Lifecycle Approach to Biotech Process Validation

This discussion paper proposes ideas for answering the questions about the application of the lifecycle approach to PV to Biotech product manufacturing. The paper discusses unique elements of application to biotech products and similarities and differences as compared with utilizing the lifecycle approach to PV to validate other drug substance/API and drug product manufacturing. The purpose of this paper is to stimulate further discussion and suggest potential practical application. Approaches to providing answers, are proposed, but more experience in implementation of the lifecycle approach to PV is needed to finalize a consensus a position. Considerable input has already been received, considered, and/or incorporated. The author team is interested in hearing about other approaches that could be used, and lessons from use of the proposed approaches described in the discussion paper and additional examples. The paper may be modified or expanded sometime in the future to reflect additional input.

Additional input in the following areas is sought:

  • Feedback (agreement/disagreement) on basic premise of paper, which is that small molecule manufacturing processes and biologics manufacturing processes have no essential differences in general application of lifecycle validation approaches. If disagreement, why?
  • Additional examples of creative solutions to issues that arise specific to validation of biologics manufacturing processes – specifically, with regard to QbD implementation.

Please direct all feedback to

Authors: David Dolgin (AbbVie), Kurtis Epp (CSL Behring), Wendy Zwolenski-Lambert (Novartis), Michael Rooney (Jazz Pharmaceuticals), Lilong Huang (Biogen Idec), Matthew McMenamin (GSK)

1 Introduction

The lifecycle approach to process validation promotes quality being designed into a pharmaceutical manufacturing process via a risk-based and science-based approach to assessing and understanding the relationships between process variables and a product’s quality attributes. This discussion paper examines the implications of the lifecycle validation concept for biotech1 processes, and moves beyond “the basics” to provide examples of the application of principles in a biotech context, focusing on risks, statistics, and sampling plans. It is not intended to be a manual on the lifecycle validation approach, as several other such documents exist.2 Rather, it is strictly focused on highlighting general (not always the case) differences that are encountered during implementation of lifecycle concepts to biotech products, as compared to small molecules, and then discussing suggested approaches to deal with the unique challenges faced. This paper is structured around the three stages of process validation described by FDA (Stage 1: Process Design, Stage 2: Process Qualification, and Stage 3: Continued Process Verification)3 because these terms, while suggested by FDA, are being adopted globally by many pharmaceutical manufacturing companies and industry organizations. The concepts, while discussed within the FDA-applied stages of process validation, are global in support and application (as observed by multiple references by global organization like ISPE, PDA, ICH, etc.).

Stage 1 (Process Design)

A thorough understanding of the relationship between process variability and product quality prior to the initiation of formal process qualification activities is probably the most fundamental component of the lifecycle validation concept. While this requirement is in place for both small molecules and biotech products, the complex nature of a biological manufacturing process typically means that Stage 1 (Process Design) carries the greatest difference with regard to extensiveness and duration of activities. A quick way to show the complexity and additional regulatory requirements for a biological product is through a figure of ICH guidelines that are specific to biologics and predominantly impact Stage 1 activities (shown in white boxes in Figure 1).

Read more by downloading Lifecycle Approach to Biotech Process Validation (Published August 2014).

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