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FDA plans to advance initiatives for ensuring reliable production of drugs and biologics in 2017.
Amidst multiple challenges to the structure and governance of the US healthcare system, bio/pharmaceutical manufacturers will face a host of issues in bringing safe and effective new therapies to patients. The demand for affordable personalized, or precision, medicines to treat lethal diseases requires efficient and cost-effective operations that promote innovation and avoid shortages. Similarly, modern, agile, and reliable production systems that adhere to standards and ensure data integrity are vital for development and access to biosimilars, cellular and gene therapies, complex dosage forms, innovative vaccines, and more combination therapies. And pressure to combat the devastating opioid epidemic across the United States highlights the need for innovative methods to produce new formulations to treat pain that also resist abuse and misuse.
Pressure will mount on FDA under the new administration to make experimental therapies available to patients faster and more predictably. As 2016 came to a close, FDA officials reported that new drug approvals for the year would fall far short of the near-record set in 2015, raising concerns about current incentives and regulatory processes for bringing new drugs to market. FDA has approved numerous breakthrough therapies for cancer and critical conditions based on limited but convincing clinical data, a development highly applauded on all fronts. This patient-centric approach is expected to gain even more support from key provisions in the 21st Century Cures legislation.
These developments raise questions about how much data and what kind of evidence are needed to approve such products, and may require policy makers to grapple with new regulatory models. These issues were highly visible in the debate over FDA approval of Sarepta Therapeutics’ treatment for Duchenne muscular dystrophy; reviewers and senior staffers in the Center for Drug Evaluation and Research (CDER) recommended against approval based on inadequate evidence that the drug had any positive effect on patients, while families of children with the condition claimed real benefit from the drug and convinced CDER director Janet Woodcock to recommend approval.
A similar situation recently emerged related to approving a new antibiotic that promises to address critical medical needs due to spreading antibiotic resistance, but has presented serious safety issues in clinical trials. Some regulatory officials and consumer advocates fear that pressure to provide early access to medicines, despite safety signals and limited evidence of efficacy, will undermine the FDA approval process more broadly.
Accelerated FDA approval of important therapies demands drug manufacturing systems able to scale up production quickly and efficiently and to maintain quality throughout the product life cycle. These challenges apply to biosimilars and cutting-edge therapies, as well as to the need for modern aseptic processing methods able to reliably produce both new and generic sterile injectables. The increase in combination products, moreover, demands more coordinated oversight of manufacturing by FDA’s centers for drugs, biologics, and medical devices.
FDA is responding with efforts to refine and clarify policies related to quality drug manufacturing, with an eye to avoiding onerous requirements that can increase production costs and cause delays. An important initiative involves collecting metrics data from drug makers that give a more precise picture of how reliably a drug facility produces quality products. In late November 2016, FDA revised a July 2015 proposal to address industry concerns about the scope and objectives of this quality metrics data submission initiative (1).
Under the new draft guidance, the program will be voluntary for a year and request three, instead of four, data elements, starting with lot acceptance rate, product quality complaint rate, and invalidated out-of-specification rate. Manufacturers have the option of submitting data by product or by site and may add comments to reports. FDA, however, is looking for strong industry participation in this voluntary phase to be able to determine the value of this kind of data. If successful, FDA proposes to initiate a formal rulemaking process to establish a mandatory metrics reporting program, an approach likely to draw opposition from the Trump administration.
Contract manufacturers able to scale up quality production quickly have emerged as particularly important to the development of precision therapies and innovative dosage forms. The need for clear policies to ensure regulatory compliance and adherence to standards by contractors is reflected in a final guidance issued in November 2016 on establishing written quality agreements between commercial drug manufacturers and contractors (2). The final version revises a draft issued in 2013 and clarifies that the owner/manufacturer of a drug (and not distributors or retailers) is responsible for ensuring that drug substances and drug products are produced to meet GMP standards and how written agreements should map out the roles and responsibilities of each party in meeting those goals.
Industry and FDA will face challenges as they continue to implement drug supply chain monitoring programs, as required by the Drug Supply Chain Security Act (DSCSA) of 2013. An immediate task is to provide a barcode on packages by November 2017 that includes a National Drug Code (NDC), serial number, lot number, and expiration date in both machine-readable and human-readable form. A broad industry group adopted guidelines on using the Electronic Product Code Information Services (EPCIS) for lot-level management and item-level traceability of pharmaceuticals (3). Achieving standardized barcodes is a key step for establishing by 2023 a fully electronic system for item-level traceability of pharmaceuticals through the supply chain from manufacturer to wholesalers and distributors, and ultimately to pharmacies and patients.
As manufacturers strive to meet the DSCSA goals for global tracking of prescription drug shipments, they will face multiple tracking and serialization systems under development in Europe, Asia, and South America. The lack of harmonization in these efforts reflects continued challenges in establishing worldwide standards for a wide range of operations involving drug testing, regulation, and production.
The International Council for Harmonisation (ICH) has changed its name to reflect expanded involvement of health authorities from additional regions and of manufacturers representing additional industry components in its standards-setting activities. An important new quality guideline on lifecycle management of pharmaceuticals (Q12) is moving forward slowly, and should complement the series of ICH quality standards developed to encourage manufacturer adoption of modern production methods.
Expanded global sourcing of pharmaceutical ingredients and products will continue to build support for regulatory mutual reliance initiatives able to streamline agency oversight while assuring quality drug production in multiple regions. A growing collaboration involves GMP inspections of APIs by FDA and regulatory authorities in Europe, Japan, Australia, Canada, and by the World Health Organization (WHO). FDA and the European Medicines Agency also seek to avoid duplicate inspections by expanding a program for information sharing on planned site visits and on inspection outcomes from pre-approval and routine GMP inspections of drug manufacturers in both regions. While increasing its own oversight of foreign drug manufacturers, FDA will continue to support reliance on other inspectorates and on policies that promote quality drug production globally.
1. FDA, Submission of Quality Metrics Data, Guidance for Industry, Draft Guidance (CDER, CBER, November 2016).
2. FDA, Contract Manufacturing Arrangements for Drugs: Quality Agreements, Guidance for Industry (CDER, CBER, CVM, November 2016).
3. GS1 US DSCSA Implementation Suite.
Vol. 30, No. 1
When referring to this article, please cite it as J. Wechsler, "Drug Quality Key to Innovation and Access," BioPharm International 30 (1) January 2017.