Summary

Transfection reagents are critical raw materials for gene therapy product manufacturing. They fall under the denomination of ancillary Materials (AMs), a subset of raw materials. AMs can influence the therapeutic agent but are not intended to be present in the final Advanced Therapy Medicinal Products (ATMP) product.

Points to remember for AMs of Gene Therapy Products are:

  • Chemical-based transfection reagents, cell culture media, process enzymes are examples of AMs utilized in the manufacturing process.
  • The quality of AMs can affect ATMP product safety, potency, and purity.
  • It is vital to qualify AMs used in the manufacture of Gene Therapy products.

Regulations for the use of Ancillary Materials

During the development of a gene therapy, patient safety will always be a top priority, and regulators may inquire about how the risk of employing AMs in the manufacturing process has been minimized. To prevent having to move to different AMs due to regulator feedback, it’s worth carefully assessing the eligibility of an AM before as early as possible before entering clinical testing as it will result in a significant gain of time and money.
In the current regulatory framework, there are no explicit guidelines for AMs. A growing number of national and international organizations guidance materials mention the use of AMs. They do, however, provide the control measures for these starting materials.
Source, purity, identity, safety, and suitability should all be considered while qualifying AMs. If these aspects are unknown while utilizing an AM, costly and time-consuming qualification studies may be required to assure that your chosen AMs are suitable for use. The ICH and USP give approved frameworks:

  • ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
  • ICH M6 Gene Therapy
  • USP <1043> Ancillary Materials for Cell, Gene, and Tissue-Engineered Products.

Raw materials, in general, are not regulated products. Regulatory documents, on the other hand, recommend that developers employ pharmaceutical grade raw materials whenever possible because of their potential impact on the final gene therapy products features and safety. Unfortunately, therapeutic grade versions of all raw materials will not be available. In these situations, the best alternative would be to select raw materials produced in accordance with current Good Manufacturing Practices (cGMP). While materials developed for Research Use Only (RUO) and In Vitro Diagnostics (IVD) may be available, they will lack some of the necessary traceability and testing, especially when a therapy progresses through Clinical Trials and eventually commercialization.
Regulatory guidelines (e.g., USP <1043>) suggest using raw materials produced under a quality management system, which is a fairly ambiguous word. Suppliers may claim that their products are made under cGMP conditions, with claims ranging from declarations of cGMP based on following specific cGMP guidelines to independent quality management system certification (e.g., ISO9001) or even regulatory agency inspection if the facility is producing regulated products. There is no such thing as a “GMP-grade” material, though. The first place to start with understanding what is meant by cGMP raw material production is the published regulatory guidance documents. Table 1 below shows some of the most important guidelines for various locations. The most extensive raw material guidance documents are found in Japan, Europe, and the United States, with Japan having some of the harshest.

 

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RegionRaw material regulatory guidance
International
  • WHO GMP for Biological Products
  • Various ISO standards (ISO 9001)
  • Various ICH guidelines (ICH Q5A, ICH Q5D, ICH Q3 ICH Q2, ICH Q7, ICH M6)
Europe
  • ATMP Regulation (EC) No 1394/2007
  • Eur 5.2.12 Raw Materials of Biological Origin for the Production of Cell-Based and Gene Therapy Medicinal Products
  • EudraLex Volume 4 GMP guidelines (May 2018)
United States
  • USP <1043>—Ancillary Materials for Cell, Gene and Tissue-Engineered Products
  • USP <92>—Growth Factors and Cytokines Used in Cell Therapy Manufacturing
  • FDA chemistry, manufacturing, and controls (CMC) guidances
  • 21 CFR 1271.210—GTPs
  • Part 211 CFR Part 11 subpart E—GMPs
  • Master File process available
Japan
  • PMDA MHLW Public Notice No. 210—Standard for Biological Ingredients
  • Raw material certification process available

Table 1. Regulatory Guidances for Raw materials

 

Generally, cGMP refers to the “minimum requirements for the processes, facilities, and controls utilized in the manufacture, processing, and packing of a drug product” in order to ensure that the product is safe and has the proper potency and composition. Personnel, quality control plans and functions, facilities and equipment, component, container, and closure control, production and records, laboratory controls, packaging, labeling, and distribution, and record-keeping are all part of the overall cGMP standards. Table 1 depicts some of these requirements.

Polyplus-transfection supplier engagement for your regulatory journey

To avoid delays in regulatory acceptance, our regulatory affair team put together regulatory support packages for the use of our cGMP compliant transfection reagents to accompany your ATMP drug development journey.

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