|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.
Sliding compensation scales based on yields create economic tipping points. Beyond these points, it makes sense for CMOs to engage in what is often a fair amount of development work that is not called for in the contract, but could potentially benefit both sponsor and manufacturer.
Product specifications are another area where sponsors (and their CMOs) get tripped up, says Steve Simmons, Ph.D., VP of Quality by Design and process knowledge at Wyeth (Collegeville, Pa.). Specifications depend on the dosage form, but in solids they usually refer to particle size distribution, dissolution behavior (especially for sustained or modified release dosage forms), and degradation products that appear during stability testing. “As you get farther along in the development timeline, and the NDA is under review, it is not unusual for industry to submit one specification and for FDA to ask that it be narrowed,” Simmons says.
Sponsors should have worked such issues out before NDA submission, but to give themselves more leeway they sometimes attempt to obtain approval of fairly wide ranges for certain specifications. Armed with a big-picture perspective based on that company’s past submissions and those of other firms operating in that molecular class, regulators can — and often do — send these specs back for reworking.
This is where the limitations of operating at a small scale are most often obvious. At Phase III, specifications are set based on a limited number of lots consisting of relatively small quantities of product and excipients. “At this point, there is not a lot of history to fall back on in setting specifications,” Simmons says.
Scale-up itself can throw specifications out of whack. After all, moving from a 50 kg batch to hundreds of kilograms entails quite different mixing and granulation strategies, and longer tabletting runs. The former may result in blend segregation, and the latter sticking and picking within the tablet press due to heat buildup. Powder delivery to tablet presses can be another source of segregation, for example, when switching from manual delivery to a gravity feed from an upper floor. “This is where you may start to see blend segregation that did not occur when you were scooping powder,” says Simmons.
Quality by Design (QbD) and process analytical technologies (PAT) present numerous challenges for industry and regulators, as processes scale from bench to pilot to commercial scale. Since Phase III manufacturing should reflect commercial production as closely as it may be approximated, QbD and PAT need to be in place by the end of Phase II, but that is not always possible.
Defining a relevant “design space” for manufacturing and unit operations is a critical exercise when moving from pilot to full (or Phase III) scale. Moreover, the design space must be as relevant for commercial manufacture as it was at smaller scale, without the need to conduct hundreds of full-scale experiments. “The main issue for QbD will be the ability to justify the design space through a limited number of small-scale tests, rather than runs on large batches,” Simmons notes.
Related is the question of when, and how frequently, to apply QbD and PAT. The idea behind these initiatives, says Simmons, is to invest in science-based manufacturing early to avoid problems later on. But such strategies take time, are resource-intensive and run counter to short-term economic interests. “The question becomes how to reconcile slowing down during Phase I or II with the idea of speeding up in Phase III, when everyone knows that most early-stage compounds are never going to make it to Phase III.”
Resolving dissonance between cost and manufacturing excellence, says Simmons, will force companies into adopting what he calls “QbD Lite.” Manufacturers will still characterize products and processes, but not from every conceivable angle as they would when the science reasonably assures them of a drug’s approval. Only after Phase II, when efficacy has been established, will companies invest in full-blown QbD. “Before then, it is not easy to justify the commitment of resources,” he states.
As the dividing line between early development and manufacturing, Phase III manufacturing becomes a fulcrum for technology transfer. Development groups prepare a dossier on the molecule and “throw it over the wall” to an in-house or contract manufacturer.
Tech transfer is always interesting to DSM’s Terry Novak. “Every customer hands over the package and thinks there is nothing more to it, but usually something in there needs to be tweaked,” he says. “Still, development efforts are such these days that most projects are reduced to an exercise in engineering and execution.” (For an in-depth view of technology transfer in Phase III and beyond, see "Tech Transfer: Don't Fumble the Hand Off," from our November/December 2006 issue.)
Even processes developed at the final manufacturing site cannot be assured smooth sailing through Phase III because “the perfect tech transfer file does not exist and cannot exist,” says Sandoz’s Nachtmann. Contract manufacturers who have worked with the sponsor throughout clinical testing will, when possible, use the same equipment for Phase III as for commercial batches.
Sponsors vary widely in terms of the tech transfer package they provide a contractor, and the stage at which they hand off the project. With biologics, there is almost always a need for optimizing downstream operations. How much work a contractor has to do to get the process up and running depends on the largest scale run up to that point, and the level of development expertise on the part of the client.
“Processes coming directly from Phase II will probably have been run at 100, and sometimes as high as 1,000 L,” says Nachtmann, “with a good deal of GMP-related information collected as well.”
Distribution and Logistics
Every aspect of Phase III should represent the commercial materials, processes and practices. “There comes a point where you have to lock it in, even though Phase III can still be quite a way from launch,” notes Jennifer Parkhurst, Director, Life Sciences Practice, at PRTM Management Consultants (Newport Beach, Calif.).
Two areas that differ substantially pre- and post-approval are distribution and packaging/labeling. Where approved products enter well-established supply avenues dominated by large distributors, contract research organizations (CROs) and even some sponsors handle the specialized distribution train for clinical products. “Distribution becomes challenging because of the need to get the product to many nodes,” Parkhurst says.
Difficulties arise when the multitudinous supply chain fiefdoms within the organization (or across several) fail to work together as expected. These dispersed competencies may be on the same schedule for planning purposes, but execution lags often cause them to move out of sync. “And it’s not always obvious who manages the process.”
Like distribution, packaging and labeling tend to be stand-alone activities with respect to their post-approval counterparts.
According to FDA statistics, just over half of all food and drug recalls during a six-month monitoring period resulted from mislabeling, and 13% more were due to faulty packaging.
“I think the numbers may be even higher during clinical trials because of how quickly things are changing,” says Kent St. Vrain, VP of business development at Paxonix (Waltham, Mass.). Often these are simple proofreading or editing errors, or using the wrong font on packages. Most of these errors result from time pressure.
Paxonix, a division of the $6 billion global packaging giant MeadWestvaco, serves brand and packaging asset management for consumer goods, pharmaceuticals and medical devices. Its software, PaxPro, helps companies track revenue, expenses and economics under 21 CFR Part 11 compliance.
Phase III packaging hardly resembles its commercial counterpart, as doses are “kitted” for easy administration. Since the number of doses is much higher than for early clinical testing, St. Vrain feels developers and service providers need to invest in automation products to eliminate or reduce the impact of human error.
One recurring issue is misapplication of the wrong file or file version to a package or label. “Version three doesn’t tell you anything if the current version is number 10,” St. Vrain points out. “Nevertheless, sometimes version three goes to the printer.”
Part 11 issues aside, the fix is to limit availability of old versions of a design to the art or design teams. Everyone else only sees the most recent version.
It seems like what reduces to an editorial production process should, by Phase III, be worked out to every dotted ‘i,’ but this is often not the case. “Phase III is where everything is non-standard, changing all the time, and where deficiencies in your protocols are most likely to show up,” St. Vrain says.
RFID in Phase III
Although uptake has been slow for radio frequency identification (RFID) tags within the mainstream, post-approval pharmaceutical supply chain, clinical researchers are beginning to appreciate the value of advanced tracking and identification technologies in pivotal clinical trials.
A report by Nanomarkets (Glen Allen, Va.) says RFID is already making inroads into clinical trials, where the cost per tag is not as critical as it is in marketed drugs. Consulting firm CapGemini Ernst & Young has called for wider use of RFID in Phase I through Phase III testing, where it claims the technology can speed up testing by up to 5%, shorten startup costs, and reduce attrition and medication errors.
In a February 2006 white paper, Simon Holloway of Microsoft EMEA made the usual arguments for RFID throughout the pharmaceutical supply chain, including during clinical testing. According to Holloway, the principal benefit would be in automating clinical trials.
Citing the need to reduce errors in dosing and tracking of clinical data, Maxell (Fair Lawn, N.J.) has begun to sell its Heliport RFID reader and chips directly to trial sponsors and CROs. Information Mediary (Ottawa, Ontario) expects to supply more than 30,000 of its Med-ic ECM (Electronic Compliance Monitor) RFID smart-sensor labels for an 1,100-patient Phase III study of a macrolide antibiotic used in subjects with emphysema. Enrollment is taking place at 17 study sites managed by 10 universities throughout the United States. Disposable Med-ic chips are part of a “smart” pharmaceutical blister pack that tracks dosing and will assist in statistical analysis of the study data. Information Mediary is marketing the RFID tags as part of an effort to stem the tide of non-compliance to treatment regimens, what it calls a “multi-billion dollar problem.” Med-ic uses sensor-grid technology and proprietary printed conductive inks from XINK Laboratories (Port Huron, Mich.).