Tech Briefing: Forced Degradation for CGT Products
The 2023 FDA Draft Guidance on Potency Assurance for Cellular and Gene Therapy Products makes the expectation clear that every lot of drug product (DP) will need to be tested for the potency to “achieve intended therapeutic effect”. Further, any lot release test(s) will need to confirm product potency meets acceptance criteria. Inherent with this concept, however, is the need to understand/know the mechanism of action for the cellular therapeutic so that one is confident that the potential bioassay/potency assay is reflective. Confounding this is the fact that CGT products often have multiple biological activities associated with them, and pinpointing those activities that are associated with the MOA (or even pinpointing the MOA itself) is not always straightforward.
Tech Briefing: HCP ELISAs for Gene Therapy Products
Over the years we’ve heard more complaints about HCP ELISAs from gene and cell therapy folks than anyone else. Many of the developmental efforts have been performed in more academic or translational research environments, where the regulatory requirements of HCP analysis were not always front-and-center in the product development pathway. As a result, HCP analysis was often done late in the development process and was considered more of a check-the-box effort. Very few of these groups had the resources to develop their own HCP ELISA, so they relied on commercial kits. Many of these products are produced in HEK293 cell lines, and there are limited options for commercial HEK293 HCP ELISA kits. Thus, limited consumer choice has been another reason for the complaints. Compounding this, many in the gene therapy field are not aware of the limitations of using a commercial HCP ELISA kit. When the kit vendor changes reagent lots or does a wholesale change/upgrade of the kit, they are left wondering how to cope with HCP ELISA results that can change by as much as three-fold.
Tech Briefing: Ins and Outs of Data Analysis for Potency Calculations
More than any other analytical method in the biopharmaceutical industry, the potency assay requires a in-depth knowledge of statistics. Most potency assays are cell-based relative potency assays. The readout is quantitative and requires assessing similarity of reference vs. test sample dose-response curves. Just to set up the data analysis, one must understand modeling and determination of similarity of dose response curves for reference material and test samples. Most analytical scientists have taken a college class (or maybe two) of applied statistics. This means that most of us know how to calculate averages, means and medians, and perhaps even calculate the confidence interval of these datasets.
Synopsis: BEBPA’s 2023 Host Cell Protein Conference in Review
Volume 1, Issue 2: Dr. Denise Krawitz provided an excellent wrap up on the last day of BEBPA’s 11th Annual HCP Conference held in May 2023 in Dubrovnik, Croatia. Her quick 10-minute summary captured the essence of the conference and highlighted topics covered during the conference, as well as providing a sneak peek into future topics.
Tech Briefing: Mass Spectrometry In HCP Analysis (USP 1132.1)
Host Cell Protein (HCP) analysis by mass spectrometry (LC-MS/MS) has obviously been growing in importance in the last decade. However, LC-MS/MS analysis is generally used for characterization, so the practitioners have been on their own to develop methods that work for their particular applications. HCP analysis has unique challenges that make it different from the MS-based general proteomics or characterization workflows that dominate the biotech and biopharma landscape. In HCP analysis, the analyst is trying to detect parts-per-million level peptides in a vast ocean of drug product (DP) peptides.
Tech Briefing: FDA Guidances for Assessing and Assuring the Potency of Cell and Gene Therapy Products
The FDA has two guidances about the potency of Cell and Gene Therapies (CGT). The most recent was released December 2023 entitled Potency Assurance for Cellular and Gene Therapy Products Draft Guidance for Industry. The older guidance entitled Guidance for Industry Potency Tests for Cellular and Gene Therapy Products has been around since 2011.
Tech Briefing: Working with Host Cell Proteins
Host cell proteins (HCPs) are a complex and diverse group of proteins produced by the cells used in biopharmaceutical manufacturing processes. We’d like to think that analytical methods used for release of a biopharmaceutical product are unambiguous – i.e., methods having well-defined target analyte(s), complete analyte coverage, high specificity, and a high degree of confidence in the results. The HCP ELISA, which is often used as a release assay, barely has any of those desirable traits. So, what other methods can we use to assess the purity of products? Outside of other immunoassays, mass spectrometry (LC-MS/MS) is most used. However, despite all the high-tech features of this method, it also is imperfect, especially when it comes to being a release assay.
Technical and Regulatory Considerations for Cell and Gene Therapy Raw Materials
Volume 1, Issue 1: Quality attributes of cell and gene therapy (CGT) products, also referred to as advanced therapy medicinal products (ATMPs) in the EU, which correlate with safety and efficacy in patients, are determined by the manufacturing process. This process includes the identification and use of appropriate starting and raw materials. A simplified flow chart of the manufacturing process of a CGT product reveals several input steps for qualified raw and starting materials.
Tech Briefing: Potency Assays for Biosimilar Products
When the concept of “generic biotech products” (Biosimilars) was first introduced in the early 2000’s, many innovator companies confidently stated that it would never happen. Their rationale? Biopharma products were inherently too complex and the manufacturing process too critical for a generic version to really be sufficiently similar to the innovator product. Oddly enough, I remember the same people attending the WCBP (Well-Characterized Biotech Products) conference in Washington DC claiming the products were so well characterized they could be regulated similar to drug products. That is to say, the product was not the process, but instead, the product is a well-defined molecule and therefore, manufacturing changes could be made without requiring new clinical trials.
Considerations for manufacturing ex-vivo therapeutic products: CRISPR, Cell Sourcing, Potency and Beyond
The first therapy using the CRISPR technology was approved in the UK on 21 November 2023, Casgevy (exagamglogene autotemcel) now has a conditional authorization from the UK Medicines and Healthcare products Agency (MHRA). This authorization is for two indications, Sickle Cell Disease (SCD) and transfusion-dependent β-thalassemia (TDT). The sponsors for Casgevy were Vertex Pharmaceuticals and CRISPR Therapeutics Casgevy is also under review by the European Medicines Agency (EMA), the Saudi Food and Drug Authority, and the U.S. Food and Drug Administration (FDA).