October 1, 2015 PAP-Q4-15-CL-002
Drug manufacturers are facing mounting cost pressures, and the industry is shifting from the traditional blockbuster model to one focused on niche products and targeted delivery. Simultaneously, drug molecules are becoming more complex and increasingly require both advanced synthesis and formulation expertise to realize cost-effective, efficacious medicines. Pharmaceutical manufacturers are consequently relying more frequently on contract development and manufacturing organizations (CDMOs) to control costs, gain access to specialized expertise, and significantly accelerate the successful development and commercialization of today’s candidate therapies.
One key trend in pharmaceutical outsourcing is the preference of sponsor companies for full-service partners that can provide support through all stages of drug development and formulation for all types of drug substances and project timelines. For instance, as the market for cancer drugs continues to grow at a healthy rate, pharmaceutical companies are increasingly seeking assistance from CDMOs with established track records for the safe production of highly potent active pharmaceutical ingredients (HPAPIs). Given the need to get drugs into clinical trials more quickly than ever before, pharmaceutical companies also choose to outsource to CDMOs that have both a thorough understanding of the investigational new drug (IND) application process, and experience determining the necessary level of information that will minimize both risk and project timelines. Drug manufacturers looking to leverage US FDA Fast Track status also require CDMO partners that are aware of the significantly shortened development times, have established lines of communication with FDA regulators, and are prepared for the additional meetings and information exchanges necessary for reducing approval times.
HPAPIs comprise the fastest growing segment of the worldwide API market, which will be valued at $15.3 billion by 2017, according to market research firm RNCOS. Also, business research and consulting company Roots Analysis reports that over 25 percent of all drugs worldwide are classified as highly potent. Given the high toxicity of these compounds, their manufacture presents many challenges. Protection of process operators must be assured, and the risk of cross-contamination must be minimized. The safety of healthcare workers and patients when using the final drug products must also be considered. Special protective equipment, manufacturing suites, production processes, management systems, transfer and packaging capabilities, and often entire facilities are required for the development and commercial manufacture of HPAPIs and formulated cytotoxic therapies.
For these reasons, many pharmaceutical companies elect to outsource these projects to CDMOs with expertise in working with highly potent substances. In particular, CDMOs with a proven track record for safely and effectively managing projects involving highly potent compounds during development and commercial production, and an excellent audit history and comprehensive regulatory records, are preferred. CDMOs can only achieve strong track records by understanding the potential risks associated with the production and handling of highly potent compounds — both at the initial stages when little direct information about the compound may be available, and later on during scale-up and commercialization — and the systems that are required to minimize those risks.
Proper facility design, approaches to barrier isolation, the incorporation of gowning/degowning areas, containment safeguards, comprehensive quality management systems, and continual operator education and training are all crucial for successful HPAPI manufacturing. The ability to perform state-of-the-art synthetic organic chemistry techniques, process development and optimization, product purification, and advances analyses, all under contained conditions, is also a must.
Overall, safety must be a priority when working with HPAPIs, and the protection of operators, contractors, healthcare workers, patients, and the general public should always be the first concern. Because it is not possible to achieve zero risk when working with highly potent compounds, CDMOs must minimize the risk as much as possible through the ongoing pursuit of new technologies, equipment, and procedures.
Collection of appropriate Chemistry, Manufacturing, and Control (CMC) data for IND applications and the use of appropriate manufacturing controls are just as imperative as having an effective clinical trial design. Decisions relating to data collection and manufacturing procedures can impact the overall project with respect to its budget, timeline, and quality, and consequently directly influence the outcome of the clinical trial and potentially patient safety.
Experienced CDMOs recognize the importance of such decisions and consider these factors when implementing IND projects. For example, while typically less data is needed for Phase 1 studies, more information will eventually be required if the drug candidate moves on to Phase II trials. Obtaining more extensive data prior to submission of the initial IND application for a Phase I study can in many cases help reduce project timelines. In addition, although the adoption of commercial current good manufacturing practice (cGMP) protocols for the production of Phase I clinical trial material may take additional time and effort, the added controls provide for reduced risk and FDA recognition and allow the use of any excess material in the subsequent Phase II study.
CDMOs supporting IND projects must also be effective project managers. Planning is crucial so that adequate time is provided for the development of a sufficient CMC package, including evidence for the structure of the active pharmaceutical ingredient (API), stability study results indicating that the drug product will be stable during the period of the clinical trial, and descriptions of both process and testing methodologies and quality control systems. Extensive experience in carefully balancing the financial, project timeline, and quality issues of an IND project is also crucial. The ability of a CMO to make rapid decisions based on all three considerations will have a direct impact on the success of an IND project.
A good relationship with the FDA and the ability to discuss the CMC package and any necessary amendments with the agency is also very important. Positive interactions with the agency can lead not only to a better clinical trial design, but a more efficient review of the IND. In essence, the CDMO plays a major role in ensuring that the agency’s CMC requirements are met on a continual basis and that FDA regulators remain satisfied that the drug product is safe for use in the clinical study.
Finally, there are several basic requirements for CDMOs that support IND projects: state-of-the-art technologies, extensive expertise in API synthesis and/or drug product formulation, an effective quality program, effective communication strategies for interacting with the sponsor company and the group performing the clinical study, a strong track record of on-time or accelerated delivery, and available capacity.
The US FDA Fast Track designation is intended to bring new drugs that treat serious conditions and that fill unmet medical needs to patients more rapidly. To leverage Fast Track status, however, pharma companies and their service providers must have excellent communication systems in place and be prepared to develop manufacturing routes and generate safety and efficacy data in much less time than they are used to.
Companies that receive Fast Track designation for a drug candidate have more frequent meetings and written exchanges with the FDA to ensure that the drug development program and data collection are proceeding appropriately. In many cases, the CMC section is submitted first, followed later by the Clinical section. Therefore, CDMOs working on Fast Track projects must be aware of not only the shortened development times (by as much as a factor of three), but also have established lines of communication with FDA regulators.
As importantly, CDMOs must have rapid process optimization and scale-up capabilities in order to develop effective routes for the production of preclinical/ toxicity testing quantities in terms of cycle times, waste minimization, and yield. CDMOs that can develop and validate an efficient and cost-effective large-scale process and the associated analytical techniques while simultaneously producing clinical trial material can achieve significant reductions in project timelines while ensuring the quality and safety of the API.
In addition, because the timelines are reduced, there is generally less information about how the process can potentially impact product API quality, which can present challenges to qualification of process performance while also allowing for a slimmer margin of error. CDMOs involved in Fast Track projects must be aware of this issue and work closely with the drug sponsor and FDA to identify and mitigate any potential issues before they arise. A quality- by-design (QbD) approach and early determination of critical quality attributes can help ensure the development of effective and appropriate analytical methods, even under accelerated conditions.
Finally, CDMOs with integrated capabilities across development and commercial manufacturing and an established network of other providers to supplement specialized capabilities can reduce the complexity of project management needs and contribute to more compact development timelines.
Dr. Stephen Munk has been with Ash Stevens Inc. since 1997, serving as President since 1998 and CEO since 2001. He is experienced in drug discovery, development and manufacturing, both as a scientist and as a manager. Prior to joining Ash Stevens, Dr. Munk worked at Allergan, Inc. as a drug discovery scientist and subsequently as the co-team leader of the adrenergic drug discovery team. Under Dr. Munk’s stewardship, Dr. Munk is also an Adjunct Professor of Chemistry at Wayne State University and has served on the Board of Directors of MichBio.