The FDA has been publishing guidance documents at an escalated pace, likely due in part to the change in Administration that we will see shortly. At the end of last week, the FDA published a new draft guidance: Considerations for Complying with 21 CFR § 211.110. The FDA released this guidance as part of the Center for Drug Evaluation and Research’s Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) Initiative, which is intended to support the adoption of advanced manufacturing to improve drug product quality and availability.
The guidance explains Section 211.110’s requirements for drug product manufacturing and considerations for the use of advanced manufacturing. While this draft guidance is brief, it will likely be useful for present decisions and future response efforts involving in-process sampling given the vagueness of some portions of Section 211.110. Section III of the guidance, General Considerations for In-Process Sampling and Testing, highlights the following points:
- The FDA provides clarity that industry has been seeking by outlining conditions that must be met for changes that do not require quality unit approval. The FDA states in the guidance that “process monitoring and control decisions that result in minor equipment and process adjustments do not typically need additional quality unit approval if all of the following conditions are met: (1) the adjustments are within the preestablished and scientifically justified limits; (2) these limits have been approved by the quality unit in the master production and control record and the control strategy; and (3) the production data is reviewed by the quality unit before approval or rejection of a batch.” Manufacturers should consider these criteria for their own procedures. The FDA emphasizes in the guidance that the determination of whether the regulatory requirements in Section 211.110 are met “primarily depends on the nature of the drug product” and the manufacturer’s process. Therefore, it is important for a manufacturer to understand its products and processes and make scientific- and risk-based decisions.
- In order to ensure conformance to drug product quality requirements, a manufacturer must identify the “critical quality attributes and in-process material attributes to monitor and control.” The FDA emphasizes that there is flexibility in Section 211.110 for the selection of “in-process controls, and testing, or examinations that are employed to ensure that processes deliver in-process materials and drug products with the appropriate quality attributes.” Rather than prescribing specific controls, tests, or examinations, the FDA encourages manufacturers to leverage their knowledge and understanding of products and processes to ensure in-process materials are of consistent quality, with the ultimate target of manufacturing drug products that have the properties they are purported to have.
- The guidance states that manufacturers should also “define and justify where and when the proposed in-process controls, and testing, or examinations … used to monitor those attributes should occur.”
- Current regulations generally allow flexibility in the determination of “significant phases.” The FDA reiterates this flexibility in the guidance by stating that manufacturers “should use a scientific- and risk-based approach to determine what constitutes a significant phase and to justify when and where the appropriate tests or examinations should occur relative to a significant phase.” Relatedly, the FDA also discusses the identification of significant phases in advanced manufacturing.
- Section 211.110 also provides flexibility in how in-process material and drug product testing is conducted. As the FDA states in its Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding Rule, a sampling plan “can mean both a plan for collection of physical units for testing, or it can mean a schedule by which an examination of some sort is done.” With considerations of advanced manufacturing in mind, the FDA confirms this position in the guidance by stating that “in-process controls, and tests, or examinations of in-process materials are required, sampling does not necessarily require steps for physically removing in-process materials to test their characteristics.”
We will continue to monitor the FDA’s actions and update you as the agency issues new guidance. If you have any questions, please do not hesitate to reach out.
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