Our “manufacturing” theme could be considered a sort of catch-all, encompassing much of what BioProcess International covers. You could argue that “the whole development process” is all about manufacturing biotherapeutics. But we instead consider this “pillar” of bioprocessing to include everything that isn’t strictly “upstream” (production) or “downstream” (processing) of biomolecules. Facility and supply-chain isssues come into play here, as do formulation and fill–finish (and of course, outsourcing). We discuss quality systems and their associated analytics in this context, as well, and product testing too. And increasingly over the past decade, the topic of cost control has entered and then begun to dominate our vernacular.
Facilities: In BPI’s 10 years, the image of a typical bioprocess facility has been transformed. What once was dominated by gleaming stainless steel and hard piping is now a vision of smooth plastics and self-contained processes. We’ve gone from “the disposables option” (our first such supplement in 2004) through “learning from experience” (the 2006 special single-use technology issue) and “putting all the pieces together” (in 2010) to our upcoming 2012 “upstream, downstream — mainstream” approach. What this has done to facility design and location cannot be understated: Flexibility is now the byword when manufacturing plants can be smaller and potentially set up anywhere (1).
“The need to streamline costs, shorten development timelines, and stretch valuable resources is driving biomanufacturers to seek innovative ways of enhancing manufacturing efficiency,” wrote managing editor Maribel Rios last year. “Analytical methods for process development and validation as well as use of production technologies such as disposables and supply chain logistics can help companies establish facility flexibility” (2). These are topics of discussion almost unheard-of just 10 years ago.
Similarly, automation has crept out from the worlds of high-throughput sequencing and other manufacturing industries into biopharmaceutical facilities (3). These inroads are only just being made, so it remains to be seen what and where bioprocessing can automate (4).
Outsourcing: Not too long ago, outsourcing was the only answer when a young biopharmaceutical company had to consider costs in the early stages of a product’s life cycle. When it was too expensive to build a GMP facility based on reusable equipment for a product that may or may not get approved for marketing, small companies could take advantage of a contract manufacturing organization (CMO). Disposables may have made that less of a “given,” but they have been a boon to CMOs as well. And outsourcing is becoming less about capacity and more about expertise.
In particular, outsourcing presents one way for biopharmaceutical companies to “think globally and manufacture locally.” The drug industry is looking toward new markets opening up as developing nations begin improving the healthcare of their citizens. But some governments require the products sold to those patients to be made close to home (5). Local contract manufacturing can be a safer, cheaper alternative to opening your own subsidiary or licensing your product in the complex legal maze that governs such multinational agreements.
Formulation, Fill and Finish: Apart from viral safety testing, the most commonly outsourced work in biomanufacturing is final product formulation and packaging (6). And this is an area that has yet to see a major paradigm-shifting advancement. We have seen some interesting trends within the parenteral model, but not a lot of progress outside it for protein products.
As plastics have proven themselves in bioprocess disposables, they are being reconsidered for final-product containers (7). And some companies — contract packagers, in particular — are coming up with innovative ways to make injectible products easier for patients to use (8). From insulin pens to prefilled syringes to clever reconstitution systems for lyophilized biologics, parenteral delivery remains by far the main route for complex and sensitive biopharmaceutical products.
That hasn’t discouraged criminals, however, from selling counterfeit versions of such valuable products (9). Internet pharmacies and market globalization have, in fact, made the problem worse than ever before. And technology has only begun to offer some optional anticounterfeiting measures — that, to be honest, only some companies are taking advantage of (10,11).
Quality By Design: The pharmaceutical industry is notoriously slow to take up new technology, and although biomanufacturers tend to be a little quicker on the uptake, no one wants to be first to explain a new approach to a regulatory authority. Even when regulators endorse new ideas, industry can sometimes have trouble figuring out how to put those into practice.
Case in point: 21 CFR Part 11, the digital security rule from around the turn of the century (12). Intended to enable regulatory industry to use technology that had been unavailable when the original GXPs were developed, it was so confusing that the FDA had to withdraw the rule and replace it with a draft guidance in 2002. To this day, that “draft” has yet to become a full-on guidance, but most companies are using a risk-based approach to determine when and where to apply the strict “electronic records, electronic signatures” rules to their operations. Throughout BPI’s decade of publication, in fact, “risk management” has been the order of the day.
That’s largely attributable to a 2003 initiative, Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach. It was intended “to encourage the early adoption of new technological advances by the pharmaceutical industry” — e.g., process analytical technology — and facilitate application of modern quality systems techniques. Risk-based approaches should focus both industry and agency attention on critical areas so that reviews and inspections are based on state-of-the-art science and technology.
A big part of that is the concept of quality by design (QbD), which together with risk management may be the most transformative regulatory initiative since the GXPs themselves. Neither is possible without better process understanding and product characterization than was ever possible before the 21st century. But increasingly, regulators are expecting more — even as the industry works to determine how to integrate new technologies and approaches into their processes in progress.
Clearly, analytics are key — so much so, in fact, that some advisors have suggested we toss the whole “manufacturing” theme in favor of “analytics” instead! For now, we’re sticking with the “if it ain’t broke, don’t fix it” approach; unfortunately, that’s not an option for biopharmaceutical companies facing biosimilar competition. And as we’ve delved into the nascent cell therapy industry, we’re helping to share lessons learned from the protein world — as you can see in the supplement polybagged with this very issue!
Cheryl Scott is cofounder and has been senior technical editor of BioProcess International since the first issue.
d Analytical Strategies. BioProcess Int. 9:S8-S14.