Plasmids release specifications are critical to the manufacture of many cell and gene therapy (CGT) products, but current regulatory guidance is limited in defining expectations for the release of plasmids as a starting material.
BioPhorum has been highly active in this area and its most recent paper BioPhorum raw materials: cell and gene therapy critical starting material – further discussion on plasmids to establish release specifications using a risk-based approach to manage supply, shares industry feedback following the publication of two previous BioPhorum papers that complement ongoing efforts in the wider CGT field.
The latest paper supplements these publications by delving into identity testing and cross-contamination for plasmid master cell banks and plasmid DNA, and other plasmid DNA release tests (including DNA homogeneity, residual DNA and host RNA, and sterility or bioburden). Building on the momentum of the previous papers, consideration is also given to testing for elemental, extractable and leachable impurities, plasmid stability studies and evaluating changes to plasmid manufacturing process. The paper also updates the previous example case study risk assessment by re-evaluating risks for supply of GMP plasmid.
The previous papers were:
- A ground-breaking 2020 paper called Cell and Gene Therapy Critical Starting Material: A Discussion to Help Establish Release Specifications for Plasmids and the Bacterial Master Cell Banks used to produce them. This aimed to reach a consensus on test attributes and release requirements for plasmids and the bacterial MCBs used to produce them. It set out an approach proposing methods and acceptance criteria to stimulate a broader industry discussion.
- Another 2020 paper entitled Raw Materials: Perspectives on raw and starting materials risk assessment for cell and gene therapy (CGT) processes, which discussed a risk-based approach to sourcing and using raw and starting materials for CGT manufacturing processes. It included a case study in the form of a simple risk assessment for plasmid DNA used as part of a CGT process.
Both were so successful; they have been downloaded more than 1,000 times in total.
Since the original paper, the EMA has given specific guidance that plasmids should be made using GMP conditions. The US Pharmacopoeia has also formed an expert panel to draft a new chapter to document and standardize plasmid release specifications where plasmid DNA will be used as a starting material for manufacturing CGTs. Applying a common standard will enable communication and cooperation across the pharmaceutical industry and simplify communication with regulators.
In the fast-moving field of CGT manufacture, there will likely be advances in applying science to plasmid release specification in the next few years. One key area will be using next-generation sequencing to determine identity and contamination control. The BioPhorum team will continue to monitor work in this arena and apply it where possible to the control of plasmid release specifications.