Being ready for a Pre-Approval Inspection (PAI) is a key milestone for the successful approval of a new product and can significantly impact the approval timeline and time to market. For companies who have experience in product development and commercialization, getting ready for a PAI is built into their development process, but small companies and biotech startups who want to get their first product approved often struggle to determine if they are ready for a PAI. Avoiding this uncertainty requires thorough preparation. Utilizing external, independent reviews and assessments minimizes the risk of surprises and maximizes the best use of limited internal resources.

PAI readiness is not a one-time event that can be achieved through assessments and training alone; it is a cross-functional process with multiples phases that include elements of technical and regulatory compliance, organizational aspects, training, and product, process, and method validation.

The FDA conducts a PAI to ensure that a manufacturing establishment named in a drug application is capable of manufacturing and/or testing a drug and that the submitted data are accurate and complete.

What does this mean for the main objectives for a PAI? Being capable of manufacturing a drug includes the methods or processes, the facilities and the controls used to manufacture a drug. It requires compliance with CGMP regulations, robust product, process and method validation, adequately established quality systems, an appropriate quality risk management system as well as compliance with other applicable, process or product specific regulations. However, being capable of manufacturing a product is by far not enough to pass a PAI. During the PAI, the FDA will verify that the actual process including test methods are in conformance with the original application and that the established approach and practices for data management ensure the integrity of the data that have been generated and used in development, manufacturing, monitoring and product testing. All this will be assessed during a PAI so that the main objectives can be summarized as follows:

• Confirm the Readiness for Commercial Manufacturing
• Verify the Conformance to Application
• Verify Data Integrity / Conduct a Data Integrity Audit

Figure 1 shows how these objectives are interconnected with each other.


Risk-based approach
The three main objectives of a PAI cover a wide field that spans for a new product from the development phase to the current manufacturing footprint, which very often includes third party manufacturing sites and contract testing labs. However, there are situations, where PAIs can be more limited like in the case of a change in the manufacturing site or a major process change. This is why the FDA typically applies risk based priority inspection criteria, making the inspection breadth decision based on the following risks:

• Facility Risk
• Product Risk
• Process Risk

A startup company with a new product and new process technology in a new facility scores high in all risk areas listed above, whereas in the case of a transfer of an approved product to a brand-new facility, facility risks would be the primary focus.

The journey
Typically we see two different scenarios in which sites or organizations need to prepare for a PAI.

Scenario 1. For established organizations experienced in CGMP operations and experienced in PAIs, a Mock PAI that simulates a real inspection situation is typically the way to go. The Mock PAI should include inspection training and coaching. Any findings or observations during the Mock PAI should be addressed accordingly.

Scenario 2. For organizations with no or limited CGMP experience that are preparing for their first PAI, a one-time status check in the form of a Mock Inspection is predictably insufficient. In these cases, the PAI preparation needs to include a significant transformation moving out of a research and development environment and mindset into the CGMP, commercial production world. This transformation challenges many parts of the organization, but it is a fundamental change that should be carefully reflected and embedded into the overall preparation plan.

Because a PAI is a critical milestone for any company, an approach that includes the sustainable and long-term development of PAI Readiness minimizes the risk of any PAI, but this requires advanced, appropriate planning to meet the key milestones on the journey to PAI Readiness.

The journey towards PAI preparedness incorporates the following milestones:

1. Technical Readiness
2. GMP Readiness
3. PAI Readiness

In cases described in Scenario 1, technical readiness and GMP readiness are theoretically already successfully established and PAI Readiness could be verified through assessments,  audits and a Mock Inspection, but for “first timers” as described in Scenario 2 this journey is an endeavor that takes significant time and resources. As with every journey into new territory a roadmap and guidance from experienced travelers helps ensure that all critical milestones are met and that the final destination is reached on time. Figure 2 shows a high level timeline and key milestones on the journey towards PAI readiness and a successful PAI.


Depending on the situation, it can take up to two years or more to achieve PAI Readiness. This estimation includes the time to get a facility to Technical Readiness and to train personnel and establish proper procedures and supporting quality systems to ensure compliance with CGMPs.

For start-up companies, the main challenge is to ensure that during this timeframe all elements that are critical to achieve Technical Readiness and GMP Readiness have been sufficiently addressed. Otherwise, the Mock inspection could uncover critical issues that would potentially impact the chances of a timely and successful PAI.

The first step is to ensure that a facility achieves the Technical Readiness milestone for technical transfer and engineering runs. This requires that the equipment is installed and operates as intended. This should be verified through successful commissioning and qualification, planned and successfully executed based on a pre-defined and pre-approved Commissioning and Qualification plan. At this point, it is also required that the process description is in final draft form. Additionally, the basic outline of the process validation plan and the process control strategy should have been developed and that appropriate test methods, change control procedures and good documentation practices are in place.

The second milestone, GMP Readiness, is achieved when the process description and the master batch records are finalized, the process control strategy has been defined and appropriate, sustainable quality systems are implemented. The verification of GMP Readiness typically requires area-specific audits, comprehensive training programs and coaching, where appropriate. From a practical perspective it should be considered that at this point critical aspects of future manufacturing performance and efficiency will be defined. All facility, manufacturing and testing related processes need to be established.  It should be verified to ensure that they are compliant with applicable CGMP regulations, but it should be also verified that they are “fit for purpose.” This applies to manufacturing and supporting process-related SOPs, Master Batch Records, environmental monitoring programs, and governing quality systems. They need to be designed in a way that all processes and procedures are clearly defined and efficient and ensure compliance. Most of us have seen batch records with 150 pages and more, but also examples with about 50 pages for comparable processes. It is also very likely that many, if not all, of us have seen change control and deviations investigation forms that are signed off by more individuals than the Declaration of Independence. It is much easier and more efficient to implement a streamlined process with clear roles and responsibilities from the beginning rather than trying to optimize it at a later point in time.  Bringing experienced coaches on board that know what to do, how to do it and when to do it, adds value, ensures that CGMP compliance, efficiencies, and “fit for purpose” are aligned while preparing for GMP readiness.

Once the two first milestones have been achieved the final phase to PAI Readiness typically includes inspection training and coaching to ensure that the logistical and organizational challenges for the PAI are understood and that the site team is properly prepared to manage them.

Hands-on training and coaching for inspection situations in different areas should be included and cover all levels of a site organization from site management to shop floor operators. Experienced coaches can provide guidance on how to respond to questions and how to handle different types of inspectional situations as well as managing the overall inspection process. The final litmus test is a Mock Inspection, which simulates a real inspection situation. Once the Mock Inspection has been executed and any potential findings of the inspection have been suitably addressed, the goal of PAI Readiness has been achieved.

Table 1 summarizes the main elements for each Readiness Milestone that need to be in place.


Conclusion
PAI Readiness has a lot of challenging aspects especially for young organizations and/or “first timers.” Like many other things that are done for the first time, it comes with a level of uncertainty. Successful preparation of PAI Readiness requires well-informed planning and diligent preparation. A PAI is much more than a routine GMP inspection that the FDA conducts on a regular basis. A PAI is the final verification that a company has the right procedures and processes in place to manufacture a product under CGMPs and that the actual process conditions and parameters are in conformance with the product filing.

The level of complexity and experience of the organization dictates the time required for planning in advance of an expected PAI to avoid last minute surprises. The use of experienced coaches who can act as guides and advisors is a way to minimize PAI inspection risks and also to ensure that process controls and quality systems are “fit for purpose,” compliant and efficient from the start. 

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Dr. Walter Matzmorr has more than 30 years’ experience in process development, manufacturing and engineering within the biopharmaceutical industry. His expertise includes aseptic processing, filling and lyophilization, good manufacturing practices (GMP), and process optimization and facility start up. He also has in-depth experience in dealing with regulatory agencies in the U.S. and Europe. walter.matzmorr@tunnellconsulting.com