The submission of your drug application (NDA, ANDA, BLA, etc.) is an exciting accomplishment, and one of the first major milestones is a pre-approval inspection (PAI) of the manufacturing sites listed in your application. The FDA will make a risk-based determination as to which sites may require a PAI. This could include active pharmaceutical ingredient (API), biologic drug substance (BDS), drug product (DP), device, labeling, and packaging sites. The PAI will assess a drug manufacturing plant’s production capability and its ability to manufacture product for commercial distribution.
If you have outsourced your manufacturing to a contract manufacturing organization (CMO), these sites will specifically be named in the drug application and will be fair game for a PAI. A key aspect in preparing for a PAI is assessing if the CMO is inspection ready and ensuring they, and your firm, have the systems and documentation to demonstrate they are capable of manufacturing your product. While the CMO is the one executing the manufacturing processes for your product, your firm is ultimately responsible for all activities related to your product.
Based on experience over eight years managing programs at CMOs, below are some key areas that may be focused on when preparing for a PAI at a partner CMO.
- Make sure you are starting the PAI preparation process early as possible in the development of your drug, at a minimum of 1 year prior to submission of your drug application. I would recommend forming a PAI readiness team to focus on preparing your firm and your partnered CMO(s).
- Understand the complete inspection history of your CMO, whether it be through your own supplier audit program or regulatory inspections. Review the most recent supplier audit report and any CAPA(s) opened from the audit observations. Ensure the CAPA(s) have either been completed or are on track for completion per target dates. If your CMO(s) have previously been inspected by a regulatory authority, partner with them to understand how they facilitated the inspection and addressed any observations.
- Review quality events (deviations, investigations, OOS, and CAPA) related to your product (e.g. registration batches) opened by the CMO. It will be important to assess these documents to ensure they are adequate and complete, and if all quality events at the CMO related to your drug have been communicated to your organization. If there were any critical deviations or investigations that have a high likelihood of being reviewed, it may be worthwhile to partner with the CMO to develop a storyboard for the occurrence to help support a potential request from the FDA.
- When assessing change controls, make sure they are in the appropriate state per your CMOs procedure and implemented changes are appropriately reflected in your drug application. Additionally, ensure any changes that directly impacts your product are captured and assessed in your change control system. Understand your CMOs plans for any facility and equipment improvements to determine if any changes will occur during your application review period. Once your application is submitted, it will be imperative that changes are minimized unless the FDA has come back during your question period requesting changes.
- Validation and batch record documentation should be assessed to make sure they are aligned appropriately with your drug application. Any changes should be reviewed to determine if they impact the drug application. CMO facility, utility, and equipment qualification documentation should be approved, with reports.
- Conduct a PAI mock inspection. This is by far one of the best ways to determine if you and your CMO are ready for an FDA PAI. This type of inspection should be performed by a qualified third-party inspector or inspection team that has demonstrated experience with PAI inspections. The mock inspection will help determine the areas that may have gaps or compliance risks. The goal will be to highlight any deficiencies and have enough time to address identified gaps or deficiencies prior to the actual PAI.
The FDA pre-approval inspection is a major milestone after submission of a drug application. Preparing for the PAI is critical for your firm and should be a part of your quality systems as you move towards approval. A well-developed PAI preparedness plan should be put in place early on in your efforts to gain approval for you drug. When partnered with a CMO, ensure you are aligned and demonstrating your firm has adequate oversight of the activities occurring with your drug. The items listed above are a few areas that will help you navigate through your PAI preparation when your manufacturing is outsourced to a CMO. Contact the compliance experts at ProPharma Group for additional support.
