Qualifying Raw Materials for
Cell Therapy Manufacturing

Incorporating GMP grade reagents in the preclinical stage or during pilot production avoids the need to re-validate and perform equivalency studies when moving into CMC manufacturing. These studies can be costly and time-consuming to perform and can easily outweigh the additional cost of incorporating GMP raw materials in the earlier development stages.

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We designed our Premium (Pre-GMP) grade solutions as an intermediate grade for users that are looking to transition into clinical manufacturing but are not quite at that development stage. These solutions are manufactured using the same source, process, and quality controls, with the exception of the more costly GMP requirements. They perform the same as their GMP counterparts, helping users easily transition to GMP grade when they reach the clinical manufacturing stage.

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Premium (Pre-GMP) and GMP grade products are manufactured from the exact same source, process, and conditions. This means that the quality and performance are identical between both grades. The difference stems from a more comprehensive QC testing panel along with stringent specifications and documentation for our GMP products.  For users earlier in the development stage, premium (pre-GMP) proteins are a cost-effective alternative that still ensures a smooth transition to clinical manufacturing.

Premium (Pre-GMP) and GMP grade products are manufactured from the exact same source, process, and conditions. This means that the quality and performance are identical between both grades. The difference stems from a more comprehensive QC testing panel along with stringent specifications and documentation for our GMP products.  For users earlier in the development stage, premium (pre-GMP) proteins are a cost-effective alternative that still ensures a smooth transition to clinical manufacturing.

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Raw materials should be sourced from qualified suppliers following a pre-established supplier qualification and monitoring process. We perform annual risk assessments for raw materials used in our GMP process along with our suppliers. This encompasses visual inspections and documentation tracking of associated documents including certificates of analysis (CoA), Certificates of Origin (CoO), TSE/BSE declarations, and animal-free statements, when applicable. Before acceptance, key raw materials are always identified and validated.

We advise cell therapy manufacturers to source either pharmaceutical or GMP-grade whenever possible. Our GMP-grade products are manufactured and tested in accordance with relevant international standards. * Raw material suppliers should have a certified quality management system (QMS) along with an ISO 9001 / 13485 certification. Independent audits, quality policies, and quality processes should be established to ensure quality that matches customer expectations. Cell therapy manufacturers should also perform due diligence by qualifying their suppliers through questionnaires, on-time delivery, SCAR, and other auditing activities. Documentation including certificates of analysis, certificates of origin, and other audit trail documentation should be received from each supplier and kept as records.

Cell therapy manufacturers should begin discussions with potential suppliers as soon as possible to avoid issues when entering production. Ensuring raw material suppliers have the ability to scale-up can prevent any last-minute changes that could require expensive revalidation studies.

Identifying a secondary supplier is also crucial. Although raw materials may look identical, there is no guarantee on how it behaves in your biological system. Do not assume that switching suppliers can be easily done – subsequent validation studies showing equivalence between raw materials from different suppliers is required. Identifying a secondary supplier can be an insurance policy if any issues arise with your primary supplier.

The quality of manufactured cell and gene therapies is directly influenced by the raw materials used in their production, which, in turn, impacts the therapy’s impact and efficacy. Relevant regulations stipulate that the selection of raw materials should consider their necessity, rationality, and safety, preferably opting for materials approved for human use or meeting pharmacopoeia standards. Although safety and quality requirements for raw materials have lower priority in the initial preclinical stage, transitioning to regulatory-compliant GMP-grade materials becomes imperative during CMC or clinical conversion. This transition involves thorough testing, safety assessments, and process validation, demanding considerable time and effort.

If the same supplier is utilized, the physical properties and biological activity of premium-grade (PG) raw material ideally mirror those of GMP-grade, differing mainly in regulatory support documentation. Rigorous safety testing of materials interacting with patients is crucial, and confirming the consistency of manufacturing processes between PG and GMP materials is recommended. We ensure that both our PG and GMP products are derived from the same cell bank source, undergo strict quality control, demonstrating biological identity through extensive trials.

For clinical applications, an early shift to GMP is recommended, even during the preclinical phase, facilitating equivalence testing at a more manageable stage. Opting for an experienced supplier well-versed in quality management, protein biochemistry, analytical testing, and regulatory affairs is advantageous. Experienced suppliers aid in navigating changing regulatory environments, providing necessary documentation like a Drug Master File (DMF) to streamline regulatory processes. Audits of supplier facilities, preferably in person or online, strengthen the strategic partnership between suppliers and customers. Maintaining strict adherence to approved operating procedures, at least for three consecutive batches, ensures consistency and compliance with predetermined acceptance criteria for our PG products developed through the GMP product line.

Biological reagents are notorious when it comes to susceptibility to variability, especially cytokines and growth factors. Only after these reagents have been successfully developed and validated through multiple successive batches meeting the stringent outlined specifications, along with the establishment of a stable process and rigorous conformance assessment, can the product be moved into large-scale manufacturing and commercialized. This process forms a robust foundation in ensuring the consistency and reliability of GMP raw materials.

Furthermore, the manufacturing of products occurs within GMP facilities and under GMP quality systems, with strict control implemented through documented Standard Operating Procedures (SOPs) and trained personnel. This crucial information should be disclosed during audits. It is reasonable to request data from multiple batches to evaluate a supplier's capability to consistently produce a reproducible protein. Ideally, materials should be sampled from various batches to assess their consistency across the entire system. We identify standard batches and compare each new production batch to the established standard before releasing it to the market. This approach mitigates variability and ensures consistent product performance. Currently, we maintain excellent control over lot-to-lot differences, specifically in biological activity, within the range of 10-15%.

Safety regarding any raw materials employed in cell and gene therapy manufacturing is critical to ensure final therapeutic quality. This emphasizes the need for safety control to prevent contamination by exogenous factors. These ‘exogenous’ factors refer to inoculants, cell matrices, residual raw materials during production, bacteria, fungi, mycoplasma, and viruses.

The FDA recommendation of using the highest-quality materials means that all raw material suppliers should ensure that their materials or reagents are produced under the appropriate quality standards to mitigate any unreasonable risks to patients. This means that strict quality control of raw materials used in CGT production is a necessary measure to reduce the risk of external contamination and ensure the safety and efficacy of cell and gene therapy products. Expanding upon this requirement, the following requirements are outlined in various international pharmacopeias, including:

Learn GMP Grade Solutions for Cell Manufacturing

Our resident team of GMP professionals has decades of experience combined interpreting and implementing regulatory guidelines. This is essential for novel therapeutics where responsibilities between raw material suppliers and cell therapy manufacturers may not be clear, or a distinct set of validation studies is required to remain compliant.

Our products are designed to follow global quality regulations from the NMPA, FDA, EMA, PMDA, and other regulatory agencies. Each facility is also ISO-certified and GMP-compliant. When it comes to documentation, we provide two levels of documentation based on each customer’s need.

Overall, our GMP product lines encompass FDA records support such as drug-master files. If there are any issues with obtaining and IND or BLA, please contact quality@acrobiosystems.com to obtain a letter of authorization (LOA). Any other support can be done online or on-site, free of charge, including any responses to regulatory questions related to raw materials.

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