Practical Tips for A Successful Pre-Approval Inspection (PAI) Outcome

Once an application is submitted, the firms and facilities mentioned are considered by FDA to be ready for inspection. 

The inspection team will determine if:

• the facility is prepared for commercial manufacturing

• the data submitted is according to site records

• the data submitted is complete and accurate

Readiness for Commercial Manufacture

The investigative team will determine whether your the firm contains a quality system that's designed to realize sufficient control over the ability and commercial manufacturing operations.

• Evaluate overall CGMP compliance because it relates to the applying product

• Evaluate the particular PAI product and process

- is that the facility adequate/qualified-building; equipment; water systems?

  - Will review the development Report.

• Will review batch records for submission batches (pivotal, qualification and/or bio batches)

• specialize in change control, deviations and trends regarding the event process to see that there's adequate evaluation

• Will evaluate sampling plans; testing of components and products

• High specialise in your supplier qualification program

• Evaluate facility and equipment procedures with a spotlight on contamination controls

• Specialise in laboratory system (SOPs; Personnel; Training) and stability data

• Evaluate test methods (validated?) and impurity profile

Conformance to Application

The investigators will verify that the formulation, manufacturing and/or processing methods, and analytical methods are according to descriptions contained within the CMC section of the application.

As a part of the inspection, they'll audit records, equipment, procedures, and also the batch records submitted within the application and furthermore inspect the manufacturing equipment and facility to assure:

That the proposed manufacturing process is the same process that was used for the manufacturing of the bio/stability batches (and other pivotal clinical batches).

Investigators will verify the following:

• Observe manufacturing operations and equipment to assure they're according to those described within the application.

• Review on-site analytical methods to assure they're according to those filed within the application

• Will assure that stability samples are stored under the conditions described within the stability protocol filed with the application.

Investigators will compare stability lots and testing conditions at the positioning versus what's listed within the application. Investigators will visit stability chambers to verify:

• Correct packaging configuration

• Correct orientation

• Audit recording charts during the period

• Alarm logs 

• Correct temp and humidity conditions

Data Integrity

The investigators will audit the data

Does the information have factual integrity?

• Data is accurately submitted within the application

• Chromatogram directly calculates to summary

Does the information have contextual integrity?

• Data is supported by additional information observed at the facility.

• Missing records

• Unexplained losses of inventory of components

• Investigators review data used to generate results

• Control/security of data

• Audit for authenticity and accuracy

• Review data for bio-batch and stability batch(es), including laboratory testing and manufacturing

• Inventory records/equipment logs

• Passing data submitted rather than failing data

• Improper investigation of OOS results which were then not submitted

• Exclusion of specific lots from the steadiness program to avoid submitting failing results

“Companies must provide truthful and accurate information in their marketing applications…. The American public expects and deserves no less.”

Product Specific findings and deficiencies that ought to lead to a part recommendation to withhold approval

-          Significant data integrity problems including misrepresented data or other conditions associated with the submission batch.

-          Serious CGMP concerns with the manufacture of a bio-batch or demonstration batch, like a change to formulation or processing which will cause the FDA to question the integrity of the bioequivalence study.

-          Significant differences between the method used for pivotal clinical batches and also the NDA submission batch.

-          Lack of complete manufacturing and control instructions within the master production record or lack of knowledge to support those instructions.

-          Lack of capacity to manufacture the drug product or the API (if the firm isn't ready for an inspection, the district should request a letter from the establishment).

-          Failure to fulfil application commitments.

-          Full scale process validation studies were attempted before the PAI, demonstrate that the method isn't in restraint and establishment isn't making appropriate changes.

-          For products that full-scale summary information is provided within the application, establishment has not demonstrated that the merchandise is reliably manufactured at commercial scale and meet its critical quality attributes.

-          Incomplete or unsuccessful method validation or verification.

-          Records for pivotal clinical or submission batches don't clearly identify equipment or processing parameters used.

-          Significant failures associated with the steadiness study that raise questions about the steadiness of the merchandise or API.

-          Failure to report adverse findings or failing test data without appropriate justification

To ensure a successful PAI

Have a proactive compliance approach:

• Firm is attentive to significant issues before inspection; CAPAs in place; if needed

• Senior management is attentive to compliance / inspection issues at site so there are not any surprises during the inspection.

• Sponsor conducts due diligence before they name contractors/suppliers in applications and prepares all sites for PAIs.

• Quality and Operations work together to analyse deviations/issues…Responsible person for issues identified and accountable.

• Quality and Operations work together to best present significant issues during inspections (identify material Experts).

• Have a development report that compiles documentation that represents a radical understanding of the appliance product and process.

• the event report adequately is the idea for justification of the method to support the filing

• Communicate product and process risks to manufacturing sites and have them reflective within the performance measurements that are collected and monitored during manufacturing to assist prevent problems after launch.

Source: https://www.fda.gov/media/94064/download