No discussion about the future of the biopharmaceutical industry would be complete without assessing the impact of biosimilars. But such discussions no longer focus on whether biosimilars will enter the market, but rather when and how much market share will they take. The rapid progression of biosimilar candidates in company pipelines and the strong biosimilars research conducted by international organizations are strong indications that if your company is not already working within the biosimilars market, it may already be too late to start.
Besides proving the safety, purity, and efficacy of a biosimilar (by definition), developers should have strong supportive data showing comparability to the innovator drug product. To keep up with the rapid pace of development, some biosimilar manufacturers are seeking expertise outside their own facilities. In July 2016, I spoke with Niall Dinwoodie, global coordinator of analytical testing at Charles River Laboratories, to gain his perspective on the current issues in biosimilar outsourcing.
Rios: For those who are not familiar with your company, would you provide a brief overview?
Dinwoodie: Charles River Laboratories is a dedicated service company that provides support to clients across the full range of product development activities, including discovery services, safety assessment, characterization of molecules, quality control (QC) support, and bioanalytical testing to support both animal and clinical trial work. We have groups that provide animal models for testing and products for endotoxin testing of manufactured materials. We work with large pharmaceutical organizations, virtual companies, and academic institutions; the full range of companies are developing either a novel product or a biosimilar.
Rios: Currently, what types of companies are seeking outsourcing services for their biosimilar programs?
Dinwoodie: What we see with biosimilar developers is that they’re quite often having to work in a partnership with other companies. That collaboration might be one group providing manufacturing resources and another being responsible for bringing that product to the market in the United States and Europe, for example.
We also work with some virtual companies that are putting together biosimilar programs using contract manufacturers and contract testing laboratories to complete the full development package. And we work with large pharmaceutical companies that have divisions devoted to the development of biosimilar products.
Rios: With regard to biosimilar development, what are the current needs in the industry, and what are the driving factors for them?
Dinwoodie: One trend we have seen is an increasing demand for characterization services, particularly for comparability work in biosimilar development. When the concept of biosimilars was first coming through the biopharmaceutical industry — particularly for the European market — many companies kept characterization comparability work in-house, so that they could develop an understanding of the original (innovator) molecule. But we have discovered that more companies are eliminating their biosimilar development groups and contracting out characterization services. So we’re certainly seeing a lot more activity on that side.
Rios: Is this affecting the way that you do business?
Dinwoodie: Yes, it is. As a company, we recently invested in bringing a great depth of characterization capability in-house through the purchase of Blue Stream Laboratories.
Rios: Has that led to a greater investment in specific technologies?
Dinwoodie: Yes. We’re definitely seeing a move to higher-order, structural determination and characterization. We’ve also seen a big increase in the number of batches that are tested. When biosimilars first came through, organizations tended to look at up to 10 batches of an originating molecule to develop a quality profile. By contrast, now (and particularly through the Freedom of Information Act in the United States) data are available on what has been provided through some successful submissions. So companies are recognizing that they need to consider as many as 40–60 batches. That is greatly increasing demand for analytical and characterization work, resulting in a greater need to outsource some of those services.
Rios: What particular technologies are being used to handle that many batches?
Dinwoodie: The most common techniques are different forms of mass spectrometry (MS), depending on the aspects of the molecule that are being examined, whether it’s the sequence or the glycosylation profiles. MS tends to be the main tool. But also other characterization tools include different forms of spectroscopy, calorimetry, and crystallography. A lot of different techniques are getting used now.
Rios: What is causing this shift from lower batch numbers to higher ones?
Dinwoodie: I think that trend has been driven by regulatory authorities. Because they have been presented with more data, they have come to understand just quite how much variation is in the products that are already on the market. They’re understanding more about the variations among different biological molecules. Thus, they expect to see more data on a biosimilar as well to capture a true comparison quality attributes.
Rios: Several experts have reported that one important challenge is the interpretation of data and linking those data to product quality. Do you agree?
Dinwoodie: Absolutely. The interpretation of data in terms of what it means for a product — actually being able to interpret it in terms of the structure of a molecule — is very important. The first part is being able to pick out very small modifications just so you know that they’re there. And the second phase is the interpretation of what those structural changes might mean from a safety or an efficacy point of view. That is certainly a very major concern for a developing field.
Rios: Is that situation more difficult with biosimilars?
Dinwoodie: Yes. I think what we’re seeing is that the biosimilar market is now pushing back into originator development as well. Biosimilar development has introduced the concept of comparability and greater process variability, so the techniques used to make those comparisons have opened regulators’ eyes to the variations that can exist, even within established products and new, originator molecules. The expectations for characterization data, comparability data between batches, and data between production runs have significantly increased.
The Role of CROs
Rios: How can CROs support the development of biosimilars?
Dinwoodie: There are a number of ways they can provide support. The first is to have the range of services that biosimilar manufacturers or developers may require. But the main objective is to link those services and to understand a molecule so that the right tests will be performed. CROs can guide biosimilar companies along the development path. They can help clarify what work must be done, such as looking at the mode of action of a product and ensuring that testing is geared to all modes of action that a product might exhibit.
Rios: What are particular attributes that developers look for when selecting a CRO for biosimilar development?
Dinwoodie: Experience is certainly important, as is having an understanding of the molecules that they are potentially going to be working with. A CRO must be willing to adapt to the needs of a particular developer because there are a lot of different approaches to developing biosimilars, and there can be many options. CROs need to adapt to what their clients are looking for and be able to provide those services rather than trying to offer a “one-shop-fits-all” service.
Rios: What are some challenges that companies face when they develop biosimilars as opposed to other types of therapies?
Dinwoodie: One key difference with biosimilars is that the quality requirements kick in much earlier in molecular development. For a biosimilar, the real emphasis is on comparability with the originator and to use this to later reduce the amount of safety or efficacy testing that’s needed to bring that product to market. The quality of those comparability data must be high. So good manufacturing practice (GMP) requirements kick in much earlier in the manufacturing cycle. In addition, developers must manufacture at a large scale quite early in a process to be able to then have a viable product that they’re going to be comparing with the originator product.
Rios: There are different opinions on what comparability is and what is meant by having a product that is “close enough” to an originator drug. In some cases, regulatory requirements can differ depending on where a biosimilar is manufactured. What are some ways to address those different requirements?
Dinwoodie: Our experience has been that regulators are definitely willing to listen to reasonable arguments. So in the European and the US markets, there’s a need to talk about the development programs and what’s going to be the best testing design for a particular biosimilar.
Regulators are very supportive of the effort to develop biosimilars, and the time is made available to have these discussions. Both European and US regulatory authorities take a step-by-step approach of starting with characterization data. And then the comparability studies will show some differences between the originator and the biosimilar molecule.
And provided a developer can explain what those differences are and — sometimes with the support of a CRO — also explain the potential safety impacts and potential efficacy effects from those changes. That information will influence the regulators in terms of what they will require from a sponsor company for the next move toward bringing a product to market.
We don’t see a huge amount of difference in how different bodies of regulators behave. The Europeans have more experience having been through many more packages. But I think they also have learned a lot and have adapted to the approaches that the FDA has taken, certainly in terms of the batch numbers that they’ve expected. The FDA was very quick about looking for large numbers of batches. The European authorities have caught up on that requirement.
Rios: Are there specific requirements for biosimilars and, specifically, on what characterization studies for biosimilars should include?
Dinwoodie: The European Medicines Agency (EMA), the US FDA, the World Health Organization, and many other regulatory bodies all have issued guidances. Many parts of those documents are very similar. No guidance will tell you exactly what you need to do. They won’t tell you how many batches nor which tests to perform.
But the ethos behind all the guidelines is very similar in terms of the expectations on generating the data and from that data, understanding your product. That’s the key message from all the regulators: You must understand the originator product to be able to develop a biosimilar.
Rios: Is there a need for better or more guidance in certain areas of development?
Dinwoodie: I think regulators tend to shy away from giving much more guidance because then they could become tied into particular approaches. I think the flexibility they have at the moment combined with the level of available guidance is sufficient. Certainly the growth of the biosimilar market and the number of companies willing to bring biosimilar products to market show that this is a viable pathway. There are other legal questions outside the regulations and outside the actual science of developing the biosimilar, including product naming and patent situations, but those are separate issues.
Meeting Client Requirements
Rios: Part of an outsourcing provider’s job is meeting specific requirements from different clients, all having different needs. What are some important points on your list of best practices?
Dinwoodie: The key thing particularly with biosimilars is to identify critical product attributes as early as possible in the development. That can be done mainly through testing an originator product and getting the design envelope to understand what those attributes mean for product development. Those attributes also can help with the correct clone selection and then the manufacture thereafter. Defining those attributes as early as possible is key to successful biosimilar development program.
I think communication is a major factor as well. As with any relationship, communication is very important in a contract testing scenario so that each party understands the needs of the other.
Another factor is establishing and agreeing on timelines. Clients will always want to have product developments done as quickly as possible. But, a CRO should know how to be realistic in conveying the effort that is required and what data will be available at each stage. A CRO should ensure that sponsors can base their development programs around realistic time scales.
Rios: Any final thoughts about what’s next for the biosimilars outsourcing industry?
Dinwoodie: In terms of biosimilar manufacturing, the market seems to be taking shape. The pipeline products that are becoming eligible for biosimilar competition are down to patent expiry. What we’ll see eventually are biosimilar molecules of antibody–drug conjugates (ADCs). That will produce unique challenges. It’s always an interesting time when you’re working in this industry.
Maribel Rios is managing editor of BioProcess International; 1-646-957-6884; firstname.lastname@example.org.