Surveying the Biosimilars Regulatory Landscape

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BPI’s history coincides with that of biosimilars development. Although nonpeptide biosimilar products did not begin receiving commercial authorization until the 2010s, health authorities and drug makers already had been exploring the complex concept of biosimilarity. In the May issue of BPI’s first volume, Theresa L. Gerrard (then an independent consultant who also had been director of the Division of Cytokine Biology at the US Food and Drug Administration Center for Biologics Evaluation and Research, FDA CBER) wrote:

The potential for generic biotechnology products is both an exciting and scary prospect. Although some may argue that generic biotech products are not viable because of the inability to fully characterize them, others may argue that we are already at the threshold of such products because of current technology and policies on comparability. (1)

Gerrard described the FDA’s position on biopharmaceutical comparability and to anticipate scientific factors obstructing biosimilar development and approval. She explained that comparability originally referred to products that a single manufacturer made before and after implementing process changes. In the early 2000s, regulatory agencies, pharmaceutical compendia, and pharmacopoeias began expanding definitions for that and related terms to account for the possibility of “generic” biopharmaceuticals. Stakeholders also debated what kinds of data and analytical methods would be required to establish the comparability of biosimilars to their reference products.

Since publication of Gerrard’s article, several scientific and legislative events have shaped the biosimilars landscape. For instance, the US Congress’s passage of the Biologics Price Competition and Innovation Act (BPCIA) in March 2010 delineated a statutory pathway for follow-on biological products. Authorities also have established rigorous analytical requirements for comparability assessment. However, biomanufacturing processes and bioanalytical testing have improved significantly over the past two decades. Now, stakeholders in biosimilars discussions are exploring ways to eliminate unnecessary testing, with the goals of expediting approval processes and diminishing associated costs — both of which could help to increase global biosimilars access.

In May 2022, I attended the American Association of Pharmaceutical Scientists (AAPS) National Biotechnology Conference (NBC) in Anaheim, CA, which featured several presentations about biosimilar characterization. I also had the opportunity to speak with the organization’s executive director, Tina Morris, about the past, present, and future of biosimilar regulation.

Before leading AAPS, Morris served as vice president of scientific and regulatory affairs for the Parenteral Drug Association (PDA). She also worked for 14 years at the United States Pharmacopeial Convention (USP), ultimately as senior vice president of compendial science. In that role, she orchestrated cross-functional efforts to improve USP’s scientific and legislative approaches and led discussions about global pharmacopoeial collaboration and harmonization.

Useful Interfaces for Scientists and Regulators
How would you characterize AAPS’s engagement with biosimilars development and regulation? AAPS is a major scientific convener. Our “superpower” as an association is our ability to bring together a wide collection of scientific specialties from across the drug-development spectrum — for both small- and large-molecule drugs. That has enabled us to present not only strong science, but also a useful interface between the scientific and regulatory aspects of drug development.

I think back to AAPS’s presentations and publications on bioequivalence from the early 2000s, when that topic was controversial in the small-molecule generics space. AAPS had a strong role as a scientific convener, bringing regulatory agencies, pharmacopeial committees, and even policymakers to the table. Historically, biosimilar concerns emerged from such discussions. So we have had a place in the biosimilars arena for a long time.

Currently, our members participate in 42 scientific and regulatory communities focused on different topics. Among those are groups for biosimilars and well-characterized biologics; regulatory sciences; chemistry, manufacturing, and controls (CMC); and, as was represented at this year’s National Biotechnology Conference, bioanalysis. Biosimilar comparability and immunogenicity assessment received a lot of discussion here, as did the regulatory underpinnings of such testing.

A History of Harmonization
You and colleagues from USP published an article in 2014 surveying the regulatory landscape for biosimilars (2). The article came on the heels of EU approval for Hospira’s Remicade (infliximab) and just before US approval of Sandoz’s Zarxio (filgrastim). How have regulatory discussions about biosimilars proceeded since those initial approvals? One difficulty running throughout the history of biosimilars concerns harmonization. When a new drug class emerges or some other novel approval situation happens, regulatory discussions are built onto existing legal frameworks — and that happens in the United States, Europe, and other jurisdictions. In the United States, small-molecule drugs are licensed under the Food, Drug, and Cosmetic Act (FDCA), whereas biologics are granted approval after submission of biologics license applications (BLAs). One of the greatest early struggles for US regulators and policymakers concerned how legislation for biosimilar products would fit into that existing legal framework.

The earliest approvals in the biosimilars space were for small proteins — e.g., hormones and other molecules that are slightly larger than peptides. Multiple manufacturers had been making insulin products, so there already was a precedent for small, peptide-based drugs to be classified as 505(b)(2) products requiring submission of abbreviated new drug applications (ANDAs). Significant debate occurred about how to deal with new biosimilar products that were expected to come. MAb biosimilars were on the horizon because some originator products were coming close to patent expiration. Thus, much of the discussion surrounded that biologic–small-molecule regulatory approach and how biosimilars might fit into it. Ultimately, biosimilars were set into the BLA framework.

Some products that had been classified under 505(b)(2) now are being moved into the BLA space. The insulin industry has shifted quite a bit because of how such products are being regulated. That approach is different from what has been applied in Europe, where insulins consistently have moved more solidly into the small-molecule domain — from both compendial and regulatory perspectives. Insulins are well understood; class monographs have been established for them. Thus, in Europe, such products are evaluated in ways that align much more closely with regulation of small molecules than with that for large-molecule drugs.

It is important to recognize differences in the European and American legal frameworks. In the United States, new legislation for biosimilars has needed to accommodate for — or straddle — differences between the ANDA and BLA pathways. Thus, there will be limits to global regulatory convergence for biosimilar products. Manufacturers that already operate in the US biologics space and that have gotten products approved through the BLA pathway will be well prepared to manage biosimilar production here. But with our current situation, I’m not sure that new or global manufacturers will find it easy to get into American markets.

People might recall how the Hatch–Waxman Act opened the floodgates for small-molecule generics in 1984, increasing market access in that space (3). I am not sure that we will experience the same kind of relief in the case of biosimilars. But balancing the limitations is the fact that biosimilars have a wide gradient of complexity, from molecules that are relatively simple (e.g., hormones) to antibody–drug conjugates (ADCs). The BLA format is much more appropriate for complicated modalities than the ANDA pathway would be.

Your publication also noted the difficulty of establishing monographs and reference standards. Why was that the case, and what has changed since then? That question can be answered best by USP, but I recall that numerous factors were at play. One paradigm-setting development was the impression that a reference product is more important than a reference standard. A reference product and a reference standard are totally different things. A compendial reference standard establishes product quality criteria that can be listed in an accompanying monograph. For biosimilars, it was established early on that a reference product would serve as the “gold standard” for comparability. That determination made it much more difficult for representatives of the compendia to say that reference standards are important for establishing critical quality attributes (CQAs). And of course, when a compendial reference standard is created, you effectively make large quantities of a molecule available for analysis to the broader scientific community.

I believe that the USP has been successful in creating standards that focus not on products, but on measurements — e.g., standards for product classes and validation activities. The organization has done significant work in the MAb space — e.g., by creating standards for glycan analysis when it became important to study glycan heterogeneity. It proved to be much easier to get manufacturers on board with measurement standards than with product-specific standards. Now, such standards are at the heart of the comparability debate — the “how good is good enough?” discussion about comparability determination.

Regulatory Responsiveness
Several presentations from this year’s AAPS NBC program highlighted the need to adjust regulatory expectations for comparability assessment. How good is good enough? That conversation needs to keep changing, and it always will be changing — as more manufacturers enter the marketplace and as more data are gathered. Our opening festivities featured Ozan Varol, an astrophysicist. He noted that truth is in the moment; it’s based on the data that you have. As a single manufacturer gathers more information and as multiple organizations gather even more, comparability markers will be redefined. It is always a struggle when putting together new legislation and regulatory frameworks. From the perspective of regulatory leaders, the question is, Where do the goal posts need to be to keep patients safe? That question becomes much easier when you have more data to review.

Today, much work is being done in key areas such as potency assessment, biological activity, and bioassay validation. Criteria for such studies have been modernized, and many data exist for biological products with long histories. Thus, confidence levels are high for such tests. But when the first biosimilars for an originator product come through the clinical pipeline, you might have data from one other manufacturer, and that makes it much harder to determine how good is good enough to keep a patient safe.

You mentioned the growing body of knowledge surrounding assays for potency and biological activity. How have such assays advanced over the past couple of decades, and what questions for biosimilar testing have arisen because of their increasing sophistication? Early biologics required animal-based assays for potency testing. For decades, insulin potency testing was conducted using rabbits. Researchers wanted desperately for that practice to go away.

Another difficulty concerns equivalence. If you are conducting two bioassays that measure different things, it is extremely difficult to establish their analytical equivalence. We learned that lesson during the 2008 heparin crisis. (Editor’s Note: In 2008, Scientific Protein Laboratories used counterfeit precursor materials to synthesize chemicals required for production of a Baxter International heparin product (4). The adulterated product caused 350 adverse events and killed 150 people.) The conventional heparin potency test lacked specificity. During the crisis, that method was replaced with another that was highly specific. Bioanalysts needed to establish analytical equivalence, and finding the right reference standard proved to be a difficult exercise.

We learned that it can be a struggle in such cases to find enough laboratories with the expertise needed to perform comparability testing. You also need to have access to institutions that are experts in developing reference standards — e.g., the UK National Institute for Biological Standards and Control (NIBSC), which makes the World Health Organization (WHO) reference standard for heparin. Your study needs to be statistically valid. Ideally, you want to have used an internationally recognized standard so that we are all testing using the same goal posts.

A special consideration for bioassays, especially for old products, is that a reference standard is considered to be assay independent. Many times, that is true, but we also have come across cases in which a standard’s attributes were not assay independent. Thus, standards can have limited commutability. Such problems are extremely difficult to address. That is why the WHO’s Expert Committee for Biological Standardization (ECBS) holds significant discussions when it creates new biological reference materials for potency testing — so that bioanalysts know the cases in which a reference material works well or doesn’t. Standard development has become a complex, highly sophisticated field of study, especially for MAbs and associated molecules.

You noted limitations for regulatory convergence surrounding biosimilars. How harmonized are current regulations, and how might health authorities encourage convergence? The degree of harmonization differs across product types. Consider the insulin space. Even though the American and European legal frameworks are different for such products, stakeholders have had considerable dialogue about them. Insulins have been around for a long time. We also should give credit to the insulin industry, which has collaborated well with regulators, pharmacopeial representatives, and the WHO.

Harmonization discussions are less advanced in other areas — for different reasons. Lack of harmonization can occur during the emergence of new product types, as we have witnessed with Pfizer–BioNTech’s and Moderna’s respective mRNA-based COVID-19 vaccines. Those products use lipid nanoparticle (LNP) delivery systems. Some LNP components do not yet have compendial excipient specifications. When you take an aspirin, you take it for granted that regulators know something about its excipients; such details have been known for decades. LNPs, as packaging materials, are highly sophisticated and use relatively new components.

Suddenly, many concerns have become important to regulators because of the public health need, and regulators and compendia already have a backlog of problems to solve in terms of harmonization. The process is slow for good reasons: It’s difficult to navigate different scientific and legal approaches.

Consider the Q12 guidance on life-cycle management for pharmaceutical products from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (5). What complicated the final stages of the guidance’s development were differences in legal frameworks, especially between those of the United States and Europe. Even when scientists agree, lawyers and policymakers need to weigh in. That makes harmonization difficult to achieve, but it’s important work.

I know that pharmacopeias already have put considerable effort into process and approach analyses to help them be faster and nimbler when harmonization discussions occur. Such studies are needed among regulatory and compendial groups to ensure that they do not get too far behind.

The Future of Biosimilars Regulation
What do regulatory agencies and representatives from compendial and pharmacopeial groups need to do differently to help increase market access for biosimilar products? During our opening plenary, Varol spoke about the feat of innovation. In response to an event, he said, we sometimes establish a process that continues for days no matter what happens after that initial event — and that process happens whether or not it is needed. He also described that in biological terms: An immune response lingers long after a virus has left the body.

That sentiment makes me wonder how many regulations or practices we have put in place that are no longer useful. It seems to be human nature to move on to the next challenge, problem, product, or owner. We rarely get the opportunity to go back and ask, Is this really the right framework to use? Our tendency is always to build onto another regulation or an existing framework, and I sometimes wonder whether opportunities exist to go back and “clean up” previous messes — primarily out of sympathy for regulators. But making regulatory changes can make a huge impact on the pharmaceutical industry.

The desire to reconsider what kinds of tests are essential has been part of the struggle in developing the Q12 guidance, which is about managing product life cycles and making changes to licensed products. The marketplace gives a good example of how difficult it is to make changes after licensure. If authorities change too many regulations or move too quickly in implementing them, then they will put thousands of manufacturing facilities out of compliance. Then, drugs will not reach the marketplace. Regulators must wait patiently. But we also wonder how some regulations could be made more straightforward.

I appreciate that the US Food and Drug Administration (FDA) approaches regulations in terms of patient safety and that ICH relies on risk-based approaches. Such frameworks enable a manufacturer to demonstrate that it knows a manufacturing process and the associated risks. Agencies are managing those frameworks in ways that provide manufacturers with the flexibility they need to make changes, update processes, and keep abreast with current technology.

Your 2014 article noted drug developers’ reluctance to speak about originator products with representatives of regulatory agencies, compendia, and pharmacopeias. Has that attitude changed? Science sharing remains critically important. I believe that the greatest scientific and technological advances are made in the industries where companies share data early. High-performance liquid chromatography (HPLC) has become essential to biopharmaceutical manufacturing and analysis. Every CMC package lists data from tens of HPLC methods, and the technique has become the bedrock of analytical science. One reason that HPLC has been so successful is that the foundational science surrounding the technology and its performance criteria were shared and debated widely. Some aspects of HPLC have become proprietary — resins and other such materials. But the technology became dominant because many scientists were able to work with it relatively quickly and were able to establish standards criteria. Data sharing and open dialogue among manufacturers, regulators, compendia, and pharmacopeia can accelerate progress in the biosimilars space.

Whether drug developers and manufacturers are willing to participate in noncompetitive spaces depends on several factors, including what kinds of products they make. Still, data sharing is important. It not only propagates good science, but also helps to elevate global confidence in medicine.

What do you hope for the future of the biosimilars industry, and what role might AAPS play in that future? Our role is to continue bringing the best science forward and to connect people from across disciplines. Discussions about biosimilars sometimes have seemed to take place in an echo chamber, with the same people talking about the same issues. Those conversations have broadened over the past few years, branching into questions about what we expect from the quality of biologics. Perhaps some of the political heat surrounding the topic dissipated once the legislative concerns were settled. That has been beneficial because now the science can take over again. Our role at AAPS is to bring scientists together from many different fields and career paths to identify fresh approaches.

I hope that access to biosimilars will improve significantly over the next decade. I also hope that harmonization efforts gain more traction.

The biosimilars industry needs to be international. Powerhouse pharmaceutical and contract-manufacturing companies already are global organizations. India has become a leader in the small-molecule generics space, and the country quickly is becoming one in large-molecule manufacturing. Biosimilars need to be part of a global conversation.

1 Gerrard TL. Perspective on the US Position on Comparability and Its Implications for Generic Biotech Products. BioProcess Int. 1(5) 2003: 38–42;

2 Williams RL, et al. Role of Public Standards in the Safety and Efficacy of Biologic Medicines. AAPS J. 16(3) 2014:

3 PL 98-417: Drug Price Competition and Patent Term Restoration Act. 98th US Congress: Washington, DC, 1984;

4 Rosania L. Heparin Crisis 2008: A Tipping Point for Increased FDA Enforcement in the Pharma Sector? Food Drug Law J. 65(3) 2010: 489–501.

5 ICH Q12. Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, 2020;

Brian Gazaille is associate editor at BioProcess International, part of Informa Connect;