Welcome to Alston & Bird’s introduction to biological products regulation. In this five-part intro-level series, we provide answers to a number of questions drug developers may have about the regulation and regulatory pathway for their products.
The series includes:
- Is the Product a Biological Product?
- What Is the Regulatory Pathway for Biological Products?
- Unlocking Reference Product Exclusivity: What Sponsors Need to Know
- Biosimilars 101
Pre-license inspections for biologics involve more considerations than pre-approval inspections for small molecule drugs. This reflects the Food and Drug Administration's (FDA) long-standing view that, for biological products, the manufacturing process is the product. Unlike small molecule drugs, which are typically manufactured through chemical synthesis or fermentation, biologics are inherently more complex. This complexity arises not only from their larger molecular size but also from structural heterogeneity.
For example, therapeutic proteins may exhibit post-translational modifications that contribute to variability. In addition, biological products often contain product-related impurities. As a result, manufacturers must rely on advanced analytical methods and extensive characterization studies. The FDA therefore places significant emphasis on process characterization, process validation, and process control during pre-license inspections.
The facility requirements for biological products are established by both statute and regulation. Sections 351(a) and 351(k) of the Public Health Service Act (PHSA) mandate that “the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.” In addition, 21 C.F.R. § 601.20 imposes a specific inspection requirement:
A biologics license shall be issued or a biologics license application approved only after inspection of the establishment(s) listed in the biologics license application and upon a determination that the establishment(s) complies with the standards established in the biologics license application and the requirements prescribed in applicable regulations.
We highlight two major ways pre-license inspections for biological products differ from pre-approval inspections for small molecule drugs. First, though the FDA’s Process Validation Guidance applies to biologics license applications (BLAs), new drug applications (NDAs), and abbreviated new drug applications (ANDAs), expectations for submission data differ significantly. For BLAs, process performance qualification (PPQ) batches must be completed before the BLA is submitted, and PPQ data must be included in the BLA. In contrast, for small molecule NDAs/ANDAs, PPQ data does not need to be included in the application so long as it is completed before commercial distribution.
Second, for NDA/ANDA pre-approval inspections, the FDA typically reviews process validation data during the inspection but does not necessarily require the site to be manufacturing the product at that time. For BLAs, however, 21 C.F.R. § 601.20 requires that the facility be in operation and manufacture the product under review during the pre-license inspection. Accordingly, applicants should consider providing a manufacturing schedule as part of the BLA submission to facilitate FDA inspection planning.
The primary goal of a pre-license inspection is to ensure that the manufacturing facility is fully prepared for commercial production of the product under review. The FDA focuses on three key objectives:
- Verify that the site is ready for commercial manufacturing of the product under review.
- Confirm that manufacturing operations align with the BLA submission.
- Assure that submitted data is authentic and accurate.
When a sponsor submits a BLA, all associated manufacturing facilities must be listed in Form FDA 356h. The FDA then conducts a risk-based assessment of each facility to determine whether an on-site pre-license inspection is necessary. This assessment considers factors such as the facility’s compliance history, any prior issues relevant to the product under review, and product- or process-specific characteristics that may warrant an on-site inspection. When the FDA determines that a pre-license inspection is not required, the FDA may use other assessment tools, such as issuing records requests under Section 704(a)(4), to evaluate facility capability and quality systems. Timely and complete response to these requests is critical to avoid delays in the FDA’s review and approval decisions.
The FDA’s pre-license inspection is rigorous and distinct from those for small molecule drugs. Applicants should plan early, ensure PPQ data is complete and included in the BLA, and respond promptly to FDA inquiries throughout the review process.
If you have questions about preparing for, or responding to findings in, a pre-license inspection or need assistance with compliance strategies, please contact us.
If you have any questions, or would like additional information, please contact one of the attorneys on our FDA: Drug & Device team.
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