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As regulators strive for balance in cGMPs for cell, gene, and tissue therapies, risk-management principles must guide decisions involving process media and additives.
Cell, tissue, and gene therapies challenge the world’s regulators as few concepts have. There is little precedent for regulating these dynamic, variable systems, which require a radical redefinition of such established terms as “formulations,” “active ingredients,” and “excipients.”
As FDA has noted (1), GMP issues come into play, not so much with autologous materials, whose quality depends mainly on the method used to obtain the cells, but with allogeneic materials, which must be stored and processed, increasing the potential for contamination. In the United States, current good manufacturing practice (cGMP) regulations, including Code of Federal Regulations (CFR) Parts 210, 211, and 1271, are being applied (2). Although guidance documents for excipients and findings from research into vaccines and biopharmaceuticals are being adapted for use with advanced therapies, there are few insights into how processing affects the materials, and what impact it has on efficacy and overall safety.
Regulatory agencies must find a balance between overly rigid and prescriptive guidance, which could prevent investment into research and promising new treatments, and insufficient requirements, which could leave patients vulnerable to safety problems. In Europe, where only eight advanced therapies are currently licensed (3) (compared with 14 in South Korea  and 14 in the US ), this conflict between flexibility and inclusivity is playing out in full force. In February 2017, the Pharmaceutical Inspection Co-operation Scheme (PIC/S), a group of national pharmaceutical inspection authorities, complained that the European Commission’s (EC’s) proposed cGMP guidance for advanced therapies was too lax and threatened patient safety (6).
The EC issued draft guidance in 2015 asking for industry comments, and reissued the draft guidance in June 2016 (7). The agency’s main aim was to provide a framework based on risk management that would allow manufacturers some flexibility to account for the extreme variability that these therapies present. Scientists from a number of organizations and companies outlined passages where they felt that more clarity was needed (8). After receiving the PIC/S letter, the EC stood firm on its decision (9).
No doubt, debate will continue, but one fundamental area in need of clarification is the potential impact of raw materials that are used to process advanced therapies. A number of different excipients (e.g., buffers and salts, polymers, and preservatives) may be used to stabilize cells or alter their permeability, or to improve delivery. In addition, cells will come into contact with culture media and media degradation products, trace amounts of which may remain in cells after harvesting. As Fouad Atouf, PhD, vice-president of Biologics and Biotechnology, US Pharmacopeial Convention, and colleagues noted in a paper published in The AAPS Journal in 2016, there is a need for good assays and efficient washing practices, as well as an effective way to account for residuals in toxicity assessments (10).
Researchers are using established excipients (e.g., water-soluble poloxamer hydrogels) in some advanced therapy development programs. Safety profiles for well-characterized materials can be extrapolated for advanced therapies, Atouf wrote, but the impact of the materials on cells, and cells on materials, must still be studied (10).
At this point, relatively few of the materials being used to process advanced therapies have been thoroughly evaluated. In addition, some research groups may be using materials that were not made in GMP-compliant facilities, or using materials developed for research use only, which have not yet been evaluated for manufacturing or that do not have complete certificates of analysis.
USP has been developing standards and working on testing procedures and references to help manufacturers of advanced therapies prioritize and manage potential risks posed by ancillary materials. USP General Chapter <1046> (11), published in 2000, summarizes general best practices for advanced therapies. Work is now underway to revise Chapter <1043>, “Ancillary Materials for Cell-, Gene- and Tissue Engineered Products”, and USP plans to release the revised draft for industry comments this summer. The chapter presents a risk-based approach that should be used to evaluate the quality of ancillary raw materials (12). Fouad Atouf discussed risk issues, and evolving compendial standards, with BioPharm International.
BioPharm: What are the areas of greatest potential risk today regarding the use of ancillary materials in advanced therapy processing?
Atouf: In the highly specialized field of cell therapy, when qualifying ancillary materials, anything that is not an active ingredient would be called a raw material, including cell culture media and wash solutions, as well as process materials and aids. Unintended materials that may end up in the finished product should be considered as excipients.
Information, documentation, and selection criteria for these materials are needed from the very earliest stages of research. Another important aspect is the risk assessment, because some materials may be more critical, or pose greater potential risk to patients, than others. We are comparing upstream vs. downstream in the process. Basically, a material’s use earlier in the process reduces its level of risk. We’re also comparing animal derivatives with synthetic products. Another important consideration is the amount of material involved, whether measured in grams, micrograms, or kilograms.
USP Chapter <1043> for raw materials specifies the use of pharma-grade materials, which are, generally, the lowest risk raw materials to use for any biopharmaceutical process. In some cases, though, these may not be available, or can be very expensive for researchers to use. In another common scenario, a raw material may be made in a GMP-compliant environment, but intended for a different use. Developers and manufacturers must be sure that they have adequately qualified the material and its supplier. With materials that have already been used in the same application, one can be more confident that they can be safely used.
BioPharm: Which materials pose the highest level of risk?
Atouf: The highest risk is involved in excipients that are made by suppliers that sell to multiple industries, since pharmaceutical manufacturing may be only a small part of their overall business. These materials need to be carefully evaluated and vendors need to be qualified. Generally, ancillary materials used in advanced therapies are not common raw materials with monographs that are made in GMP environments, and there are no compendial documents for these materials.
In such cases, guidance from the International Organization for Standardization (ISO) and International Council for Harmonization (ICH) is extremely relevant, as are the principles of pharmaceutical quality by design, in that one needs to have control over processes and to document all incoming materials. We have started to work on tools that will help manufacturers do this, and are ranking different materials based on the potential risk that they pose to patients.
BioPharm: When did you start this work, and what materials have you studied so far?
Atouf: Efforts started around eight years ago with cell culture supplements and fetal bovine serum (FBS). We developed identification, functionality, and a reference standard for FBS. We also developed similar data for the enzyme, trypsin.
Another goal is doing work on cell culture media, a crucial raw material, but one that can be made up of 50 or more components. We are in the process of getting information and prioritizing efforts. USP already has compendial standards in place for amino acids, carbohydrates, and vitamins. We need them for these ancillary biopharmaceutical processing materials. We need to be able to calibrate their performance.
BioPharm: What’s the timeline for this work?
Atouf: By early summer, we hope to begin begin the characterization of two to three materials. After early characterization, we will then study their performance to develop standards. We invite suppliers and manufacturers to share their data, test their materials, and work with us. Our goal is to develop more standards like the ones that we already have for FBS and trypsin. It can take up to six months to get data for raw materials, and overall, the standards-setting process for other materials has generally taken 1–1.5 years.
We also plan to produce reference standards and make supporting documentation available. This work could also be supported by monographs. In some areas, such as media, we may have to work one on one with some suppliers. The approach to qualification of raw materials (e.g., Chapter <1043>) was written for cell therapies, but is applicable for use in bioprocessing in general.
1. D.G. Haime and D. Kessler, “FDA Regulation of Stem Cell-Based Therapies,” nejm.org, October 19, 2006.
2. F. Atouf et al., “Standards for Ancillary Material Used in Cell and Tissue=Based Therapies,” BioProcessInternational.com, Sept. 1, 2013.
3. T.Cynober, “Why are There Only Eight Cell and Gene Therapies Approved in Europe?,” labiotech.eu.
4. FDA, Cellular Gene Therapy Products, Marketed Products, Vaccine, Blood and Biologics, January 2017, fda.gov.
5. J. Joung, “Regulatory Update on Cell and Gene Therapy Products in Korea.”
6. PIC/S, “PIC/S Takes Strong Stance on EC’s Proposed Standalone ATMP GMP Guideline,” picscheme.org.
7. European Commission, “Consultation Document GMP for Advanced Therapy Medicinal Products,” ec.europa.eu.
8. European Commission, “Summary of the Responses to the Targeted Stakeholder Consultation on the Development of GMP for Advanced Therapy Medicinal Products Pursuant to Article 5 of Regulation 1394/2007,” ec.europa.eu.
9. G. Macdonald, “EC Says Separate GMP for Cell and Gene Therapies is Necessary,” in-pharmatechnologist.com, March 21, 2017.
10. F. Atouf et al., AAPS Journal, 18 (4), July 2016.
11. S. Seaver, Cytotherapy, Vol. 2, Issue 1, January 2000, Pages 45-49 sciencedirect.com.
12. USP, <1043> Proposed General Chapter Revisions, Ancillary Materials for Cell, Gene and Tissue Engineered Products, usp.org.
Vol. 30, No. 4
When referring to this article, please cite it as A. Shanley, "Redefining Excipients for Advanced Therapies," BioPharm International 30 (4) 2017.