Avoiding Approval Risks at Your CMO Facility

By Mickey Koplove

The Incident

In August 2024, Regeneron received a Complete Response Letter (CRL) from the FDA for its multiple myeloma treatment candidate. The FDA cited compliance problems in its contracted fill and finish facility, a Chinese contract manufacturer. While specifics of the compliance gaps were not published, events of this nature should concern all of us in the biologics industry. The consequences of publicly failing a critical benchmark raise the specter of arriving late to market. It is important to anticipate vulnerabilities in our CMC processes and address potential problems before those processes are complete and submitted for review.

Relevant Background: Transfer of Responsibilities from CBER to CDER

During 2003, presumably due to a substantial increase in submissions and approvals, the FDA transferred responsibilities for regulating certain classes of biological products from the Center for Biologics Evaluation & Research (CBER) to CDER, the Center for Drug Evaluation & Research. CDER had a long-standing history of focusing on strong cGMP compliance.

The products that passed on to CDER included:

• Monoclonal antibodies (MAbs) used in vivo,
• Therapeutic proteins such as cytokines and enzymes,
• Proteins and peptides that are immunomodulators,
• Growth factors, cytokines, and MAbs that alter cellular production in vivo.

Additionally, CDER became responsible for these products’ CMC and facility inspections.

Maintaining Control of Your Product

One of the FDA’s cardinal rules is to maintain complete control of the licensed product. The company who holds the manufacturing license is the commercial manufacturer, not a CMO. Therefore, the commercial manufacturer must have the expertise and personnel to monitor and control all contract manufacturers and other purchased cGMP goods and services. Insufficient staff size and competency to perform these duties is a serious cGMP deficiency.

The license holder cannot delegate authority of its product. In the early days of biotechnology, the FDA had a difficult time accepting contract manufacturing. It took a long time to work through what was needed to ensure that the license holder had supervision at all stages and locations where the product was at risk.

One result of this was the Man-in-Plant (now known as Person-in-Plant) requirement. The "in-plant" people were stationed in the contracting facility and served as communication points between the license holder and the contractor. In some cases, companies found that having representatives from both Manufacturing and Quality gave even more compelling coverage. Overall, it was an effective way to satisfy the interest of all stakeholders.

At the beginning of the biotech era, it was also difficult to envision a future tipped so heavily towards using manufacturing contractors with lighter-staffed license holders who can rely on external consultants to do what used to require FTEs.

A Word to the Wise (with Actions You Can Take Today)

It is unfortunate that the FDA cannot release even general information about the cause for the initial Regeneron submission rejection. Doing so would help many companies avoid similar fates. It is interesting that it occurred under CDER at a distant contractor. There may be a message in this action from CDER that it is time for the biologics industry to tighten up cGMP compliance in a similar manner to the stronger message the FDA sent the pharmaceutical industry several decades ago.

Even without knowing the specific issues that led to the CRL, there are lessons that the senior management of small and medium-sized biological companies need to consider.  Here are a few suggestions for companies who do significant outsourcing (i.e., virtual biotechs) to protect themselves in the frenzy to get commercial licensure:

• Preparing for a regulatory filing is an extremely labor-intensive process and requires extensive project management. If your strategy is to avoid investment in permanent headcount, make sure to hire experienced contractors. Don’t try to do it with insufficient staffing.
• In addition to CMC, make sure you have experienced and well-staffed QC, QA, and Regulatory Affairs teams. These supporting groups can help form a productive working relationship with CDER.
• Be very specific in your contracts with third-party CMOs. Your program may succeed or fail by them. Before signing, review your contracts diligently with relevant representatives of technical, legal, and financial executives or their delegates.
• Clearly define roles, responsibilities, and business processes with your contract managers. Be specific in ordering and delivery instructions, as well as penalties for missed targets. Specifically define QC and QA responsibilities, including release and acceptance criteria of the product as it transfers between parties.
• Make sure your contracts allow for any Person-in-Plant to attend both routine and special joint team meetings.
• Develop acceptable exit strategies in case either partner wishes to terminate the project.

Having discussions on operating principles and agreements of these sorts in place before you commit to key contracts will help you avoid many obstacles on your journey to contract facility approval.

For guidance or support in implementing any of the suggestions above, contact the Converge team today at info@convergeconsulting.com.