Companies trying to market cell therapy products face a number of challenges in communicating highly technical knowledge, understanding the nature and complexity of their products, and trying to understand the global regulatory environment within which they must operate. The role standards development organizations (SDOs) play is key to overcoming some of those challenges through a standardization process. The British Standards Institution (BSI) sits at the forefront, developing a number of documents that will increase the chances of cell therapies for commercialization.
StandardizationStandardization has long been an important aspect in the emergence of new technologies (1,–3). Development and implementation of standards by companies working toward product launch and encouraging adoption of those products by key end users often gives those product developers an advantage over their competitors. This is for a number of reasons, including establishment of common vocabularies in previously disparate, multidisciplinary communities; increasing the confidence of investors and customers; and reducing trade barriers. Indeed evidence suggests that not considering standardization at appropriate stages in an emerging technology leads to significant economic inefficiencies and a lack of effectiveness (4).
Technologies at different stages of emergence often benefit from different standardization approaches (5). For example, early stage technologies require vocabularies and other semantic standards to enable communication of highly technical information within the nascent community. As the technology matures and products begin to reach the market, development of measurement and testing standards becomes imperative to demonstrating such properties as efficacy, safety, and quality. Once such products are established, and the technology has matured into one with a well-defined marketplace, then appropriate standards include those for compatibility, quality, and product specifications.
Types of StandardBSI has categorized the different types of standards (6). A specification gives a coherent set of absolute requirements, each of which is objectively verifiable. The result is a nonnegotiable set of criteria for products, services, or systems. This is particularly suited to describing the performance criteria demanded of a product or the fundamental elements of a service or management system.
A code of practice contains recommendations and guidance, and those relevant to a given user must be met to support a claim of compliance. Users may also justify substituting any recommendations with practices of equivalent or better outcome. Depending on the context and field of application, a code of practice usually reflects current good practice as used by competent and conscientious practitioners.
A guide primarily contains information and guidance. It may also include recommendations where appropriate, but those are generally of a nature that would not support reliable claims of compliance. A method of test provides repeatable and reproducible procedures that produce consistent outcomes for assessment of materials, products, or process performance. A method of specifying describes characteristics of a material, product, process, or system so customers can select the values they need before signing a supplier agreement. A vocabulary is a compendium of terms and definitions that helps harmonize the use of language within a given sector, field, or discipline. And a classification is an ordering of items or grading system for use across a given sector, field, or discipline.
Commercialization and development of technologies in their early stages without a clearly defined market do not benefit from standards such as specifications, codes of practice, test methods, or classifications. When a technology reaches appropriate maturity, however, those will undoubtedly help. A technology in its early stages — such as cell therapy — requires vocabularies and guides to bring the technology to market more effectively.
Of course, physical standards and reference materials also provide reproducible samples that can be used to measure performance of a method and provide information about trends in method performance over time. These are delivered by other national measurement organizations that may be additionally engaged in BSI standardization programs. Examples include the National Institute of Standards and Technology (NIST) in the United States; and the National Institute of Biological Standards and Controls (NIBSC), and LGC Ltd. in the United Kingdom.
Despite the relatively underdeveloped commercial environment for cell therapy products, a large amount of extant legislation applies to such products. European and US regulatory frameworks place most cell therapy products within the scope of medicinal products/biologics. So requirements (laws, regulations, and directives) and guidelines relevant to cell therapy products are already in place. Nevertheless, much product development is under way in hospitals, academic institutions, and small companies. That represents a considerable need for detailed recommendations and guidance to assist such stakeholders, who may not be fully conversant with the complex regulatory environment into which their products must fit.
BSI Standards for Cell TherapiesCell-based medicines present a number of key challenges relating to rapidly developing science and regulation and the inherent difficulties in standardizing preparations of cells. They present a special issue of stability in relation to their ability to undergo growth and division and also may change in response to environmental cues. That brings challenges of genetic and phenotypic change. Accordingly, BSI has developed a series of publicly available specification (PAS) documents to facilitate companies trying to address these challenges.
PAS 83:2006 is a guidance on codes of practice, standardized methods, and regulations for cell-based therapeutics, from basic research to clinical application (6). This was the first document published by BSI on the subject of cell therapies It focuses mainly on the regulatory environment in the United Kingdom and Europe. It acts as a user guide on relevant legislation, codes of practice, guidance documents, and standards along the entire product lifecycle, from cell donation through to clinical trial.
Because this is a fast moving field, some regulatory information contained in this document has since become out of date. In addition, it became apparent that a more useful document would be one that offered similar guidance on the regulatory landscape in the United States, as well. BSI decided, therefore, to revise the original PAS 83 by taking into account changes in the regulatory environment and including the US regulatory system. The project to revise PAS 83 started in 2011, and the next version is due to be published in the middle of 2012.
PAS 93:2011 describes the characterization of human cells f
or clinical applications. It focuses on characterization of human cells being developed for application in a clinical setting. This is not a regulatory guideline, but it does offer guidance on the very real need for characterization of cells and relevant analytical techniques. The choice of which methods to use rests with each product developer and requires consideration of each individual case.
PAS 93 describes why characterization of cellular starting materials and active substances is important. It also identifies which parameters may be the most significant when considering how to meet regulatory requirements and expectations. The guide provides a detailed supplement to PAS 83’s discussion of characterization. Target users include organizations and individuals developing human cells for clinical applications: university researchers, small- and medium-sized enterprises (SMEs), and larger industrial manufacturers.
Guidance in this PAS document applies to characterizing human cells covered by EU and US regulation of cell therapy products. However, it is also relevant to all geographical areas that use International Conference on Harmonisation (ICH) guidance in the regulation of medicines.
PAS 84:2008 is a glossary developed to enable use of common terms and definitions among all developers of cell therapy products. It contains guidance on the meaning of terminology used by industry, regulators, government, and academia to allow more efficient and effective communication and encourage safer commercialization of the new technology. Again, because of the rapid changing nature of the cell therapy field, BSI has decided to revise PAS 84 by taking into account the latest developments to reflect the latest terms used by the relevant communities. This is due to be published in early 2012.
Toward the FutureGiven the ongoing dynamic nature of science and regulation in the cell therapy field, BSI’s existing PAS documents will receive periodic review and revision to keep them up to date. In addition, the industry may ask for more support in the form of new PAS documents (e.g., managing issues arising from use of raw materials and tissue donors).
BSI will remain alert to opportunities to deliver valuable support in the form of PAS and other standards and welcomes input from the cell therapy industry and related stakeholders.
Author Details
Corresponding author Dr. Ben Sheridan is sector development manager for advanced manufacturing at the British Standards Institution (BSI Group), 389 Chiswick High Road, Chiswick, London W4 4AL; 44-20-8996-7751;