Critical drug shortages and contaminated compounding of sterile injectables have heightened public concern about drug quality and safety. Despite a decade of encouragement and guidance from FDA, manufacturers have failed to adopt a “continuous improvement model,” according to Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER). FDA is seeking new strategies to spur compliance with GMPs and to limit drug production errors that lead to supply problems, Woodcock explained at a July 10, 2013 seminar on “Understanding cGMPs” sponsored by the Food and Drug Law Institute (FDLI). Achieving drug quality has become more complex--and more vital--with industry globalization, she acknowledged, emphasizing the importance of manufacturers producing quality products batch after batch.
To further encourage quality production, FDA seeks to establish clear, written, clinically relevant public standards that it can enforce through review and inspections. This effort is supported by the FDA Safety and Innovation Act (FDASIA), which requires FDA to draft a strategic plan for preventing and mitigating drug shortages. Policy makers want to know if FDA compliance actions lead to supply problems and how the agency can better inform health professionals and the public on potential shortages.
In crafting the shortages plan, an FDA Drug Shortages Task Force has been examining more broadly how drug manufacturing problems may precipitate plant closings and product discontinuations and what strategies pharmaceutical companies use to track and prevent such failures. Most obvious are reports of company recalls, poor inspection outcomes, and adverse events that are visible to FDA and can indicate broader deficiencies in manufacturing process and control strategy.
In addition, FDA wants to know how manufacturers use quality metrics internally to monitor production and to select contract manufacturers. In a Feb. 12, 2013 Federal Register notice (1), FDA solicited such information, and manufacturers and industry trade associations submitted comments describing a variety of industry standards and quality assurance approaches (2). The filings indicate that pharmaceutical and biotech companies regularly monitor error rates, for example, to identify non-conformances, discrepancies, and deviations; high error rates are considered evidence of poor process control, poor training of operators, lax oversight by supervisors, poorly maintained equipment and facilities, or poor product and process characterization, according to the Generic Pharmaceutical Association (GPhA) and the Pharmaceutical Research and Manufacturers of America (PhRMA).
Longer cycle times may signal more errors and product failures that must be identified, documented, investigated, remediated and closed before a lot or batch can be released. Conversely, a shorter cycle time may indicate that a facility operates in a high state of control. Process and product performance index (Ppk) values similarly can be a sign of an optimal control strategy supported by in-depth understanding of the causes of variability for both products and process. A “batches-right-the-first-time” measure, based on number of lots released compared to lots initiated, similarly can demonstrate that processes are robust and products are made consistently in a state of control.
Leading indicators of manufacturing quality may cover a range of company actions and policies, such as adequate investment in manufacturing facilities, sufficient funding for routine maintenance, and support for training programs. Organizational health also can be assessed through worker safety, employee satisfaction, staff retention/turnover, and training effectiveness, comments the Parenteral Drug Association (PDA). Predictive or forecast metrics include maintenance backlogs, complaint trends, internal audits, and the findings of regulatory inspections. Yield analysis or abnormalities of product per batch over time can be an advance sign of other process or raw materials problems.
In its comments, Pfizer describes four levels of quality performance indicators, starting with staffing adequacy, workload, and increased turnover. Further signals of potential quality or compliance issues may appear as increased documentation errors, unplanned quarantine shipments, or complaints per units produced. The next level captures higher average disposition cycle times or operator errors per batch. Documented quality events, overdue regulatory commitments, or an increase in rejected batches may signal the need for action to maintain product quality control.
To assess contract manufacturers, PDA notes that pharmaceutical and biotech companies use metrics such as supply assurance over the past 10 years, redundant facilities, minimum raw material stocks, and contingency plans for Act-of-God situations such as pandemics. Firms generally consider metrics for contractors similar to those applied internally, but also weigh supply-chain security, sterility assurance, and product and process knowledge.
While manufacturers see value in quality metrics, they are less enthusiastic about proposals that FDA encourage redundant manufacturing sites as a strategy for preventing shortages. Language in FDASIA proposes that FDA identify a list of “qualified manufacturers” with capability and capacity to produce vital drugs rapidly. But without funding to support manufacturer participation in such undertakings or some kind of guaranteed purchase program, industry is pessimistic about that approach.
PDA notes in its comments that certain regulatory actions might encourage manufacturers to expand capacity, such as expedited review of new manufacturing lines and post-approval changes to improve process capabilities. Other ideas are for FDA to waive Prescription Drug User Fee Act (PDUFA) establishment fees for redundant production sites; implement shelf-life extension policies; and reduce preapproval requirements for site transfers, assay improvements, and extended comparability protocols particularly for “good actors” in GMP compliance.
From the agency’s perspective, production quality metrics could help establish a more rigorous and objective way of evaluating facilities during inspections, said Douglas Stearn, deputy director for policy and analysis in CDER’s Office of Compliance, at the FDLI conference. Such standards could provide a look across a company and industry to better assess materiality and clinical relevance of a GMP issue and to avoid FDA enforcement actions that aggravate drug shortages. FDA recognizes that there always is tension between ensuring that drugs are not contaminated, and providing access to life-saving medicines.
A new Office of Pharmaceutical Quality in CDER could support these efforts by collecting performance metrics and conducting trend analysis to identify both compliant operations and outliers. An upgraded IT platform could compile information from all sources on sites and products to support a streamlined, risk-based inspection process. This initiative also could evaluate FDA performance, such as in issuing citations and enforcement letters, to see if the agency meets its own standards.
Woodcock acknowledged at the FDLI meeting that intensive regulation of drug manufacturing is partially to blame for industry’s reluctance to implement innovative quality strategies. While producers of food products and fine chemicals have engineered precise controls that yield defect-free products, she finds that pharmaceutical companies focus more on complying with regulations. For FDA, however, to efficiently assess and approve hundreds of applications for new generic drugs to meet tight review timeframes, manufacturers need to ensure that products consistently meet high quality standards. To move more breakthrough drugs quickly through the approval process, pharmaceutical and biotech companies need to establish high quality production systems early in development. These imperatives put drug quality high on FDA’s radar screen.
1. FDA, Federal Register, Vol. 78, No. 29, p 9928-9929, Feb. 12, 2013.
2. Comments available at the Federal eRulemaking Portal: www.regulations.gov, Docket No. FDA-2013-N-0124.
About the Author
Jill Wechsler is Pharmaceutical Technology’s Washington editor, Chevy Chase, MD, 301.656.4634, email@example.com. Read Jill’s blogs at www. PharmTech.com/wechsler.