In the heady days of the biotech boom of the early 1990s, the ground shook as salvo after salvo of innovative regulatory guidance documents emerged from the US Food and Drug Administration (FDA). Even their titles were innovative: “Points to Consider in the Production…” rather than the stodgy “Code of Federal Regulations, Volume X, Part XX.” The FDA was supporting the development of the emerging biopharmaceutical industry through rapid uptake of technological and clinical developments and speedy conversion into guidance documents. The Europeans appeared to be following the FDA’s lead and developing their own versions of guidance documents reflecting similar themes and emphasis. However, as biopharmaceutical production has matured into the industrial manufacturing phase, the European Union is becoming the driving regulatory force on biopharmaceutical manufacturing.

Harmonious Disharmony

Despite a prodigious production of paper by the International Conference on Harmonisation (ICH), when it comes down to making a biopharmaceutical product, harmony is in three parts, with the EU voice often singing loudest. Despite efforts for pharmacopoeial harmonization, simple differences have existed for standards as mundane as room temperature (USP = 20–25 °C, JP = 1–30 °C. EP = 15–25 °C) and appropriate testing of water for injection (1). In the absence of a common standard, the choice is often to heed the direction of the loudest voice.

Howdy, Stranger

The EU Clinical Trial Directive requires a “Qualified Person” (QP), to ensure that a product is manufactured according to good manufacturing practices (GMP) (2). When QPs inspect manufacturing facilities abroad, they favor the EU standards. The uniquely EU requirements, such as water for injection (WFI) testing for heavy metals, aluminum, nitrates, and other elements, are often some of their first stops on the inspection. Thereby, compliance with EU requirements is emphasized, and these standards must be monitored for change by manufacturers undertaking clinical studies in Europe. More stringent EU standards allow adoption to the satisfaction of most inspectors — though it is not without cost.

Hand Over the Loot

For biopharmaceutical CGMP manufacturing and aseptic processing, the uniquely EU standards for air quality, water testing, and facility design expectations translate to very real costs that must be accommodated in facility design, engineering, validation, monitoring, sampling, and staffing. The EU standards for air-pressure differentials between adjacent areas in a manufacturing facility are a good example of the compounded cost for compliance (3). To maintain specified differentials, a manufacturer must install heavier air handing units, which may require additional structural support and higher utility costs. Additionally, requirements for routine testing of water, step-downs between classified areas, and air sampling requirements in aseptic processing areas all translate into real capital and operating costs.

Is That You, Sheriff?

Despite the differences in current US and EU standards, each day brings greater convergence through the harmonization efforts of the Pharmacopeial Discussion Group and the ICH. But what of the FDA? There are those among us that believe that FDA may already be back out in front again. Amid the timidity that accompanies an election year, the FDA will be working to structure guidance and direction with potentially dramatic and far-reaching implications in “Personalized Medicine.” Within the fall 2007 FDA Strategic Action Plan, under the heading of “Signature Initiative: Critical Path for New Products,” the FDA has identified programs to support and integrate useful biomarkers, to define how to apply them in efficient and effective clinical studies, and to expand their application to oncology (4). The FDA’s effective ignition here will transmit shock waves that will fundamentally alter the biopharmaceutical industry. They will create smaller market segments for therapies that receive products made at smaller scale, which are substantiated by more directed and economical clinical trials, and shown as safe and efficacious through effective monitoring and preclinical studies. Many current regulatory processes and guidances will need to accommodate the personalization of biopharmaceuticals, and it may be then that the FDA’s efforts provide the beacon for regulatory orientation. Perhaps our soft-spoken sheriff isn’t riding off into the sunset after all.

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