g. reagents and reference standards)
should be indicated on the container. Instructions for use and storage should
be followed. In certain cases it may be necessary to carry out an
identification test and/or other testing of reagent materials upon receipt or
before use.
Animals used for testing components, materials
or products, should, where appropriate, be quarantined before use. They should
be maintained and controlled in a manner that assures their suitability for the
intended use. They should be identified, and adequate records should be
maintained, showing the history of their use.
Specifications and Testing Procedures
Testing procedures should be validated in the
context of available facilities and equipment before they are adopted for
routine testing.
All testing operations described in the
marketing authorization should be carried out according to the approved
methods.
Specifications and testing procedures
established for each starting material, intermediate, bulk and finished product
should include specifications and testing procedures for identity, purity,
quality and strength.
Testing procedures should 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; and
target value and tolerance allowable for each
test.
Testing procedures should include frequency for
re-assaying each starting material determined by considering its stability.
All tests should follow the instructions given
in the relevant test procedure for each material or product. The result,
especially where calculations are involved, should be checked by the supervisor
before the material or product is released or rejected.
Records of Analysis
Records of analysis should include:
name and batch number of sample and dosage form;
name of the individual who takes the sample;
methods of analysis;
all data, such as weight, burette readings,
volumes and dilutions made;
calculation in units of measurement and the
formula of calculation;
statement of permitted tolerances;
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; and
total quantity and number of containers of
starting material, packaging material, intermediate, bulk or finished product
of each batch analyzed.
CONTROL OF STARTING MATERIALS,
INTERMEDIATE, BULK AND FINISHED PRODUCTS
Specifications
Each specification should be approved and
maintained by the quality control unit except for finished products which
should be approved by the head of Quality Management (Quality Assurance).
Specification of starting materials, intermediate, bulk and finished products
is referred to Sections 10.10 – 10.14; and
Periodic revisions of the specifications are
necessary to comply with the latest edition of the national pharmacopoeia or
other official compendia.
DOCUMENTATION
Laboratory documentation should follow the
principles given in Chapter 10. An important part of this documentation deals
with Quality Control and the following details should be readily available to
the Quality Control Department:
specifications;
sampling procedures;
testing procedures and records (including
analytical worksheets and/or laboratory notebooks);
analytical reports and/or certificates;
data from environmental monitoring, where
required;
validation records of test methods, where
applicable; and
procedures for and records of the calibration of
instruments and maintenance of equipment.
Any Quality Control documentation relating to a
batch record should be retained for one year after the expiry date of the
batch.
For some kinds of data (e.g. analytical tests
results, yields, environmental monitoring) it is recommended that records in a
manner permitting trend evaluation be kept.
In addition to the information which is part of
the batch record, other original data such as laboratory notebooks and/or
records should be retained and readily available.
SAMPLING
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 should receive
initial and on-going regular training in the disciplines relevant to correct
sampling. This training should 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; and
the importance of recording any unexpected or
unusual circumstances.
Starting Materials
The identity of a complete batch of starting
materials can normally only be ensured if individual samples are taken from all
the containers and an identity test performed on each sample. It is permissible
to sample only a proportion of the containers where a validated procedure has
been established to ensure that no single container of starting material will
be incorrectly identified on its label.
The quality of a batch of starting 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.
Packaging Material
The sampling plan for packaging materials should
take account of at 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 the knowledge of
Quality Assurance system of the packaging materials manufacturer based on
audits. The number of samples taken should be determined statistically and
specified in a sampling plan.
Sampling Operations
Sampling should be carried out so as to avoid
contamination or other adverse affects on quality. The containers which have
been sampled should be marked accordingly such as the contents, the batch
number, the date of sampling and the containers from which samples have been
drawn. The containers should be carefully resealed after sampling.
All sampling tools and containers should be made
of inert materials and kept scrupulously clean.
Sampling instructions should 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 sub-division of
the sample;
the type of sample container to be used i.e.
whether it is for aseptic sampling or for normal sampling;
the identification of containers sampled;
any special precautions to be observed,
especially in regard to sampling of sterile or noxious materials;
the storage conditions; and
instructions for the cleaning and storage of
sampling equipment.
Each sample container should 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;
the signature of the person who takes the
sample; and
the date of sampling.
Sampling equipment should be cleaned, if
necessary sterilized, before and after each use and stored separately from other
laboratory equipment.
Care should 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 should be clean.
Some particularly hazardous or potent materials may require special
precautions.
Retained Samples
An appropriately identified retained sample
representative of each batch in each delivery of starting material should be
retained for a specified period.
An appropriately identified retained sample
representative of each batch of finished product in its complete packaging form
should be retained for a specified period. These finished product samples
should be stored under conditions which simulate market conditions as indicated
on the labelling.
Retained samples should consist of at least
double the quantity necessary to perform all the required tests, except those
for sterility.
Retained samples should be representative of the
batch of materials or products from which they are taken. Other samples may
also be taken to monitor the most stressed part of a process (e.g. beginning or
end of a process).
Retained samples from each batch of finished
products should be retained till one year after the expiry date. Finished
products should usually be kept in their final packaging and stored under the
recommended conditions. Samples of starting materials (other than solvents,
gases and water) should be retained for at least two years after the release of
the product if their stability allows. This period may be shortened if their
stability, as mentioned in the relevant specification, is shorter.
TEST REQUIREMENTS
Starting Materials
Each starting material should be tested for
conformity with specification for identity, strength, purity and other quality
parameters.
Packaging Materials
Packaging materials should conform with
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 which may prejudice the quality of the
product should be examined.
Intermediate and Bulk Products
To ensure batch uniformity and integrity,
in-process control should be conducted by testing representative samples of
intermediate and bulk product of each batch for identity, strength, purity and
quality as appropriate. 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.
Rejected intermediate and bulk products should
be identified and controlled under a quarantine system designed to prevent
their use in further processing, unless such product is judged suitable for reprocessing
later on.
Finished Products
For each batch of pharmaceutical
product, there should be appropriate laboratory determination of satisfactory
conformance to its finished product specifications prior to release.
Pharmaceutical products failing to meet the
established specifications and any other relevant quality criteria should be
rejected. Reprocessing may be performed if feasible but the reprocessed product
should meet all specifications and other quality criteria prior to its
acceptance and release.
Environment Control
The following controls should be performed :
regular monitoring of the process water,
including at the point of use, for chemical and microbiological quality. The
sample size and test method employed should be capable of detecting the
presence of low levels of indicator organisms, e.g. Pseudomon
periodic microbiological monitoring of the
production environment;
periodic testing of the environment around the
production areas for the presence of other drug product that will contaminate
the product being processed; and
control of airborne contaminants.
In-Process Control
All the in-process controls, including those
made in the production area by production personnel, should be performed
according to methods approved by Quality Control and the results recorded.
Retesting of Approved
Materials
There should be an appropriate time limit for
storage of each starting material, intermediate, bulk and finished product.
After this period the material or product should be retested by the quality
control unit for identity, strength, purity and quality. Based on the retest
result the material is either re-approved for use or rejected.
If a material is subjected to unusual storage
condition, it should be retested and approved for use by the quality control
unit prior to processing.
Reprocessing
Additional testing of any finished product which
has been reprocessed should be performed as required.
Follow-up stability study of the reprocessed
product should be conducted as necessary.
Quality Control Evaluation on
Production Procedures
The quality control unit should participate in
the development of Master Processing Procedures and Master Packaging Procedures
for each batch size of a drug product to assure uniformity from batch to batch
manufactured.
The quality control unit should participate in
development of production equipment cleaning and sanitation procedures.
Stability Study
A stability testing program should be designed
to assess the stability characteristics of pharmaceutical products and to
determine storage conditions and expiration date.
The written program should be followed and
include:
sample size, test intervals based on statistical
criteria for each attribute examined to assure estimate of stability;
storage conditions;
reliable, meaningful and specific test method;
testing of the product in the same packaging
form as that in which the product is marketed; and
testing of the product for reconstitution before
and after it has been reconstituted.
A stability study should be performed under the
following situations :
new products (usually performed on pilot
batches);
new packages i.e. those differing from the
prescribed standard;
change in formula, processing method or source /
manufacturer of starting materials and primary packaging materials;
batches released by exception e.g. batches with
properties differing from standard or reworked batches; and
marketed products.
