A Global View Of Bio Process And Product Quality

By Wayne Koberstein, contributing editor

USP meeting advances standards for new biotech and biosimilar drugs.

First was the word: Quality. Aside from the conference title — the U.S. Pharmacopeia (USP) Science and Standards Symposium on Biologics & Biotechnology — “quality” was ubiquitous as a theme or term in almost all sessions, whether alone as an ideal goal or together with other terms such as control, monitor, and release. Quality was the key to unlocking the larger meaning of a highly technical program. Second, the people: a diverse, international crowd of mostly scientists and engineers from companies large and small, all united behind the goal of maximizing quality in bioprocessing. Third, the agenda, which addressed in minute detail the technical standards and procedures that underlie strategically important and often controversial issues for the life sciences industry. All three elements made for a fascinating, if at times bafflingly arcane, conference over four days in Seattle (Oct. 3-6).

Research, development, commercialization, regulation, and reimbursement are some of the broad areas affected by quality standards for biologics and biotechnology. At the same time, biotechs and biologics cover a wide range of technologies, products, and disease areas that vastly complicate everything from the measurement and control to the setting of quality standards. The USP has helped lead the setting of standards for natural and small-molecule drugs going back to the 1820s. Now, it is trying to seize the initiative on a global level with “bio” therapies, diagnostics, and assays.

The Seattle meeting was just one example of the USP’s global outreach. Convergence of standards is by no means complete, and to an observer it seems that among all parties there is too much redundancy of effort with too little harmony in return. But, the various pharmacopeia and related bodies appeared headed in the right direction in an international session, where the USP’s CEO Roger Williams was careful to characterize his group’s influence as “collaborative.”

Truly, what may appear as redundant efforts by national/regional groups could well be mainly organization building — and perhaps a bit of healthy competition for scientific leadership. But, the conference crowd was obviously focused on building something bigger than any one group could do on its own.

It would be impossible to communicate even one percent of the seminar’s technical content in this article because of the highly specialized structure of the related science and technology. Not just layperson trade journalists, but scientists and engineers were challenged by the unique and insular jargon of each other’s deep-welled disciplines.

One of the speakers summed it up this way: “I spend every day in my lab speaking a special language with my immediate colleagues. But, if I go to another department — or to a different session in this conference — it is like going to a foreign country. Every area and sub-area of bioprocessing and quality control has its own lingo and knowledge base.” Yet, he added, there is also a larger community of interest that unites all the discrete disciplines behind the larger purpose of quality in process and product.

Opening Path
Significantly, the first morning session featured a speech by the FDA’s Steve Kozlowski, director, Office of Biotechnology Products, on the new regulatory pathway for “biosimilar or interchangeable” products. It was a tacit recognition that the growing demand for biosimilars supplies much of the drive toward new biotech and biologics standards.

The Biologics Price Competition and Innovation Act (BPCI Act) of 2010 included proteins as “biological products” for the first time and defined a biosimilar as “highly similar” to an FDA-licensed biological product (the reference product), rather than identical. The FDA may depend largely on “analytical studies” rather than new preclinical/clinical data to approve a biosimilar according to the new legal criteria: “no clinically meaningful differences in safety, purity, and potency.” Presumably, with no evidence to the contrary, the product will then be “interchangeable” with the original, expected to produce the same result in “any given patient” at no higher risk if substituted.

Biosimilars must employ the same mechanism of action, conditions of use, administration route, dosage form and strength, and manufacturing quality of the original. Future discussion will undoubtedly address thorny questions such as, “What sort of data will satisfy the ‘any given patient’ criterion?”

Kozlowski illustrated the complexity of biotech/biologics standardization with a slide showing a molecular diagram of a monoclonal antibody dwarfing a tiny group of atoms representing aspirin. His next slide diagrammed a protein molecule displaying many of the “attributes and combinatorics” that later sessions would discuss: deamidation, methionine oxidation, glycation, high mannose fucosylation, sialylation, and so on. Each term represents almost endless permutations adding to the complex challenge of characterizing large biomolecules and comparing one to another. The complexity is too great for the simple chemical equivalency tests used with generic small molecule drugs. Just as clinical trials may carry surrogate endpoints, testing and validation of biotech and biologic agents must rely on indirect measures from bioassays and statistical analysis.

As numerous companies shared their experiences, it became apparent that originators must use the same methods in their own bioprocesses. That may explain why they would reveal so much to the larger community — to constantly improve their methods using new science and technology that is only available outside a company’s closed system.

Reference standards — product-specific information sets and physical samples — will underlie the analytical studies for biosimilars, relying on suites of bioassays now being revised and augmented. As with small molecule agents, the USP issues broad guidelines called chapters for use of the assays that assess and compare biotech/biologic molecules. Subchapters break down the guidelines and procedures for particular classes such as monoclonals and vaccines. Monographs then characterize the constituents, structures, and other identifying attributes of specific products. Some monographs may refer to general chapters with enforceable guidelines. Monographs also describe product uses, both on and off-label, based on practical experience and literature support. Insurers commonly use the monographs to determine what uses are reimbursable.

Convergent Tracks
After the opening session, the seminar split into two tracks. Track one began with a review of new USP bioassay chapters now being implemented after years of public feedback and work by a large expert committee. After a final vote by the committee, the chapters will be published in Supplement 1 of USP 35, May 2012, and will become official on Aug. 1, 2012, with another review and update scheduled after two years. Robert Singer, chair of the USP Statistics Expert Committee, and Susan Kirshner of the FDA’s therapeutic proteins division discussed the chapters as a new central resource for bioassay analysts and regulators.

For traditional biologics, such as naturally derived hormones, the standard criteria for quality was safety, purity, and potency. Originators could thus make incremental changes in the manufacturing process without new clinical studies. The new chapters reflect the additional criterion for biosimilars in the BPCI Act: interchangeability with the originals based on their effects on individual patients. If interchangeability is to be assessed with nonclinical data, the targeted critical quality attributes (CQAs) and the assays and analyses that measure them must be extremely accurate.

Track two, with the informal tag “Quality by Design” (QbD), logically built upon Track one; it envisioned new production models to measure and control CQAs, using tests and testing procedures at multiple stations along the process flow. Such models, used widely in other industries, could boost output quality, and thus efficiency, in state-of-the-art bioprocessing. Track Two was rich in the details of manufacturers’ experiences with applying analytic techniques to entire processing systems.

But, practical lessons and management principles also emerged from the deep technical recesses of the separate but convergent tracks. Simon Szeto of Amgen was especially adept at qualifying his advice on EPO (Erythropoietin) reference standards with comments that accounted for the disparate resources of small and large companies.

In a later conversation, Szeto placed his thoughts in a higher context: “When regulators come to inspect our operations, a primary concern for them is the level of commitment they see in the QA/QC managers. We must show in large and small ways that we passionately believe in quality and take every means possible to ensure it at every step of the process.” Those words reflected all the core aims of the USP seminar: quality, collaboration between people, and integrity in setting high standards for the future fruits of the life sciences industry.