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Regulation of Biopharmaceutical Products: Government Perspectives
Facilitator: Kenneth Seamon, University of Cambridge
Antibody Drug Conjugates
Session Co-Chairs: Laura Bass, Pfizer, Inc. and Lotte McNamara, LKM CMC Consulting
Antibody-Drug Conjugates (ADCs) are monoclonal antibodies conjugated to small cytotoxic molecules using chemical linkers. ADCs are complex molecules with multiple sources of heterogeneity derived from the incoming mAb (size, charge, glycan variants) and small molecule (charge, chemical variants) components as well as from the conjugation reaction (drug distribution, sites of attachment, conjugation side-products). Although traditional analytical methodologies can be utilized for the intermediates (mAb and small molecule), modification of these technologies are often required to ensure sufficient control of the final drug conjugate in terms of detecting changes in both the ADC and the cytotoxin, linker and/or mAb in the presence of the ADC. To develop an appropriate control strategy for the ADC and its intermediates it is important to identify the ADC quality attributes that impact safety and efficacy. The ADC quality attributes will dictate the mAb and cytotoxin quality attributes and thus the control strategy for these intermediates. The testing strategy and associated specifications for the ADC are thus defined by the combination of control strategies which in addition to release and stability testing of the ADC includes testing of raw materials and intermediates (monoclonal antibody and drug / drug linker molecules) as well as identification of appropriate process and procedural controls to ensure delivery of a consistent, safe and efficacious product that meets regulatory expectations.
This plenary will focus on industry approaches to and regulatory perspectives on ADC control strategies and how these strategies have evolved during the past decade from the approval of Mylotarg to the latest ADC BLA filing in 2011. In addition, an update of the regulatory review process for ADC will be provided.
Session Co-Chairs: John (JR) Dobbins, Eli Lilly and Company and Edwin Moore, Baxter Healthcare Corporation
Pre-filled syringes (PFS) are a preferred delivery system for many biopharmaceuticals. Developing biopharmaceutical products in syringes present a number of challenges including the choice of container (including plastic versus glass), choice of closure, compatibility of the protein and formulation with the syringe materials, stability of the protein in the syringe, and integrity of the container and closure system. Evolution of analytical methods to differentiate and quantify protein aggregates from silicone particles presents new means of characterizing PFS products. In addition to the quality aspects related to the container closure functionality of the PFS, the classification of a PFS as a combination product brings to the forefront additional considerations such as the potential applicability of device standards, and the potential need for user and human factors studies. Furthermore, transitioning a product from a PFS presentation to an auto-injector during development and / or post-licensure presents challenges and could result in the need to conduct additional clinical studies. This plenary session will address the above challenges faced by industry and by regulatory authorities throughout the development of biopharmaceuticals combination products.
Cell and Gene Therapy Complex Biological Products – What Will It Take To Make Them Well-characterized?
Session Co-Chairs: Steven Bauer, CBER, FDA and Yuan Xu, Genomics Institute of the Novartis Research Foundation
Cell and gene therapy products are frequently classified as “complex” based on their methods of manufacture, their intricate molecular composition and structure, and the challenge of relating their analytical characteristics to their functional properties. Many chemical, physical, and biological properties can be measured but thorough structural characterization is limited due to their complexity. Incomplete structural characterization means there is a lack of comprehensive product and process knowledge, so the challenge becomes a need to identify and clearly link specific quality attributes with clinical performance. Biological/ functional assays may provide links to clinical performance, but these assays are often challenging to implement as validatable in-process or lot release assays due to factors such as high inherent analytical variability, length of time, and the amount of product needed for assay performance.
The goal of this session is to further our understanding of characterization strategies and explore the challenges faced in the manufacture and licensure of these products. The session will include case-studies illustrating strategies used for gene transfer vectors products and for cell-based products. Concepts of Quality by Design paradigm and Risk-based approaches will be discussed when applicable.
Sequence Variants: What, Why, When, How, and then What?
Session Co-Chairs: Anthony Lubiniecki, Johnson & Johnson Pharmaceutical R & D, Arne Staby, Novo Nordisk A/S
Protein sequence variation is an inevitable consequence of the imperfections inherent in replication, transcription, and translation processes within living cells. Although some sequence variants are product-related substances, not impurities, they should be avoided and/or adequately controlled. This session will address what modern science can show about how frequently these events can occur, and what their effects may be on biopharmaceutical product quality attributes and on product development. The session will present the technologies commonly used to detect sequence variant presence, what are the options are to remove them or to mitigate their presence, and the implications they may have on regulatory filings.
New & Emerging Technologies
Session Co-Chairs: Roman Drews, CBER, FDA, John Hennessey, NovaDigm Therapeutics, Inc. and Susan Kirshner, CDER, FDA
This plenary session will focus on new and emerging technologies that advance analytical evaluation and manufacture of new biological macromolecular entities with improved clinical performance. There are several technical aspects of these biological products where the more we know, the more questions we seem to have. As examples, there are:
- challenges associated with the characterization of post-translational modification variants – how detailed do we need to get?
- new chemically or genetically modified products – can we distinguish relevant changes from “silent” changes
- the measurement and evaluation of potency as related to clinical biomarkers – can these be tied to efficacy
- and formulations/delivery systems incorporating nano-particles – do we need to understand the mechanism of action or just show that they are effective?
These and other aspects of characterization of biological products and the processees that make them beg for new tools and analytical approaches to address the new questions posed. These new tools and approaches are the intended focus of this plenary session.
Advances in the Development and Characterization of Vaccines
Session Co-Chairs: Arifa Khan, CBER, FDA and Stefanie Pluschkell, Pfizer, Inc.
This session will highlight recent advances in the development and manufacture of vaccines. Regulatory Agency as well as the industry’s perspective will be presented, discussing current the opportunities and challenges of developing and manufacturing a vaccine for the US and the global market. Life cycle management aspects will be addressed. Additionally, there will be a focus on advances in developing product and process understanding of vaccine candidates, e.g. via Quality by Design approaches, including improvements in the development of control strategies and analytical characterization tools to identifying vaccine quality attributes that may be critical to clinical performance.
Assay Lifecycle Management: It’s Not a Mistake, It’s a Design Feature
Session Co-Chairs: Marjorie Shapiro, CDER, FDA and Robert Sitrin, Sitrin Solutions
Release assays for biotech products developed and licensed many years ago are often associated with widely variable and dated technologies. In many cases, the original potency assays were animal based and susceptible to wide variation. In other cases, the instrumentation described in the original license application is obsolete and no longer supported by the vendor. There may also be examples where an evolving technology provides a better quantification of results. Furthermore, as older processes are themselves being modernized or revalidated (perhaps because they are being moved to new facilities), appropriate analytical tools with higher levels of precision are expected.
Introducing new technology brings with it many challenges – bridging data between methods, understanding offsets, reacting to new data, applying appropriate statistical methods and resetting specifications. In this session, examples of strategies for assay life cycle management as well as examples of implementation of new assays will be presented.
Reference Standards: You Have Questions, We Have Answers!
Session Co-Chairs: Brian K. Nunnally, Pfizer, Inc., Timothy Schofield, Arlenda and Sally Seaver, Seaver Associates LLC
Reference standards are an important component of a pharmaceutical quality system. They help assure continuity of assessment throughout product development and into commercial manufacture. There are many questions surrounding the use and maintenance of reference standards for biological products. These are associated with methods for producing reference materials, as well as the selection, characterization, and maintenance of these standards throughout the lifecycle of the product. What constitutes a reference standard? When should it be introduced? What are the necessary properties of a reference standard? Reference standard or reference material – is there a difference? It is impossible to answer these questions in a single plenary session, but we expect to begin the discussion and more!
This plenary session will include speakers from industry and government. The speakers will discuss the challenges associated with determining the presentation and storage of the standard, qualification of the standard (including re-qualification), and developing international standards. In addition, stability (or continuing suitability for purpose) of a reference standard will be discussed. A panel discussion after the talks will afford attendees the opportunity to express their opinions and ask their own questions about reference standards.