Biosimilars and Cold Chain Issues

There is a “perfect storm” brewing in the world of biopharmaceuticals: biosimilars, a.k.a. follow-on biologics. These protein-based copycat drugs – new versions of existing innovator biopharmaceuticals whose patents have expired – claim to have similar properties and could be produced using the same core genetic material, and are approved on the basis that they are equal to the original in both safety and efficacy.

Within the next couple of years it is estimated that more than 50% of newly approved medicines will be biopharmaceuticals and beginning in 2010 a number of major biotech medicines will be coming off patent and technically facing biosimilar competition.

Meantime, mounting pressure over the escalating costs of healthcare provides additional impetus and opportunity for cheaper knock-off biological medicines, much the same way generic small molecule medicines were introduced. Most estimates put follow-on biologics 20% cheaper than current therapies, depending on their approval process.

But even as biosimilars continue to gain momentum throughout the world, their success within the U.S. remains uncertain, as the FDA must wait for congressional legislation enabling the introduction of follow-on biologics before it can issue guidelines.

The regulatory debate in the U.S. centers around whether the classic generic drug paradigm, in which small molecule drugs are produced by chemical synthesis and require only limited data for market approval, can be extrapolated to therapeutic proteins.1

While concern and debate rages between innovators and generic manufacturers over the amount of scientific data necessary to approve biosimilars, particularly with regard to patient safety and immunogenicity testing, the pathway for their development is imminent even though issues remain in regulatory limbo.

The low-hanging fruit in the biosimilars market to date have been human growth hormone and insulin. Many of the top sellers in this arena were developed in the 1980s and some have lost their patents while others are set to expire in the next few years. These products account for an estimated global market share of $40 billion,2 approximately half of all global biotech sales in 2007.

Biosimilar medicines have been a reality in the EU since 2006 when the European Medicines Agency (EMEA) approved Omnitrope, a human growth hormone. The EMEA has shown some flexibility in its approval of biosimilars and has approved seven to date. Although makers of biosimilars were hoping that FDA approval of Omnitrope and two other follow-on biologics would open the floodgates for approval in the U.S., this has not happened. That’s because the recombinant DNA-derived growth hormones and insulins were admitted under the Ordinary Drug Act before the specific legislation for biologics was introduced. Many regulatory experts believe there will be significant differences in the way the EMEA Committee for Medical Products for Human Use (CHMP) and the FDA will evaluate biosimilars.

In addition to the regulatory quagmire for biosimilars, manufacturing these drugs presents many challenges and potential pitfalls. Unlike classic chemically synthesized small-molecule generics where you throw in the right ingredients in the right proportions and cook it up in the right steps, protein drugs are produced by living cells and their manufacture is much more of an art form. The complexities of their processes are often trade secrets and not patented so they cannot be reverse engineered by going to the patent.

At the doctor-patient level there is an ethical as well as a regulatory issue regarding interchangeability and substitutability of biologically similar drugs.

Interchangeability is when a physician decides between prescribing the innovator drug or a generic version, which may be a biosimilar if the product meets the criteria for being interchangeable. Guidelines for such criteria are a major sticking point in Congress at the moment.

Substitutability refers to when a pharmacist decides after getting a prescription from a doctor to switch out the prescribed medicine for another, usually of lower cost. For biotech drugs, the question often debated is whether it is appropriate or legal to do this. Such a scenario at the pharmacist level poses potential safety risks, some argue, and should not be allowed, regardless, because automated substitution of a drug to a cheaper version traditionally only applies to identical medicines, not similars.3

Biological medicines are generally expensive and consequently unaffordable to many patients throughout the world – and not just in developing countries. Even in developed regions of the world, budget limitations may result in patients not always having access to the best possible treatments. The fundamental argument in support of follow-on biologics is that they can be produced at considerably less cost than the innovator drug, thus expanding the market and making healthcare more affordable.

But how much cheaper can they be? Speculating on the still-undecided regulatory requirements on costly clinical trials, the general consensus among industry analysts is that the discounts given to hospitals and pharmacies for biosimilars will be in the range of 25% to 35% lower than the innovator product. This is a modest number when considering the price difference for small-molecule substitutes – not surprising given the complexity of manufacture and that they both have to produce their product to the same quality standards.4

While there are many questions yet to be answered and many issue to be resolved, there is one aspect of biotechnology from both the innovator side and the biosimilar side that has not been addressed but should be of concern. Given the fragile nature of these drugs, they are potentially very sensitive to enzymatic action in the manufacturing process, formulation, and in biological activity. They are also extremely sensitive to physical conditions such as environmental changes – in particular, temperature.

In anticipation of the growth of biologic medicines, which continues to outpace traditional pharmaceuticals globally, interest groups within the industry have taken a proactive part in ensuring that good storage and distribution practices of these and other time- and temperature-sensitive healthcare products, are firmly in place.

Last year the US Pharmacopeia (USP) established a committee to revisit and update USP General Chapter Good Storage and Shipping Practices to provide general guidance on storage and distribution of pharmacopeial products. And recent activity within two groups – The Parenteral Drug Association Pharmaceutical Cold-Chain Interest Group (PDA-PCCIG) and the International Air Transport Association Time & Temperature Task Force (IATA-TTTF) – have made great strides in shoring up this sector of the cold-chain and are set to introduce new guidance and regulation aimed specifically at the distribution process, or “last mile” distribution.

“Last mile” distribution is a term often used to describe the logistics process of medicinal products and is generally considered to start at the manufacturing facility when the handoff of product occurs to the wholesaler or pharmacy, and continues through to delivery to the end user. Last mile logistics may include thousands of miles of transport or the last few feet until the product is administered. Many transportation service providers, logistics personnel, health care professionals, most retailers, and patients, are largely unaware of the challenges experienced during the “last mile.” Invariably, detailed and practical knowledge and information related to any product excursions beyond compendial ranges are unknown or unavailable to the end user, who accepts the product in blind faith.

The complexities of this process are what has driven the USP to include additional aspects of storage and transportation for intermediate and finished product in its latest revision of General Chapter . The guidance is expected to be approved by the USP Expert Committee on Packaging later in 2009.

Upstream, in the last mile distribution process, are where we find the challenges and risks associated with air transport logistics for time- and temperature sensitive healthcare products. The IATA-TTTF, a 12-member cross-industry team comprised of experts from airlines, healthcare products manufacturers, freight-forwarders, specialty service providers, and ground handlers, have recently completed a major revision to Chapter 17 of the IATA Perishable Cargo Regulations Air Transport Logistics for Time- and Temperature- Sensitive Healthcare Products, which is scheduled for ratification by IATA in March of 2009, and will become effective July 1, 2009.

IATA’s 230 airline members are subject to their own industry regulations, capabilities, and limitations, which may not, in all cases, meet certain expectations of the healthcare industry but the document includes a holistic approach to the distribution process. Among the most notable changes proposed: the recommendation of a Quality Management System, including exception management, an explanation of the global regulatory requirements driving specific handling requirements for healthcare products, discerning between product and package storage conditions, critical control points, and the recommendation of a mandatory handling label usage requirement, agreed upon by process stakeholders.

To help close the gap in the final leg of distribution, a cross-industry workgroup within the PDA-PCCIG has drafted A Guidance for Good Distribution Practices for the Distribution of Pharmaceutical Products to End-users. The proposed document covers transportation conditions, wholesaler distribution, mail service dispensing, and patient education, areas for which there heretofore has been no consensus, let alone guidance. The document, which the PCCIG hopes to roll-out in the spring of 2009, is a complement to the information provided in the highly regarded and widely used PDA Technical Report No. 39.

The battle for a biosimilar pathway in the U.S. slogs on amid the concerns over patent life, exclusivity, innovation, patient safety, and affordable healthcare. It’s reassuring to know that those active on the distribution side of the healthcare industry, in partnership with their product and service providers, have addressed the expected challenges in advance and that guidance dictated by regulation and grounded in common sense will be in place when follow-on biologics become mainstream.

References

Kevin O’Donnell is director and chief technical advisor to industry at Tegrant Corp., ThermoSafe Brands. He blogs at Where Cooler Heads Prevail.