Crossing the Finish Line: Preparing for and Passing a Preapproval Inspection

Ray Marzouk, vice president of quality, Avid Bioservices.

Since Avid’s first commercial approval in 2005, the company has been inspected multiple times by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Brazilian Health Regulatory Agency, and Health Canada. Avid makes drug substance for products that are approved and marketed in more than 90 countries. The company has succeeded in eight preapproval inspections (PAIs), the most recent five of which had no 483 observations.

PAIs differ in focus from routine-surveillance inspections. The latter typically focus on a company’s ability to maintain manufacturing within approved, validated, and qualified parameters since a previous inspection. Such activity verifies adherence to current good manufacturing practice (CGMP), including extensive reviews of quality systems, facilities, equipment, and controls of raw materials and operations.

PAIs are distinguished by additional in-depth focus on the product in review. This includes qualification of equipment and utilities specifically for that product’s manufacturing. It includes how the process is validated. And it will verify the information submitted in the licensing application.

A regulatory agency will sent a full PAI inspection team, including chemists, microbiologists, and/or facility experts. Off-site product reviewers often work with the on-site team. PAIs typically are scheduled in advance to ensure that operations can be observed for a specific product being evaluated. The main focus is to demonstrate a company’s understanding of both its product and manufacturing process. The FDA assesses a company’s readiness for commercial manufacturing, conformance to applications, and data integrity. With those objective in mind, the team will determine whether to recommend or withdraw product approval.

An apparent lack of capacity to manufacture the product at commercial scale to meet the product’s critical quality attributes (CQAs) can jeopardize that product’s chances of approval. Significant differences could be found between the processes used to make pivotal clinical batches and used for batches that are referenced in a submission. Incomplete manufacturing instructions/data to support those processes could jeopardize a product’s approval. So can data integrity issues and a lack of traceability.

“No amount of preparation will get you through an inspection,” Marzouk said, “if you don’t have strong quality systems that you comply with throughout the year.” He called that the most critical element in determining PAI success or failure. Documentation should speak for itself. Standard operating procedures (SOPs), protocols, reports, and discrepancy records must be thorough and clear.

Marzouk’s key recommendation was to perform routine internal audits that ensure compliance with company SOPs. Gaps should be identified, documented, and justified, with a defense strategy in place in case they come up during the PAI. Subject-matter experts (SMEs) should be trained on interacting with investigators, such as being truthful while answering only the questions that are asked.

Marzouk highlighted the importance of inspection management with a backroom support team. Performing a mock inspection can show how quickly the team can respond to document requests. It also helps to identify which SMEs will be best for face-to-face interactions with a PAI team.Preparation should include reviewing validation documents, submission contents, and product-development reports. SMEs need to be familiar with process-validation results, facilities, and utilities used to manufacture a product, as well as batch records used to support the submission. Findings from a mock PAI can help in development of remediation plans based on ranked-risk prioritization.

Investigators will want to tour a facility. Preplanned routes typically follow the process flow, starting from raw-material receipt and proceeding through to shipping of finished goods. Someone should walk that route ahead of the PAI team — e.g., to confirm that sufficient laboratory coats, gowns, and personal protective equipment will be available. Flexibility is important because investigators may want to see something that’s off the tour route. Investigator requests can come in rapid succession, so they need to be logged and tracked. Designated runners can facilitate movement of documents.

Trust requires truthfulness in responses and speed in fulfillment of document requests. Delays can raise suspicions or give the impression that a company doesn’t have control over its systems. “Don’t be afraid to challenge (respectfully) an investigator’s opinion if the facts are on your side,” Marzouk said. If gaps are identified, immediately implementing corrective actions shows commitment to continuous improvement. He cautioned, however, against acting rashly.

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