Tuesday, March 19, 2013

Review - Quality control of parenteral products

In a pharmaceutical organization a quality control deals with testing, sampling, specification, and documentation, release procedure which ensure that all tests are actually carried out prior to release of material for sale or use. Four basic area of testing parenteral are Sterility, Freedom form Pyrogens, Freedom from particulate matter and leakers. The achievement of sterile, non pyrogenic and particulate free parenteral product provides a significant challenge to ingenuity and creativity of parenteral scientist and technologist.

The Basic quality control tests which are performed on sterile parenteral products include:-
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 complete absence of all viable Micro-organism. 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 an 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 error in operator technique. 
B)    Membrane Filtration method:- It is official in U.S.P. 1970. This method basically involves filtration of Sample through membrane filters of porosity 0.22 micron and Diameter 47mm. The filtration is assisted under Vacuum, after filtration completion the membrane is cut into 2 halves and one halve 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
2) Pyrogen Test: - Pyrogens are products of metabolism in microorganisms Gm-ve bacteria produces most potent pyrogens. These are lipopolysacchrides chemically and heat stable and are capable of passing 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 there are test performed to detect the presence of pyrogens in sterile parenteral products they are  C) Rabbit Test D) LAL Test.

C)   Rabbit test:- This test basically involves the injection Sample solution which is to be tested into a Rabbits Which are use as test animals through ear vein. The Temperature sensing probe (Clinical Thermometer, Thermosistor or similar probe) into a rectum cavity of Rabbit at the depth of 7.5 cm, the test solution must be warmed at 37 degrees prior to injection. Then Rectal temperature is recorded at 1,2,3 hr subsequent to injection. This test is performed in separate area designed solely for this purpose under environmental conditions similar to animal house should be free from disturbances that likely to excite them. Initially this test is performed on 3 Rabbits but if required results are not obtained this test is repeated on 5 additional Rabbits with same sample solution administer to initial 3 rabbits. Prior to 1hr of injecting sample solutions the control temperatures of rabbits are determined. Use only those rabbits whose control temperature is no vary by more than 1 degree Celsius.

*Interpretation:- The solution is judged to be non pyrogenic if no single rabbit show 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 same preparation administer.
D)   LAL test:- It is an 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 horse shoe crab; the basic procedure is the combination of 0.1 ml of test sample with LAL Reagent after incubation for 1 hr at 37 degree Celsius the mixture is analyzed for the presence of Gel clot. The LAL Test is positive indicating that the presence of endotoxin.  Its applications are mainly to Pharmaceutics, Biological, devices, disease states, food, and validation of heat cycles. This method has several advantages of Rabbit test they are Greater sensitivity andreliability specificity, less variation, wider application, less expensive and simplicity.
3)     Leaker Test: - The leaker test is intended to detect incompletely sealed ampoules, so that they may be discarded. Tip sealed ampoules are more prone to leak than pull sealed. In addition to that crack my present around seal or at the base of ampoule as a result of improper handling leakers are usually detected by producing negative pressure within the incompletely sealed ampoule usually into a vacuum chamber while those ampoules 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 rubber closure is not rigid however bottles are often sealed while vacuum is pulled so that 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 form 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 particle. Further U.S.P. states that GMP Requires that all containers be visually inspected and that with visible particle be discarded. The visual inspection is done by holding the ampule by its neck against highly illuminated screens. White screens for the detection of black particle 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 bubble. The instrumental methods are based on principles of light scattering, light absorption, electrical resistance as in coulter counter. A method which utilizes a video image projection could detect a moving particle without destruction of product unit.

Quality control  should  be  a  fundamental  segment  of parenteral  products  manufacturing.   All  of  the  4  basic  tests  which  are performed  are  essential  and  have  its  own  importance  in  parenteral production. All of these tests ensure that product meet its quality which has been judged to satisfactory also. Each test is unique and provides detailed assessment of quality control for parenteral products.
1)  Mehta  R.M,  Sterilization,  pharmaceutics-I.  Delhi:  Vallabh prakashan, 2002. P. 227-228.
2)  Lachman.L,  Liberman  HA,  Kaniz  JL,  Editions,  The  Theory  and  practice  of industrial pharmacy Bombay, Varghese publication House; 1986. P. 673-675. 
3) Akers.MJ, Larrimor DS, Guazzao morton D, Parenteral Quality control, New York, Marcel Deckker; 2006. P. 1-183


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