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05-16 FDA澄清稳定性指南问答中的重要变化

2014-05-16

15日召开关于新修订ANDA稳定性研究问答文件的新闻发布会上，仿制药办公室(OGD) 的Radhika Rajagopalan博士澄清了3个重要问题，这将对仿制药企业影响重大。

1) 关于在初始稳定性批中使用多个批次API的问题。Rajagopalan博士澄清，在C.Q4 A4中的有效语句是：在3批初始稳定性批次中最少使用2个批次的API。为明确这一事实，将改写第一句话。

2) 关于E. Q1及回答 – OGD已听取企业意见，并删除了对加速条件下第4个点的绝对要求。Rajagopalan博士表示，6个月中间条件时间点应可以排除对第4个时间点的需求，即使产品在第3个月或第6个月时间内发生显著变化。她还表示，如果根据第3个月时间点的结果发现产品将会发生显著变化，企业可以添加额外的加速试验点。
OGD从未真正使用ICH的中间条件以从稳定性的角度支持ANDA批准。OGD之前要求3个月加速稳定性研究的4个时间点（0、1、2、3个月），OGD习惯于审评加速稳定性的4个时间点，他们认为可以通过提供更多的数据发现趋势。而新的指南恢复到ICH对加速稳定性3个时间点的要求。我在发布会时要求OGD澄清应如何应对其推荐的变化，这一变化为由原始Q&A文件中加速稳定性需要0、3、6外加一个额外的时间点（第4个月或第5个月）变为0、3、6个月三个时间点，同时参阅ICH Q1A(R2)（其中规定了如果发现产品在加速条件下的将产生显著变化的附加条款）。Rajagopalan博士解释说，现在OGD要求中间条件，所产生的6个月中间条件数据将对解决6个月加速条件下产品的显著变化非常有帮助。或者说，如果在第3个月的时候，发现由于在3-6个月期间降解速率的增加到第6个月时间点时6个月加速稳定性研究的产品可能会发生显著变化，企业可以选择在3-6个月期间增加第四个时间点，或者选择依靠中间贮存条件数据解决可能或已经在6个月加速条件下发现的显著变化。
如果6个月的中间和加速稳定性研究失败，OGD将需要依靠完整的实时室温稳定性研究建立有效期。如果6个月的加速稳定性失败，而第6个月的中间条件数据在规定范围内，OGD可能会考虑依靠稳定性数据的统计学评估来指定有效期，如果室温和加速稳定性数据分别在12个月和6个月下可接受，他们指定的有效期可能小于完整的24个月。在6个月加速失败的情况下，OGD可能仅会指定比如18个月的初始有效期。

3) 根据与固体口服制剂包装有关的漫长历史将在不经意间真的发生的最大变化是，OGD将接受在3个初始稳定性批次中最少100,000个剂量单元的包装。因此满足100,000剂量单元要求的数量可以是批次1的40,000剂量单元、批次2的30,000剂量单元和批次3的30,000剂量单元。之前人们认为至少一批初始批次应满足至少100,000个剂量单元的包装。但是现在不是了。这与过去的实践相比发生了翻天覆地的变化。只是确定你在决定稳定性包装需要时将所有包装类型、21CFR211cGMP要求以及法规中强调的稳定性留样需要均考虑在内了。

Lachman CONSULTANTS - Bob Pollock先生 2014-05-15
编译：识林-椒 2014-05-15

More Clarifications on Some Significant Changes re: Generic Stability Program Implementation
Written by Bob Pollock • May 15, 2014

In the Press Briefing Call this morning on the newly revised Q&A document on ANDA stability, three important and significant issues were clarified by the Office of Generic Drugs' (OGD) Radhika Rajagopalan, Ph.D. that will have important implications for the generic industry.

1) As noted in my blog post of yesterday (here), there was some uncertainty regarding the issue of the use of multiple lots of API for the primary stability batches. Dr. Rajagopalan clarified that the operative sentence in C.Q4 A4 is that a minimum of two lots of API must be used in the three primary stability batches. The first sentence is being rewritten to clarify this fact.

2) Relative to E.Q1 and the response – OGD has listened to the industry and removed the absolute requirement for a fourth time point on accelerated conditions. Dr. Rajagopalan indicated that the 6-month intermediate time point should obviate the need for the fourth time point if the product undergoes significant change at the 3-month or 6-month time station. She also indicated if there appears that there will be a significant change based on the results of the 3-month time point; the firm can always add an additional accelerated testing point.

3) The biggest change that may have really gone unnoticed based on the long history relative to the packaging of solid oral dosage forms is that OGD will accept the 100,000 dosage form minimum for packaging from the three primary stability batches – so it could be 40,000 from batch 1, 30,000 from batch 2 and 30,000 from batch 3 to satisfy the 100,000 requirement. Previously it was thought that at least one primary batch would need to have at least 100,000 dosage units packaged. But that is not the case now. This is a huge change from past practice. Just be certain you take into account all container closure systems, cGMP under 21 CFR 211, and the need for reserve samples outlined in the regulations when deciding on your stability packaging needs.