Successful clinical translation of a cell therapy product hinges on early process- and material-selection decisions that impact manufacturing. Not only do materials present in the final approved drug (i.e., excipients) need to meet certain specifications, but raw materials (or ancillary materials) used in the manufacturing process must meet stringent quality standards. If the raw materials chosen early in product development do not satisfy the necessary regulatory criteria at clinical trials and commercialization stages, they will need to be replaced with materials that do. Those substitutions can result in significant increases in costs and time.
The best practice to support successful clinical trials and commercialization of a cell therapy requires a raw material strategy with the end goal in mind. This longer-term view focuses on the use of higher grades of raw materials earlier in cell therapy product development to meet the necessary regulatory qualifications for clinical trials, and ultimately commercial manufacturing of the final approved therapeutic. This strategy can increase the probability of success and head off costly surprises that could cause an untimely demise for a promising cell therapy candidate.
In this section, we will provide a high-level overview of the considerations used to select raw materials that mitigate risk and align with current regulatory guidelines. For deeper discussion on this topic, please see additional resources at the end of this section.
What are raw materials
Raw materials, also referred to as ancillary materials materials in US regulations*, are components that come in contact with the cell therapy product during manufacturing, but are not intended to remain in the final therapeutic. Cell culture media and growth factors would be examples of raw materials employed in manufacturing a cell therapy. While not present in the final product, raw materials are still important because of their potential impact on the safety, purity, and potency of the final cell therapy product.
Generally speaking, raw materials are not regulated products. However, regulatory guidelines recommend that developers use therapeutic-grade raw materials whenever possible because of their potential influence on the characteristics and safety of the final cell therapy product. Unfortunately, therapeutic-grade versions will not exist for every type of raw material used. In these cases, the best option would be to choose raw materials manufactured under the appropriate current good manufacturing practices (cGMP). While the same materials developed for research use only (RUO) and in vitro diagnostics (IVD) uses might be available, they will lack some of the necessary traceability and testing that will be required, particularly as a therapeutic moves further into clinical trials and hopefully commercialization. Raw materials designed for RUO or IVD use should be avoided in a long-term cell therapeutic manufacturing strategy.
No specific cGMP guidance exists for raw material manufacturing, unlike that found for medicines and medical devices. Regulatory guidance (e.g., USP <1043> and ISO276) only recommends choosing raw materials made under an appropriate quality management system, a rather vague term. Suppliers may say their products are manufactured under cGMP conditions, with claims ranging from declarations of cGMP based on following particular cGMP guidelines; independent quality management system certification (e.g., ISO9001); or even regulatory agency inspection if the site is manufacturing regulated products. However, there is no such thing as a defined “GMP-grade” material.
The first place to begin to understand what is meant by cGMP manufacturing of a raw material is the published regulatory guidance. Table 1 presents some of the main guidelines across different regions. Japan, Europe, and the United States have the most detailed raw material guidance, with Japan having some of the strictest.
*There can be some confusion around the terms “raw materials” and “ancillary materials” across regions -- Europe uses the term “raw materials”, whereas the US uses the term “ancillary materials”. Ancillary materials are also synonymous with “processing materials", as defined in 21 CFR Part 1271 and “components” in Pharma cGMP Part 211.
Table 1. Raw material regulatory guidance from major jurisdictions.
|Region||Raw material regulatory guidance|
In general, cGMP refers to the “minimum requirements for the methods, facilities, and controls used in the manufacturing, processing, and packing of a drug product” to ensure the product is safe and is of the correct potency and composition . These general cGMP requirements entail specifications for personnel; quality control plans and functions; facilities and equipment; control of components, containers and closures; manufacturing and records; laboratory controls; packaging, labeling, and distribution; and record keeping. Table 2 provides examples of some of these requirements.
Table 2. Some examples of essential components of cGMP manufacturing .
|Control of materials||Quarantine and release process at warehouse with incoming goods|
|GMP analytics||Quality control laboratory with quality assurance oversight|
|Standard operating procedures||Batch record documentation with process for deviations and corrective and preventative action (CAPA)|
|Qualified operators||Required training for gowning, safety, and operations|
|Controlled access with environmental control||Keyed access to ISO 7 environment with ISO 5 space for aseptic processing|
|Environmental monitoring and cleaning cycles||Drop plates, swab testing, particle monitoring, and regular disinfection and cleaning|
One of the most globally recognized raw material guidance documents is USP <1043>. USP <1043> presents a risk-based model based on 4 risk categories that are used to assess each raw material (Table 3). These risk categories are defined by specific activities required of the manufacturer . The required activities of each risk level are phased, with a subset required of all products (e.g., Certificates of Analysis and lot-to-lot testing). As the risks associated with the raw material increase, different activities are also required (e.g., safety testing for residual materials containing animal products). Risk also increases as the product moves into later phases of clinical testing. Product developers should aim to source tier 1 and 2 raw materials; tier 3 is less favorable; and tier 4 should be avoided for clinical work. Zero risk is unattainable, so developers will strive to maintain the lowest risk possible when selecting raw materials while still maintaining performance.
Table 3. USP <1043> raw material risk categories.
|1||Lowest||Highly qualified and suited for CGT* manufacturing||Rh-insulin for injection used as a cell culture medium additive|
|2||Low||Well-characterized, intended for use as raw material, manufactured under a quality management system in compliance with GMP||Gibco CTS media and reagent products|
|3||Moderate||Not intended to be used as a raw material||RUO or IVD materials such as some cell culture media|
|4||High||Not produced under a recognized quality management system, not intended for use as a raw material; can be animal-derived, toxic, and variable in biologic activity||Animal cells or animal sera, cholera toxin used in cell culture or selection agents for transgene expression|
|*CGT = cell and gene therapy|
Critical quality attributes of raw materials in cell therapy manufacturing
When choosing raw materials for use in cell therapeutic manufacturing, developers typically focus on four key product characteristics:
- Material identity
- Purity and presence of impurities
- Lot-to-lot consistency
- Storage and stability
Table 4 summarizes some of the important details to consider for each of these characteristics. With the lack of global standards for critical quality attributes, cell therapy manufacturers will choose raw materials that will meet the standards of the region with the most stringent requirements.
Table 4. Considerations for four key raw material characteristics.
|Identity and freedom from microbial or viral contamination|
|Purity and impurity|
|Storage and stability|
With regards to a material’s identity, cell therapy manufacturers should pay close attention to biosafety characteristics to determine any risks a material might bring to the facility, to the operator, and in the final cell therapy product. The preference is to avoid animal origin components when possible. When this is not possible, a risk-based approach to these raw materials will become important, using the following considerations:
- Possible alternatives (e.g., recombinant proteins)
- Viral inactivation process
- Upstream vs downstream use (risk increases the further downstream a raw product is used)
- Grade of material (e.g., cGMP compliance vs RUO)
- Demonstrated product traceability and documentation (from supplier)
- Country of origin (important for CJD, BSE and TSE risk)
It is within this biosafety area where some of the terminology used can become confusing. When selecting affected raw materials, a cell therapy manufacturer should gain a clear understanding of a supplier’s definitions at all levels of manufacture for terms such as “animal origin free”, “serum free”, and “xenofree” to fully understand the potential risks associated with the raw material.
Cell therapy manufacturers need to also consider the performance testing of raw materials in their final material decisions. The supplier should provide performance data that are reflective of a product’s intended use as a raw material. For example, a performance test for media using a CHO cell line is of little use if the intended use of the media is to grow T cells. The data should also enable developers to determine the performance consistency of a raw material, with quantitative data being better than pass/fail results. To assess the data accurately and determine their relevancy to the intended use, the supplier should provide the assay methodology used, preferably using reference test methods (e.g., United States Pharmacopeia or USP).
Whenever possible, developers should choose USP/EP grades of raw materials with monographs. Monographs ensure the raw material meets specific quality standards for identity, strength, quality, and purity determined by specific tests, procedures, and acceptance criteria. If monographs are not available, some (if not all) of the important attribute information discussed should be found in a supplier’s material documentation (see key raw material documentation below). However, it is possible that the developers will need to perform additional testing to make final robust material decisions and mitigate risks associated with any raw material. Even though no global quality standards exist, it is best for manufacturers to choose raw materials that are fully characterized in order to ascertain the risks associated with them, including:
- Numerical specifications for test methods on Certificates of Analysis to demonstrate lot-to-lot consistency
- Performance tests focused on intended use in the manufacturing process, with stability tests linked to performance
- Traceability of biological-derived raw materials to primary, secondary, and tertiary levels, provided on Certificates of Origins
- USP test methods or validated in-house methods used and reported on the Certificate of Analysis
Key raw material documentation
Much of the information on raw material quality attributes discussed above can be found in various supplier documentation (Table 5, Figure 1). Besides determining the appropriateness of a raw material for cell therapy manufacturing, some of the information found in these various documents will be necessary for a variety of regulatory filings. In cases where raw materials contain proprietary components or formulations, developers should look for suppliers who can provide that information through Regulatory Support Files, which are provided under signed confidentiality agreements. Some regions (e.g., the United States) support Master Files provided by suppliers for the sharing of proprietary materials with the appropriate regulatory agencies. Master Files do not require signed confidentiality agreements and can be a faster way to get the necessary information for regulatory filings.
Table 5. Raw material supplier documentation types.
|Certificate of Analysis (COA)||COAs contain information on product lot; product shelf life and expiration; identity; quantity; purity and impurities; safety; and biological activity.|
|Certification of Origin (COO)||A COO demonstrates supply chain control (traceability), which is particularly important for human- and animal-derived products.|
|Safety Data Sheet (SDS)||SDSs, provided as applicable, contain information on the properties of each material and their physical, health, and environmental hazards and subsequent protective measures associated with them. They also contain necessary safety precautions for handling, storing, and transporting the material.|
|Certificate of Compliance (COC)||COCs may be provided to support compliance claims about quality systems or standards.|
|Regulatory Support File (RSF)||Under a confidentiality agreement, this summary provides product performance, stability, quality control, and analytical testing methods specifically designed to meet cell therapy raw material regulatory requirements. Used when Master Files are unavailable.|
|Drug Master File (DMF)||A detailed submission to a regulatory body that provides confidential information about facilities, processes, and raw materials used in the manufacturing, testing, processing, packaging, and storage. MFs are only available in the United States, Canada, and Japan.|
- GMP manufacturing (21 CFR part 820 and certified to ISO 13485)
- Detailed Certificate of Analysis (COA) and Certificate of Origin (COO)
- Drug Master File (DMF) or Regulatory Support File (RSF)
- Aseptically sterile product (validated SAL 10-3)
- Endotoxin and Mycoplasma tested
- Performance tested (T cell functional assay)
- Adventitious viral testing of human-derived proteins and access to viral inactivation data
- Proven use in cell therapy manufacturing
Figure 1. Example of important product characteristics that cell therapy manufacturers should look for in various product documentations. The Gibco CTS Immune Cell Serum Replacement is an example of a reagent specifically designed for use in cell therapy manufacturing that meets documentation requirements. It complies with the raw material guidances in the United States, Europe, and Japan. The reagent is intended to replace the use of human serum when performing ex vivo culture of human lymphocytes.
Supplier and developer responsibilities
Ultimately, it is the drug manufacturer’s responsibility to assess the risks associated with and suitability of the chosen raw materials, with much of this assessment occurring during the vendor qualification process (read more about Vendor Qualification). Table 6 provides some of the important items to address during this process to mitigate risk associated with the cell therapy.
Table 6. Some key considerations for raw material risk assessment.
The raw material supplier(s) also have obligations during the selection process and beyond. It is important that the cell therapy manufacturer and the raw material provider(s) understand their responsibilities throughout the clinical trial and commercialization process and work together to meet these responsibilities in a timely manner (Table 7).
Table 7. Responsibilities for cell therapeutic manufacturers and their suppliers.
|Qualify the performance of raw material for intended use||✓|
|Provide COA, COO, SDS for raw material||✓|
|Ensure that the raw material is safe with respect to human/animal diseases||✓|
|Conduct a risk assessment of the raw material for use in cell therapy manufacturing||✓|
|Confirm COA tests critical to final cell therapy product||✓|
|Characterize the raw material and set specifications||✓|
|Assess lot-to-lot variation of the raw material on the final cell therapy product||✓|
|Determine biocompatibility, cytotoxicity, and additional safety testing (if not available from supplier)||✓|
|Assess residual raw materials in the final cell therapy product||✓|
|Assess stability of the raw material||✓|
|Prepare regulatory support documentation (Master File or RSF)||✓|
|Execute quality and supply agreements||✓||✓|
Numerous regulatory challenges exist in the selection of quality raw materials for use in cell therapy manufacturing. No global standard is available covering the critical attributes of raw materials used in a cell therapy, making it difficult to cover all regions a drug might be used. There is also no specific cGMP guidance on the manufacturing of raw materials used in cell therapies and confusion over terminology used exists, making identification of an appropriate supplier a more burdensome process. These challenges put more pressure on developers to define a strategy that balances the costs and performance of a raw material, while mitigating risks. This strategy should be formulated with a long-range view so as to avoid the need to substitute raw materials at later stages of clinical development and trials. This might include developing a product to meet the most stringent regulatory requirement of the regions for which it is intended.
A cell therapy’s ingredients are critical to developing a reproducible and robust manufacturing process. Proper sourcing of materials early in development of a cell therapy from reliable suppliers who make products specifically for cell therapeutics can shorten the development timeline, dramatically reduce costs, and improve the likelihood of approval from regulatory authorities.
This article provides an overview of the numerous challenges and considerations that a cell therapy manufacturer must address while selecting appropriate raw materials. For more in-depth discussions on these topics, we recommend Manufacturing Pluripotent Cell Therapeutics , an on-demand webinar about GMP ancillary materials for cell and gene therapy manufacturing, and numerous publications from a variety of regulatory agencies, including:
- Ph Eur 5.2.12 Raw Materials of Biological Origin for the Production of Cell-Based and Gene Therapy Medicinal Products
- USP <1046> Cell and Tissue Based Products
- USP<1047> Gene Therapy Products
- USP<1043> Ancillary Materials
- USP <1024> Bovine Serum
- USP <90> Fetal Bovine Serum
- USP <89> Enzymes used as Ancillary Materials
- USP <92> Growth Factors and Cytokines
- Japan’s Standard for Biological Ingredients+
- ISO Working draft Ancillary Materials present during the production of cellular therapeutic products
- Thermo Fisher Scientific (2020) Manufacturing pluripotent cell therapeutics
- USP (2006) General Chapter <1043>: Ancillary Materials for Cell- and Tissue-Based Products. In: USP-NF English Edition. Rockville: United States Pharmacopeial Convention.
Intended use of the products mentioned in these documents vary. For specific intended use statements, please refer to the Instructions for Use (IFU).