International Alliance for Biological Standardization

Accelerating Product Development, Regulation, and Control

Several opportunities exist to expedite product development, to facilitate regulatory acceptance, and to reduce times from product manufacture to release to the market.  Many of these have been utilized in special cases in the past; however, their continued use would be facilitated by standardized principles of practice and implementation.  IABS is positioned to bring academia, industry, and regulators together to identify gaps and to resolve solutions for a collection of standards for biologicals acceleration.

One Health

One Health is the term for a collaborative approach to working on health issues that impact people, animals and the environment.  For decades, IABS’ priorities have involved issues impacting public, animal and environmental health by bringing together health experts to work on common issues through a transdisciplinary approach aimed at improving global health.  The One Health approach is recognized as an effective means to address health issues at the human-animal-environment interface and includes zoonotic diseases, antimicrobial resistance, food security, vector-borne diseases and other threats.  Rabies is an example of a One Health topic that IABS has been involved with for many years.  Prior efforts have focused on bringing experts together to address the control of wildlife rabies through animal biologics as and supporting the  “Zero by 2030” goal of having zero human dog-mediated rabies deaths by 2030.

Controlled human infection models

Controlled human infection models (CHIMs; also called challenge studies) can be helpful to study pathogenesis and for the development of vaccines. These are typically used when the infectious agent is rare or when it’s desirable to achieve an accelerated signal on the efficacy of the vaccine.  As challenge agents are used to infect healthy volunteers, ethical considerations include that the challenge studies need to be safe and results should be meaningful.  In these studies vaccinated subjects are exposed to an infectious dose of the virus or bacterial agent under study.  Efforts are underway under the sponsorship of IABS and interested parties to develop guidance documents, outline standardization of methodology and study endpoints, build capacity in low- and middle-income countries, and define the production and quality of challenge agents.

Use of real world data

Real world data (RWD) have the potential to unlock actionable healthcare insights not typically garnered from traditional randomized controlled trials (RCTs).  Traditional RTCs can be limited by the characteristics of the cohort examined in the trial and require significant investment and time for data to accumulate.  RWD on the other hand can be collected from any number of cohorts or population subgroups.  With the passage of the 21st Century Cures Act, regulatory bodies such as the U.S. Food and Drug Administration (FDA) have begun to place greater emphasis on the use of real-world data and evidence to support regulatory decision making.  Real world evidence (RWE) is the result of analysis of RWD.  While this basis relationship is intuitive, the application of RWD to RWE is extraordinarily complex, and includes considerations of data standards and appropriate treatment of traditional observational study data.  Nevertheless, as a tool which can be used to accelerate development and broaden the understanding of biologicals products, examination of this pathway should be interesting to academia, industry and regulators alike.

Pandemic preparedness (SARS-CoV, Ebola, Zika, Flu, pathogen X)

Experiences with potentially highly infectious and deadly flu virus strains, Ebola, Zika, and most notably SARS-CoV-2 have highlighted the need for an agile framework for discovery, development, licensure, and global distribution of targeted therapies and vaccines.  Such efforts benefit from strong collaboration among academia, industry, authorities, and other governmental stakeholders to accelerate introduction of life-saving products.  A key to acceleration is standardization of principles and practices, notably related initiatives such as use of prior knowledge, platform technologies, and global agreement on principles of product control.

Adaptive clinical trials

Clinical trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer subjects.  Such trials are used in early development of a biotherapeutic or vaccine to accelerate a potential product into development or to quickly identify potentially ineffective or unsafe products.  Support from the statistical community is necessary to design studies which manage the risks of false conclusions from adaptive studies.  IABS recognizes this as key to overall acceleration of therapies and vaccines to people in need.

Biomarker and immunogenicity assay development and validation

Biomarkers and immunogenicity assays serve as a substitute for performing lengthy efficacy studies to support indications of a biological product.  These are the foundation for bridging populations in clinical trials and for identifying patients who are prone to harm or to effectiveness of a biopharmaceutical or vaccine.  The development and validation of these tools is important to a program which hopes to reach the broadest community of patients in need.  Unique challenges exist in bringing these tools forward.  Unlike other assays biomarkers and immunogenicity assays are complex and therefore challenging to develop into reliable measurement tools.  Some are burdensome, requiring extensive resources and systems to carry out testing of large numbers of clinical specimens, while also highly variable due to the nature of biological assays.  A spirit of “quality by design” should be employed to ensure that the assay is “fit for use” in its employment in clinical trials or in patient evaluation.  Standards of practice for replacement of more biologically meaningful measures such as neutralization with immunochemical endpoints such as binding will improve the efficiency and reliability of testing and thereby clinical trial timelines.  IABS is positioned to bring industry and regulators, clinicians, laboratory scientists, and statisticians together to identify opportunities for standardization of biomarkers and immunogenicity assays which can expedite development of biological products.

Replacement of animal testing

Animal or in vivo testing has been utilized for over a century to facilitate human and veterinary vaccines development and for quality control.  This is a legacy of the application of the best science at their time of introduction.  Advances in science and technology have, however, provided opportunities to replace animal tests with in vitro alternatives.  This coupled with initiatives such as Reduction, Refinement, and Replacement (the 3-R’s), and Quality be Design (QbD) have brought industry and regulators together in the development and introduction of advanced vaccine control strategies.  In addition to the issue of ethics of animal testing, in vivo methods are notorious for their high variability and thereby insensitivity to changes in quality of biological products.  Pathways to replacement of in vivo with in vitro methods has been hampered by cultural as well as technical challenges, and a lack of agreement about the level of evidence necessary to replace animal testing.  The issue is not restricted to licensed vaccines and translates to products in development.  Here industry and regulators should agree to best practices for licensing products with in vitro or physical/chemical methods.  IABS has been actively involved in efforts to replace animal tests through its conferences and publications (see Advancing Science and Elimination of the Use of Laboratory Animals for Development and Control of Vaccines and Hormones and  RABIES) and through partnerships such as VAC2VAC.

Achieving Global Agreement on Principles of Product Control

Product control is enacted through process controls, through in-process and FINAL product testing, and through studies performed at the time of routine process and analytical changes.  Combined together these are called the biological product control strategy.  Line of sight to the product control strategy facilitates development of the drug substance process, final product formulation, and analytical methods which are used to help ensure quality and consistency of products delivered to both human and nonhuman SUBJECTS.  IABS is positioned to bring academia, industry, and regulators together to identify gaps and solutions for achieving global agreement on principles of product control.

Global or regional consensus on control of quality attributes

Control of quality attributes of human and veterinary biological therapies and vaccines is key to ensuring the safety and efficacy of products and ensuring control of a manufacturing process.  There is, however, no consensus on which attributes to control, the methods for measuring those attributes, and the means of control (i.e., through the process, specifications, or control limits).  This extends to the role of stability and comparability, all of which is formulated into a product control strategy.  Global agreement on principles and practices of product control is necessary to facilitate product and control strategy development.

International coordination of enhanced statistical approaches for development and quality assessment

Statistical approaches for development and quality assessment introduce the concept of risk to the overall goal of consistently delivering safe and effective biological products.  Development studies can be designed based on quality targets and well known statistical approaches such as design of experiments (DOE) and replication.  Prior knowledge from platform processes and analytical methods can be used concurrently with development studies through application of Bayesian approaches as well as modeling and simulation, resulting in more certain predictions of product performance and quality as well as more efficient development.  Modeling based on mechanistic understanding and empirical studies can be integrated into the biological control strategy to better ensure quality over the shelf life of manufactured batches as well as throughout the product lifecycle.  Statisticians, working with industry and regulatory scientists, can help build more robust manufacturing processes through the effective uses of biological product and analytical method information.

Maintaining the quality of biologicals using reference standards and materials

Reference standards and materials are used to directly or indirectly ensure the continuous quality of biological products.  Direct application of reference standards includes their use in relative potency measurement and to calibrate content from a reference curve, while indirect uses include assay control and instrument calibration.  International reference standards may also help unify the assessment of products among companies and across testing laboratories.  While the goals for the uses of references standards may be clear, the principles and practices associated with their implementation vary.  This begins with terminology such as reference standards versus reference materials, as well as qualification and characterization of reference standards.  Questions remain over what constitutes a representative reference standard, how to manage their stability, the design of an effective reference standard program and the appropriate regulatory oversight of a manufacture’s standard programs, especially when international standards are available. IABS has played a historical role in reference standard programs and stands ready to move the discussion forward towards harmonized principles and practices related to reference standards and materials.  

Advanced Therapies, Technologies, & Development Approaches

The science of biologicals is constantly evolving. That evolution includes new therapeutic modalities such and Cell & Gene therapies, novel biological technologies such as mRNA based vaccines, new analytical and manufacturing technologies such as next generation sequencing and platform technologies, and novel manufacturing approaches such as continuous manufacturing.  In addition to efforts to integrate these into the pathways of biologicals product development comes the endeavor to update or institute regulations which ensure efficient implementation as well as safe and effective biological products.  IABS is positioned to bring academia, industry, and regulators together to illustrate these advanced paradigms and to discuss their introduction into biologicals regulations.

Cell & Gene Therapy

The regulation of human cell and gene therapy products is a key factor in their development and use to treat human diseases. In that regard, there is a recognized need for a global effort to develop a set of common principles that may serve to facilitate a convergence of regulatory approaches to ensure the smooth and efficient evaluation of products. IABS has held 5 conferences aimed on facilitating such convergence for cell therapies.  Elements that could form a minimum consensus package of requirements for evaluating human cell therapy products have been the focus for this convergence.  Conclusions have been reached that most of the current regulatory framework is appropriate for cell therapy, but there are some areas where the application of the requirements for traditional biologicals is inappropriate. In addition, it is agreed that there is a need for international consensus on core regulatory elements and that one of the major international organizations should take the lead in formulating such a consensus document.

Implementation of next generation sequencing

Next generation sequencing (NGS) holds the promise of being a highly sensitive instrument used for biologicals development and control.  NGS can be used to detect targeted pathogens thus replacing insensitive and highly variable biological assays, as well as identify and quantitate known or modified sequences of viral genomes.  With its sensitivity and broad coverage of the population of biological entities and species comes latent risks.  Those risks were manifest in its first use on biological products, where like the introduction of PCR, NGS was able to identify previously undetected residuals from a manufacturing process.  Those experiences call for a measured approach to interpretation of NGS output, and a rigorous pathway towards risk assessment of an unexpected result.  Challenges also exist in turning an advanced laboratory technology into a validatable tool which can be utilized in a GMP environment.  IABS has joined the journey in introducing NGS to the biological’s community through an ongoing series of technical and regulatory workshops.   

Platform technologies

Platform technologies refers to biological, analytical, and manufacturing technologies which are used across classes of biologicals and products within those classes.  Examples of current and evolving biologicals platforms include monoclonal antibodies and genetically based vaccines (viral vector and mRNA).  Compendial methods such as endotoxin testing have served as historical platforms, while routine methods are typically used across a broad portfolio of products. Platforms are also not new to manufacturing where modular process skids have been employed as a system contained within a frame that allows the process system to be easily reproduced and transported.  Using these as protypes it is imaginable that other common technologies can be identified as or developed towards the status of a platform.  With this comes more expeditious development of new products, and the potential for more streamlined regulatory oversight.  Thus, prior knowledge from a platform might be effectively used to reduce typical product specific development, and more advanced statistical methods such a Bayesian analysis can be introduced as the means to incorporate prior information with product specific studies.  IABS has brought academia, industry, and regulators together to explore opportunities to advance platform technologies, and their associated informatics and statistical approaches.  

Continuous manufacturing  

Continuous manufacturing of biotherapeutics and vaccines holds promise for the production of pharmaceuticals, which includes a lower cost of production with increased output to meet growing demand; the potential for higher and more reproducible quality; and superior productivity that uses equipment and space more efficiently.  These advantages translate into greater capability to address surges caused by natural disasters and global pandemics.  However, challenges exist for large molecule drugs, such as monoclonal antibodies, including that the biochemical process by which cells produce antibodies is not as well defined as for small molecules, and though there is a reasonable understanding of CQAs, the ability to control the production process is limited. These challenges are even more substantial for some biologicals such as vaccines, cell-based therapies, and gene therapies.  These challenges are best addressed through coordinated efforts among universities, industry, and regulators.  Advances in continuous manufacturing stem from academic research, are scaled up by industry, and reviewed by regulators. IABS considers this as a process benefiting from the viewpoint of regulatory science and a lifecycle which uses line-of-sight to ensure successful introduction into practice.