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.
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).
Which sites generally trigger a facility evaluation for a pre-approval inspection?
- Finished dosage manufacturers
- 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:
- Intermediate manufacturers
- Exhibit batch manufacturers
- Component manufacturers (syringe, vial, or stopper manufacturer)
- Excipient manufacturers (unless it is a novel excipient)
- Secondary packager/labeler
When does FDA perform PAIs?
Use risk based Priority Inspection Criteria to make the decision based on the following risks:
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
Product Risk
- New molecular entity
- First application filed by applicant
- First ANDA filed for an approved drug
- RLD has complaints, ADEs, stability issues
- Patient population or for serious condition
- Breakthrough therapy, shortage situation
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 facility
Pre-Approval Inspection team
- Investigators
- Other Specialists (Chemistry Expert, Microbiology Expert, Process/Facility Expert, Formulation Expert)
PAI Objectives
- Readiness for Commercial Manufacturing
- Conformance to Application
- Data Integrity Audit
PAI Outcomes
- Recommend Approval
- Recommend Withholding of Approval
FDA Pre-approval Inspection Guidance
- Firm is aware of significant issues before inspection; CAPAs in place; if needed
- Senior management is aware of compliance / inspection issues at site so there are no surprises during the inspection
- Quality and Operations work together to investigate deviations/issues
- 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 reflective in the performance measurements that are collected and monitored during manufacturing to help prevent problems after launch
PAI Readiness Checklist
- Conformance to the application
- Manufacturing reliability and cGMP compliance
- Using suitable and validated analytical methodologies
- Robust manufacturing process
- Producing authentic and accurate data
- Good documentation practice (GDP)
- Standard quality system
FDA Pre-approval Inspection Checklist
- Review past inspections, responses and outstanding items, if any
- Conduct a walk-through examining instruments for calibration status, log books
- Prepare lists of commonly requested items
- Rework/reprocessing events
- Recalls
- Product failures
- Complaints
- Media fills
- Deviations, OOS investigations, CAPAs
- Determine the roles of individual members of the inspection team
- Pre-determine the “Go To” lead person within each area of the tour
- Review production schedules
- Schedule routine products and activities
- Best to avoid rework or other challenging activities
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