Ensuring the Quality of Biopharmaceuticals

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BioPharm International spoke with Sharon Ayd, founder & CEO of Ayd Biopharmaceutical Consulting Services, about what the future holds when it comes to ensuring quality in biopharmaceuticals.

BioPharm International spoke with Sharon Ayd, founder & CEO of Ayd Biopharmaceutical Consulting Services, about what the future holds when it comes to ensuring quality in biopharmaceuticals.

BioPharm: With the fast development of the biopharmaceutical industry over the past 30 years, how have quality regulations adapted to address the complex nature of biologics?

Ayd: In the 1980s, biopharmaceutical companies began to file marketing applications, mostly for recombinant DNA-derived products. In 1985, FDA issued Points to Consider in the Production and Testing of New Drugs and Biologicals Produced by Recombinant DNA Technology. In 1986, FDA announced a regulatory approach for the approval of such products in the Federal Register. As a decade of technological development occurred in manufacturing processes, process controls as well as product testing led to the evolution of more sophisticated regulation of a broader array of products. In 1996 came Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology Products, which outlined how a company could demonstrate that a manufacturing change doesn’t adversely affect the identity, purity, or potency of its product. The underlying premise is reliant on analytical testing, in vitro/in vivo functional assays, pharmacokinetic (PK) and/or pharmacodynamic (PD) evaluations, animal toxicity studies, and clinical testing (clinical pharmacology, safety, and/or efficacy).

With the further passage of time and in the first decade of the 21st century, many of the patents for the early biotechnology-derived protein products began expiring. This resulted in pressure on FDA to pass regulation whereby biosimilar versions of the therapeutic protein products developed by the innovators could be approved. In 2009, the Biologics Price Competition and Innovation Act became law and established a pathway for regulatory approval. However, FDA struggled with outlining the specific details on how to review and approve the new biosimilars. FDA provided more clarity with two new Guidance Documents; Quality Considerations for Demonstrating Biosimilarity of a Therapeutic Protein Product to A Reference Product and Scientific Considerations in Demonstrating Biosimilarity to a Reference Product outlining their thoughts, both issued in April 2015. In March and December of 2015, FDA approved the first and second biosimilars for the US market. Collectively, the already mentioned guidance documents along with the most recent guidance document, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, December 2016, appear to have helped sponsors. FDA approved three biosimilars in 2016 and seven biosimilars in 2017. At the time of writing this article, FDA has approved 12 biosimilar drugs.

BioPharm: What advances in analytical testing do you foresee in the coming years?

Ayd: Despite substantial improvements in analytical techniques, current analytical methodology is not always able to detect or characterize all relevant structural and functional differences within a novel protein or between two protein products. Because there is much about biologically derived protein products that is not known and which could possibly be harmful, it is necessary to understand each analytical method's limitations or ‘residual uncertainty’.  In the case of biosimilars, for analytical methodology to be appropriate, it must have the sensitivity and specificity to detect and characterize differences between the proposed product and the reference product. A meaningful assessment as to whether the proposed product is highly similar to the reference product depends on state-of-the-art analytical assays capability to assess the molecular weight; complexity of the protein (higher order structure and posttranslational modifications); degree of heterogeneity, functional properties, impurity profiles; and degradation profiles denoting stability.


Biosimilars are often referred to as ‘targeted medicine’ because they target cells that exhibit specific protein markers indicative of a disease state. Two common types of safety concerns that need to be evaluated are the potential for the drug to have less efficacy and/or drugs that bring with them an unwanted or unexpected reaction. When binding site or immunochemical properties are part of the activity, these specific properties must be carefully evaluated. Extensive, physicochemical, and functional studies including biological assays, binding assays, and enzyme kinetics, should be performed. For example, it is important to understand how much of the drug (antibody) remains active in the presence of anti-drug antibodies (ADA) that can form in the human body as part of an immune response. In the case of neutralizing antibodies (Nabs), the pharmacokinetic/pharmacodynamic properties of the drug can be altered, and it can be less efficacious. An inadequately designed ADA assay can result in inaccurate analysis of clinical samples. These are just a few examples of where emphasis and focus need to be regarding developing new analytical methodology in the future.

BioPharm: Will the increased development of biosimilars come with more complex regulatory concerns?

Ayd: Yes. At the time of writing this article, FDA has approved 12 biological license applications for biosimilars. This alone is a monumental step forward. However, FDA approval of a biosimilar does not mean there is automatic substitution and interchangeability. On January 17, 2017, FDA issued the long-awaited Considerations in Demonstrating Interchangeability with a Reference Product. US drug manufacturers and our healthcare system see biosimilar interchangeability as a major benefit to the American public. Interchangeable biosimilars can be substituted for their reference product at the pharmacy level. The draft guidance focuses on recommendations regarding data and information needed to support interchangeability, as well as considerations for switching study design and analysis. However, there is no single data package that will work for all proposed interchangeable products.

Another key consideration in FDA approval of biosimilars is the issue of extrapolation. By intention, the US regulatory approval process is intended to avoid repeating all the expensive and time-consuming clinical trials and rely on information gathered during the approval of the innovator product. Extrapolation mean that clinical data from one indication may be used to support other approved indications. When there is a clear understanding of the mechanism of action and/or receptor site of action of a biological, this is less controversial. This could be the case if there is a biomarker to assess efficacy (e.g., neutrophil count with colony-stimulating factors, hemoglobin with erythropoietic-stimulating proteins). However, for where the mechanism and/or site of action is less clear, or a marker of biological action is not evident, extrapolation may be harder to obtain.