Pharmaceutical Quality Control

Quality Control is the part of GMP concerned with sampling, specifications and testing, and with the
organization, documentation and release procedures which ensure that the necessary and relevant
tests are carried out to ensure that products released for sale or supply have fulfilled all safety
requirements.
Components of QC are :
1. Analysis of finished products
2. Sampling
3. Validation of test methods
4. Batch inspection and sampling
5. Records
6. Retained samples.
7. QC labs
Sources of quality variation are Materials (variation of suppliers and within batches), Machines
(variation in equipment and difference in adjustments), Methods (wrong or inadequate procedure),
and Men (training, skills, work conditions)
Quality control tests of tablets
Quality control tests of tablets or evaluation of tablets is a systematic determination of physical, chemical,
mechanical, biological, or microbiological properties of tablets based on Non-official (Non-Pharmacopoeial),
Pharmacopoeial standards such as BP, USP, Ph. Eur., Ph. Int., or other guidelines such as ICH etc.

A variety of methods are used for the evaluation of tablets or conducting quality control tests of tablets. All of
the quality control tests of tablets or evaluation tests of tablets are classified into three categories:

Non-Official Tests Pharmacopoeial or Official Specific Pharmacopoeial Tests

Tests
1 Appearance/ Description Identification Tests Microbiological Examination of Tablets
2 Thickness and Diameter Friability Test Acid-Neutralizing Capacity
3 Hardness Disintegration Test Quality test of Splitting Tablets with
Functional Scoring
4 Organoleptic properties Weight Variation Test Water content
5 Uniformity of Dosage Unit Microbiological Examination of Tablets
Test
6 Dissolution Test Acid-Neutralizing Capacity
7 Assay Test Quality test of Splitting Tablets with
Functional Scoring
8 Impurities Test Water content
Quality control tests for capsules
Finished capsules are subjected to a few tests in accordance with compendial standards and regulatory
requirements for unit dose capsule products. These batteries of tests help identify whether the batch is
acceptable for marketing or its intended usage, the finished capsules are evaluated by the following tests:

1. Permeability and sealing

Soft gelatin capsules are tested for physical integrity (absence of leakage) by visual inspection. Similarly, hard
gelatin capsules are tested for any breach of physical integrity (breakage or opened cap and body).

2. Potency and impurity content

All capsules are tested for drug content (potency, as a per cent of label claim). In addition, most drug products
are tested for related substances or impurities. These must meet predefined specifications for a batch to be
acceptable.

3. Weight variation test

The uniformity of dosage units may be demonstrated by determining weight variation or content uniformity. The
weight variation method is as follows.

a. Weight variation test for hard gelatin capsules

b. Weight variation test for soft gelatin capsules

4. Uniformity of content

This test is performed only when the content is specified in the individual monographs and when capsules fail
weight variation test. If the weight of capsules is completely filled no need of this test. Unless otherwise stated in
the monograph for an individual capsule, the amount of drug substance, determined by assay, is within the range
of 85.0% to 115.0% of the label claim for nine (9) of ten (10) dosage units assayed, with no unit outside the range
of 75.0% to 125.0% of the labelled drug content. Additional tests are prescribed when two or three dosage units
are outside of the desired range but within the stated extremes.

5. Disintegration time test for capsules

Disintegration of hard and soft gelatin capsules is evaluated to ensure that the drug substance is fully available
for dissolution and absorption from the gastrointestinal tract. The compendial disintegration test for hard and
soft gelatin capsules follows the same procedure and uses the same apparatus described in the article “Quality
Control Tests for Tablets”. The capsules are placed in the basket-rack assembly, which is repeatedly lowered 30
times per minute into a thermostatically controlled bath of fluid at 37 ± 2 ˚C and observed over the time
described in the individual monograph.

6. Dissolution test for capsules

Drug absorption and physiological availability depend on the drug substance being in the dissolved state at the
site of drug absorption. The rate and extent of dissolution of the drug from the capsule dosage form is tested by
a dissolution test. This test provides means of quality control in ensuring that, different batches of the drug
product have similar drug release characteristics and also, a given batch has similar dissolution as the batch of
capsules that was shown initially to be clinically effective.
 7. Moisture content

Water content of the entire capsule or the capsule contents are determined by Karl Fisher titrimetry to enable
the correlation of water content with the degradation profile or drug-release characteristics of capsules.

8. Moisture permeation test

The USP requires determination of the moisture permeation characteristics of single-unit and unit dose
containers to assure their suitability for packaging capsules. The degree and rate of moisture penetration is
determined by packaging the dosage unit together with a colour-revealing desiccant pellet, exposing the
packaged unit to known relative humidity over a specified time, observing the desiccant pellet for colour change
(indicating absorption of moisture) and comparing the pre-test and post-test weight of the packaged unit.

9. Microbial content

The capsules are tested to ensure lack of growth of bacteria and mould by microbiological tests. These tests are
usually carried out by incubation of the capsule contents in a growth medium and counting the colonies formed
after a predefined period of time. Selection of the growth medium and duration of the test, as well as
maintenance of aseptic conditions during the testing, are critical to successful assessment of microbial
contamination by this method.

10. Shelf-life test

These tests are frequently carried out after defined periods of storage at predetermined conditions. They help to
assign and verify the shelf life and usability of the drug product.

11. Stability testing of capsules

Stability testing of capsules is performed to determine the physicochemical stability of the drug substance in the
finished drug product under specified package and recommended storage conditions intrinsic stability of the
active drug molecule and the influence of environmental factors (e.g., temperature, humidity, light), on
formulation components, and the container and closure system. The battery of stress-testing, long-term stability
and accelerated stability tests help determine the appropriate storage conditions and the product’s anticipated
shelf life.

Quality control tests for sterile parenteral products

Quality control is concerned with sampling, specifications, testing, documentation, and release procedures which
ensure that necessary and relevant tests are carried out and products are not released for use or sale, until its
quality has been judged to satisfy requirements of safety and efficacy.

1) Sterility Tests.

2) Pyrogen Tests.

3) Leaker Tests.

4) Particulate matter testing.

1) Sterility tests:- Sterility is the most important and Absolutely Essential characteristics of Parenteral
products. Sterility means the complete absence of all viable micro-organisms. It is an absolute term. The
methods which are used to perform sterility tests are a) Direct transfer method. b) membrane filtration
method.

a.) Direct Transfer method: - it is a traditional sterility test method which involves a direct inoculation of required
volume of a sample in two tests tube containing a culture medium that is FTM, SCDM. This method is simple in
theory but difficult in practice when the demand for repetition in opening container, sampling Transferring,
and mixing increases causes potential fatigue to the operator and deterioration in operator technique. So,
chances of accidental contamination are possible.

b.) Membrane Filtration method: - It is official in U.S.P. 1970. It is a more popular and widely used method over
direct transfer method. Successful Employment Requires a more skill and knowledge than Direct transfer
method. This method basically involves filtration of Sample through membrane filters of porosity 0.22 micron
and Diameter 47mm with hydrophobic characteristics. The filtration is assisted under vacuum. After completion
of filtration the membrane is cut into 2 halves and one half is placed in two test tubes containing FTM, SCDM
medium.

*Interpretation: - If no visible evidence of microbial growth in culture medium in test tube, then it is interpreted
that the sample representing lot is without intrinsic contamination. If visible microbial growth is seen or if the
test is judged to be invalid because of inadequate environmental conditions the sterility test is repeated such
interpretation must be made by those personnel who have adequate knowledge of aseptic processing,
industrial sterilization methods, and environmental control procedures used in test facility.

2) Pyrogen Test: - Pyrogens are products of metabolism in micro-organisms gram-negative bacteria produces
most potent pyrogens. These are lipopolysaccharides chemically and heat stable and can pass through bacteria
retentive filter. When these pyrogens are introduced into a body, they produce a mark response of fever with
body ache and vasoconstriction within an onset of 1 hour. Basically they are tests performed to detect the
presence of pyrogens in sterile parenteral products they are a.) Rabbit Test b. ) LAL Test.

a ) Rabbit test:- This test basically involves the injection of a sample solution which is to be tested into rabbits
which are used as test animals through the ear vein. The temperature sensing probe (Clinical Thermometer,
Thermosistor or similar probe) is inserted into the rectum cavity of the rabbit at the depth of 7.5 cm. The test
solution must be warmed to 37 degrees Celsius prior to injection. Then the rectal temperature is recorded at
1,2,3 hourly periods after injection. This test is performed in a separate area designed solely for this purpose
under environmental conditions like the animal house and should be free from disturbances that are likely to
excite them. Initially this test is performed on three rabbits but if required results are not obtained, then this test
should be repeated on five additional rabbits with the same sample solution administered initially. One hour
prior to injecting the sample solutions, the control temperatures of rabbits should be noted. Use only those
rabbits whose control temperatures do not vary by more than 1 degree Celsius.
*Interpretation:- The solution is judged to be non-pyrogenic if no single rabbit shows a rise in temperature of 0.5
degree Celsius but if this condition is not met then the test if repeated on 5 additional rabbits with the same
preparation administered to the initial 3 rabbits. The solution is judged to be non-pyrogenic if not more than 3
out of 8 rabbits show an individual temperature rise of 0.5 degree Celsius.

b.) LAL test:- It is a recently developed in-vitro test method for pyrogen, utilizing gelling property of lysates of
amebocytes of limulus polyphemus which is found only at specific locations along the east coast of North
America and along southeast Asia. It is derived from the horse-shoe crab, The basic procedure is the
combination of 0.1 ml of test sample with LAL Reagent after incubation for 1 hour at 37 degrees Celsius. The
mixture is analyzed for the presence of gel clot. The LAL Test is positive indicating the presence of endotoxins. Its
applications are mainly to pharmaceutics, biologicals, devices, disease states, food, and validation of heat cycles.
This method has several advantages over the rabbit test such as greater sensitivity, reliability, specificity, less
variation, wider application, less expensive and simpler.

3) Leaker Test: - The leaker test is intended to detect incompletely sealed ampules, so that they may be
discarded. Tip sealed ampoules are more prone to leak than pull sealed. In addition to that cracks may present
around the seal or at the base of the ampule because of improper handling. Leakers are usually detected by
producing negative pressure within the incompletely sealed ampule usually into a vacuum chamber while those
ampules are submerged into a colored dye solution of 0.5 to 1% methylene blue. Vials and bottles are not
subjected to such leaker test because the rubber closure is not rigid, however bottles are often sealed while in a
vacuum so that the bottle remains evacuated during its shelf life.

The presence of vacuum is detected by striking at the base of bottle sharply with the heel of hand to produce
typical water hammer sound. Another test is to apply a spark tester probe outside to the bottle, moving from
liquid layer into air space a blue spark discharge occur is air space is evacuated.

4) Particulate matter testing:- Particulate matter is primary concern in the parenteral products given by I.V.
Route, all parenteral products should be free from insoluble particles. Further U.S.P. states that GMP Requires
that all containers be visually inspected and that with visible particle be discarded. It is found that formation of
pathologic granulomas in vital organs of body can be traced to fiber, rubber fragment and other solid particles
present in intravenous solutions. The visual inspection is done by holding the ampule by its neck against highly
illuminated screens. White screens for the detection of black particles and black screens for the detection of
white particles. To detect heavy particles, it may be necessary to invert container, but care must be exercised to
avoid air bubbles. The instrumental methods are based on principles of light scattering, light absorption,
electrical resistance as in the Coulter counter. A method which utilizes video image projection also detects a
moving particle without destruction of the product unit.