May / June 2018

Regulatory Update: Opportunity to Advance Pharma Quality

Christopher John Potter, PhD

In March 2017, ISPE submitted an extensive and detailed response1 to the 2016 US Food and Drug Administration (FDA) draft guidance "Submission of Quality Metrics Data,"2 the associated Federal Register Notice,3 and webinar.4 These comments reflected ISPE's conclusion that the program, as proposed, has low or no value, and the burden on companies would be substantial.

Consequently, ISPE recommended that the agency issue a final guidance for a limited, carefully structured pilot program. The program and associated guidance, designed in concert with industry representatives, could clarify requirements and a relative value to the burden. ISPE also recommended that the pilot be based on common mechanisms of engagement. A small but diverse group from industry, for example, could work with the FDA Quality Metrics Team to establish a structured, multiphase approach with measurable goals, milestones, and evaluation points. 

As an alternative, ISPE also proposed that the FDA further review the stated goals of the quality metrics program and consider alternative approaches to its guidance, which is currently based on industry submission of harmonized data elements. ISPE indicated its willingness to work with the agency to develop such an alternative approach. 

ISPE representatives had an additional series of interactions with the FDA, during which the agency requested further explanation of ISPE’s recommendations for definitions related to the 2016 draft guidance for lot acceptance, product quality complaint, and invalidated out of specification (OOS) rates. ISPE also shared some preliminary thinking about the limited, carefully structured pilot.

To develop ISPE’s thinking further, ISPE conducted a workshop that included representatives from several companies that participated in its Quality Metrics Pilot Program, Waves 1 and 2,5 ,6 in October 2017. Using learnings from these interactions and workshop feedback, ISPE submitted further recommendations7 to the FDA docket, including:

  • Further elaboration of ISPE recommendations for definitions of lot acceptance, product quality complaint, and invalidated OOS rates
  • Alternative programs meeting FDA and industry goals
  • Carefully structured FDA pilot program

Advancing Pharamceutical Quality

At the participants’ workshop, ISPE drafted preliminary thoughts for processes to achieve FDA goals. Suggested design elements included: 

  • Voluntary 
  • Phased 
  • Well-defined assessment criteria 
  • Inclusion of incentives/recognition

ISPE further recommended that the voluntary program could be self-propagating through engagement of early adopters/change ambassadors to show industry leadership and commitment. To encourage participation, benefits should be demonstrable and could include those recognized to support a continual improvement culture, such as reduced inspections and optimized post-approval filing processes.

Instead of submitting standardized quality metrics, ISPE also proposed that companies provide information “in advance of or in lieu of an inspection,” as stated in the FDA Safety and Innovation Act,7 which could include operational excellence elements. Further discussion on this early thinking was identified as a key next step.

This alternative program, tentatively entitled “Advancing Pharmaceutical Quality,” would demonstrate value to industry, regulators, and patients by integrating tools and experience from quality culture, quality metrics, and operational excellence. It could be based on existing programs such as the US Occupational Safety and Health Administration Voluntary Protection Program and the FDA Case for Quality Program. It could also take elements from the UK Medicines and Healthcare Products Regulatory Agency pre-inspection information-request process. Further exploration and discussion between industry and FDA is needed to advance these ideas.

Proposed deliverables from this program include:

  • Assessment and continual improvement tools
  • Benchmarking forums
  • Interactions with regulators, especially the FDA 
  • Educational tools (conferences, articles)
  • Industry engagement workshops 

“Advancing Pharmaceutical Quality” could provide value to industry by encouraging self-improvement as well as supplier improvement, even if it is not adopted by regulators. Parts of the program could be considered for adoption by regulators, either initially or after implementation, leading to benefits to industry through regulatory interaction and potential regulatory relief.

Proposed goals are to:

  • Enable and foster industry ownership of quality beyond compliance 
  • Integrate quality, cultural, and operational excellence 
  • Support and incentivize continual 
  • Promote efficient use of resources by improving operational execution 
  • Increase reliability of product supply (improve could work with the FDA Quality Metrics Team to supply chain robustness
  • Fuel benchmarking, sharing, and among companies 

The vision for this program would remain that elucidated by the Research Director of the FDA’s Center for Drug Evaluation, Janet Woodcock: “A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight.”8

Program Design

A project core team—senior representatives from companies with a range of responsibilities, including quality, operations, information technology, and regulatory—and a series of subteams are working on different elements of the program:

  • Alternative program design
  • Integrated approach to quality and operational excellence
  • Applied quality cultural excellence
  • Evaluating FDA Quality Metrics submission portal
Figure 1: "Advancing Pharmaceutical Quality" Proposed Structure
Figure 1: ""Advancing Pharmaceutical Quality"" Proposed Structure - ISPE Pharmaceutical Engineering

Figure 1 is based on ICH Q10 Annex 2.9 To deliver quality product to customers on time and in full, a site in a supply chain delivering that product should have a quality system underpinned by and compliant with the site’s operational excellence practices. 

  • As recommended in the ISPE Operations Management Good Practice Guide,10 a company is likely to have a company manufacturing operations strategy that could be applied across a series of manufacturing sites. Different technologies, locations in the supply chain, and geographies, for example, would lead to differences in regulations and organizational cultures. As a result, sites may have different key performance indicators (KPIs) to balance operational efficiency and service within an acceptable cost structure.KPI values and, more importantly, changes in KPI values could be used to assess maturity of a site by benchmarking performance and comparison with other sites within the same company or in other companies. 
  • As demonstrated in the ISPE Quality Metrics Pilot Program, Waves 1 and 2,5 ,6 quality culture excellence is required to deliver robust and sustained quality metrics performance. Other studies, such as the University of St. Gallen’s work with the FDA,11 have shown that cultural excellence is positively associated with good business performance. In Figure 1, therefore, culture underpins all elements.

First Steps

Initial thinking is that sites would select from standardized tools relevant to the phase and maturity of their development. The team intends to identify tools and methodologies that could be used to assess site performance for management responsibilities, as well as knowledge management and quality risk management enablers. The “four pillars” included in ICH Q10—process performance and product quality monitoring, corrective action and preventive action, change management, and management review of process performance and product quality—would also be included. See the ISPE Cultural Excellence Report12 for examples of tools to assess and improve cultural excellence.

Subteams plan to develop the tools and methodologies required, identifying those that exist in the pharmaceutical or other industries. Dialogue with regulators would incorporate their perspectives and input, since a major goal of this program is that regulators consider adoption, at least in part, and/or help evolve relevant sections to help achieve their goals.
A cross-functional subteam has also been established to evaluate the FDA quality metrics portal and share its feedback with ISPE members and companies. The subteam will share industry approaches and best practices for local collection, management, and use of metrics data, and will also provide feedback on any further FDA quality metrics guidance or announcements. All of these experiences, learnings, challenges, and opportunities will be considered for input to the Advancing Pharmaceutical Quality program.

Next Steps

The project core team will meet with senior industry leaders and practitioners in early June for input and concept testing. As the program evolves, further proposals for next steps will be reviewed with ISPE leadership.