Quality Assurance and Control: The importance of undertaking every possible means to ensure the quality of the finished product cannot be overemphasized. Every component and step of the manufacturing process must be subjected to intense scrutiny to be confident quality is attained in the finished product. The responsibility for achieving this quality is divided appropriately in concept and practice into Quality Assurance (QA) and Quality Control (QC). QA relates to the studies made and the plans developed for ensuring quality of a product prospectively, with a final confirmation of achievement. QC embodies the carrying out of these plans during production and includes all of the tests and evaluations performed to ensure quality exists in a specific lot of product.
1. Sterility test: All lots of injectables in their final containers must be tested for sterility, except products that are allowed to apply parametric release (i.e., terminally sterilized by a well-defined, fully validated sterilization process, has a sterility assurance level sufficient to omit the sterility test for release). The USP prescribes the requirements for this test for official injections. The FDA uses these requirements as a guide for testing official sterile products.
The primary official test is performed by means of filtration, but direct transfer is used if membrane filtration is unsuitable. To give greater assurance that viable micro-organisms will grow, if present, the USP requires that all lots of culture media be tested for their growth-promotion capabilities.
In the event of a sterility-test failure, the immediate issue concerns whether the growth observed came from viable micro-organisms in the product (true contamination) or from adventitious contamination during the testing (a false positive). The USP does not permit a retest, unless specific evidence is discovered to suggest contamination occurred during the test. Therefore, a thorough investigation must be launched to support the justification for performing the retest and assessing the validity of the retest results relative to release of the lot of product.
Isolator technology has been applied to significantly reduce the incidence of false positives in the conductance of the sterility test.
2.Pyrogen test: The USP evaluates the presence of pyrogens in parenteral preparations by a qualitative fever response test in rabbits, the Pyrogen Test, and by the Bacterial Endotoxins Test. Rabbits are used as test animals, because they show a physiological response to pyrogenic substances similar to that of man. Although a minimum pyrogenic dose (MPD), the amount just sufficient to cause a positive USP Pyrogen Test response, may produce uncertain test results, a content equal to a few times the MPD will leave no uncertainty. Therefore, the test is valid and has continued in use, since introduced by Seibert in 1923.
The Bacterial Endotoxins Test (BET) is an in vitro test based on the formation of a gel or the development of color in the presence of bacterial endotoxins and the lysate of the amebocytes of the horseshoe crab (Limulus polyphemus). The Limulus Amebocyte Lysate (LAL) test, as it also is called, is a biochemical test performed in a test tube and is simpler, more rapid, and of greater sensitivity than the rabbit test.
To provide standardization for the test, the USP has established a reference standard endotoxin (RSE) against which lots of the lysate is standardized. Thus, the sensitivity of the lysate is given in terms of endotoxin units (EU).
3.Particulate matter evaluation: The particle size of particular concern has not been clearly delineated, but it has been suggested that, since erythrocytes have a diameter of approximately 4.5 μm, particles of more than 5 μm should be the basis for evaluation. This is a considerably smaller particle than can be seen with the unaided eye; approximately 50 μm is the lower limit, unless the Tyndall effect is used, whereby particles as small as 10 μm can be seen by the light scattered from them.
The USP specifies that good manufacturing practice requires each final container of an injection be subjected individually to a visual inspection and containers in which visible particles can be seen should be discarded. This 100% inspection of a lot of product is designed to prevent the distribution and use of parenterals that contain particulate matter.
The USP has identified two test methods, Particulate Matter in Injections.
The first test used is the light obscuration test, which uses an electronic instrument designed to count and measure the size of particles by means of a shadow cast by the particle as it passes through a high-intensity light beam. If the injection formulation is not a clear, colorless solution (e.g., an emulsion) or it exceeds the limits specified for the light obscuration test, it is to be subjected to the microscopic count test.
The latter method consists of filtering a measured sample of solution through a membrane filter under ultraclean conditions and then counting the particles on the surface of the filter, using a microscope and oblique light at 100× magnification. The time requirements for performing the latter test are very long. These standards are readily met in the United States today by the manufacturers of LVIs and the specified SVIs.
4.Container/Closure integrity test: Ampoules that have been sealed by fusion must be subjected to a test to determine whether or not a passageway remains to the outside; if so, all or a part of the contents may leak to the outside and spoil the package, or micro-organisms or other contaminants may enter. Changes in temperature during storage cause expansion and contraction of the ampoule and contents, and will accentuate interchange, if a passageway exists, even if microscopic in size. This test is usually performed by producing a negative pressure within an incompletely sealed ampoule, while the ampoule is submerged entirely in a deeply colored dye solution. Most often, approximately 1% methylene blue solution is employed. After carefully rinsing the dye solution from the outside, color from the dye will be visible within a leaker. Leakers, of course, are discarded.
Vials and bottles are not subjected to such a leaker test, because the sealing material (rubber stopper) is not rigid. Therefore, results from such a test would be meaningless. However, assurance of container-closure sealing integrity should be an integral part of product development, by developing specifications for the fit of the closure in the neck of the container, the physical characteristics of the closure, the need for lubrication of the closure, and the capping pressure.
5.Safety test: The National Institutes of Health requires, of most biological products, routine safety testing in animals. Under the Kefauver Harris Amendments to the Federal Food, Drug, and Cosmetic Act, most pharmaceutical preparations are now required to be tested for safety. Because it is entirely possible for a parenteral product to pass the routine sterility test, pyrogen test, and chemical analyses, and still cause unfavorable reactions when injected, a safety test in animals is essential, particularly for biological products, to provide additional assurance that the product does not have unexpected toxic properties.
Multiple choice questions:
1.QA stands for
2.QC stands for
3.QA embodies the carrying out of these plans during production and includes all of the tests and evaluations performed to ensure quality exists in a specific lot of product.
4.QC relates to the studies made and the plans developed for ensuring quality of a product prospectively, with a final confirmation of achievement.
5.Which of the following tests are carried out for parenterals?
c)Container/Closure integrity test
d)All of these
6.The primary official sterility test is performed by means of
d)dry heat method
7._____ has been applied to significantly reduce the incidence of false positives in the conductance of the sterility test.
b)Media fill method
d)Particulate matter testing
8.The Bacterial Endotoxins Test (BET) is an ____ test based on the formation of a gel or the development of color in the presence of bacterial endotoxins.
d)a and b
9.EU stands for
10.The first test used for particulate matter evaluation is
a)light obscuration test
b)filtration through membrane filter
c)both of these
d)none of these
11.For ampoules Container/Closure integrity test which of the following solution is employed?
a)1% methylene blue
d)all of these
12.Vials and bottles are not subjected to such a leaker test, because the sealing material (rubber stopper) is not rigid.
13.MPD stands for
a)maximum pyrogenic dose
b)minimum pyrogenic dose
c)multiple pyrogenic dose
d)missed pyrogenic dose
14.BET stands for
a)Bacterial Endotoxins Test
b)Bacterial Exotoxins Test
c)Biological Endotoxins Test
d)Bacterial Enteric Test
15.RSE stands for
a)reference standard endotoxin
b)reference standard exotoxin
c)referred standard endotoxin
d)real standard endotoxin
- a)Quality Assurance
- b)Quality control
- d)All of these
- a)Isolator technology
- a)endotoxin units
- a)light obscuration test
- a)1% methylene blue
- b)minimum pyrogenic dose
- a)Bacterial Endotoxins Test
- a)reference standard endotoxin
- Remington Essential of Pharmaceutics, 1st edition 2013, page no. 528-530.
- Ansel’s Pharmaceutical Dosage Forms and Drug Delivery systems, 10th edition, page no. 526-531, 543,544.