Good Manufacturing Practices Questions and Answers
Health Canada / Health Products and Food Branch Inspectorate
Raw Material Testing - C.02.009 & C.02.010
Q.1 What are requirements of maintaining an impurity profile?
A.1 The United States Pharmacopoeia (USP) defines an impurity profile as “a description of the impurities present in a typical lot of drug substance produced by a given manufacturing process.” (ref. USP <1086>). Each commercial lot should be comparable in purity to this standard release profile which is developed early on and maintained for each pharmaceutical chemical. We can also call this profile a “Reference Profile” because the quality control unit refers to it (1) when assessing the purity of each batch of active pharmaceutical ingredient (API), and (2) when evaluating the viability of proposed process changes.
For further information regarding the control of impurities, please consult Impurities in New Drug Substances- ICH Q3A (R) (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q3a(r)-eng.php) & Impurities in New Drug Products - ICH Q3B (R) (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q3b(r)-eng.php).
Q.2 Does every individual container of a raw material need to be sampled for identification (ID) purposes regardless of the number of containers of the same lot available or are composite samples acceptable provided they are obtained from a maximum of 10 containers?
A.2 For human drugs, according to Interpretation 6.1 under C.02.009 Raw Material Testing, each container of a lot of a raw material must be tested for the identity of its contents. Therefore, each container of all raw materials, including excipients and active pharmaceutical ingredients (API), must be opened and sampled. Then, 2 options are available:
1) To test every sample for ID using a discriminating method (it is not mandatory to perform all ID tests in the specifications, for example United States Pharmacopoeia (USP), but the test must be specific).
2) If the raw material can be tested for potency, the other option is to mix and pool individual samples taken from each containers in a composite sample but without exceeding 10 individual samples in a composite. A specific ID test is then performed on each composite and, in addition, a potency test is performed to assure the mass balance of the composite. (In such cases, an equal quantity of each individual sample in the composite must be weighed to ensure that the mass balance is representative.) As an example, say 72 containers of the same lot of a raw material are received. Each and all containers must be opened and a sample taken from each container. After that, the first option is to test each sample for ID (which implies 72 ID tests). The second option is to combine equal quantities of those individual samples in a way that the number of samples in any composite does not exceed 10 and test those composites for ID and potency. In this case, the easiest way to combine those samples would be 8 composites of 9 individual samples. For a given composite, a potency result of 88.8 % or so would indicate that one of the containers does not contain the right material as each individual sample contributes 1/9 or 11.11% of the total mass of the composite (similarly a result of 77,7 % would indicate 2 containers with the wrong material). In such case, each container selected for this particular composite would have to be tested for ID to pinpoint the one (or more) containers with the wrong material.
However, the use of a composite sample to establish the ID of a raw material cannot be used when the potency limits are too wide or, similarly, when the precision of the assay method is not sufficient to properly establish the mass balance.
Q.3a An active pharmaceutical ingredient (API) can be used after the retest date assigned by the API fabricator if a re-analysis done immediately before use shows that it still meets its specifications. Can the new data generated be used by the drug fabricator to assign a longer retest date to future lots of this API obtained from the same fabricator?
A.3a No. The extension of the retest date originally assigned to the API should be supported by data generated through a formal stability protocol. This may require the filing of a notifiable change submission. Please refer to the appropriate review Directorate.
Q.3b What about inactive ingredients?
A.3b Normally, any inactive raw material should bear an expiry date. When an inactive raw material is received without an expiry date, the fabricator should assign either an expiry date or a re-test date based on stability data or other documented evidence that this raw material is not subject to chemical / physical modifications or is not susceptible to microbial contamination.
Q.4 With respect to the re-test date of the drug substances, we have the stability data of a drug substance for up to 24 months at real time stability condition. The re-test period is assigned up to 24 months. According to the “Evaluation of Stability Data - ICH Q1E”, 2.4.1.1(the proposed retest period or shelf life can be up to twice, but should not be more than 12 months beyond, the period covered by long-term data), the retest period can be assigned up to 36 months. Can we assign the retest period up
36 months? If yes, does it require retesting of the active pharmaceutical ingredient (API) at 24 months?
A.4 Retest period and expiry date for APIs should be based on stability data. If an expiry date has been assigned to an API then its batches cannot be used after the expiry period. However, if a retest period has been assigned to the API, then after the retest period is over the API batch can be tested and used immediately (e.g., within one month of the testing). In the scenario presented above extrapolation of expiry date beyond 24 months should be based on stability data both at long-term and accelerated storage conditions. If the test results are satisfactory the retest period can be extended to a period not exceeding 36 months. Once the retest period of the API has been extended to 36 months, testing batches at the 24 months time point would be part of the ongoing stability protocol (it will not be considered retest). For further guidance on retest period and expiry period please consult Stability Testing of New Drug Substances - ICH Q1 A (R2) (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q1a(r2)-eng.php) & Evaluation of Stability Data - ICH Q1E (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q1e-eng.php).
Q.5 We are a subsidiary of a United States (US) corporation. This US corporation supplies us with active pharmaceutical ingredients (APIs) that are fully tested after receipt on its premises. Can the US site be certified for the purpose of testing exemptions for the Canadian site?
A.5 The US parent company cannot be considered the vendor. To be certified, the vendor must be the original source of the API. In this instance, the US company would be acting as a contract laboratory and should meet the requirements under Interpretation 6.10, Section C.02.015 Quality Control Department. When received by the Canadian site, a specific identity test must be performed and if for an API, the testing must be as per Interpretation 6.1, Section C.02.009 Raw Material Testing (i.e., each container sampled and tested). The above mentioned would be acceptable based on the fact that no repackaging is done by the US site (i.e., the materials must be supplied in their original containers with the original labels and Certificate of Analysis (C of A) as received from the vendor).
Q.6 What documentation does a laboratory have to have in place to be considered qualified to run a test method for raw materials (drug substances and excipients) in order to satisfy Health Canada Regulations?
A.6 Documentation should include a summary of the analytical method validation, an assessment of the results and comparison to the acceptance criteria, and a conclusion as to the acceptability of the data as they relate to the ability of the laboratory analysts to successfully perform the procedure in the particular laboratory.
Q.7 Is the sampling plan based on the (/n+1) acceptable for identifying the number of containers of raw material to be sampled?
A.7 Sampling plans and procedures must be statistically valid and should be based on scientifically sound sampling practices taking into account the risk associated with the acceptance of the defective product based on predetermined classification of defects, criticality of the material, and past quality history of the vendor. In some circumstances, such as for large number of containers, a sampling plan based on (/n+1) may be acceptable. However, a sampling plan based on (/n+1) may present a significant risk of accepting defective goods in certain circumstances, such as the sampling of a small number of containers. As with all sampling plans, documented justification must be available.
Q8. If we already test each batch of our finished product for the absence of Staphylococcus aureus and Pseudomonas aeruginosa, is it required to test it also for the purified water?
A8. Yes, you are required to test the purified water for the absence of Staphylococcus aureus and Pseudomonas aeruginosa. It is the general expectation that raw material testing support finished product testing.