Biomanufacturing of human therapeutics is beginning a global transformation. New technologies, improved processes, the emergence of biosimilars, and growing worldwide demand for vaccines and biologic drugs to serve local populations are driving this transformation.
Over the next few years, diverse new markets will open, creating opportunities for a range of companies seeking to enter the field while putting pressure on established biomanufacturers to reassess their operating models. Many traditional barriers-to-entry in biomanufacturing are diminishing. Yet other challenges — including access to cell lines, support services, and a properly trained workforce — arise when developing an “in market, for market” biologics capability in many parts of the world. Here, we examine those trends and explore some best practices that are taking shape on the horizon of this evolving industrial landscape.
Moving Past Maturity
Since 1982, when Eli Lilly shipped the first approved recombinant therapeutic — human insulin p...
+1The US Food and Drug Administration (FDA) granted 18 new biopharmaceutical product approvals in 2012, covering a broad range of innovation, novelty, and healthcare and market impact. The total includes 16 full/original approvals: biologics license applications (BLAs) and new drug applications (NDAs). The other two products received supplemental approvals, both of them influenza vaccines. Among the 18 approvals were eight recombinant proteins, including two monoclonal antibodies (MAbs) and one engineered antibody-like “trap” molecule. Table 1 lists them all.
Table 1: FDA new biopharmaceutical approvals in fiscal-year 2012
The overall healthcare impact and projected peak sales of 2012-approved products are both rather limited. Many of these products (perhaps even a majority) are biobetter, me-too, or similar follow-on (more of much the same) products, and many are orphan products — thus inherently limited in terms of their innovation, novelty, and/or markets. The list of approved products does not include a...
Biological product and process characterization are not new to this quality by design (QbD) and process analytical technology (PAT) era. In the 1990s we saw the FDA introduce the concept of well-characterized biologics: an acknowledgment that analytical technology had advanced to the point where the bioprocess did not necessarily (or not fully, anyway) define a biopharmaceutical product. That ultimately led to the regulation of some types of products within the United States moving from the purview of FDA’s Center for Biologics Evaluation and Research (CBER) to its Center for Drug Evaluation and Research (CDER). Now some biopharmaceuticals go to market through the biologics license application (BLA) process whereas others use the new drug application (NDA) instead. While the regulators were adjusting to this new scientific reality, suppliers of analytical equipment continued to improve their instruments, making it ever more possible for bioprocess engineers to build quality into their manufacturing proces...
In the 1970s, life-science researchers envisioned protein therapeutics as the ultimate targeted therapy. Companies could use them to address genetic deficiencies and cancer, among other disease classes, as well as to nudge the immune system for treating autoimmune disorders. The first therapeutic proteins were derived from animal or microbial cells, so patients launched immune responses to them that could curtail their activity and produce dangerous side effects.
PEGylation was initially used to prevent immune responses with such drugs. PEG is
polyethylene glycol,
which typically exists in the form of long polymer chains. Simultaneously hydrophilic and lipophilic, water soluble, and nontoxic, PEG is synthesized from chains of ethylene oxide, which can branch or stretch to any length. Typically, PEG is linked to a protein or peptide through reactive molecular groups on amino acid side chains — most often lysine (Figure 1).
PEG has long been used as an excipient in pharmaceuticals, as well as a base for c...
Biomanufacturing of monoclonal antibodies (MAb) involves a number of unit operations, including cell culture in a bioreactor followed by chromatography and filtration. Purification is intended to remove impurities, such as protein aggregates, but some such operations may actually generate protein aggregation (
1
). Table 1 summarizes potential sources of aggregate formation during biomanufacturing processes. Aggregates are multimers of native, partially denatured, or fully denatured proteins. Their presence in biological formulations can trigger detrimental immunogenic responses upon administration (
2
). Moreover, aggregates can lower the efficacy and stability of a biopharmaceutical product. During biomanufacturing, therefore, it is imperative to remove aggregates to an acceptable level, which is typically <1% for MAbs.
Table 1: Potential sources of aggregation during antibody manufacturing
Removing aggregates, especially soluble ones, is highly challenging because of their close physical and/or chemica...
Contract manufacturer DSM Biologics — at its current good manufacturing practices (CGMP) facility in Groningen, The Netherlands — provides services for clinical development and commercial production based on mammalian cell culture technology (Photo 1). During the 2011–2012 year, the facility went through a major expansion project to enlarge its capacity and fulfill a growing customer demand. From a business point of view, the project had a well-defined target for future production capacity as well as investment volume.
Photo 1:
A major part of the project focused on restructuring downstream operations to match upstream capacities. The objectives required full understanding of the annual output that is possible if the facility is extended by one or two downstream processing suites. The optimal solution would be to achieve target capacity with minimum investment. M+W Group supported DSM Biologics to find the right approach and identify the best solution.
PRODUCT FOCUS:
ALL BIOLOGICALS
PROCESS FOCUS:
MANUF...
+3 While a constantly developing market puts increasing pressure on pharmaceutical companies to provide advanced and personalized therapies, the industry is investing heavily in the development of targeted biologics. The aim is often to take new therapeutics through clinical trials and to market as quickly as possible and to develop more novel, tailored drugs. One common challenge for many biologics is their short plasma half-life. That often leads to reduced bioavailability, meaning that an administered drug will clear from a patient’s system within a matter of minutes. So patients with chronic conditions need regular high dosages, which increases costs to patients and the likelihood of side effects. Frequent administration of a drug may also decrease patient compliance with treatment regimes.
Addressing the half-life challenge has been a focus of industry product development in recent years. Real progress has been seen in development of technologies to modulate the serum half-lives of protein-based therape...
This spring, Cambridge Healthtech Institute (CHI) will host its ninth annual
PEGS: The Essential Protein Engineering Summit
at the Seaport World Trade Center in Boston, MA. Record attendance is expected in 2013. Its growth and success is attributable to the quality of scientific programming, expanded exhibit hall, and ample networking opportunities.
In addition to the new venue on Boston’s waterfront, the 2013 PEGS event now offers six programming streams and 16 conferences in protein and antibody engineering, oncology, expression, analytical, safety, and purification. The highly focused streams enable researchers to discuss and find solutions to challenges faced in their laboratories and hear about research that has yet to be published.
Engineering Stream
Strategies and Tools for Creating the Next Generation of Biologics:
Learn how the versatility of phage and yeast display — coupled with vast improvements in antibody engineering and production — are expanding possibilities for creating therapeutic en...
Driven by significant opportunity and a perceived lower risk strategy for taking a slice of the booming biologics market, companies have been investing heavily in biosimilars to capitalize on a market that’s forecast to be worth US$3.5 billion by 2015. To exploit this opportunity, companies have embarked on a hearty meal of deal-making. Since the biosimilar market’s formal inception in Europe in 2005, deal flow has been solid. Generics companies made early forays, seeking to leverage relationships with payers and drive long-term growth. Over time, more companies — including several originator pharmaceutical and biotechnology companies — have invested in the market.
To date, biosimilar deals have focused on building synergies and derisking investments. Companies have joined forces to maximize the potential of combined resources or use licensed assets or capabilities to fill internal gaps. Rarely have companies hit the acquisition trail. When they have, biosimilars have been part of the deal rather than the...
