May 29, 2018 PAP-Q2-18-CL-011
Identity verification of raw and starting materials used in the production of biologic drug substances and drug products must take place before manufacturing can proceed. The identity, purity and quality of raw materials must be confirmed to be suitable for use, to ensure patient safety, product efficacy and process consistency and to avoid costly production problems.
According to the European Biopharmaceutical Enterprises, raw materials for biopharmaceutical manufacturing must be safe, of consistent quality, well characterized and understood with respect to their role in drug production processes, compliant with regulations and compendial requirements, and backed by supplier agreements with qualified vendors and purchased through transparent supply chains.1 In addition, “only raw materials that perform a specific role in a manufacturing process should be used, and in all cases, they should be of the highest quality available.”1
Table 1 presents a list of the main raw and starting materials used in viral vector manufacturing. Some of these materials present more challenges than others. All biologic (animal- or plant-derived) raw materials require testing for contamination by adventitious agents (e.g., viruses, bacteria, fungi, mycoplasma, endotoxins, etc.).
Animal-derived materials such as se-rum have inherent variability and greater potential for contamination by pathogens than other biologic raw materials. The supply and production of serum are also complex and require acquisition from certain select regions of the world and from herds that are well characterized to be pathogen free; they also must be accompanied by certificates of analysis and certificates of origin. In addition, regulatory authorities are increasingly requiring more extensive testing of animal-derived raw and starting materials. Serum, therefore, requires a higher level of management than, for example, chemicals used as buffer components.
For cell lines, in addition to testing for adventitious agents, it is necessary to confirm identity and purity (e.g., that no cross-contamination has occurred with other cell lines during generation, maintenance and banking). Viral vector manufacturing may also require large amounts of high-quality plasmid DNA for transient transfection, dependent on the scale of the viral vector lot needed to be manufactured. There are limited vendors capable of suitable plasmid DNA affecting the supply of this critical custom raw material.
Viral vector manufacturers involved in all stages of clinical-trial-material and commercial product production rely on single-use (SU) technologies to meet the needs for manufacturing flexibility and to prevent product-to-product cross-contamination. While there are many advantages to SU equipment, its use does introduce new risks over conventional stainless steel/glass equipment and puts a high reliance on vendors to ensure adequate supply and control of secondary suppliers (e.g., film manufacturers), where extractables and leachables may be a concern.
SU materials that come in direct or indirect contact with cell culture and viral vector products can impact their performance, quality, safety, stability and/or efficacy. As such, their sourcing must be achieved in a manner similar to the sourcing of other critical raw materials used in GMP manufacturing.2 For instance, with the adoption of SU equipment, the verification of process container integrity must also be performed for each SU bag used in critical operations.3
To ensure that raw materials are fit for purpose and of the appropriate quality, viral vector manufacturers employ risk management strategies. Risk assessments of the manufacturing process are conducted to determine the criticality of each raw material at each step of the process, which in turn determines the level of testing and vendor management necessary to ensure the consistent supply of high-quality materials.4
Those raw materials (i.e., chemicals) that inherently present a lower level of risk may require less testing and vendor audits. Biologic or animal-derived raw and starting materials have greater inherent variability, and the potential for adventitious agent contamination carries a higher risk and thus requires a higher level of risk mitigation to ensure security of supply. Similarly, SU equipment that comes in direct contact with the biologic drug substance or drug product will carry a higher risk than noncontact components and may involve leachables and extractables testing.
When conducting risk assessments, factors to be considered include risks presented by the vendor, the amount of material used throughout the process, the grade of material (i.e., pharmaceutical vs. research), the process context (i.e., where the material is used in the process, such as cell culture or final formulation) and the maturity of the program (i.e., preclinical development vs. commercial).5
Based on their criticality as determined via risk assessments, raw and starting materials are placed into different risk categories that in turn determine the level of risk management required.6 For instance, in USP <1043> Ancillary Materials for Cell, Gene and Tissue-Engineered Products, raw materials are placed into four different tiers according to the level of risk they present.5
The maturity of the process will impact the types of raw materials used and the level of testing and supplier auditing that are required. At the preclinical development stage, research-grade material may be appropriate, whereas pharmaceutical grade material may be essential for clinical stage and commercial production.6 The number of audits of vendors for critical raw materials also increases as the project moves through the development stages. Similarly, the depth within the supply chain for which on-site audits are conducted increases as projects progress to commercialization.
For SU components, factors to be considered include whether or not they have direct, indirect or no contact with the biologic drug substance or drug product, manufacturing controls and vendor risks.4
Testing is required to enable the identification and purity of raw and starting materials used in viral vector manufacturing. The level of risk associated with a given raw material dictates the appropriate testing that should be conducted for that material. Table 2 lists potential categories for raw materials used in viral vector manufacturing and the types of testing they may require.
Specific testing requirements for certain classes of raw materials may be established by regulation, regional pharmacopeias (Europe, U.S., Japan) and other industry standards and guidelines. For critical raw materials, manufacturers also often develop proprietary in-house test methods (non-compendial) in order to be confident in the quality/consistency of these key process components.7
Regardless of the test methods that are performed, however, testing strategies must be developed within the context of the entire production process and be an integral component of the quality system. In addition to the criticality of raw materials, the level of testing and control needed increases as a project matures. For raw materials used in early-phase projects, it may be sufficient to check the certificate of analysis. As the project moves closer to commercial production, more in-depth testing may be appropriate, including identity verification and performance of compendial testing. Critical raw materials require additional testing beyond identification, such as performance confirmation, because these materials are being qualified for eventual commercial manufacturing processes.
It is worth noting that the current trend is towards more extensive testing to provide a higher level of quality assurance for incoming raw materials. FDA’s quality initiatives emphasize the need to design quality into the manufacturing process from the start. To achieve this goal, an understanding of the role that each raw material plays and the information that analytical testing methods must provide is needed.6 This knowledge combined with effective vendor qualification enables proactive change management, which is essential to maintaining consistent processes and steady supply of lifesaving medicines.
Ensuring security of supply for raw materials used in viral vector manufacturing presents ongoing challenges. As this new sector of the pharmaceutical industry matures and more therapies that require viral vectors graduate from the clinic to the market, viral vector producers need to be prepared to overcome availability and quality challenges for basic and critical raw materials. Going forward, hurdles are anticipated ranging from greater unreliability in serum supply to increasing use of SU technologies with a concomitant rise in quality and testing requirements to further raising of the bar with respect to GMP guidelines.
Dr. Snyder was the founder of Florida Biologix, which was spun out of the University of Florida in 2015 and merged to create Brammer Bio in 2016. Dr. Snyder has been investigating virus biology, vector development, cGMP manufacturing and analytical technologies, and viral vector–mediated gene transfer for over 32 years. Dr. Snyder received his doctoral degree in microbiology from the State University of New York at Stony Brook and obtained his BA in biology from Washington University in St. Louis.