Authors: Mette Bryder (Lundbeck), Harold Etling (Eli Lilly), Jeff Fleming (Pfizer), Yanhui Hu (Abbott), Peter Levy (PL Consulting)
Since the adoption of the ICH Q9, Quality Risk Management (QRM), by the Pharma industry, the importance of the QRM approach and its benefits has become evident. This trend invites re-examination of well-established practices. One such example is the widely adopted concept that validation is a one- time activity and that three consecutive successful validation batches is sufficient to demonstrate process reproducibility. It has long been recognized that successful manufacture of three consecutive batches may not necessarily provide assurance of process reproducibility, as routinely relying on three sequential batches alone does not always provide strong confidence that the process will continue to deliver product that consistently meets quality acceptance criteria.
The revised Process Validation (PV) Guidance from FDA (January 2011) aligns process validation activities with a product lifecycle concept, emphasizing the expectation that process validation starts with process design and spans the entire lifecycle of the marketed product. More specifically, the Guidance recommends that Process Performance Qualification (PPQ) approaches (PPQ being an activity that is part of what the Guidance describes as Stage 2, where process design is evaluated to determine if it is capable of reproducible commercial manufacture) should be based on well-grounded scientific justification, an appropriate level of product and process understanding and adequate demonstration of control. The FDA Guidance does not define a regulatory expectation for the number of process qualification batches. It is expected that manufacturers make a rational decision for the number of validation batches and design of the PPQ study based on product knowledge and process understanding. A sufficient number of batches should be included in the study(ies) to demonstrate reproducibility and an accurate measure of between batch variability. This will provide sufficient evidence that the process is reproducible and that commercial release of the product to the market is justified.
The science and risk based approach described in this paper is applicable to the manufacture of human and animal drug and biological products, including drug products, the drug constituent of a combination (drug and medical device) product, active pharmaceutical ingredients (APIs) and drug substances. It is applicable both to validation of new manufacturing processes and to validation of changes to existing processes (e.g. changes in site, process scale, equipment, etc.).
The suggestions described in this paper focus on how the task of justifying a number of PPQ batches might be addressed and are not intended to represent an industry consensus. The approaches described in this paper are intended primarily for prospective validation. For concurrent validation other approaches not described here may be more relevant.
The application of these recommendations assumes that a manufacturer has established a robust Quality Management System as described in ICH Q10 for documentation, training, etc.
The 2011 FDA PV guide advises us to look at knowledge acquired from development and historical performance of a process to help define the expectations for process validation. This information is assessed in the context of the product’s clinical use (or from other sources of product knowledge) and its potential impact on patient safety and product efficacy. For example:
“Process knowledge and understanding is the basis for establishing an approach to process control…. Strategies for process control can be designed to reduce input variation (or) adjust for input variation during manufacturing… Process controls address variability to assure quality of the product.”
“Manufacturers of legacy products can take advantage of the knowledge gained from the original process development and qualification work as well as manufacturing experience….”
“…activities …. such as experiments or demonstrations at laboratory or pilot scale also assist in evaluation… and prediction of performance of the commercial process.”
During the process qualification stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. The goal of PPQ is to confirm the process design and demonstrate that the commercial manufacturing process performs as expected. This includes providing scientific evidence that the process is reproducible and will consistently deliver quality products. How much process knowledge/understanding and other evidence is needed to achieve this aim? For the purpose of this paper, this question can be restated as:
How many qualification batches are required for the PPQ studies, when considered along with Stage 1 activities, to demonstrate that the process implementation and control strategies are sufficiently robust?
Based on the extent of process knowledge and process understanding, there may be cases where the number of validation batches needed to show process reproducibility may be less than or greater than three. Any applicable regulatory requirements for a minimum number of validation batches should also be taken into account.
This discussion guide is intended to provide suggestions that will stimulate further thought and discussion of this topic; it does not reflect a consensus position of the industry. This paper describes a framework for systematically assessing the level of product knowledge and process understanding, and how well the control strategies are linked to the Critical Quality Attributes (CQAs). The residual risk identified from this assessment may then be translated to a number of validation batches. The overall approach described in this paper is outlined in Figure 1. Following this, data from the PPQ batches are analyzed using appropriate statistical methods to determine the out-come of the PPQ study and to help identify what the appropriate level of sampling and analyses may be in Stage 3 (the commercial manufacturing stage of the product lifecycle). A discussion guide “Applying Continued Process Verification Expectations to New and Legacy Processes” that describes some practical approaches to fulfilling the requirements during Stage 3 was issued at the same time as original issue of this discussion guide. For a process where different steps may be validated separately, such as can be the case for a multiple-step drug substance process, the evaluation may indicate that different steps necessitate different numbers of PPQ batches, based on the science and risk associated with each step.
Read more by downloading Stage 2 Process Validation: Process Performance Qualification Batches Discussion Paper.