Sterile Products - C.02.029
Q.1 Does the supervisor of a sterile product manufacturing facility need to have a degree in microbiology?
A.1 Section C.02.029(b) of Division 2 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.
Q.2 If water that has already been used in compounding is later found to contain endotoxins, what actions need to be taken?
A.2 Water can be used for production prior to obtaining microbiological testing results but the results of these tests must be available prior to final release of the product. Good Manufacturing Practices permit release only after raw material and finished product testing is completed and results demonstrate compliance of the product with its specifications.
The appropriate action would include an investigation into: (i) the potential sources of endotoxins;
(ii) the sanitation and maintenance of the water system.
Q.3 Are sterile products in amber glass and plastic ampoules exempt from 100% visual inspection?
A.3 No. Each final container of injections must be subjected to a visual inspection. The 100% visual inspection test does not limit itself to particulate matter but includes sealing defects, charring, glass defects, underfills and overfills, missing print, etc. Please refer to Interpretation 84 under Section C.02.029 Sterile
Products. For parenterals, there are additional requirements for packaging (i.e., the immediate container shall be of such material and construction that visual or electronic inspection of the drug is possible). Please refer to Section C.01.069 of the Food and Drug Regulations.
Q.4 What are the requirements in terms of monitoring/testing for the release of sterile gowns to be used in a controlled environment (Grades A or B) when those are obtained from a supplier?
A.4 There is no specific requirements in the “Goo d Ma nuf act uri ng Practices Gui del ines, 200 9 Ed ition (G UI-
0001)” (http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0001-eng.php) for the sterility testing of the protective garments to be worn in Grades A and B areas. However, the sterility cycle used by an outside supplier to sterilize these garments should have been validated according to scientifically sound procedures. Among other aspects, validation should address penetration/distribution studies of the sterilizing medium (gas, radiation, heat, etc.), load patterns of the sterilizers, determination of the Sterility Assurance Level with Bio indicators, etc. Also, the integrity of the outside wrapping in order to maintain sterility should be demonstrated.
Q.5 What are the room classification requirements for the preparation of containers and other packaging materials to be used in the fabrication of sterile products?
A.5 The preparation (cleaning, washing, etc.) of containers and packaging materials is normally performed in a “clean” room (Grades C or D). After these operations, the containers and materials used for drugs sterilized by filtration (and not further subjected to terminal sterilization in their final containers) must be
depyrogenated and sterilized before being introduced in the aseptic rooms by the use of double-ended sterilizers or any other validated method. The depyrogenation step can be done using pyrogen-free water for injection (WFI) for the last rinse prior 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 with a Grade B background.
For products submitted to terminal sterilization, it is not mandatory to use containers and packaging materials that are sterile but those that are in direct contact with the product should be free of pyrogen. This is usually achieved by using pyrogen-free WFI for the last rinse of these materials unless they are subsequently depyrogenated by another method (e.g., dry heat oven).
In addition, the initial bioburden of these materials should meet pre-established limits (that are based on sound science) and the risk of contamination during their introduction in the filling areas should be kept to a minimum.
Q.6 For the validation of moist heat sterilization cycles, will the new standards include the use of prions as the organism of choice instead of Bacillus stearothermophilus?
A.6 At the present time, it is recognized in the scientific and pharmaceutical community that the spores of Bacillus stearothermophilus are the organisms of choice for the validation of moist heat sterilization cycles. Validation of such cycles is based on biological indicators containing a known count of organisms in order to determine a lethality factor for a given cycle. Those studies are based on parameters such as the “D” value of certain organisms and also imply a microbiological testing of these indicators at the end of the cycle in order to establish a survival rate. The use of prions (infectious proteins) could be inadequate in that their detection
and quantification, which is based on animal models, is very difficult. Moreover, these proteins are very difficult to destroy and could present a danger should they accidentally be spread in a plant.
Q.7 According to the monograph on parenteral products (0520) of the 4th edition (2002) of the European Pharmacopeia (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?
A.7 Yes, this interpretation is correct but this exemption is not applicable in Canada.
As per Section C.01.067(1) of the Food and Drug Regulations, it is required that each lot of a drug for parenteral use be tested for the presence of pyrogens using an acceptable method and be found to be non- pyrogenic. The Bacterial Endotoxins and Pyrogen test methods described in the United States Pharmacopoeia (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 demonstrated to be justified (more appropriate) or has been approved by a review Directorate. Therefore, the specification of all drug products for parenteral use intended for the Canadian market should include a test for Bacterial Endotoxins or Pyrogens and the EU current "15 mL exemption" is not applicable in Canada.
The only acceptable exemptions are those provided by Section C.01.067(2) (i.e., for parenteral drug products inherently pyrogenic or those which cannot be tested for the presence of pyrogens by either test methods). In other words, not testing a parenteral drug product for the presence of pyrogens would be considered acceptable only if documentation is available demonstrating that the parenteral drug product is inherently pyrogenic or that it cannot be tested by any of the methods.
Q.8 For radiopharmaceuticals, can it be acceptable to verify the integrity of the sterilizing filter only after use and to not perform the pre-filtration integrity testing?
A.8 As per Interpretation 4.7 under Section C.02.029 Sterile Products, the integrity of the sterilizing filter must be verified before and after use. However, the pre-filtration integrity testing for that type of products could lead to radioactive contamination as a result of the venting process of the filter assembly that must be performed before the start of product filtration. This would pose an unacceptable health risk for the operators and could result in disruption of production until the facility is decontaminated. It is therefore acceptable to use two filters of a minimum filter rating of 0.22 micron and to verify the integrity of the sterilizing filters after use only for these products. However, data should be available from the filter manufacturer that the filters are supplied pre-assembled and individually integrity tested by the filter manufacturer.
Q.9 What is the Inspectorate’s position on pooling of samples within the same batch (e.g., 7 samples in one pool) for testing for sterility? The European Pharmacopoeia (Ph. Eur.) does not mention explicitly a pooling of samples for testing for sterility.
A.9 It is acceptable if companies pool samples for sterility testing with the membrane filtration method. However, it is not acceptable to pool samples when the direct inoculation method is used. Exceptions can be tolerated, when the volume of the sample-pool does not exceed 10% of the culture medium volume.