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Approval of breakthrough therapies requires expedited quality assessment.
FDA’s success in speeding the approval of new drugs and biologics for patients suffering from serious diseases reflects manufacturer efforts to produce high-quality medicines within tight timeframes. Shortened clinical programs based on early evidence of a drug’s high efficacy and acceptable safety level often reduce timelines from 8–10 years to 3–5 years for product and process assessment and commercial scale-up. And while struggling to devise assays and provide data to support registration, manufacturers still must produce clinical supplies for ongoing clinical trials.
To meet these multiple challenges, all parties need to agree early on about what quality information is necessary for market approval, and which data can be provided after the therapy comes to market. This calculation centers on determining how the risk of providing less chemistry, manufacturing, and controls (CMC) information at product launch compares to patient benefit from earlier access to treatment. Manufacturers and regulators are exploring ways to achieve an appropriate balance in such equations, and how quality-by-design (QbD) and continuous manufacturing (CM) strategies can facilitate these efforts.
At FDA, the Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER) plays a central role is devising more efficient approaches for evaluating manufacturing development and production methods for drugs eligible for fast track, breakthrough, and other accelerated development and review initiatives. This involves new risk-mitigation strategies to ensure product safety and acceptable levels of risk, explained Sarah Pope-Miksinski, director of OPQ’s Office of New Drug Products and acting director of its Office of Surveillance. FDA has been flexible in the timing and scope of data required for drugs to treat serious diseases, working with manufacturers to approve critical medicines with less than complete stability data, validation strategies, and manufacturing readiness. But even though the agency may allow firms to submit abbreviated quality data upfront, that does not reduce the need for high-quality products at all stages, Miksinski noted at the April 2017 CMC workshop sponsored by the Drug Information Association (DIA).
Manufacturing innovation does not permit any compromise on product quality, even when development programs are compressed and experience with manufacturing and testing is limited, added Silke Click, director of regulatory CMC at AstraZeneca, Sweden, during the workshop. Product development in half the usual time, moreover, may require twice the resources and delay work on other projects, she noted.
The most common information gap in accelerated drug development involves stability data, as such programs often cannot supply 12 months’ stability data prior to product launch. In these cases, FDA may approve the product with a reduced shelf-life until obtaining further results. In addition, OPQ often encounters breakthrough candidates with inadequate drug substance characterization, less understanding of drug product formulation, limited data on critical quality attributes, or inadequate analytical testing. Significant differences in clinical and commercial manufacturing processes, moreover, may delay facility inspections and raise uncertainties about conformance to GMPs, which may hinder product launch.
In calculating potential risks related to accelerated development, clinical relevance is the defining factor, Miksinski said. Overall specifications are key in assessing whether a drug product will perform as indicated on the label, and data on impurities and dissolution are important in evaluating how a therapy will affect patients. CDER is developing a Product Quality Benefit Risk Framework to help all parties consider quality deficiencies within the clinical context of a proposed product. The aim is to provide a template for identifying and evaluating risks and how they can be mitigated to support OPQ recommendations for expediting development and defining post-marketing commitments.
Modeling techniques can help a manufacturer design CMC development timelines of three years or less by combining methods to assess the complexity of the product, availability of platform knowledge for drug substance production, and the timing of CMC development activities related to clinical studies, explained Earl Dye, director of CMC regulatory policy at Genentech. He emphasized at the DIA workshop that each program is unique, as seen in accelerated development of a monoclonal antibody, which was facilitated by performing product validation using clinical drug-substance batches; simplifying process characterization studies; and filing with a limited stability data package. The effort required considerable resources up front and benefited from the ability to leverage prior knowledge and platform data.
Dye noted the importance of starting early to identify sites for production of drug substance and product and to select assays for critical quality attributes, impurities, potency, and dissolution to ensure control system suitability. Sponsors also should determine which process development activities will have less effect on patient safety or product supply and thus can be delayed to post-approval. An internal Manufacturing Readiness Plan can help map out a CMC/GMP development strategy related to the clinical program and document how deferred testing activities will be conducted, documented, and completed later, possibly under a post-approval lifecycle management plan.
The benefits of early patient access to critical therapies is prompting efforts to harmonize policies for streamlining accelerated development approaches in the United States, Europe, Japan, and other regions. The European Medicines Agency (EMA) has established a PRIority Medicines (PRIME) scheme to accelerate the review and approval of breakthrough therapies. Similarly, the SAKIGAKE Designation developed by Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) offers early consultation that can lead to reduced review times for treatments of diseases in “dire need.” Health Canada’s accelerated review program permits approval based on less than 12 months’ stability data, as do authorities in Switzerland and Australia. Chinese FDA officials are talking about establishing a priority review procedure that would align with other major markets. While these initiatives emphasize accelerated clinical testing of promising therapies, the regulators also offer early face-to-face CMC meetings with sponsors to discuss testing and validation methods and stability data requirements.
Manufacturers are working with regulatory authorities to harmonize standards for streamlined clinical programs and accelerated CMC activities with an eye to enabling simultaneous submissions in multiple markets. EMA and FDA officials are exploring opportunities for joint discussion and evaluation of innovative products handled by the EMA’s PRIME and FDA breakthrough programs, building on their experience from a joint pilot program for the parallel assessment of applications containing QbD elements. An EMA report on the QbD pilot notes interest in extending such collaboration to accelerated assessments, as well as to continuous manufacturing and other “emerging technologies” (1).
An added benefit of accelerated drug development is that it may spur industry adoption of QbD manufacturing approaches. Sharmista Chatterjee, acting division director in OPQ’s Office of Process and Facilities, pointed out at the DIA workshop how continuous manufacturing (CM), with on-line monitoring and controls, can help streamline product development and support scientific experimentation, while increasing assurance of product quality. OPQ’s Emerging Technology Team already is assisting manufacturers in implementing methods to support more robust, predictable, and efficient production processes. Some CM systems, moreover, can accommodate smaller-scale modular and portable production systems and equipment that uses less materials, making such operations particularly suited to fast scale-up and production of small amounts of multiple therapies. Ultimately, such systems could lead to virtual, risk-based inspections and other innovations that further accelerate drug development and review.
1. EMA and FDA, “Report from the EMA-FDA QbD Pilot Program,” 2017, www.ema.europa.eu/docs/en_GB/document_library/Other/2017/04/WC500225533.pdf.
Vol. 30, No. 6
When referring to this article, please cite it as J. Wechsler, "Efficient Manufacturing Critical for Accelerated Drug Development," BioPharm International 30 (6) 2017.