FDA Process Validation Guidance (Guidance for Industry: Process Validation- General Principles and Practices, Jan. 2011) outlines process validation activities in three stages - Stage 1: Process Design, Stage 2: Process Qualification and Stage 3: Continued Process Verification. Completion of Stage 2 subsequent to Stage 1 is a major milestone in the Process Validation Lifecycle as it confirms the process design and demonstrates the expected consistent performance of the manufacturing process. Knowledge and information gained from the design stage through the process qualification stage is used to complete this assessment. Stage 2 demonstrates suitability for successful commercial distribution where the data indicates that the process meets the conditions established in the protocol. Continued Process Verification is initiated for the subsequent commercial batches. Stage 3 assures that the process remains in a state of control during commercial manufacture.
21 CFR 211.180(e) regulations require evaluating and determining the need for change in manufacturing or control procedures on an ongoing basis. ICH Q8 (Rev 2) recommends an enhanced Quality by Design (QbD) approach that is comprised of a process validation lifecycle with a process verification stage. The March 2012 EMA Guidance on Process Validation requires continued process verification during commercial manufacture. This ensures a continued state of process control throughout commercial production.
Implementing Stage 3-Continued Process Verification makes business sense as it allows for freeing up of production lines and a higher throughput of the manufacturer’s portfolio. The ultimate result of a well-implemented Process Verification Process is an uninterrupted product supply that provides enhanced client service levels.
COMMERCIAL PRODUCT LAUNCH
As recommended by FDA and EMA (QbD), a design space is established at early stages of product development based on experiments conducted at pilot scale. The commercial process is operated in a specific area of the design space, i.e., Normal Operating Range (NOR), close to target operating conditions. NOR for a commercial process is defined upon evaluation of potential scale-up effects. Continuous Process Verification is to occur within the NOR. The continuous monitoring plan for quality attributes and/or process parameters as part of the routine control strategy will further strengthen a QbD-based product submission.
Stage 1, Process Design regulatory expectations are clear for a commercial product launch. The FDA’s Compliance Policy Guide (CPG) Sec. 490.100 - Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval - requires proof of process validation be obtained through rational experimental design and systematic evaluation of data, beginning from the process development phase and continuing through the commercial production phase.
Preliminary Risk Assessment and multivariate design of experiment (DOE) studies help to reveal manufacturing relationships and interactions and to establish operating ranges. These findings are documented in the product development report. For a typical solid dose manufacturing process, information available from the product development stage is leveraged in the technical transfer/scale-up studies. A technical risk evaluation (see Figure 1) prior to technical transfer/scale-up studies for solid dose products include elements such as:
• Review of API characteristics (solubility, polymorphism, hygroscopicity, particle size)
• Critical excipient characteristics (ex. MCC)
• Dissolution profile (ex. immediate release, modified release)
• Formula (API%, use of well-established excipients, etc.)
• Equipment and tooling (ex. new press, tablet shape)
• Manufacturing process (powder flow, new mfg. technology)
• Product development batches and parameter range studies (ex. blend time studies, Compression Specification Range Determination study, coating study)
• Bulk hold time results
• Evaluation of CPP
• Stability and stress studies
• Packaging configuration
A Risk Priority Number (RPN) is calculated based on development data, process understanding and historical performance data for similar products. The continuous monitoring program is a prime resource for gathering historical process performance data. The data from similar product/process can be used for a probability risk assessment.
BENEFITS FOR NEW PRODUCTS
Stage 2 Validation study batches are targeted at substantiating the parameters defined during the Stage 1 - Process Design (process development, ranging studies and scale up studies), where the commercial manufacturing process is defined. Conformance batches (Stage 2 - Process Qualification) are prepared to demonstrate that under “normal conditions and operating parameters” the process produces an acceptable product. Post commercial launch monitoring is critical for new products where there is limited product data or experience. Though the FDA guidance (Guidance for Industry: Process Validation - General Principles and Practices dated Jan. 2011) does not require splitting of Stage 3, a specific Continued Process Verification stage involving a statistically relevant number of batches to gather adequate trending data is highly recommended for new commercially launched products where historical product data is not available. For the sake of convenience, this new stage is referred to as “Stage 3A.”