Quality control tests for parenterals

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Parenterals are the sterile dosage forms intended for administration other than enteral route (parenteral = per+enteral) and exerts their action by directly entering into the systemic circulation.

The quality of parenterals is the sum of all parameters that contribute to safety, efficacy and therapeutic efficacy of the drug.

The USP compendial requirements has recommended the following tests for parenteral products 1

1. Weight variation or content uniformity
2. Particulate matter in injections
3. Bacterial endotoxin test
4. Pyrogen test
5. Sterility test

1. Weight variation or content uniformity test

This test is intended for sterile solids used for parenteral preparation. The weight of 10 individual sterile units is noted and the content is removed from them and empty individual sterile unit is weighed intern. Then net weight is calculated by subtracting empty sterile unit weight form gross weight. The content of active ingredient in each sterile unit is calculated by performing the assay according to the individual monographs. The content in 10 sterile units is calculated by performing the assay. The dose uniformity is met if the amount of active ingredient is within the range of 85-115.0% of label claim as determine by the content uniformity method or weight variation method. The dose uniformity is also met if the potency value is 100% in the individual monograph or less of label claim multiplied by average of limits specified for potency in individual monograph divided by 100 provided that the relative standard deviation in both the cases is equal to or less than 6.0%.If one unit is outside the range of 85-115.0%, and none of the sterile unit is outside the range of 75-125.0% and if the relative standard deviation of the resultant is greater than 6.0% then, the fore mentioned test is carried for 20 more sterile units. The sterile units meet the requirements if not more than one unit is out side the range of 85-115%, no unit is outside the range of 75-125.0% and the calculated relative standard deviation is NMT 7.8%.

2. Particulate matter in injections

The preparations intended for parenteral use should be free form particulate matter and should be clear when inspected visually. Two methods are described by USP according to the filled volume of the product to be tested.
For large volume parenterals (LVP's), a filtration followed by microscopical examination procedure is used. For small volume parenterals (SVP's)a light obscuration based sensor containing electronic liquid-borne particle counter system is used.
The USP standards are met if the LVP's under test contain NMT 50 particles per ml of 10 um, and NMT 5 particles per ml of 25um in an effective linear dimensional fashion.
The USP standards are met if the SVP's under test contain NMT 10,000 particles per container of 10 um, and NMT 1000 particles per container of 25um in an effective spherical diameter.

3. Bacterial Endotoxin test

LAL (Limulus Amebocyte Lysate) test is used to characterize the bacterial endotoxin that may be present. The USP reference standard contains 10,000 USP endotoxins per vial. The LAL reagent is used for gel-clot formation.The test is performed using stated amounts of volumes of products, standard, positive control, negative control of endotoxin. The tubes are incubated at 37+-10C FOR 60+-2 minutes.When the tubes are inverted at 1800C angle, formation of firm gel confirms positive reaction. While formation of a viscous gel that doesn't maintain its integrity or absence of a firm gel confirms negative reaction. The test is invalid if the standard endotoxin or positive product control doesn't show end point within +-1 two fold dilution from label claim sensitivity of LAL reagent or if the negative control shows gel-clot end point.

4. Pyrogen test

It is performed by using rabbits as test animals.Initially 10 ml/kg body weigh of animal is injected through rat vein at 37+-20C within ten minutes from start of administration.The temperatures are recorded at 1, 2 and 3 hours after injection. The requirements of USP are met if the rise in temperature of individual rabbit is NMT 0.60C and the sum of rise in temperature of three rabbits is NMT 1.40C. If any one rabbit shows a rise in temperature of 0.60C and sum of rise in temperature of three rabbits exceeds 1.40C then the test is repeated using 5 rabbits. The requirements are met if 3 out of 8 rabbits shows an individual rise in temperature of NMT 0.60C and sum of maximum rise in temperature of 8 rabbits is NMT 3.70C.

5. Sterility test

Growth promotion medium and incubation conditions are selected based on the test microorganism according to USP and is listed in table 1. The sterility test is done using direct transfer and membrane filtration techniques. Membrane filtration technique is suitable for liquids, soluble powders with bacterio static or fungi static properties, oils, creams and ointments. Sterility test by direct transfer is performed by aseptic transfer of specified volume from test container (table 2) to culture medium and incubated for 14 days and visual observation of medium is done on 3rd, 4th, 5th, 7th, 8th and 14th day. A membrane filter with porosity of 0.45um with diameter of 47mm with flow rate of 55-75 ml of water per minute at a pressure of 70 cm of mercury should be used.The test meets the requirements when no growth is observed and if growth is observed then the test is repeated in the second stage and generally second stage is repeated with double the number of specimens tested in first stage when the test was found to be conducted under faulty or inadequate aseptic techniques.

Table 1. USP sterility tests growth promotion microorganisms

Medium

Test microorganisms

Incubation

Temperature (0C)

Conditions

Fluid thioglycollate

Bacillus subtillis (ATCC No. 6633)

30 to 35

Aerobic

Candida albicans (ATCC No. 8482)

30 to 35

Bacteroides vulgatus (ATCC No. 8482)

30 to 35

Alternative thioglycollate

Bacteroides vulgatus (ATCC No. 8482)

30 to 35

Anaerobic

Soybean-casein digest

Bacillus subtillis (ATCC No. 6633)

20 to 25

Aerobic

Candida albicans (ATCC No. 10231

20 to 25

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Table 2. Liquid quantities for USP sterility test

Container content (ml)

Minimum vol taken from each container for each medium

Minimum volume of each medium

Use for direct transfer of volume from each container (ml)

Used for membrane representing total volume from the appropriate number of containers

Number of containers per medium

Less than 100

1ml or entire contents if less than 1 ml

15

100

20 (40 if each does not contain sufficient vol for both media)

10 to less than 50

5 m l

40

100

20

50 to less than 100

10 ml

80

100

20

50 to less than 100 intended for i.v. administration

Entire contents

-

100

10

100 to 500

Entire contents

-

100

10

>500

500 ml

-

100

10

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Reference:

1. Hanna SA, Quality Assurance. In: Avis KE, Lieberman HA, Lachman L, editors. Pharmaceutical dosage forms:Parenteral Medications.2nd ed. Vol. 1. Newyork: Marcel Dekker; 1996. p. 1-65.

About the Author

Indu Roy's picture
Author: Indu Roy

Indu Roy is post graduate in pharmacy and working as Research Officer, Formulation-IPR Department at Mylan Laboratories Limited (A subsidiary of Mylan Inc) .
G Profile : https://plus.google.com/105328821168414118220/about

Comments

A.R.Khan's picture

You are one of the learner presnting book pages in an excellent manner. I did go through dissolution pages and they are very good . Hope to see similar "good & complete" articles from you and your team in future.
P.V.ABHIGNA's picture

Dear Indira, Thats a good and a complete info about QC of parenterals.It will definitely be a good source of information for everyone. Regards,

ABHIGNA.P.V.

Lakshmana Pramod's picture

It is very useful information.

G.L.Pramod, B.Pharmacy, MS.c(Ph.Regulatory Affairs), Executive, EU Regulatoty Affairs, ELC, Ahemdabad.