Quality by Design: Enhancing Biopharma Validation and Microbial Retention Assurance in Sterilizing Filters

Quality by Design and its Impact on Biopharma Validation

Quality by Design was a FDA initiative to encourage companies to utilize a more systemic approach to the development, including development of the manufacturing process, of pharmaceutical products.  During development there would be an increased emphasis on process understanding and control with particular emphasis on the molecular attributes of the drug molecule that are linked to efficacy and safety.  There would be a proposed Design Space in the BLA that would encompass the totality of the process parameter ranges in the manufacturing process.  If approved, there would be post approval freedom to move the manufacturing process in the Design Space without prior FDA approval.  It is important to note that utilizing a QbD filing is not mandatory.

FDA and the biotech industry spent considerable time determining how QbD would actually be implemented for protein drugs that were larger, more complex than small molecule drugs with more elaborate manufacturing operations.  The outcome utilized risk assessments at multiple points in the development of the manufacturing process to define critical quality attributes, experimental design of process characterization studies, process parameter ranges, and critical process parameters.  These concepts and approaches are now a regulatory expectation regardless of whether the BLA filing is QbD.

Presented by Gregory S. Blank, Ph.D. Independent Consultant and retired Director, Late Stage Purification Department at Roche Genentech

Dr. Blank is a recognized global leader in Bioprocess development.  He spent over 23 years at Genentech most recently as Director of the Late Stage Purification Department responsible for development of commercial processes, post approval changes, and process validation.  Also reporting to Dr. Blank was the virus validation group.  He received his Ph.D. in cell biology from the University of Southern California in 1981.  Following post-doctoral fellowships at Case Western University School of Medicine and Becton Dickinson Monoclonal Center he joined the Recovery Sciences Department at Genentech in 1987.  He became department director in 2000.  While at Genentech he has focused on monoclonal antibody process technology and has led the development and commercial scale-up of recovery processes for both full-length antibodies (including Rituxan, Herceptin, and Raptiva) from mammalian cells and antibody fragments from bacteria.  The purification processes Dr. Blank developed for Herceptin and Rituxan have formed the purification platform for all of Genentech’s monoclonal antibodies.  He has also helped develop Genentech’s approach to process validation including virus validation, modular validation, and Quality by Design. 

Since 2010 Dr. Blank has consulted for organizations across the globe in the areas of purification process development, scale-up of manufacturing operations, process validation and characterization, virus validation, and regulatory filings.

He has over 40 publications and patents in areas of process development, process validation, manufacturing operations, virus validation, documentation and has lectured extensively in these areas.  He has had an appointment as an Adjunct Professor in the Department of Pharmaceutical Chemistry, University of Kansas and is on the Editorial Board of BioProcessing Journal. 

Assuring performance in sterilizing filters: a supplier’s perspective

The implementation of a Quality by Design approach to how sterilizing filters are designed, validated and manufactured illustrates how filters are designed to meet regulatory and industry requirements for sterility assurance. Critical process parameters are monitored to ensure consistent quality of the product, supporting the requirements for sterility assurance. This approach will be discussed, as well as studies that varied process and product parameters (pressure, product concentration, time, temperature) to determine their effect on microbial retention, data which can be used to define a design space for pharmaceutical manufacturers.

Presented by Annie Leahy, Senior MSAT Manager at MilliporeSigma

Annie Leahy is an Senior MSAT Manager in the North American Manufacturing Sciences and Technology (MSAT) group within MilliporeSigma. She leads a highly technical team that ensures successful implementation and ongoing operation of customer applications across the manufacturing process. Her area of expertise focuses on virus and sterilizing filtration operations, supporting customers during their manufacturing process to provide best practices and ensure optimal processing conditions. Annie has over 15 years of experience, which has included developing improved methods for virus spike preparations and mycoplasma retention methods as well as conducting virus and sterilizing filtration applications studies at both small and large scale. She holds a BS in Biology from Dickinson College and an MS in Biotechnology from Northeastern University.

A Quality by Design (QbD) Approach to Microbial Retention Validation of Sterilizing Filters

Regulatory and manufacturing requirements exist to perform product-specific microbial retention testing on sterilizing filters.  The implementation of a Quality by Design approach to microbial retention testing supports a paradigm that would obviate the need for product-specific testing for early-stage products that do not have the quantity of material required to easily and efficiently perform such testing.  Process and product parameters were varied to determine their effect on microbial retention. To minimize the burden of filter validation retention studies for early-stage (Phase 1) manufacturing, it is recommended that manufacturers perform a risk assessment to confirm their product and process conditions are within the established design space.

Presented by Jennifer Juneau, Senior Principal Scientist at Pfizer

Jennifer Juneau is a Senior Principal Scientist with over 30 years experience in Pharmaceutical Research and Development at Pfizer, Andover MA.  She has developed and transferred both liquid and lyophilized drug product manufacturing processes for several commercial products and many clinical products.  Her area of responsibility and expertise include process/product development, scale-up, tech transfer, and filter validation.  She received her Bachelors degree in Chemical Engineering from Worcester Polytechnic Institute (WPI). 

Followed by a live Questions and Answers session

Sponsored by MilliporeSigma

The Life Science business of Merck KGaA, Darmstadt, Germany, which operates as MilliporeSigma in the U.S. and Canada, has more than 27,000 employees and more than 55 total manufacturing and testing sites worldwide, with a portfolio of more than 300,000 products focused on scientific discovery, biomanufacturing and testing services. Merck KGaA, Darmstadt, Germany, a leading science and technology company, operates across healthcare, life science and electronics.

Around 63,000 employees work to make a positive difference to millions of people’s lives every day by providing products and services that accelerate drug development and manufacturing. In 2023, Merck KGaA, Darmstadt, Germany, generated sales of € 21 billion in 65 countries.

The company holds the global rights to the name and trademark “Merck” internationally. The only exceptions are the United States and Canada, where the business sectors of Merck KGaA, Darmstadt, Germany, operate as MilliporeSigma in life science, EMD Serono in healthcare and EMD Electronics in electronics. Since its founding in 1668, scientific exploration and responsible entrepreneurship have been key to the company’s technological and scientific advances. To this day, the founding family remains the majority owner of the publicly listed company.