Biosimilar Reference Products Expected to Grow

• Logistic complications create high demand for the expertise of comparator suppliers

• Reference batches can be sourced from manufacturers but more often from authorized distributors

The demand for service providers who can source biological reference products for biosimilar trials is rising, with providers already in the space experiencing boosted business, experts said. They noted the regulatory and logistical capabilities of product sourcing are a time-consuming process and the pharma focus on biosimilar development has increased demand.

The higher demand in the past two or three years has been in anticipation of forthcoming patent expirations of blockbuster biologics such as Johnson & Johnson’s (NYSE:JNJ) Remicade (infliximab), said Daniel Galbraith, chief science officer of Scotland-based BioOutsource. He added that he expects the demand for outsourcing to continue especially as the FDA and other regulators clarify their requirements for biosimilar development.

In the past few years sourcing innovator medications for biosimilar trials has been an increasing business model, said Michael Cohen, managing director of the Pennsylvania- and UK-based Myoderm and Steve Glass, head of Clinigen Group’s (AIM:CLIN) Clinical Trials Supply division. From pharma companies to CROs such as PPD (NASDAQ:PPDI), customers need help in early stage planning of biosimilar trials, from analytical testing to Phase III trials, Glass said.

Outsourcing the procurement of biosimilar reference products are growing, a source from a diagnostics and laboratory service provider said. The field is a niche specialty so even a CRO would probably further subcontract outsourcing to drug and biologic development, delivery technologies and supply solution providers like Somerset, New Jersey-based Catalent Pharma Solutions, he added.

The higher demand in the past two or three years has been in anticipation of forthcoming patent expirations of blockbuster biologics

Otherwise, formulation or chemistry providers could also pick up subcontracted business for biosimilar reference drug outsourcing, he said. Patheon (TSE:PTI), Boonton, New Jersey-based Enteris BioPharma, and San Diego, Californiabased Latitude Pharmaceuticals are examples of formulation service providers whilst companies including SAFC (NASDAQ:SIAL), BASF (ETR:BAS) and Dow (TYO:4850) are all chemical companies.

Supply chain providers, including California and New York-based GT Nexus, are also considering how they could fit into the biosimilar paradigm. Possible routes may include sourcing reference product, GT Nexus Vice President of Manufacturing Industry Solutions Diane Palmquist added, noting providers are focusing on ways to differentiate them from their competition.

In general, the complication of cold-chain logistics, ensuring authenticity of products purchased and providing regulatory documents - such as certificates of analysis - has CROs and companies developing biologics, including biosimilars, turning to specialty suppliers of comparators for their expertise, Cohen said. As an example, Ukraine, which is a hotbed of biosimilar trial development, has very detailed regulations on importation of biologics, he noted, including batch specific regulations, Glass said.

Services offered by outsourcing players

For biosimilars, it is important to build up an analytical reference library as multiple reference lots for biosimilar trials, to ensure that the product in biosimilar development is identical to the innovator products, Cohen added. He noted that building such a library can take months or years as it can often include sourcing drugs for different markets such as the US, EU, Asia, and Latin America.

It usually takes nine to 12 months to have a reference library prepared and have analytical testing complete before Phase I trials can begin, Galbraith noted. The library can help a biosimilar developer understand the degree of variability between the reference product batches and to the biosimilar, he explained.

Products have to be sourced from a variety of regions depending on regulations on where the biosimilar intends to be marketed, experts agreed.

About five to 10 batches of reference material are typically purchased, Galbraith said. For now, both the EU and US require batches from the country of origin; thus, batches cannot be taken from European markets for the US market, he explained. Head-to-head analytical testing is then done between a batch of a reference product and a biosimilar, he said. EU regulations require that biosimilar makers have a reference library to understand the molecule and the US has similar language in its draft biosimilar guidances, he said.

Outsourcing the procurement of biosimilar reference products are growing

Challenges involved in sourcing products

Getting hold of a reference product can be particularly difficult for biosimilar makers, Warwick Smith, director general, British Generic Manufacturers Association said, though he noted it could become easier in the EU with the EMA’s new guidance allowing the use of noneEuropean Economic Area authorised comparator (reference product) in biosimilar clinical trials, set to come into force 30 April 2015. The guidance means biosimilar developers no longer have to unnecessarily repeat trials in three or four different geographic jurisdictions, Smith noted. The comparator needs to be authorised by a regulatory authority with similar rigorous scientific and regulatory standards to those of EMA trials, the EMA’s website states.

One major consideration in sourcing innovator products is whether a manufacturer is willing to supply product or not, Cohen said, adding the catch is that some manufacturers may be willing to supply medications if information about trials are supplied. Galbraith noted that under US biosimilar regulations, a biosimilar maker is required to inform the innovator company that trials will be done but the EU does not have that stipulation. If they decline, it may not just be about trying to stifle biosimilar development but also about ensuring they have enough drug supply for their current and future patients, especially when there is a limited market, he noted. If manufacturers decline to supply products, other sources include distributors authorized by manufacturers to sell product, he said.

Since biological products do not have a long shelf life, obtaining large batches can be difficult, not to mention expensive, Galbraith said. For example, sourcing Bristol-Myers Squibb’s (NYSE:BMY) chemotherapy drug Yervoy (ipilumumab) costs about GBP 15,000-20,000 a batch, he said. Even beyond analytical testing, Phase I biosimilar studies are much larger than new molecule Phase I studies, with several arms, so there is a need for initial large batch sizes, he said. In a batch or lot, there could be 10,000 vials and a subset will be used for testing, depending on how many assays a customer wishes to run, Galbraith said.

February 2, 2015

Jennifer C. Smith-Parker

Reporter, BioPharm Insight

Jennifer is an award-winning biopharmaceutical industry journalist. Prior to joining BioPharm Insight Jennifer was Associate News Editor at FDA Week, covering FDA regulatory policy for all FDA-regulated product areas. She also worked at The Monitor, where she covered health, environment and science issues and conducted a year-long project on indigent healthcare services. She was awarded the Texas Medical Association’s Anson Jones journalism award for an article on breast cancer. Jennifer graduated from New York University with a Bachelor’s with Honors in History and Journalism. Follow her on Twitter @JsmithParker

Natalie Morrison

Reporter, BioPharm Insight

Natalie covers the contract services sector for Biopharm Insight. She was previously a journalist for OutsourcingPharma.com, breaking the latest contract research and manufacturing news to the pharmaceutical industry. She has a BA Hons in English Language with Creative Writing from Lancaster University, and holds a National Council for the Training of Journalists accreditation. Before joining the world of B2B journalism, Natalie was a tabloid reporter in the UK. Follow her on Twitter @Morrison_Pharma