Mitigating Risk and Ensuring Security of Supply by Selecting Appropriate Quality Materials for Viral Vector Production

The Importance of Raw Materials Selection for Gene Therapy

The raw materials used throughout the different stages of gene therapy manufacturing are a source of risk. They must meet regulatory requirements, be available throughout the lifecycle of the therapeutic, and their suppliers must be able to meet current and future demands. Identification of appropriate raw materials should begin as early as possible during preclinical development as this will ensure use of appropriate quality materials and help minimize delays resulting from the need to rework a process.

The Regulatory Landscape for Gene Therapy Raw Materials

Many types of viral vectors are used for gene therapy including adeno-associated virus (AAV) and lentivirus. Major steps in the vector manufacturing workflow include cell culture, transfection, clarification, DNA digestion, chromatography, tangential flow and sterile filtration, formulation, and final fill.  Across this workflow, hundreds of materials are required for production and formulation, from sodium chloride and sucrose, to poloxamers and endonuclease.

Raw materials (called ancillary materials in the United States), are defined as materials used in the manufacturing process but not intended to be present in the final product. The United States Food and Drug Administration and European Medicines Agency, as well as ISO Standards, provide regulatory guidance on raw materials as they can affect safety, potency, and purity by introducing adventitious agents or other impurities. Excipients are materials used in the formulation of gene therapies and are present in the final product. They include buffers, salts, polymers, and preservatives and should comply with the guidance in the United States Pharmacopeia and National Formulary (SUP-NF) General Chapter 1078, Good Manufacturing Practices for Bulk Pharmaceutical Excipients.

The viral vector manufacturer must ensure that materials are of the appropriate quality, accompanied by the necessary documentation to satisfy regulatory requirements, and are traceable throughout the supply chain.  Given the potential risk introduced by raw materials, the complexities of manufacturing advanced modalities, and accelerated development timelines, the regulatory review process for gene therapies places a great deal of emphasis on chemistry, manufacturing, and controls (CMC).[i] Currently, there are no explicit regulations in terms of the cGMP guidance required for raw/ancillary materials used in gene therapy production processes, as long as the material is manufactured under a suitable quality management system and has the required documentation needed for regulatory filings.

Selecting Fit-for-Purpose Raw Materials for Viral Vector Production

Choosing fit-for-purpose raw materials can be challenging and regulatory guidelines assign responsibility for raw material quality to the drug manufacturer, not the supplier. An understanding of relevant regulatory requirements, along with a robust quality risk management strategy, provides the foundation for selection of appropriate raw materials. The raw material user must verify the quality, documentation for regulatory approval and ensure the supplier provides change notification support. The level of oversight should be proportionate to the risks posed by the individual materials, taking account of their source, manufacturing process, supply chain complexity, and the final use to which the material is put in the medicinal product.

It is important to have visibility of material origins and manufacturing processes used by raw material suppliers as supply chain consistency and transparency can be quite varied. Suppliers should employ a risk-based approach to assess the quality of raw materials, manage change, and hold their suppliers to equivalent standards with the same transparency. A robust change notification process should be in place. Changes in the source and specifications of raw material do happen and strategies are needed to minimize the impact including long-term supply agreements and maintenance of sufficient stock to carry customers through the process to implement such a change.

Another factor in selecting raw materials is avoidance of those having an animal origin. If this isn’t possible, the material should be treated and tested and have documentation to confirm there are no contaminants, especially of a viral nature, and ensure complete traceability. Overall, the supplier should have a clear policy and manage and document animal component free (ACF) and animal component containing (ACC) products according to ISO Technical Standard 20399 which covers raw materials present during the production of cellular therapeutic products and gene therapy products.

Raw Materials have Different Grades

Careful selection of raw materials early the development of a viral vector production workflow can mitigate risks related to supply and ensure a seamless transition from preclinical through commercial. It is important to understand that raw materials may be available in different quality grades, and the accompanying documentation can vary significantly between suppliers and even across different catalog numbers from an individual supplier.

Higher grade materials or those manufactured under GMP conditions typically come with a higher price; this may drive preference for lower quality grade materials, such as those designated for research use only (RUO), in early development. RUO products are not intended for therapeutics.

Raw Materials have Different Grades

Careful selection of raw materials early the development of a viral vector production workflow can mitigate risks related to supply and ensure a seamless transition from preclinical through commercial. It is important to understand that raw materials may be available in different quality grades, and the accompanying documentation can vary significantly between suppliers and even across different catalog numbers from an individual supplier.

Higher grade materials or those manufactured under GMP conditions typically come with a higher price; this may drive preference for lower quality grade materials, such as those designated for research use only (RUO), in early development. RUO products are not intended for therapeutics.

Roadmap for Choosing Fit-For-Purpose Raw Materials

As a supplier of over 300,000 products, many of which are raw materials for biopharmaceutical manufacturing, we understand the importance of quality and consistency, and the need for transparency regarding regulatory and quality information that accompanies our products. To facilitate selection of fit-for-purpose raw materials, including those for viral vector production, and ensure availability of documentation for regulatory purposes, we created the M-Clarity™ and Emprove^® programs.

The M-Clarity™ program defines product quality levels and provides transparency and traceability for comparing quality, support, and documentation for almost all of our products.  Each product is classified into one of six “MQ” levels from MQ100 to MQ600, with each level providing an increasing and defined minimum amount of documentation and services. MQ levels provide full transparency on the quality attributes and change notifications provided for each product and defines the quality and regulatory attributes.

The program allows users to distinguish between products that have the necessary quality and regulatory attributes and eliminate those that cannot be supported with additional documentation. 

The transparency provided by the M-Clarity™ program is taken to the next level by our Emprove^® Program which provides documentation for more than 400 raw and starting materials in the form of comprehensive dossiers.

The Emprove^® Program helps manufacturers minimize disruptions and conduct thorough risk assessments. Raw and starting materials that are included in the Emprove® Program are qualified stringently according to industry-leading standards. These products are supported by comprehensive online documentation dossiers that meet the information needs of biopharmaceutical manufacturers for qualifying raw materials, completing risk assessments, and optimizing manufacturing processes. Dossiers provide comprehensive, up-to-date documentation, in submission-ready format, to aid in navigating regulatory challenges, managing risks, and improving manufacturing processes.

The Right Raw Materials Set the Stage for Viral Vector Production

Use of raw materials with the appropriate quality and supporting documentation is essential for successful development and manufacturing of viral vectors for use in gene therapies. Materials should be selected with an eye towards the stringent regulatory requirements that are imposed during clinical and commercial stages of the product life cycle. With this approach, the need for costly and time-consuming changes is minimized. Partnering with the right supplier further mitigates risk during development and manufacturing by ensuring raw material quality, supply, and transparency, and that documentation for regulatory submissions is complete and readily available.