In Part I of this two-part series, we explored sourcing and supplier management of Regulatory Starting Materials (RSMs), and how effective designation and justification of RSMs begins with supplier market analysis, feasibility studies, lab validation, and source differentiation.
These stages reduce the available supplier options. But there are additional steps to take on the path to a commercial launch. This brings us to Part II of our in-depth dissection of the selection process for RSMs.
1. Due Diligence
The initial stages of sourcing and supply management of RSMs generate massive amounts of data. Therefore, API manufacturers have a significant amount of information at their disposal for shortlisting of sources. Due diligence then kicks in to ensure only verified data is used when further narrowing the shortlist. Performing due diligence is vital for critical starting materials to ensure accurate risk assessment.
The first step in data verification involves getting information directly from the supplier, in addition to information sourced from external sources. A tailored and detailed supplier questionnaire is typically sent out, and the collected information should match details from external sources.
The second step in this process involves a site visit by the due diligence team. This allows for more detailed verification of critical aspects, including capacities and infrastructure, health, safety, quality culture, and general compliance.
What the due diligence team finds on the ground should corroborate previously collected information. The assurance of contracting with the right supplier can only happen by conducting appropriate due diligence beforehand. The combined data is then condensed into a report. Ultimately, the final go or no-go decision rests with senior management.
Things to Consider
- Is the due diligence team well-selected, and does it possess relevant expertise?
- Have all critical touch points been covered during due diligence, including material specifications, quality systems, regulatory status, safety, health, and environmental factors?
- If critical regulatory issues are identified, what’s the mitigation or remediation plan?
- Is there sufficient documented evidence to support the final recommendation and green light?
- Does the supplier have enough capacity and sufficient capabilities to justify a long-term business relationship?
- Is there a need for additional feasibility and lab validation before the conclusion of this stage?
2. Material Audit and Plant Validation
At this stage, teams tasked with the selection of RSMs turn to audit plan implementation and plant validation. Audit plans and validation are necessary to support the final ‘Go’ or ‘No-Go’ decision. Both processes should be tailored to the particular chemical, precursor, or intermediate incorporated into the API manufacturing process.
Generally, an audit is based on key parameters such as material classification, risk level as identified during due diligence, assurance of supply at a commercial scale, and the acceptance criteria for regulatory approval.
The audit plan is a valuable quality assessment tool that ensures the procurement process is headed in the right direction in the final stages. It culminates in an audit report that will potentially drive the finalization of the quality assessment and signing of the quality agreement.
With plant validation, the central focus is procuring starting materials for the commercial phase. The validation process encompasses the production of 3-4 batches of the API to ensure process repeatability and establish if the yield, quality, and impurity profiles generated from prior lab experiments remain acceptable at the commercial scale.
Plant validation also includes the validation of equipment, labs, and processes as part of regulatory compliance for pharmaceutical manufacturing facilities. Doing this early can reduce time-to-market and increase budget optimization.
Things to Consider
- Are the preliminary batch products adequately tested and are the results thoroughly reviewed before the release of the finished product?
- Does the facility meet all requirements related to material specifications, such as proper equipment design and size?
- Does a review of audit reports show that each supplier satisfied the required manufacturing controls?
- Do test results on starting materials support the information provided on the supplier’s Certificate of Analysis?
- Is there a plan to periodically inspect and audit suppliers and perform plant validation?
3. Data Analysis and Regulatory Filing
Data is consistently generated at each stage of the procurement process. This presents an opportunity for continuous data analysis to better ensure compliance with regulatory standards. In other words, a systematic evaluation of collected data allows for the judicious selection of RSMs and increases the chances of regulatory acceptance.
For instance, if a synthetic route has been developed using the proposed RSM, data analysis shows if there are enough chemical steps from the final drug substance. Shorter synthetic routes are unpopular with regulators since they typically don’t leave enough time or space to effectively remove impurities and isolate APIs.
Once an analysis of the data shows the appropriate level of alignment required for commercial approval, it’s time for regulatory filing and review. Regulatory review of the proposed RSM generally depends on the location and the type of regulatory agency involved. So, knowing location-specific regulations and regulator protocols helps with accurate data analysis and anticipation of potential risks.
Data analysis and regulatory filing are better off performed before developing downstream processes, since failures in upstream processes could cause an expensive redo of downstream development work.
Things to Consider
- Is there flexibility for consultation or dialogue with regulators to ensure compliant starting material selection?
- Are all RSM-related documents in place, and have they been reviewed, updated, approved, and submitted according to plan?
- Is there sufficient evidence of processes and controls to prove compliance?
- Does the entire process conform to good document practices, including proper records retention?
- What’s the protocol if a regulator rejects the RSM designation?
The sourcing and supply chain management of regulatory starting materials is a critical factor in the balancing act of meeting or exceeding regulatory requirements – while maximizing commercialization and de-risking supply. Investments made into the process allow stakeholders needs to be addressed and operational sustainability to be met.