Special Reports
September / October 2018

ISPE Proposes an Advancing Pharmaceutical Quality Program
Christopher John Potter, PhD
ISPE Proposes an Advancing Pharmaceutical Quality Program

The basic framework of the program is to "assess and aspire" quality maturity. 

The ISPE Quality Metrics team has proposed an industry-led approach to advance pharmaceutical quality beyond the submission of data for three harmonized, reportable metrics: the Advancing Pharmaceutical Quality (APQ) prog ram. The basic framework of the program is to “assess and aspire” quality maturity. Evolving concepts, assessment tools, and key performance indicators of the APQ framework are:

  • Quality culture maturity and improvement
  • Preliminary quality appraisal (PQA)
  • Corrective and preventive action (CAPA) maturity

ISPE has continued to have a team at readiness for responding to further advances in the FDA Quality Metrics program and this team has highlighted some best practices from across the industry regarding collection, management, and use of data for metrics. 

BACKGROUND

ISPE’s Quality Metrics program has been active since 2013 (Figure 1).  

Figure 1: Quality Metrics Time Line
ISPE Proposes an Advancing Pharmaceutical Quality Program Figure 1 - ISPE Pharmaceutical Engineering

In March 2017, ISPE submitted an extensive and detailed response1 to the 2016 FDA draft guidance2 “Submission of Quality Metrics Data,” the associated Federal Register Notice,3 and webinar.4 These data-driven comments were informed by: 

  • Four years’ work with industry leaders and experts by the Quality Metrics core team
  • Two pilot programs (Waves 1 and 2) involving 83 sites and 28 companies
  • A workshop with 22 companies 

After concluding that: 

  • Requirements are complex and preclude standardization due to challenges with unclear definitions 
  • Lack of clear and standardized quality metrics data elements will confound attempts at data analysis 
  • Burden is significant

ISPE recommended that the agency issue a final guidance for a carefully structured FDA pilot program before a program commences.

As an alternative, ISPE suggested that FDA review the stated goals of its quality metrics program and consider other approaches to its 2016 guidance, which is based on industry submission of harmonized data elements.

ISPE representatives had a further series of interactions with FDA to seek clarity about its comments. Following these interactions, FDA requested further explanation of ISPE’s recommendations for definitions of lot acceptance rate, product quality complaint rate, and invalidated out-of-specification rate as they related to the FDA 2016 draft guidance, as well as alternative approaches. These recommendations and some preliminary thoughts on alternative approaches were provided in October 2017.5  

APQ PROGRAM

Goals, benefits, and concepts

At a September 2017 workshop for Wave 1 and 2 participants, preliminary proposals were developed on potential processes for achieving FDA goals.

Emergent themes included:

  • Voluntary
  • Phased
  • Well-defined assessment criteria
  • Incentives/recognition inclusion

A voluntary program, it was considered, would self-propagate through engagement of early adopters/change ambassadors and would show industry leadership and commitment. To encourage participation, benefits should be demonstrable.

Processes for developing an alternative program could be based on existing programs such as OSHA’s Voluntary Protection Program (VPP) and the FDA’s Case for Quality Program, which is administered by the agency’s Center for Devices and Radiological Health. It could also take elements from the UK Medical and Healthcare Products Regulatory Agency (MHRA) pre-inspection information request process.

To move these early proposals forward, the industry-led “Advancing Pharmaceutical Quality” program is being developed. The vision for this developing program continues to be that elucidated by FDA as:

A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight.6

The proposed program would:

  • Evolve the primary focus of the ISPE Quality Metrics team from the FDA quality metrics program to establishing a platform for advancing the state of pharmaceutical quality that could be leveraged by industry and FDA to achieve quality metrics program objectives
  • Integrate tools and experiences in culture, quality, and operational excellence disciplines that demonstrate value to industry, regulators, and patients
  • Assign deliverables that include assessment and continual improvement tools, education (conference, articles), industry engagement workshops, benchmarking forums, and interactions with regulators, especially FDA

Proposed program goals are: 

  • Enable and foster industry ownership of quality beyond compliance 
  • Integrate quality, cultural, and operational excellence principles and learnings 
  • Support and incentivize continual improvement 
  • Promote efficient use of resources by improving execution 
  • Increase reliability of supply for quality product
  • Fuel benchmarking, sharing, and learning among companies 
  • Provide a program that has value to industry whether it is adopted by regulators or not 
  • Encourage self-improvement and supplier improvement 
  • Have potential competitive advantage 
  • Program could be adopted by regulators, providing additional benefits to industry through regulatory interaction and regulatory relief 

Guiding principles are: 

  • “By industry, for industry,” at least at the outset 
  • Must have value and benefits to industry 
  • Be seen as attractive to and beneficial for regulatory agencies I
  • Be applicable across all sectors of the pharmaceutical industry 
  • Use “as-is” company data and site procedures as much as possible 
  • Minimize additional work 
  • Leverage existing methodologies and principles where relevant (e.g., ISO, VPP, MHRA, ICH Q10) 
  • Engage FDA and others in design 
  • Complement existing FDA initiatives (e.g., quality metrics, New Inspection Protocol project, data analytics) 
  • Simplicity

These principles were tested at a workshop of industry representatives in March 2018, and supported for further development and testing at a June 2018 workshop with wider industry participation. 

Proposed framework

An overview of the proposed program framework is given in Figure 2. The core of the program is shown in the middle two columns, where there are two components. The first component would be to “assess” your own quality maturity and decide, based on this assessment, how much you “aspire” to improve. Should you decide that you wish to improve, the program would point to tools and key performance indicators (KPIs) that would be the “architect” of your improvement.

Figure 2: ISPE APQ Framework
ISPE Proposes an Advancing Pharmaceutical Quality Program Figure 2 - ISPE Pharmaceutical Engineering

As a first step, in the left-hand column we are considering a PQA in which the goal would be to use a low-resource step to evaluate if you were justified in spending more resources to conduct a fuller quality maturity assessment.

In the right-hand column, there is the possibility of introducing a more formal assessment of quality maturity, potentially at a later stage, using a third party. This could be recognition of performance using some sort of certification system. More detail of the middle two columns is given in Figure 3.

Figure 3: APQ Framework Detail
ISPE Proposes an Advancing Pharmaceutical Quality Program Figure 3 - ISPE Pharmaceutical Engineering

In summary, tools and KPIs to conduct a PQA, along with those to assess, benchmark and improve quality maturity would be identified from those that are already available. Where tools and KPIs do not exist, ISPE teams would propose new or alternative options.

A key element of both the PQA and the fuller assessment would be an exercise to calculate the cost of quality—essentially the cost of poor quality. An ISPE team has been considering how to conduct these assessments and will provide suggestions and possibly even case studies.

A major vision of this program is that regulators may become involved in the design of its framework and ultimately adopt and/or evolve relevant parts of the program to help achieve their goals. 

ICH Q10

A fundamental basis of the developing program is ICH Q10 Pharmaceutical Quality System Model,7 as shown in Figure 4. 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 that is underpinned by and fits with the site’s operational excellence practices. As recommended in the ISPE Good Practice Guide: Operations Management,8 a company’s manufacturing operations strategy is likely to be applied differently across a series of sites due to differences in technology, geography, regulations, or location in the supply chain. Given this, sites may have slightly different KPIs to balance operational efficiency and service within an acceptable cost structure.

Figure 4: Overview of Relationship to ICH Q10
ISPE Proposes an Advancing Pharmaceutical Quality Program Figure 4 - ISPE Pharmaceutical Engineering

As demonstrated in ISPE Quality Metrics Pilot programs, Waves 1 and 2,9 ,10 excellence in quality culture is required to deliver robust and sustained quality metrics performance. It is well understood from other studies, such as the University of St. Gallen work with FDA,11 that cultural excellence is positively associated with good business performance. Hence in Figure 4, culture underpins all other elements. Tools for assessing and improving cultural excellence are given in the ISPE Cultural Excellence Report.12

The Parenteral Drug Association (PDA) has also developed and implemented a quality culture assessment tool.13 ISPE and the PDA are engaged in preliminary discussions regarding future potential collaboration in quality culture assessment and improvement.

Continued Fda Engagement

In October 2017, following its submission of detailed further recommendations regarding definitions for FDA’s harmonized quality metrics program, ISPE established a cross-functional subteam (working title: “Metrics Reporting and Analytics”) to evaluate, summarize, and provide feedback on the FDA quality metrics portal experience, sharing those learnings with ISPE members and companies. The ISPE team has also discussed and shared approaches and best practices from across the industry regarding the local collection, management, and use of data for metrics. These experiences, learnings, challenges, and opportunities will be considered for input to the APQ program. 

2018 Federal Register Notices

In June 2018, the FDA published two Federal Register notices (FRNs) announcing new voluntary efforts to gather stakeholder feedback on the use of quality metrics.

The first notice described a quality metrics feedback program with efforts that include formal and pre-ANDA meeting requests, as well as a pilot study to gain feedback from establishments.14 The second announced a 2018 CDER and CBER staff experiential learning site visit program to provide learning opportunities for FDA staff involved in the agency’s Quality Metrics program and to give stakeholders an opportunity to explain the advantages and challenges associated with a robust quality metrics program.15 Stakeholders are encouraged to participate in these efforts.

In conclusion, it is very pleasing that FDA recognized that “it should perform further studies of the FDA Quality Metrics program through a pilot program and additional discussions with stakeholders.” As requested in the first FRN, ISPE will continue to engage with FDA to gather feedback from industry subsectors and to provide industry options to advance pharmaceutical quality to achieve the stated vision.

  • 9International Society for Pharmaceutical Engineering. “ISPE Quality Metrics Initiative: Wave 1 Report.” June 2015. https://ispe.org/products/ispe-quality-metrics-initiative-wave-1-report
  • 10International Society for Pharmaceutical Engineering. “ISPE Quality Metrics Initiative, Wave 2 Report.” June 2016. https://ispe.org/products/ispe-quality-metrics-initiative-wave-2-report
  • 11Friedli, T., S. Koehler, P. Buess, P. Basu, and N. Calnan “FDA Quality Metrics Research, Final Report.” July 2017, www.tectem.ch
  • 12International Society for Pharmaceutical Engineering. Cultural Excellence Report, April 2017, www.ISPE.org
  • 13Parenteral Drug Association. PDA Quality Culture Program. www.pda.org
  • 14US Food and Drug Administration. “Modernizing Pharmaceutical Quality Systems; Studying Quality Metrics and Quality Culture, Quality Metrics Feedback Program.” Docket No. FDA-2018-N-1903. Federal Register, 29 June 2018. https://federalregister.gov/d/2018-14005
  • 15US Food and Drug Administration. “Quality Metrics Site Visit Program for Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research Staff; Information Available to Industry. Docket No. FDA-2018-N-1896.

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