July 1, 2007 (Vol. 27, No. 13)

Expanding Targets and Novel Drug Delivery Strategies Drive Manufacturing Demands

With an annual growth of greater than 15%, an increasing number of new projects, and a growing number of peptide drug candidates moving into late-stage clinical trials, the GMP peptides market remains strong. Rising interest in therapeutic peptides among big pharma, driven by an expanding number of new drug targets and novel strategies for peptide drug delivery, is helping fuel this growth. Peptide drug developers are not only advancing projects but are also demanding GMP-manufacturing standards earlier in the developmental pipeline. Uncertainty over evolving regulatory guidance in the industry regarding purity, quality control, and analytical requirements for clinical-grade peptides is a key concern among contract manufacturers.

The average annual growth rate has exceeded 15% since 2003, and industry sources do not anticipate that figure declining any time soon. As more peptide drug candidates progress into Phase II and III trials the need for larger quantities of peptide drugs for efficacy and dosing studies is driving advances in scale-up technology and putting pressure on CMOs to increase capacity through internal expansion, acquisition, or merger.

For new GMP peptide projects, NeoMPS (www.neomps.com) is quoting up to six months for delivery as it finds itself, together with other leading CMOs servicing the GMP peptide sector, happily on the receiving end of an abundance of new orders and reorders for clinical-grade peptides.

“It is clear that Big Pharma is becoming more interested in peptides,” says Pierre Barthélemy, general manager at Peptisyntha (www.peptisyntha.com), a fully owned subsidiary of the Solvay Group.

Robert Hagopian, director of business development at NeoMPS, is also seeing rising investment in peptides by larger pharmaceutical companies, which is translating into new projects for the CMO community, as outsourcing of manufacturing remains an attractive mechanism.

“NeoMPS has also seen a big surge in peptide need in Japan,” comments Hagopian. He attributes this in part to the cultural emphasis on natural approaches to healing and the increasing use of peptides in therapeutic cancer vaccines.

“I think there is a wave of peptides that we need to ride right now; that wave is pretty big and it’s just starting,” says Hagopian.

Reinventing Peptides

Following on the heels of the completed expansion of its solid-phase cGMP peptide-synthesis capacity in Torrance, CA, Peptisyntha recently embarked on the expansion of its pilot-scale capacity for solution-phase cGMP peptide production in Brussels. The company is “adjusting assets and overall capacity” to accommodate both a growing number of projects and more advanced projects, according to Barthélemy.

“For the moment, I think there is sufficient capacity in the market,” he says, although the competitive landscape continues to evolve, and he expects continued consolidation.

Companies expand when they are confident that the future is bright and market demand is on the rise. Bachem (www.bachem.com) is expanding its capacity on both sides of the Atlantic, having completed a $12-million expansion in Torrance, CA, in 2006, the company is planning another addition to its existing 60,000 ft2 facility in the near future. Expansion is also anticipated for the parent company in Bubendorf, Switzerland.

Philip Ottiger, president and COO of Bachem California, points to strong growth as driving the need for increased capacity. “Emerging biotech companies are reinventing peptides,” says Ottiger. As the biopharma industry matured, it developed a continually growing knowledge base of how to synthesize peptides more reproducibly and efficiently. Interest in peptide drugs has been fueled by a combination of advances in the synthesis process, related primarily to enhanced automation and engineering technology, and by novel approaches to pharmaceutical formulation that have improved the stability of peptide drugs in biological fluids.

Newer resins are also contributing to more robust syntheses. But as Ottiger points out, the make-up of the resin itself is not as important as selecting the optimal resin for a particular application. This requires a clear understanding of the reaction kinetics, the chemistry, the coupling reagents, and the properties and potential advantages and limitations of the resin.

Bachem recently signed a long-term supply contract with Intercell to provide a peptide component (KLK) for the company’s B- and T-cell vaccine adjuvant IC31™. In May, Bachem reported the expansion of its cooperative alliance with Immatics, which has included the production of synthetic peptides for the company’s IMA901 clinical development program. IMA901 is a cancer vaccine composed of a combination of ten peptide antigens. The vaccine will enter Phase II trials in renal cell carcinoma later this year.

Bursting at the Seams

PolyPeptide Laboratories (PPL; www.polypeptide.com) underwent substantial expansions in 2006 at both its U.S. site in California and at its facilities in Malmo, Sweden. The expansion in Torrance includes new laboratory space for pre-GMP development projects.

PPL’s newest facility, in Ambernath (near Mumbai), India, which will be operational in 2008, has a 35,000-ft2 footprint, similar in size to the current Torrance site and includes a full second floor to enable future expansion. Situated on an acre of land, the site offers the potential for future growth.

NeoMPS plans to invest nearly $14 million to triple the size of its facility in Strasbourg, France, with construction under way and scheduled for completion in mid-2008. Capacity at its European facility is mainly for solid-phase synthesis, with some liquid-phase synthesis capability as well. The emphasis at NeoMPS’s San Diego, CA, production site is to maximize use of the existing capacity.

An emerging problem is the availability of qualified employees with experience in peptide manufacturing, according to Hagopian. “We’re seeing shortages now,” he says, “and it takes time to train people.” Experience and on-the-job training are critical.

Scaling Up

The emphasis at PPL is on solid-phase synthesis. Rodney Lax, director of sales and marketing, notes that the scale of projects has been increasing overall, with projects that averaged 50–200 g a few years ago now moving to kilogram scale.

Scale-up of peptide synthesis presents a variety of issues, including the need for large solvent volumes, and, importantly, longer hold times at multiple stages of the manufacturing process. This increases the risk of product degradation and aggregation, both of which result in the loss of pure product.

The key to robust, efficient, and cost-effective scale-up of peptide production under GMP conditions is a combination of regulatory expertise on the part of the CMO and a close, trusting relationship between the CMO and the customer, in the view of Barthélemy of Peptisyntha.

“To be a leading player in peptide APIs you need both liquid- and solid-phase synthesis technology,” he says. Some would say solid phase can do everything, but each has its own advantages. Solid-phase technology has evolved and improved in recent years, but in the long-term, with demand for increasing quantities, liquid phase has advantages as well.

Although the cost of cGMP peptide production is trending downward, due largely to a modest decline in raw material costs and increasing yields achieved by tweaking solid- and liquid-phase synthesis processes, the economics of peptide manufacturing have not changed substantially in recent years. Novel strategies designed to reduce the number of chemical steps needed to synthesize a given sequence will have a greater overall impact on production costs, particularly as scales increase, predicts Barthélemy. The ability to work with non-protected amino acids offers a significant advantage.

Regulatory Uncertainty

No detailed regulatory guidelines or standards exist for manufacturing synthetic peptides. They are subject to general ICH guidelines, but otherwise fall into a somewhat blurry zone between biotherapeutics and small molecule drugs.

“We need official guidelines for peptides from the FDA or EMEA,” says Hagopian. The current guidance for organic molecules—not including synthetic peptides, at least for now—requires identification of any impurity present at a level of >0.1%. But some in the industry suspect a shift in direction by the regulatory agencies.

At present, “the interpretation of the guidelines is the issue, and that depends on the reviewer,” says Hagopian. Most of the “impurities” result from truncation of the growing peptide molecule or the deletion of amino acids. More stringent guidelines could require companies to generate a detailed impurity profile.

Some peptide drug developers take a conservative approach and request GMP quality product for use in preclinical toxicology and pharmacokinetic studies.

The lack of any regulatory guidance regarding impurity profiles of complex peptides is a source of major concern in the peptide industry for both CMOs and customers.

Rodney Lax of PPL describes two extremes, with some customers treating peptides like small molecules, even in the early stages of development, and insisting on the ICH Q3A specifications for impurities throughout. This not only makes the peptides more expensive, especially for very long peptides, but also the need to meet the stringent specifications associated with these guidelines presents significant challenges. For example, complex peptide species containing single amino acid deletions “are unlikely to separate from the main product peak,” notes Lax. “Moreover, the guideline limits are often close to the limits of detection as well as the theoretical achievable purity for solid-phase procedures.”

At the other extreme, “underkill” is a problem for some other customers who do not address the issue of impurity profiles until later in development, when it can become more difficult to implement changes to make the synthesis protocol more robust and to minimize impurities.

According to Lax, no single regulatory recommendation would likely be suitable for all peptide APIs, which can range from as few as 2 to 50 or more amino acids in length. Risk assessment should take into account the complexity of the peptide and the expected human dose.

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