Posted: 28 Jun 2018 06:50 PM PDT
In 2016, FDA published the Q7 cGMP Guidance for Active Pharmaceutical Ingredients. It outlines best practices for everything from quality management issues, personnel, buildings and facilities, equipment and recordkeeping, to validation, change control, complaints and recalls. While it provides very useful information to stakeholders, in some instances, it raised more questions than it answered.
As a result, earlier this year FDA published a companion Question/Answer guidance that seeks to deal with some of the more salient questions that stakeholders have had regarding the 2016 Q7 Guidance.
For example, regarding the “scope” of the 2016 Guidance, should the cGMP practices outlined in the Q7 Guidance be applied for manufacturing steps prior to the introduction of the API starting materials? No, however, there is an expectation that an “appropriate level of controls” suitable for the production of the API starting materials should be applied.
Regarding “quality management”, can departments outside of the quality unit be held responsible for releasing product? Yes, as long as oversight and the overall responsibility of the system to release/reject remains with the quality unit.
Regarding the cleaning of “dedicated process equipment”, is the concept of “visually clean” acceptable for the verification of cleaning effectiveness, in other words, that there is no expectation for a specific analytical determination? “Visually clean” may be acceptable for dedicated equipment based on the ability to visually inspect, so long as one has sufficient supporting data from cleaning studies, such as, for example, an analytical determination to demonstrate cleaning effectiveness.
Regarding “documentation and recordkeeping” what is meant by the phrase “completely distributed” where ICH Q7 states that records related to production, control, and distribution should be retained for at least 3 years after the API batch is “completely distributed”? This is understood as the complete distribution of the entire batch of the API by the API manufacturer to the next party in the supply chain. In the case of APIs handled by agents, brokers, traders, distributors, repackers, and relabelers, “completely distributed” refers to distribution of the received quantity of the batch of API.
Regarding “materials management” what is meant by performing a “full analysis” on batches of raw materials to qualify a supplier? A “full analysis” should include all tests specified by the user of the raw material in the regulatory filing. In cases where no filing is required, the full analysis should include tests in other formal written specifications issued by the user of the raw material. A raw material supplier’s Certificate of Analysis may not necessarily align with the user’s specifications.
Regarding “production and in-process controls” can yield ranges defined for the first batch differ from latter batches within a campaign? Yes, differing yield ranges may be described and justified in the manufacturing procedure/master batch record explaining the ranges.
Regarding “laboratory controls” in cases where an API test method is changed, which method should be used for stability studies already in progress? The company should decide and justify which method they decide to use. All test methods for stability studies should be validated and demonstrated to be stability indicating prior to use. Any changes to stability test methods should be documented.
Regarding “recalls” must a quality related return, at the request of the API manufacturing site, from another site within the same company, be recorded as a “recall”? No, provided that no portion of the batch left direct control of the company for sale or use. The return must be clearly visible in the API site’s quality system as a return triggered by the API manufacturing site so this fact is clear in quality system trend reporting and in the product quality review.
Regarding Certificates of Analysis (CoA), who is considered to be the original manufacturer of the API? The original manufacturer would be the facility where the final purified API/intermediate is produced. Further physical processing (e.g., drying, micronization, milling, sieving) of an API would not make the manufacturer performing such operations the original manufacturer.
For the complete answers to the above questions, as well as for the list of the other questions/answers please review the guidance here.
As a result, earlier this year FDA published a companion Question/Answer guidance that seeks to deal with some of the more salient questions that stakeholders have had regarding the 2016 Q7 Guidance.
For example, regarding the “scope” of the 2016 Guidance, should the cGMP practices outlined in the Q7 Guidance be applied for manufacturing steps prior to the introduction of the API starting materials? No, however, there is an expectation that an “appropriate level of controls” suitable for the production of the API starting materials should be applied.
Regarding “quality management”, can departments outside of the quality unit be held responsible for releasing product? Yes, as long as oversight and the overall responsibility of the system to release/reject remains with the quality unit.
Regarding the cleaning of “dedicated process equipment”, is the concept of “visually clean” acceptable for the verification of cleaning effectiveness, in other words, that there is no expectation for a specific analytical determination? “Visually clean” may be acceptable for dedicated equipment based on the ability to visually inspect, so long as one has sufficient supporting data from cleaning studies, such as, for example, an analytical determination to demonstrate cleaning effectiveness.
Regarding “documentation and recordkeeping” what is meant by the phrase “completely distributed” where ICH Q7 states that records related to production, control, and distribution should be retained for at least 3 years after the API batch is “completely distributed”? This is understood as the complete distribution of the entire batch of the API by the API manufacturer to the next party in the supply chain. In the case of APIs handled by agents, brokers, traders, distributors, repackers, and relabelers, “completely distributed” refers to distribution of the received quantity of the batch of API.
Regarding “materials management” what is meant by performing a “full analysis” on batches of raw materials to qualify a supplier? A “full analysis” should include all tests specified by the user of the raw material in the regulatory filing. In cases where no filing is required, the full analysis should include tests in other formal written specifications issued by the user of the raw material. A raw material supplier’s Certificate of Analysis may not necessarily align with the user’s specifications.
Regarding “production and in-process controls” can yield ranges defined for the first batch differ from latter batches within a campaign? Yes, differing yield ranges may be described and justified in the manufacturing procedure/master batch record explaining the ranges.
Regarding “laboratory controls” in cases where an API test method is changed, which method should be used for stability studies already in progress? The company should decide and justify which method they decide to use. All test methods for stability studies should be validated and demonstrated to be stability indicating prior to use. Any changes to stability test methods should be documented.
Regarding “recalls” must a quality related return, at the request of the API manufacturing site, from another site within the same company, be recorded as a “recall”? No, provided that no portion of the batch left direct control of the company for sale or use. The return must be clearly visible in the API site’s quality system as a return triggered by the API manufacturing site so this fact is clear in quality system trend reporting and in the product quality review.
Regarding Certificates of Analysis (CoA), who is considered to be the original manufacturer of the API? The original manufacturer would be the facility where the final purified API/intermediate is produced. Further physical processing (e.g., drying, micronization, milling, sieving) of an API would not make the manufacturer performing such operations the original manufacturer.
For the complete answers to the above questions, as well as for the list of the other questions/answers please review the guidance here.
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