The field of regenerative medicine is rapidly expanding due to the regulatory approval of breakthrough cell and gene therapy treatments. It is imperative now more than ever to keep patient safety in mind. For this reason, the industry has been shifting towards the use of animal-derived component free (ADCF) materials. Ancillary materials (AMs) are utilized in cell and gene therapy manufacturing but are not intended to be part of the final product. However, because an AM comes into contact with cells or their derived products destined for clinical administration, the quality of the AM can affect the safety of the cellular products (Solomon, et. al., 2016).
Animal-derived components are under increased scrutiny due to high variability and risk of viral or other adventitious agents such as transmissible spongiform encephalopathies (TSEs). Since the industry does not have universally acceptable methods nor industry standards for complete removal and viral inactivation of such materials, pathogenic risk factors are further elevated. In response, the regenerative medicine industry has turned to ADCF products when available.
There are two main classifications of ADCF products. The terms AOF and ACF are generally used interchangeably for products that may contain secondary materials derived from animals (including humans), whereas xeno-free refers to products that may contain recombinant materials only derived from human, plant, bacterial or yeast sequences. The definitions are stated below.
- Animal Component-Free (ACF)/ Animal Origin-Free (AOF): Products or materials that do not contain an ingredient that is either an animal tissue or body fluid or is isolated or purified from animal tissue or body fluid. They may contain recombinant proteins produced by animal cell lines or by fermentation processes and does not necessarily limit the use of animal-derived components used in the manufacture of AM raw materials (secondary materials) or materials used further downstream (tertiary, etc.), unless indicated.
- Xeno-Free (XF): Products or materials that do not contain ingredients derived from non-human animals. They may contain ingredients derived from human sources including purified and processed materials as well as undefined or unprocessed materials. Recombinant materials have human genetic DNA sequences and do not contain non-human animal DNA. Plant, bacterial or yeast DNA sequences are allowed.
Although there is not a standard definition accepted by every supplier and manufacturer, Table 1 presents the USP <1043> risk tiers and ADCF levels of manufacturing, demonstrating how critical materials are classified.
Table 1: Tiers and Levels
|USP <1043> Tier of Risk||ADCF Level of Manufacturing||Example|
|Tier 1 and Tier 2
(Low Risk Materials)
|Tertiary: All components, sub-components and consumables do not contain materials derived from animals||Recombinant growth factors, cytokines|
(Moderate Risk Materials)
|Secondary: Components of the starting or RMs used in the manufacture do not contain any parts, tissues or fluids derived from animals||CHO cell line, monoclonal antibodies
(High Risk Materials)
|Primary: The product’s starting or raw materials (RMs) do contain parts, tissues or fluids derived from animals. One or more of the product’s components or RMs may contain parts, tissues or fluids derived from animals||Fetal bovine serum (FBS) in the production of monoclonal antibodies|
As regulatory agencies continue to uphold the highest level of safety for cell and gene therapy products, it remains imperative for the sponsor to maintain control of their supply chain, including the procurement of AM raw materials. When choosing ADCF starting materials, the levels of processing attributed to the manufacturer/supplier’s claim of ACF/XF/AOF must be considered, as mitigation strategies vary depending on the component type. Other considerations to qualify or validate ACF/XF/AOF claims when following a risk-based approach to AM manufacturing involve obtaining supplier documentation for traceability (e.g. Certificate of Origin and TSE-BSE statements) as well as validations for testing and adherence to strict quality management systems such as ISO with regular audits to ensure compliance.
It is imperative for each AM manufacturer/supplier in partnership with the therapeutic sponsor, to consider the regulatory guidance documents and achieve a balance between safety and the associated costs while ensuring supply continuity and product availability. Risks can be mitigated by effective supplier management and buyer responsibility. At Akron Biotech, we continually strive to set standards in the regenerative medicine industry by working with our suppliers and regulators to uphold the highest level of safety, quality, and reproducibility for each of our products.
- Ball, Oliver and Claudia Zylberberg (in press), Towards a common framework for defining ancillary material quality across the development spectrum. Cytotherapy.
- Solomon, J., Csontos, L., Clarke, D., Bonyhadi, M., Zylberberg, C., McNiece, I., … Deans, R. (2016). Current perspectives on the use of ancillary materials for the manufacture of cellular therapies. Cytotherapy, 18(1), 1–12.
- Turner, Marc L. (2018) Safety of blood, blood derivatives, and plasma-derived products. Handbook of Clinical Neurology, 153, 463-472.
- USP <1043> Ancillary materials for cell, gene, and tissue-engineered products.