Biomanufacturer Raw Material Control on Regulatory Front Burner as Analytical Power and Formulation Challenges Intensify


A more powerful analytical toolbox is allowing industry and regulators to better understand how biotech product manufacturers can improve the control strategies for the raw materials they are using. However, there are still significant knowledge and control gaps, and experts from industry, regulatory agencies, and pharmacopeias are actively sharing insights on how best to fill them.

In this three-part story, IPQ explores the current industry/regulator dialogue on raw material control for biological products – where the regulatory concerns lie and how industry control practices are evolving as the knowledge base increases in depth and breadth.

A central focus is the discussion at a USP workshop on “best practices and quality standards” for raw materials used in biomanufacturing, which was held virtually in April 2021. Also shedding significant light on the issues was a CASSS CMC Strategy Forum on “the impact of excipients and HCPs on the formation of particles in biologics,” held in conjunction with the 2020 CASSS annual WCBP conference, and the story includes valuable insights from that forum as well.

● Part I focuses on the presentations by FDA biotech product regulators at the opening session of the USP workshop. The reviewer perspective was provided by CDER Office of Biotechnology Products’ Ashutosh Rao. CBER’s Ekaterina Allen then reviewed how agency inspectors evaluate the compliance of raw material management systems in biomanufacturing and shared some of their current findings.

● Part II explores how the raw material quality considerations facing manufacturers of conventional biopharmaceuticals expand in both complexity and significance as one moves into the realm of cell and gene therapies (CGTs). Reviewed are the insights provided at the USP workshop by: ● consultant Gary du Moulin and BMS’ Lilly Belcastro, representing BioPhorum, on the issues that companies are facing in addressing gene therapies in particular ● Stefan Yohe on Roche/Genentech’s learnings and evolving program in handling CGT raw materials, and ● Paul-Ehrlich-Institut’s Johannes Blűmel on the viral safety of raw materials for cell-based medicines.

● Part III homes in on the challenging issues that biomanufacturers are facing in improving their understanding of and control strategies for polysorbates. In focus are the presentations at the USP workshop by: ● USP committee members Richard Cawthorne and Dominic Moore on the polysorbate challenges and how the compendia could be updated to help address them, and ● Lonza’s Michael Jahn on the analytical issues for addressing polysorbate QC. Also reviewed are the discussions on the impact of polysorbates and HCPs on particle formulation that took place at the CASSS forum, where OBP’s Rao provided a regulator’s perspective on the excipient/product quality attribute (PQA) relationship and the opportunities and expectations for reducing the interfacial tension. A summary of the CASSS forum presentations and panel discussions provided at its conclusion is included.

[Editor’s Note: Complementing the in-depth IPQ coverage of selected key presentations at the USP raw materials workshop is a recently published overview of the workshop discussions and related USP initiatives by USP Global Biologics Education and Training Senior Scientific Fellow Maura Kibbey. Click here to access Kibbey’s write-up.

A review of the starting material issues facing peptide and oligonucleotide developers and manufacturers was provided in Part IV of our recently released story on the quality and regulatory developments impacting peptides and oligos (see IPQ August 9, 2021). That story is focused heavily on the peptide/oligo workshop held by USP in March 2021, which was similarly structured to the April raw materials workshop and similarly informative.

Also highly relevant to the discussions that took place at the April USP raw materials workshop is a multipart story released last year (see IPQ March 20, 2020) exploring the industry/agency/pharmacopeia dialogue around the need for: ● a more qualified-for-purpose excipient toolbox that can help address the formulation, quality, and manufacturing challenges posed by a new generation of medicines, and ● a regulatory process that can better accommodate novel excipients. FDA is about to launch a pilot program for that novel excipient review process.]

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