FDA just posted a Draft Guidance "Considerations for Complying With 21 CFR 211.110" (https://www.fda.gov/media/184825/download) in Jan 2025 for further comments (closed 04/07/25). Why is the FDA addressing 211.110 when there is really no change to the regulation?
I will provide my explanation in 3 parts and offer my quality solutions to 211.110
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First, 211.110 "Sampling and testing of in-process materials and drug products" has 4 subsections (a, b, c, and d) to ensure batch uniformity and drug product integrity - see https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-F/section-211.110.
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Second, in 2024,
211.110(a) or Control procedures are not established which [monitor the output] [validate the performance] of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product was cited 34 times
211.110(a) or Written procedures are not [established] [followed] that describe the [in-process controls] [tests] [examinations] to be conducted on appropriate samples of in-process materials of each batch was cited 4 times
211.110(a) or Control procedures fail to include [tablet or capsule weight variation] [disintegration time] [adequacy of mixing to assure uniformity and homogeneity] [dissolution time and rate] [clarity, completeness or pH of solutions] was cited 1 time
211.110(b) or Your examination and testing of samples did not assure that the drug product and in-process material conformed to specifications was cited 5 times
211.110(c) or In-process materials are not tested for [identity] [strength] [quality] [purity] and approved or rejected by the quality control unit [during the production process] [after storage for long periods] was cited 3 times
211.110(d) or Rejected in-process materials are not be [identified] [controlled] under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable was not cited at all.
Note: FDA breaks down their citations further than just 211.110 (a), (b), (c), or (d) to cite on FDA-483. Not all regulatory languages in each subsection were cited.
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Third, in this draft guidance, FDA provides its current thinking focusing on "advanced manufacturing (i.e. 3 D printing, continuous manufacturing)" particularly not accepting "process models" alone without in-process material testing or process monitoring. In other words, process models alone may not be able to capture all disturbances during manufacturing especially unplanned disturbances and therefore would not satisfy 211.110. Can you justify based on "process models" alone that you can capture all unplanned disturbances without in-process material testing or process monitoring?
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Conclusion and Quality Solutions:
FDA still expects that companies should apply a scientific- and risk-based approach to controlling processes and ensuring drug product quality regardless of advancing manufacturing. In other words, companies should still justify with confidence or rationale by conducting in-process material testing or process monitoring (pH, dissolution, bioburden, etc.) to ensure batch uniformity and drug product integrity whether process models are used or not. Risks should be evaluated particularly at significant phases of manufacturing. It is up to the manufacturers to define what is significant in their manufacturing processes and ensure that products achieve their quality attributes.
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