FDA Guidance Process Validation: General Principles and Practices (P. 11) recommend use of credible experience with sufficiently similar products and processes. The cumulative data from all relevant studies (e.g., designed experiments; laboratory, pilot and commercial batches) are used to establish Stage 2 requirements. Bracketing of multiple strengths may be possible with an assessment that demonstrates low risk due to the change based on the Stage 3B trend. A possible candidate for such an approach is wherein an API change has a minor impact to the process and there is very solid Stage 3B trending. A bracketing approach to Stage 2 re-validation, such as three batches of the high and low strengths and one each of the middle strengths, may also be employed.
Another measure of interest, especially during development of a re-validation strategy, is the Stage 3B capability score for routine blend and dosage uniformity results. A low score may indicate a potential segregation concern. The Stage 2 re-validation sampling and testing plan must be developed in a manner that, though low, mitigates the identified risk. A risk-based (stratified beginning and end) sampling plan and an example outcome is provided in Figure 5.
Stage 3B control limits (UCL and LCL) are developed based on statistical analysis of historical product data (Stage 1, Stage 2 and Stage 3A) for trending of the CPPs and CQAs. These limits are tighter and different from the in-process/finished product Out Of Trend/Out Of Specification (OOT/OOS) criteria developed. Any recommendation to update applicable master/specifications/test profile with the Stage 3B limits may be provided in the Stage 3A report. Under most protocols, an OOT or OOS result automatically triggers an investigation, however deviation from Stage 3B limits would not necessarily trigger an immediate investigation. Instead it may require either: 1) a scientific rationale (that justifies minimal or no impact to patient safety and efficacy) for continuing with the process; 2) initiation of a change request or 3) commencement of a continuous improvement remediation project.
Additional periodic re-assessment of the validated status of a process is not relevant due to the continued process verification Stage 3B, where this is being assessed on an ongoing basis by an experienced process analyst. However, an Annual Product Review, which is a holistic review of the product encompassing review of complaint trends, field alerts, etc. is still required. Stage 3B continued process verification may begin after Stage 2 without undergoing Stage 3A in cases where data are sufficient and risk is low. The trending tools can be defined in the Stage 3B procedure and the acceptance criteria defined in Stage 3B specifications. A product specific protocol may not be required for the continued process verification stage 3B.
The Stage 3B trend report is comprised of documented evidence of CPPs, in-process and finished product CQA trend plots, as well as their analysis and recommendations. Some of the attributes/parameters that may be trended during Stage 3B for a solid dosage manufacturing (see Table).
Instances where the product data appear to trend in an adverse manner are evaluated in more detail. Stage 3B is part of the PV Lifecycle and only terminates upon product discontinuation. This stage potentially collects the most comprehensive process data for the product during its lifecycle (i.e., Stage 1, 2 and 3). Existing validated manufacturing processes with a large amount of product/process data, that have undergone multiple annual product reviews, may be placed directly at the 3B Continued Process Verification stage.
There are multiple qualified automated solutions available for implementing the Stage 3B continued process verification. The primary requirement is to identify the data sources depending on manufacturing solutions (e.g. SAP) implemented at the manufacturing site. Due to the high resource requirement, time and potential for data error, a manual data collection process is not recommended for stage 3B. Stage 3B typically requires powerful statistical software for capability trending and building statistical models. FDA Guidance for Industry: Process Validation- General Principles and Practices (P. 14), recommends that a statistician or person with adequate training in statistical process control techniques develop the data collection plan and statistical methods for procedures used in measuring and evaluating process stability and process capability (Stage 3B). The FDA Guidance further recommends having procedures for guarding against overreaction to individual events as well as for failure to detect unintended process variability.
ADVANTAGES OF IMPLEMENTATION
Dr. Pradeep Sanghvi, executive vice president, Global R&D, Apotex Inc. highlights the significance of Stage 3 validation by noting that “the continued monitoring phase proposed by FDA is the logical enhancement of the Quality by Design approach.” A QbD based approach as part of Stage 1 (Process Design) works in tandem with the principles illustrated in the FDA PV Guidance, EMA Guidance on PV, and ICH Q8, 9 and 10. The agencies encourage firms to adopt innovative approaches such as Process Analytical Technology (PAT) wherever applicable with a goal to reduce process variability that may impact the CQA’s. Stage 3-Continued Process Verification is an effective quality risk management tool for detecting trends and implementing preventive measures prior to CQA failures.
As outlined above, implementing Stage 3-Continued Process Verification and the elimination of process related failures makes business sense due to the resulting:
• Reduced cost of quality.
• Improved process control and process understanding.
• Continuous supply chain which will enhance client service levels.
• Better manufacturing planning.
• Possibility for addition of more products to the manufacturer’s portfolio.
• Reduced regulatory and compliance risk.
Regulatory agencies such as U.S. FDA expect positive outcomes from these novel initiatives. Their commitment to the guidance is reflected in recent Warning Letters where excerpts from the 2011 Guidance are referenced. Being pharmaceutical professionals serving a critical patient population, we must ensure that we utilize data from all stages including Stage 3 (Continued Process Verification) and employ scientific methods, principles to shape the foundation of our conclusions.
About the Authors:
Daniel Alsmeyer is currently Scientific Leader, Statistical Support at Apotex Inc. the largest Canadian-owned pharmaceutical company. He received his PhD in Analytical Chemistry from The Ohio State University and holds multiple patents related to PAT. He has previously led analytical labs for a major chemical company and has also worked as an independent industrial statistics consultant in the United States. He can be reached at email@example.com.
Ajay Pazhayattil M. Pharm is currently Technical Operations-Process Validation Manager at Apotex Inc. He is a certified GMP professional who has previously lead Validation, QA and Compliance groups at major Pharmaceutical brand name, generic and contract manufacturing organizations in North America and India. He can be reached at firstname.lastname@example.org
FDA Guidance for Industry: Process Validation- General Principles and Practices (2011).
EMA Draft Guideline on Process Validation (2012).
ICH Q8 (R2), 9 and 10.
FDA Guidance for Industry PAT.
FDA Questions and Answers on Level 2 Guidance- Production and Process Controls.
Conclusions of FDA-EMA Parallel Assessment of Quality-By-Design Elements.
FDA Compliance Policy Guide (CPG)- Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval.