FDA's Pre-Approval Inspection (PAI) Process

The Pre-Approval Inspection (PAI) process conducted by the U.S. Food and Drug Administration (FDA) is a critical step in ensuring the safety, efficacy, and quality of drugs entering the market. The PAI evaluates the manufacturing facilities, processes, and data submitted as part of a drug application to determine if they meet the required standards. In this article, we will delve into the key elements of the PAI process and provide practical tips for a successful outcome, along with case studies highlighting proactive takeaways and common pitfalls.

Pre-Approval Inspection Compliance Program

The Food, Drug, and Cosmetic Act provides that FDA may approve an NDA or an ANDA only if the methods used in, and the facilities and controls used for, the manufacture, processing, packing, and testing of the drug are found adequate to ensure and preserve its identity, strength, quality, and purity.

Site Evaluation

Before approval, FDA evaluates the establishments by on-site inspections and/or by establishment file review when the firm is named in the Chemistry, Manufacturing, and Controls (CMC) section of a New Drug Application (NDA), Abbreviated New Drug Application (ANDA) or Biologic License Application (BLA).

Facility Evaluation and Risk Assessment

Before conducting a PAI, the FDA evaluates various sites involved in the drug manufacturing process. 

• Finished dosage manufacturers, 
• Active pharmaceutical ingredient (API) manufacturers, 
• Finished dosage and API testing sites
• Primary packaging and labeling sites
• For animal-derived APIs, the facility that performs the crude extraction

FDA generally does not evaluate the following sites for a pre-approval inspection

1. Intermediate Manufacturers

• On a case-by-case basis; evaluated only if the intermediate is considered critical to the quality of the drug product.

2. Exhibit batch Manufacturers (if not proposed commercial site)

3. Component Manufacturers

• Includes syringe, vial, or stopper manufacturers and component-only sterilization sites
• OPF/DIA generally does not evaluate these sites unless the for-cause basis
• It is the drug product manufacturer’s responsibility to qualify their suppliers.

4. Excipient Manufacturers

• OPF/DIA generally does not evaluate these sites, unless it is a novel excipient, and/or the excipient manufacturing process is considered a critical step in the overall drug manufacturing process.

5. Secondary Packager/Labeler

• OPF/DIA generally does not evaluate these sites

Note: all above sites are required to meet the statutory cGMPs per FD&C Act and may be routinely inspected if registered as a drug manufacturer.

When does FDA perform PAIs?

Use risk-based Priority Inspection Criteria to make the decision based on the following risks:

1. Facility Risk
2. Product Risk
3. Process Risk

1. Facility Risk

• cGMP issues relevant to application product
• Recent FARs relevant to application product
• Recent recalls relevant to application product
• Numerous applications filed at once

2. Product Risk

• New molecular entity
• First application filed by an applicant
• First ANDA filed for an approved drug
• RLD has complaints, ADEs, stability issues
• Patient population or for a serious condition
• Breakthrough therapy, shortage situation

3. Process Risk

• Narrow therapeutic range (95%-105%)
• API derivation is high-risk (derived from animal tissue)
• PAT, NIR, QbD
• Development data is incomplete
• Batch records non-specific
• Complicated process
• Substantially different process than previously covered at a facility.

The Pre-Approval Inspection Team

• If a PAI is deemed necessary, the FDA sends a team of investigators and specialists to conduct the inspection. The team typically comprises investigators along with experts in chemistry, microbiology, process/facility, and formulation.
• The involvement of multiple experts underscores the growing trend toward a comprehensive assessment during inspections. These experts evaluate various aspects of the facility, including quality systems, manufacturing operations, formulation, analytical methods, and data integrity.

Pre-Approval Inspection Program

A pre-approval inspection (PAI) is performed to contribute to FDA’s assurance that a manufacturing establishment named in a drug application is capable of manufacturing a drug, and that submitted data are accurate and complete.

PAI is product specific

• Limited or no commercial manufacturing
• More focus on development data
• More emphasis on the authenticity of data and application commitments
• Process validation is commonly not completed
• Application actions are administrative; typical enforcement used for marketed products does not apply
• The trend toward more experts involved in the inspection

Objectives of the PAI

The PAI serves three primary objectives.

First, It assesses the readiness of the establishment for commercial manufacturing by evaluating the quality system's control over the facility and manufacturing operations. 

• This includes ensuring compliance with current Good Manufacturing Practices (cGMPs), adequacy of equipment and infrastructure, and appropriate documentation practices. 

Second, it verifies the conformance of the formulation, manufacturing or processing methods, and analytical methods with the descriptions provided in the drug application. 

• This involves assessing the consistency between the filed application and the actual manufacturing practices. 

Third, it conducts a data integrity audit to authenticate and ensure the completeness and accuracy of the data submitted in the application. 

• Data integrity is a critical aspect of the PAI, as it ensures the reliability of the information provided by the manufacturer.

ALSO READ: Audit Checklist for the New Drug Approval Process by FDA

Practical Tips for a Successful PAI Outcome

1. Be Prepared For the PAI
Once an application is submitted to the Center, the firm and all facilities mentioned are considered by FDA to be ready for inspection.
The inspection team will determine if:

• The site is ready for commercial manufacturing
• The information submitted is consistent with site records
• The information submitted is complete and accurate

2. Readiness for Commercial Manufacture:

One of the key areas of focus during a PAI is the evaluation of the facility's readiness for commercial manufacturing. To ensure readiness, manufacturers should:

• Evaluate overall cGMP compliance as it relates to the application product. This includes conducting thorough internal audits and addressing any identified deficiencies.
• Assess the facility's adequacy, equipment, water systems, and data supporting the manufacturing process and specifications.
• Thoroughly review development data, batch records, and the quality system, focusing on deviations, change control, and supplier qualification.
• Ensure robust contamination controls, a comprehensive laboratory system, and validated test methods.

3. Conformance to Application:

The PAI aims to verify that the manufacturing operations, equipment, and analytical methods align with the descriptions provided in the drug application. To ensure conformance, manufacturers should:

• Verify that the manufacturing operations and equipment used in the facility align with the descriptions in the application. Any deviations or discrepancies should be appropriately addressed and documented.
• Review on-site analytical methods to ensure consistency with the submitted methods. Validation data, if available, should support the analytical methods used.
• Evaluate the consistency of batch records, including manufacturing and packaging records, with the application. Any discrepancies should be resolved and documented.
• Conduct a comprehensive comparison of stability lots and testing conditions at the site with the application data.

4. Data Integrity:

Data integrity plays a critical role in the PAI process, as it ensures the reliability and accuracy of the information provided by the manufacturer. To maintain data integrity, manufacturers should:

• Establish robust data management systems and controls, including secure storage, access controls, audit trails, and data backups.
• Implement training programs for employees to ensure they understand the importance of data integrity and their responsibilities in maintaining it.
• Conduct periodic internal audits and reviews to identify any data integrity issues and take appropriate corrective actions.
• Adhere to complete and accurate reporting of adverse findings or failing test data.
• Investigators review raw data used to generate results
• Control/security of raw data
• Audit for authenticity and accuracy
• Review raw data for biobatch and stability batch(es), including laboratory testing and manufacturing
• Inventory records/equipment logs
• Passing data submitted instead of failing data
• Improper invalidation of OOS results which were then not submitted
• Exclusion of specific lots from the stability program to avoid submitting failing results.

FDA will take action against companies that commit data fraud or provide false information to the agency.

“Companies must provide truthful and accurate information in their marketing applications”

Product Specific findings and deficiencies that should result in a district recommendation to withhold approval

• Significant data integrity problems including misrepresented data or other conditions related to the submission batch
• Serious cGMP concerns with the manufacture of a biobatch or demonstration batch, such as changes to formulation or processing that may cause the FDA to question the integrity of the bioequivalence study.
• Significant differences between the process used for pivotal clinical batches and the NDA submission batch.
• Lack of complete manufacturing and control instructions in the master production record or lack of data to support those instructions.
• Lack of capacity to manufacture the drug product or the API (if the firm is not ready for an inspection, the district should request a letter from the establishment).
• Failure to meet application commitments.
• Full-scale process validation studies were attempted prior to the PAI, demonstrating that the process is not under control and the establishment is not making appropriate changes.
• For products for which full-scale summary information is provided in the application, the establishment has not demonstrated that the product can be reliably manufactured at a commercial scale and meet its critical quality attributes.
• Incomplete or unsuccessful method validation or verification.
• Records for pivotal clinical or submission batches do not clearly identify the equipment or processing parameters used.
• Significant failures related to the stability study raise questions about the stability of the product or API.
• Failure to report adverse findings or failing test data without appropriate justification.

To Ensure a Successful PAI

Have a proactive compliance approach:

• The firm is aware of significant issues before inspection; CAPAs in place; if needed.
• Senior management is aware of compliance/inspection issues at the site so there are no surprises during the inspection.
• The sponsor conducts due diligence before they name contractors/suppliers in applications and prepares all sites for PAIs.
• Quality and Operations work together to investigate deviations/issues…Responsible person for issues identified and accountable.
• Quality and Operations work together to best present significant issues during inspections (identify Subject Matter Experts).
• Have a development report that compiles documentation that represents a thorough understanding of the application product and process.
• The development report adequately serves as the basis for justification of the process to support the filing.
• Communicate product and process risks to manufacturing sites and have them reflected in the performance measurements that are collected and monitored during manufacturing to help prevent problems after the launch.

ALSO READ: FDA Inspection Preparation Guide

Case Studies

Case 1: Failure to Report Failing Data

There is no assurance that the finished product will consistently meet its finished product specifications. For example,

• A review of the development batch records revealed that several batches failed dissolution. This data was not reported in the filing submitted to the agency. The investigations conducted into the failures stated that the assignable cause was the wet granulation process, compression of the core tablets, and/or the enteric coating of the core tablets, without further explanation. During the inspection, the firm hypothesized that the root cause was the dew point during the enteric coating step. The firm does not have the capability of controlling the dew point in any of its coaters.
• The firm does not have sufficient control of the tablet press. In a memo, the firm stated "At this point, manufacturing operations only operate the press with the presence of the vendor due to the difficulty of optimizing the start-up."

Recommendation

Withhold for failure to report adverse findings

What happened

• Different batches would require different tablet press settings, and the firm had no idea why.
• Investigators also found failing dissolution release testing without a root cause identified. This failing data was not reported.
• During the inspection, the firm hypothesized that the root cause for the dissolution failures was the dew point during the enteric coating step. The firm does not have the capability of controlling the dew point in any of its coaters.

Takeaways

• Investigate deviations/issues prior to the PAI…Responsible person for issues identified and accountable
• Have SME ready to present significant issues during inspections
• Process design (Stage 1) must be completed and adequate prior to the PAI inspection. Need evidence/data to support the manufacturing process
• Knowledge gained during development should be incorporated into the process design/control strategy.

1. Dissolution failure investigations may result in manufacturing changes depending on the root cause
2. Manufacturing changes may result in gaining sufficient control of the tablet press

Case 2: Nonconformance to Application

The firm lacks data for the qualification of the proposed container closure system (LDPE bags) to store the finished API. For example, the firm lacks storage stability data. The current stability studies were performed on samples packaged in amber glass bottles. However, the drug substance is packaged in LDPE bags.

Recommendation

Withhold for failure to meet application commitments

What happened

• The drug substance is packaged in LDPE bags; however, the stability studies were conducted in amber glass bottles. The firm had no data to support the qualification of the proposed container closure system (LDPE bags) to store the finished API.
• The firm responded that they will package the API in amber glass bottles until they collect adequate stability data to support packaging in LDPE bags.

Takeaway

Know your commitments and be prepared for the inspection!!

Case 3: Knowledge Management

There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. There is no assurance that the product solutions are uniform. For example,

The firm manufactured 10 production-size lots of drug products. 9 of 10 batches failed for API X. The draft investigation has identified that due to the small quantity of API X required for each batch … minor drug loss can yield OOS results. The firm manufactured a batch …. to evaluate the method of dispensing API X into a separate flask of excipient y directly after drug weighing to eliminate any non-recoverable loss …This engineering report has not been finalized and the investigation in the 9 failures is still open.

Recommendation

Withhold for unsuccessful scale-up

What happened

• Firm X purchased a drug product solution from Firm Y without the development report or batch record and had no experience with this type of complex formulation. Firm X used current in-house equipment for manufacturing.
• After Firm X experienced problems in scale-up, they contacted Firm Y and found that there were significant differences in their manufacturing process as compared to Firm Y’s manufacturing process
• R&D personnel from Firm Y visited Firm X and shared their manufacturing knowledge.

Takeaway

• Knowledge dissemination is not only useful within a company but beyond as well. Information (product knowledge) should be part of the transfer of the product between companies.
• Communication between companies is key to a successful transfer.
• Knowledge gained during scale-up should be incorporated into process design/control strategy. In this case, manufacturing scale-up issues were the root cause.
• Knowledge Management can assist in the preservation of prior knowledge (including between companies) during technology transfer.

Conclusion

The Pre-Approval Inspection (PAI) process conducted by the FDA is a critical step in ensuring the safety, efficacy, and quality of drugs. By following the practical tips discussed in this article, drug manufacturers can increase their chances of a successful outcome in the PAI. Through proactive measures, such as conducting comprehensive facility evaluations, adhering to regulatory requirements, and maintaining data integrity, companies can foster a culture of compliance and consistently deliver high-quality drugs to patients.

Disclaimer: The information provided in this article is based on general knowledge and understanding of the PAI process and should not be considered legal or regulatory advice. It is recommended to consult with experts and refer to FDA guidelines for specific requirements.

ALSO READ: FDA Audit Preparation