Annex 1 to the Good manufacturing practices guide – Manufacture of sterile drugs (GUI-0119): Questions and answers

Does the supervisor of a sterile drug manufacturing facility need to have a degree in microbiology?

Section C.02.029 (b) "Sterile drugs" of the Food and Drug Regulations requires that "a drug that is intended to be sterile shall be produced under the supervision of personnel trained in microbiology." The expression "trained in microbiology" does not mean that this person must have a university degree in microbiology. However, the person must have taken university courses in microbiology.

If water that has already been used in compounding is later found to contain endotoxins, what actions need to be taken?

Water can be used for production before obtaining microbiological test results, but the results of these tests must be available before final release of the product. Good manufacturing practices permit release only after raw material and finished product testing is completed and results show the product complies with its specifications.

The appropriate action would include an investigation into:

• the potential sources of endotoxins
• the sanitation and maintenance of the water system

Are sterile products in amber glass and plastic ampoules exempt from 100% inspection?

No. You must inspect each final container of injections. The 100% inspection test does not limit itself to particulate matter. It also includes, for example, sealing defects, charring, glass defects, underfills and overfills, and missing print. Please refer to interpretation in the section on Finishing of sterile drugs. For parenteral products, there are more requirements for packaging (for example, the immediate container must be of a material and construction that allows visual or electronic inspection of the drug). Please refer to section C.01.069 "Limits of Variability" in the Food and Drug Regulations.

What are the room classification requirements for preparing containers and other packaging materials to be used in fabricating sterile drugs?

Normally, you would prepare (for example, clean, wash) containers and packaging materials in a "clean" room (Grades C or D). Afterwards, for drugs sterilized by filtration (and not further subjected to terminal sterilization in their final containers), you must depyrogenate and sterilize (using double-ended sterilizers or any other validated method) the containers and materials used before introducing them into aseptic rooms. The depyrogenation step can be done using pyrogen-free water for injection (WFI) for the last rinse before sterilization or by performing the depyrogenation and sterilization in one operation using a dry heat oven. Filling of these products normally takes place in a Grade A area with a Grade B background.

For products that are terminally sterilized, you do not have to use containers and packaging materials that are sterile. However, those in direct contact with the product should be free of pyrogen. This is usually done by using pyrogen-free WFI for the last rinse of these materials, unless they are later depyrogenated by another method (for example, using a dry heat oven).

Also, the initial bioburden of these materials should meet pre-established limits, based on sound science. Keep the risk of contamination during their introduction in filling areas to a minimum.

For the validation of moist heat sterilization cycles, will the new standards include the use of prions as the organism of choice (instead of Geobacillus stearothermophilus)?

At the present time, the scientific and pharmaceutical community recognizes the spores of Geobacillus stearothermophilus as the organisms of choice for validating moist heat sterilization cycles. The use of prions (infectious proteins) could be inadequate because their detection and quantification (which is based on animal models) is very difficult. Also, these proteins are very hard to destroy and could present a danger should they accidentally be spread in a plant.

According to the monograph on parenteral products (0520) of the 10th edition of the European Pharmacopoeia (Ph. Eur.), injections for veterinary use with a volume dose of less than 15 mL are exempted from bacterial endotoxins/pyrogen testing by the European Union (EU). Is this interpretation correct? If so, would this EU exemption be applicable in Canada?

Yes, this interpretation is correct. But this exemption does not apply in Canada.

As per section C.01.067 (1) "Limits of Variability" in the regulations, each lot of a drug for parenteral use must be tested for the presence of pyrogens using an acceptable method. Each lot must be found to be non-pyrogenic. The bacterial endotoxins and pyrogen test methods described in the United States Pharmacopeia (USP) and Ph. Eur. are considered acceptable methods for that purpose.

For all parenteral drug products, the bacterial endotoxins test should be preferred over the pyrogen test, unless the latter is shown to be justified (more appropriate) or has been approved by a review directorate. The specification of all drug products for parenteral use intended for the Canadian market should include a test for bacterial endotoxins or pyrogens. The current EU "15 mL exemption" does not apply in Canada.

The only acceptable exemptions are those provided in section C.01.067 (2) "Limits of Variability." In other words, not testing a parenteral drug product for the presence of pyrogens would be considered acceptable only if documentation is available to show that the parenteral drug product is inherently pyrogenic or that it cannot be tested by any of the methods.

What is Health Canada's position on pooling samples within the same batch (for example, 7 samples in 1 pool) for testing for sterility? The European Pharmacopoeia (Ph. Eur.) does not mention explicitly a pooling of samples for testing for sterility.

It is acceptable to pool samples for sterility testing with the membrane filtration method. But it is not acceptable to pool samples if you use the direct inoculation method. Exceptions can be tolerated when the volume of the sample pool does not exceed 10% of the culture medium volume.