As the product moves from clinical development to commercial manufacturing, regulatory landscapes change. At the clinical development stage, safety and efficacy are not established, process knowledge is under development, stability data is being generated and the product is released with provisional specifications. At the commercial stage, the label is approved, the shelf life is established, and the product is released with filed regulatory specifications.
PAI readiness for virtual companies outsourced operations, when multiple contract manufacturers are involved to manufacture a product, could be challenging. FDA PAI focuses on the following four areas:
- Readiness for Commercial Manufacturing
- Conformity to application
- Data Integrity
- Quality Systems for commercial manufacturing
A comprehensive readiness plan is developed in collaboration with CDMO for inspection readiness activities, timelines, and managing CAPA arising from mock audits. There may be quality issues (backlogs, inadequate investigations, and CAPA) that need to be resolved before PAI, therefore it is prudent to add 3-4 additional months to inspection readiness plans. Generally, it takes 6+/- 3 months from the assessment start to the final remediation and readiness, depending on the complexity of the supply chain and the Quality status of the CDMO.
PAI readiness starts with conducting a gap assessment of CDMOs, internal systems for outsourcing, BLA gap assessment, and data integrity review. Once gaps are remediated, a mock audit is conducted to ensure outsourced operations and personnel are ready for PAI. If additional gaps are identified during the mock audit, then gaps are remediated, and another mock audit is conducted.
The following are examples of gap assessments conducted to identify gaps in PAI readiness:
- Assessment of quality and operations organization: An organization that is highly effective for clinical manufacturing may not be adequate for commercial manufacturing. A gap assessment is needed to address the following aspects:
- CVs, expertise, right roles, gaps
- Update the job descriptions.
- Additional training for post-marketing activities
- Is re-Org needed to support commercial manufacturing?
- Gap assessment of policies, procedures, and QMS
- Are Quality systems for commercial manufacturing in place?
- Are personnel trained in PAI readiness?
- Gap assessment for regulations
- Are there any new regulations that may impact PAI?
- Gap Assessment for Readiness for commercial manufacturing
- Are CDMOs ready for commercial manufacturing?
- Is there a backlog of deviations, change control, and CAPA?
- Quality Audit of regulatory submission
- Pre-BLA QC Checks by regulatory
- Pre-BLA quality Checks by quality
- Data integrity audit
- Independent review of data for data integrity
- Part 11 Compliance with Computer Systems
- Gap assessment for outsourcing Quality Systems for Commercial Manufacturing
- Commercial quality agreement
- Outsourcing quality systems