|Image courtesy of foundation.nsabp.org (National Surgical Adjuvant Breast and Bowel Project).
Compounds in Phase III clinical testing are somewhat like your typical high school junior — adult and ready to break away in so many respects, yet childlike in others. In this stage, manufacturing makes the most obvious break with the past. From this point on, manufacturing is done at production-scale, in terms of equipment, final process and site.
A make-or-break point for collaborators in any drug development project, Phase III is a “milestone,” when all activities related to product launch, including capacity planning, production, processing and marketing begin to gel, says Friedrich Nachtmann, who heads Biotech Cooperations at Sandoz (Kundl, Austria). Ideally, he says, all these activities work together, in unison. Sandoz is currently manufacturing Cinzia, a pegylated antibody fragment for treating rheumatoid arthritis and Crohn’s disease that is now in Phase III. This work has brought them together with pegylation inventor Nektar Therapeutics and with UCB for drug development.
Outsourcing: The Usual Benefits
Outsourcing’s benefits of speed, flexibility and optimal capacity utilization can be magnified in Phase III. Drivers for outsourcing late-stage manufacturing include acceleration or compression of development programs, accessing proprietary formulation and dosage technology, and easier entry into global regulatory jurisdictions where the contractor may be experienced. Contracting (or in-licensing) to access proprietary chemical technology, such as a patented asymmetric hydrogenation, probably would have occurred before this stage.
For example, regulatory bodies differ in the permitted use of dyes and other excipients, which can affect not only incidental properties like color, but significant characteristics such as crystal morphology and dissolution. Since some jurisdictions demand that drugs sold in their territory be manufactured there as well, manufacturers should take note of process equipment and/or unit operations that differ from the requirements at headquarters. Together, manufacturing and excipient changes might bring on long delays in deploying a process for Phase III and beyond.
By late stage testing, sponsors are more likely to seek assistance with formulation or drug delivery. The contract manufacturing organization (CMO) Patheon (Mississauga, Ontario), for example, offers a liquid-fill, hard-shell technology for filling potent or low-soluble liquid or semi-solid compounds into capsules. “Pharmaceutical companies that need this type of technology are unlikely to invest in it themselves,” says Anil Kane, Ph.D., director of pharmaceutics and process technology. Patheon counts among its Phase III customers several “virtual” pharma/biotech firms that lack a manufacturing or regulatory infrastructure, and for whom the outsourcing decision is a no-brainer.
Kane recommends that drug sponsors planning to outsource Phase III manufacturing consider moving the project to their CMO of choice earlier in development, even perhaps at Phase I. While tech transfer for an early-stage molecule unlikely to reach Phase III may seem like a waste, the experience gained by the contractor if the drug does reach late-stage testing and approval, can provide substantial savings in time and cost. “We encourage clients to think and plan for the next stage in manufacturing,” Kane says.
Where It’s At
Phase III manufacturers usually, but not always, become the “producers of record” once a drug is approved. The CMO DSM (Parsippany, N.J.) typically expects to conduct post-approval manufacturing for its Phase III projects, but sponsors shift the final production site “more than we’d like them to,” according to Terry Novak, executive VP. This generally happens because capacity opens up at one of the sponsor’s facilities. Switching at this point involves an extra tech transfer step, Novak says, because “by Phase III you should not be playing around with either the process or the formulation.”
DSM manufactures sterile, solid-dose and semi-solid dosage forms as well as tablets, capsules and vials on a contract basis for pharmaceutical firms. DSM’s current portfolio, which includes some key injectible biologics, is split approximately evenly between new and mature drugs.
In early January 2007, DSM completed an expansion to its sterile parenteral manufacturing facility in Greenville, N.C., adding a clinical-trial material manufacturing suite for large- and small-molecule liquid and lyophilized products for Phase I through Phase III trials. DSM expects that the new facility, combined with long-standing QA, audit, regulatory, analytical and process support services, will convince sponsors of sterile products to begin their outsourcing with DSM and stick with the company through commercial launch.
Too Many Cooks in the Kitchen
One aspect that can delay implementation of a Phase III manufacturing project is incomplete validation, particularly of analytical methods but sometimes of unit operations.
How can this happen? “We ask the same thing,” Novak jokes. “Sometimes there are too many cooks in the kitchen before the project gets transferred out, and sometimes people underperform simply because of pressure or time constraints. I’ve never seen a Phase III tech transfer project where we had the luxury of time.”
Since CMOs are paid per batch, not per dose, it benefits everyone to improve yields (dose per batch). “This is the most significant area where a CMO has leeway,” Novak says. Efficiency improvements at constant yield, or increasing batches per run, reduce the contractor’s costs and improve profit per batch. Furthermore, yield improvements directly benefit the client, since they obtain more doses per batch. This is why outsourcing contracts often incorporate a sliding payment scale for improving yield above a level established during the first few manufacturing runs (especially for high-cost biologics). In one instance, DSM improved the isolated yield of a biologic from one particular step from 95% to 98%, which added 8,000 more doses per batch. Conversely, the manufacturer will agree to take a cut for yields that go south. “Most sponsors are more than willing to enter such agreements,” Novak states.