Authors: David Dolgin (PSC Biotech), David Hughes (Sandoz), Matthew McMenamin (GSK), Parab Parkash (BMS), Domenico Schiavone (Fresenius-Kabi), Chris Stevenson (Baxter)
This Discussion Paper examines some of the topics and challenges related to the implementation of current Good Manufacturing Practice (“cGMP”) Process Validation (PV) lifecycle concepts in the management of Quality Systems for existing (“legacy”) commercial products. The paper aims to identify common issues related to the application of lifecycle principles in a legacy product context, and to discuss potential responses to various scenarios that may be encountered.
Among the topics to be discussed:
Current Validation Lifecycle expectations for legacy products
Strategies for assessing and prioritizing requirements for legacy process/process validation remediation
Expectations for revalidating a modified legacy process
Expectations for revalidating an unmodified legacy process based on existing PV “gaps”
This Discussion Paper is focused on the challenges of implementing a current process validation lifecycle approach in the quality management of a set of products initially validated and commercialized prior to the formal introduction of the current lifecycle architecture. This includes cases where the process was not necessarily developed, characterized, and/or documented in accordance with current concepts (e.g., as described by the current version of ICH Q8(R2)  such as “Quality by Design” (QbD)).
Regarding the legacy product processes that it addresses, the assumptions of this paper are as follows:
Products were previously validated, are currently being marketed commercially, and are typically in the lifecycle stage referred to in this paper as Ongoing Process Verification (OPV), (also known as Continued Process Verification (CPV)), or ongoing monitoring phase
Original or previous process validation(s) were conducted in compliance with predicate GMP rules current at the time of validation
A Pharmaceutical Quality System (PQS) consistent with ICH Q10  is in place at the manufacturer
The intended scope of this paper includes both Active Pharmaceutical Ingredients (APIs) (Drug Substances) and Drug Products. It also includes both large and small molecule products, and all routes of synthesis and dosage forms. The principles and practices described and discussed are generally applicable, and are intended to comply with understood and accepted international Good Manufacturing Practice (GMP) expectations for pharmaceutical process validations. Products made by,or for, Third Party Manufacturers (TPMs) and/or Contract Manufacturing Organizations (CMOs) are also included.
This paper focuses on issues related to establishing and/or maintaining the “validated state” for legacy products for which some current lifecycle concepts may not have been formally established and implemented.
Organizational strategies will be presented for the prioritization of remediation of legacy product validation lifecycles based on:
Product risk (dosage form, criticality of clinical effect, etc.)
Product history (available data, quality history, manufacturing experience)
Prioritization of products, for which gap closures may be needed
This paper is not intended to be a discussion of the lifecycle validation approach per se, as numerous other articles and information sources exist on that topic. It is not intended to examine issues or practices around process development, technology transfer, qualification of facilities and systems, planned changes to existing products or supporting process validations (such as validation of cleaning or analytical methods). It does, however, consider such topics where they intersect with the general intent of monitoring and maintenance of the validated state, and the actions taken in response to quality data signals to maintain that state.
In addition, this paper does not discuss the mechanics of OPV (such as determining which parameters and attributes to track, setting control/action limits, frequency of process analysis, etc.), as these topics are covered in detail in another ISPE PQLI PV Group Discussion Paper: “Stage 3 – Process Validation: Applying Continued Process Verification Expectations to New and Existing Products” .
Updated process validation guidance documents from the US FDA, EU, ASEAN, and other regional regulatory authorities have described similar 3-phase validation lifecycles, based on process knowledge and quality risk management in alignment with ICH Q8(R2) /ICH Q9 /ICH Q10 . The Validation Lifecycle discussed in this paper consists of three “stages”, with the starting point of this paper being products that are currently validated and being marketed commercially (in the OPV stage below). In the terminology of the Process Validation Guidelines [5, 6], such products are referred to as “legacy products”. The lifecycle stages referred to in this paper are:
Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.
Process Qualification: During this stage, the process design is evaluated to determine if the process, along with supporting equipment and facilities, is capable of reproducible commercial manufacturing. This typically includes manufacture of the initial validation lots (or Process Performance Qualification (PPQ) lots).
Ongoing Process Verification: This is post-commercialization and ongoing assurance during routine production that the process remains in a state of control. OPV is actually a two-phase stage, with initial monitoring of new or redesigned products being monitored more intensively based on less historical data and process experience, with more reduced levels of monitoring as statistical confidence builds. The initial phase of OPV is often referred to as “Enhanced” OPV, while the normalized sampling, periodically adjusted in response to the voice of the process, is referred to as “routine”.
Prioritization of perceived gaps, generally, should precede programmatic efforts at remediation. In some instances, a comprehensive assessment of the product may already be available as an output from the Annual Product Review, OPV (if implemented), past site inspection readiness efforts, or recent audits. For such instances, these assessments may be used to support the gap/risk assessment process accordingly. The associated output from the previous assessment should be formally documented and attached as supporting documentation for this protocol.
In all cases for the recommendations and contents of this paper, there will be the intent to conform to the two primary principles of ICH Q9 “Quality Risk Management” :
The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient.
The level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk.
The flowchart in Figure 1 depicts a two-part “decision-tree”; the top of the chart illustrating the organizational evaluation, followed by an example of a process-specific evaluation with potential options for responses to various scenarios.
Read more by downloading Process Validation Lifecycle Implementation for Existing Products Discussion Papers.