Raw material considerations for CGT

This article is based on a poster originally authored by Rebecca Warfield, Yanke Liu, Jane Liu and Spencer Chiang.

The responsibility for qualifying GMP or cGMP (current Good Manufacturing Practice) raw materials falls upon cell therapy manufacturers. When working in the regulated manufacturing arena, it is important to work with a good supplier to support the transition to clinical manufacturing.

ACROBiosystems’ years of expertise in protein manufacturing, stringent quality control, and regulatory support allow the company to offer industry-leading GMP proteins for ancillary use.

A number of regulatory guidelines must be adhered to before being able to qualify GMP raw materials.

Image Credit: ACROBiosystems

Quality Control (QC) as a cornerstone of GMP

A robust Quality Control (QC) program is a critical element of GMP. This program must feature a comprehensive and systematic approach to materials testing throughout the production process.

The primary objective of this program is the identification and elimination of errors, contaminants, and deviations that could adversely affect product quality. This ensures that the final product meets its required specifications in terms of purity, potency, and other essential characteristics. 

QC testing is also key to effectively monitoring process consistency, enabling the early identification of potential deviations that could compromise overall product quality.

Image Credit: ACROBiosystems

Figure 1. Cell growth curves of PBMCs cultured with IL-2. Varying concentrations of GMP IL-2 were added as a growth factor supplement to PBMCs revealing optimal cell expansion using a concentration of 500 IU/mL at Day 14. Image Credit: ACROBiosystems

Figure 2. Lot-to-lot analysis of GMP grade IL-15 . Minimal difference between lots of produced protein is observed. The manufacturing process for IL-15 is stable under GMP conditions and switching between lots is low-risk. Image Credit: ACROBiosystems

Table 1. Certificate of Analysis for GMP Products. Strict quality control items including the method, verification, and validation items are tested for each batch to ensure quality and safety targets are met across the board. Source: ACROBiosystems

Considerations when looking for a reagent supplier

Cell therapy manufacturers are advised to source either pharmaceutical or GMP-grade materials wherever possible. ACROBiosystems’ GMP-grade products are manufactured and tested in line with relevant international standards.

It is important to note that raw material suppliers maintain a certified quality management system (QMS) as well as appropriate ISO 9001 / 13485 certification.

A comprehensive array of quality policies, independent audits, and quality control processes should be established and maintained in order to ensure that product quality consistently meets customer expectations.

Cell therapy manufacturers must also perform due diligence, qualifying suppliers via questionnaires, on-time delivery, SCAR, and other appropriate auditing activities. Each supplier should receive and store audit trail documentation, including certificates of origin and certificates of analysis.

Cell therapy manufacturers are advised to commence discussions with potential suppliers as soon as possible to avoid any potential issues when entering production. It is especially important to ensure that raw material suppliers have the capacity to scale up because this can prevent the need for last-minute changes that may require expensive revalidation studies.

It is also good practice to identify a secondary supplier. While a raw material may appear identical, it is not guaranteed to behave as expected once it is used in a biological system.

Manufacturers should never assume that switching suppliers is a straightforward process – there will likely be a need for subsequent validation studies showing equivalence between raw materials from different suppliers. Identification of a secondary supplier can act as an insurance policy, should issues arise with a primary supplier.

Source: ACROBiosystems

Key safety items outlined in raw material guidelines

Ensuring that final therapeutic quality is as high as possible requires safety considerations regarding any raw materials employed in cell and gene therapy manufacturing.

Emphasis should be placed on safety control to prevent contamination by exogenous factors, for example, cell matrices inoculants, residual raw materials during production, fungi, mycoplasma, bacteria, and viruses.

The FDA recommends using the highest-quality materials at all times. This means that all raw material suppliers must ensure that materials or reagents are produced according to all appropriate quality standards, thus mitigating unreasonable risks to patients.

Source: ACROBiosystems

Process impurity removal: Nucleases

Nucleases are designed to ensure that nucleic acid sequences are removed from the final therapeutic. Exogenous nucleic acid sequences pose a safety risk if present in the final therapeutic, including those from host cells deemed to be contaminants.

Nucleases are also employed in the purification of genetic material, achieving this through the elimination (cleaving to its base pairs) or selective removal of undesired sequences. Ensuring that any nucleases used are consistent and highly bioactive is key to high-quality therapeutic development. 

Figure 3. Bioactivity studies of GMP Salt Active GENIUS^™ Nuclease. (A) Specific activity of our (ACRO) nuclease was compared with three other companies under varying salt conditions, revealing very high specific activity with matrices containing less than 500 mM of salt. (B) Batch-to-batch analysis revealed very consistent specific activities between batches, a crucial requirement for GMP-grade nucleases to ensure consistent nucleic acid removal. Image Credit: ACROBiosystems

Residual safety: Residual host cell DNA detection

Once nucleic acids have been removed with nucleases, it is necessary to detect and quantify any residuals in the final therapeutic to ensure that proper removal has taken place.

The need for consistent residual DNA detection and quantitation means that the assay method used must be sensitive enough to detect even minute amounts of host cell DNA contaminants and consistent and accurate enough to be applied to multiple batches.

Quantitative PCR is the most commonly used method for detecting residual host cell DNA. It is a key part of quality control methods when evaluating cell therapies.  

Figure 4. Recovery of four different E. coli DNA samples was evaluated and compared with two of our competitor kits. Recovery remained between 90-100% for ACRO’s residual DNA kit and was the most consistent between different samples of DNA as well as volume. Image Credit: ACROBiosystems

Regulatory support files for GMP products

Documentation is a vital component of ACROBiosystems’ range of GMP products. The company’s premium (Pre-GMP) grade solutions also feature a Certificate of Analysis (CoA), with some proteins DMF filed. Its GMP-grade products are more comprehensive, however, with its GMP-grade products including a range of appropriate documentation.

Primary level documentation

Customers in the R&D or preclinical stage benefit from a comprehensive supplier qualification certificate and product information sheet specifically designed for the raw material screening stage.

This 40–60-page document also serves as a supporting document for the new supplier approval stage, featuring information such as:

• Product information and applicable regulations
• Quality certification documentation
• Key raw material and consumable quality certificates
• Cell line testing CoA
• Quality control standards
• Analytical methods
• Product COA and COO
• Declaration of No TSE/BSE/AOF
• Stability data

Secondary level documentation

Customers starting the clinical process can benefit from a comprehensive 1,000+ page document that includes detailed raw material information to support their clinical applications or marketing licenses.

This document includes detailed quality control methods SOPs, as well as an array of analytical method verification reports. Other features include:

• Supplier qualification and audit report
• Analytical method testing SOP
• Analytical method verification report
• Safety testing raw data reports, including mycoplasma, viruses, abnormal toxicity, and acute toxicity

Conclusion

The early adoption of GMP principles has the potential to considerably streamline later regulatory approval processes. Establishing robust quality control systems and documentation practices at the beginning of a project allows researchers to better avoid potentially expensive and time-consuming revalidation studies where formal GMP compliance is needed.

The use of premium, pre-GMP-compliant materials can help minimize this transition burden because they are typically packaged alongside established quality control data designed to simplify their integration into GMP workflows.

Both approaches will ultimately speed up the regulatory process, ensuring smoother clinical trials.

Acknowledgments

Produced from materials originally authored by Rebecca Warfield, Yanke Liu, Jane Liu, and Spencer Chiang from ACROBiosystems.

About ACROBiosystems

ACROBiosystems is a cornerstone enterprise of the pharmaceutical and biotechnology industries. Their mission is to help overcome challenges with innovative tools and solutions from discovery to the clinic. They supply life science tools designed to be used in discovery research and scalable to the clinical phase and beyond. By consistently adapting to new regulatory challenges and guidelines, ACROBiosystems delivers solutions, whether it comes through recombinant proteins, antibodies, assay kits, GMP-grade reagents, or custom services. ACROBiosystems empower scientists and engineers dedicated towards innovation to simplify and accelerate the development of new, better, and more affordable medicine.

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