With an increasing number of products being considered for accelerated development, both the industry and regulators are looking for ways to safely hasten product development and approval times to ensure availability of innovative and low-cost drugs for patients. The development and validation of test methods during the regular product development lifecycle is a challenge. Not surprisingly, an accelerated timeline magnifies this challenge. Many developers struggle with bridging early-stage, fit-for-use test methods with the validated late-stage methods needed for process performance qualification (PPQ)/validation, routine production and post-approval requirements (1).
For biosimilars, the rigor of method development, qualification, and/or validation for specific quality attributes needs to be commensurate with their impact on analytical similarity demonstrated between the biosimilar and reference product, and consideration should be given to the potential for delays in product development and/or approval. Risk-based, practical concepts for how and when analytical methods are qualified, transferred and validated should be used and supported by industry and regulatory agencies. The method type, intended use (Tier 1, 2, or 3 quality attributes), and/or prior experience (e.g., analytical platform technology) should also be considered.
When demonstrating analytical similarity between the biosimilar product and the reference product, a grouping of the critical quality attributes (CQA) into three main risk categories is performed according to their criticality. Following a risk ranking for quality attributes, the CQAs are then grouped into Tier 1-3 categories (Tier 1 is the highest risk group) based on their potential impact on activity, PK/PD, safety, and/or immunogenicity (2). For example, the mode of action is typically a Tier 1 CQA and equivalence testing is, therefore, expected. Table 1 lists the expected study model for each of the three criticality (Tier 1-3) levels.
Recently, an industry survey evaluated how manufacturers transfer analytical methods for biological drugs. Significant variations were observed among the surveyed manufacturers, specifically in the use of analytical method transfer (AMT) models, sample size, and setting of acceptance criteria (3). These results indicate that more pragmatic guidance is needed across the globe to support accelerated product development, such as pathways for biosimilars.
Industry Reps Make Case to FDA
Last September, the author presented an industry perspective on how to reduce analytical CMC steps in support of accelerated biological product development to CDER representatives at the U.S. FDA headquarters (4). This presentation followed up on a 2012 presentation delivered at CDER of the draft content from PDA Technical Report No. 57: Analytical Method Validation and Transfer for Biotechnology Products (5).
At the most recent meeting, strategies for the analytical method lifecycle steps were discussed along with how they may minimize the risk of potential product development and approval delays. The suggestion to use analytical platform technology (APT) methods, and with it, the benefit of executing lower-risk, reduced method validation studies, was well received by CDER.
An APT method is an analytical method used for multiple products and/or types of sample matrix without modification of the procedure. Similar to compendial methods, an APT method may not require full validation for each new product or sample type(3). A test method becomes an “approved” method when included in a marketing license application, and the license is approved.
Many Benefits to APT Methods
Additionally, the author emphasized further advantages of APT methods to the CDER representatives, highlighted here:
- APT status can be extended to additional products, if the test method remains essentially unchanged through proper use of change control
- Similar to compendial method verification, “approved” test methods can be verified (versus validated) for use of additional products
- Reduced method qualification and transfer studies could then be executed, provided the same sending and receiving units are used
- For additional product license applications, the sponsor should resubmit the initial method validation study report together with product-specific verification results (and reports)
- For bioassays, product specifications, such as 50–50%, should be tightened as early as possible as FDA has significant concerns with regard to the Mode of Action (MOA) potency assays; conversely, there are less concerns for APT methods, such as typical separation tests, e.g., HPLC Size Exclusion
- For separation tests, an actual manufacturing batch should be used for test system control as test result drift and/or variation could be observed over time; degraded batch samples closer to the out-of-specification (OOS) level could provide better system suitability control, and they may also provide more confidence in the test results when results are close to the OOS level.
This article originally appeared in the PDA Letter, a publication produced by the Parenteral Drug Association. April 19, 2016
- Mire-Sluis, A. et al., “Accelerated Product Development: Leveraging Industry and Regulator Knowledge to Bring Products to Patients Quickly.” BioProcess International 12 (2014)http://www.bioprocessintl.com/analytical/downstream-development/accelerated-product-development/
- Chow, SC, “On Assessment of Analytical Similarity in Biosimilar Studies.” Drug Des 3:e124.
- Krause , S. “Survey Results of Analytical Method Transfer Conditions Used by Global Biologics Manufacturers.” BioPharm International 28 (2015): 22-30http://www.biopharminternational.com/analytical-method-transfer-conditions-used-global-biologics-manufacturers
- Krause, S. “Specifications and Analytical Method Lifecycle for Accelerated Biologics.” Presented at FDA headquarters. September 28, 2015.
- Krause, S. et al., PDA Technical Report No. 57: Analytical Method Validation and Transfer for Biotechnology Products. Bethesda, Md.: PDA, 2012.
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