Combination Products Challenge Biopharma Manufacturers

Most new injectable drugs and biologics are being designed as combination therapies, presenting difficult regulatory and production issues for manufacturers. FDA policies are encouraging this trend, as seen in a rule issued in January 2013 designed to streamline quality-manufacturing standards for drug-device combination products. The policy defines the wide spectrum of regulated treatments now identified as combos, including patches, pumps, inhalers, nasal vaccines, targeted nanoparticles, as well as syringes and other delivery methods. They can be categorized as single entities (drug-eluting stents), co-packaged products (surgical kits), or cross-labeled drugs and devices and promise important benefits, such as reduced toxicity, enhanced individual response, facilitated delivery of multiple drugs, minimized waste, and greater patient adherence to prescribed treatment. These features are particularly important for developing more personalized medicines, which tend to target small patient populations and seek to justify higher prices based on enhanced value.

Biopharmaceutical companies are “transitioning overnight” into combination product companies, commented Dave Anderson, associate director for R&D quality at MedImmune/Astra Zeneca. Anderson noted at an October meeting in Washington, D.C. on combination products sponsored by the Drug Information Association (DIA) that delivery of multiple sclerosis therapy has evolved from just pre-filled syringes to more sophisticated injection devices that can guide the patient through the injection process in 26 languages, adjust needle speed and depth, and record time of injection.  

Such product development often requires expanded preclinical testing programs with “human factor” testing to ensure that patients are able to use a device delivery system appropriately. Manufacturing controls and quality systems vary considerably for drug and device components, as well as product labeling and post-marketing requirements.

Streamlining questions
The stated aim of FDA’s final rule on cGMPs for combination products is to encourage innovation and avoid duplicative requirements by allowing adherence to either drug GMPs or device quality systems, explained James (Barr) Weiner, associate director for policy of FDA’s Office of Combination Products (OCP), at the DIA conference. Manufacturers may establish one set of GMP regulations as a foundation and incorporate provisions from other centers as appropriate. This “streamlined” approach applies to co-packaged and single-entity combos, but not to biologics regulated by the Center for Biologics Evaluation and Research (CBER), including vaccines, cellular therapies, and blood products.

FDA also indicates, however, that design controls for devices and release requirements for drugs apply to the whole combination product, which raises questions about just where streamlining occurs. A larger issue is how manufacturers should meet these requirements for thousands of legacy products, many developed years ago under different rules and often by different firms, creating gaps in production records, design information, plant inspection histories, and stability data for various components. Manufacturers expected to have some time to bring existing products into conformance with the new GMP rule, but faced a rude awakening from a January 2014 warning letter to Amgen citing inadequate design validation and documentation of product changes, as well as failure to establish purchase controls for suppliers and contractors for leading Amgen therapies now defined as combination products.

FDA is receiving many questions on the GMP rule, particularly on stability testing, reserve samples, calculation of yield, and design controls for combination products, agency staffers reported at the DIA conference. OCP has promised to issue guidance this year on how industry should address these issues, a document that evidently has become quite hefty. OCP can help manufacturers determine if a product is a combination and which FDA center should oversee its development program and market approval, based on primary mode of action. OCP received more than 800 requests for consultations in fiscal year 2013 and 330 combination product submissions.

At the same time, European regulatory authorities are revising EU medical device regulations, which may have a notable impact on combination product development. Drugs and medical devices are regulated differently in the EU and other regions; only the US has a special process for approving treatments as combination products. The development of more drugs with customized delivery systems, though, has brought to the fore multiple “borderline issues” involving EU classification and authorization of these products, which may lead to policy changes in Europe and elsewhere.