January / February 2017

Quality State of Mind - ISPE & PEW Release Drug Shortages Report


Quality issues continue to be a driving force behind sterile injectable drug shortages in the United States. This is one of the key conclusions of a Pew/ISPE joint study that interviewed 50 executives from 10 pharmaceutical companies in the United States. Released on 11 January, the report, Drug Shortages: An Exploration of the Relationship between U.S. Market Forces and Sterile Injectable Pharmaceutical Products, indicates that drug shortages revolve around several factors. Consequently, reducing shortages will require a multi-dimensional solution. “By reaching out to industry leaders to understand the factors affecting their relationship with market forces in the US,” said ISPE CEO and President John E. Bournas, “we have firsthand insight into possible solutions.”

Sterile injectable products are often cited as being the most vulnerable to supply disruption. They are also some of the most technically challenging products to manufacture. Choosing to look at sterile injectable products was a deliberate choice, added Dr. Theodora Kourti, ISPE’s Senior Vice President, Regulatory Affairs. “By zooming in on this niche market, we were able to see if the macro theories and hypotheses that we have been addressing since the first ISPE survey of drug shortages in 2013 hold true in more ‘micro’ environments.”

The joint study was announced in October 2015 and conducted over a six-month period with 50 executives from 10 pharmaceutical companies in the United States. To maintain confidentiality, PricewaterhouseCoopers was engaged to conduct the interviews with the participating companies and aggregate the anonymized data for analysis.

Findings support ISPE research

The Pew/ISPE study sought to look at manufacturing, supply chain, and US market forces that have a bearing on drug shortages, explore the relationship between these forces, and how they contribute to the shortage of sterile injectable products. The study further sought to determine whether the decisions companies made to reduce risks of future shortages were influenced by elements other than quality-focused factors.

Among the elements identified by the 10 participating pharmaceutical companies as the reasons for shortages are market withdrawals, ineffective supply chain design, few purchaser-manufacturer incentives, limited market insight into future demand, and regulatory expectations. In addition to improvements in product and manufacturing quality and current Good Manufacturing Practice (cGMP) compliance, the report concludes that drug shortages could be reduced with improvements in internal- demand-forecasting abilities; overall supply chain maturity; and the relationships between a manufacturer, a provider, and regulators.

The Pew/ISPE study’s key findings are:

  • Product supply chains are increasingly complex and need strengthening. Instead of a uniformly strategic approach to the portfolio, a product-by-product approach is often used, although patient needs are generally prioritized.
  • Limited incentives inhibit the ability to mitigate shortages, deterring companies from entering a market to resolve a shortage issue or build the systems needed to prevent shortages.
  • Inadequate forecasting mechanisms are inhibiting investments to mitigate or prevent shortages. Companies worry that their inability to reliably predict the economic returns for investments in new capacity may result in financial losses, especially for legacy products with low volumes and low margins.
  • Perceived regulatory challenges to expanding or updating capacity are limiting investments.

“These findings are consistent with ISPE’s 2013 drug shortages survey,” stated Bournas. “However, market forces are also contributing to drug shortages as companies wrestle with investment decisions with uncertain regulatory or economic outcomes.” The Pew/ISPE study makes several recommendations for industry in this regard:

  • Develop a collaborative approach to improve market forecasts.
  • Establish or enhance incentives between purchasers and manufacturers.
  • Strive for further collaboration opportunities with regulators, for example, identifying a simplified process that enables a more effective way to update market authorizations for legacy products.
  • Develop systems to proactively identify and resolve quality issues across increasingly complex supply chains. Improve understanding of the risks across the supply chain.

ISPE has been conducting research and collecting data on global drug shortages since 2011. Its 2013 survey found that issues within the quality systems of manufacturing were identified as the leading cause of drug shortages. At that time, the number of drug shortages in the United States stood at 204, according to the University of Utah Drug Information Service. By 2015 that number had dropped to 142, and further declined to 49 by the end of first-quarter 2016. Yet few would disagree that hurdles abound before the industry can confidently claim to have eliminated drug shortages altogether.

ISPE published the ISPE Drug Shortages Prevention Plan (DSPP) in 2014 and the ISPE Drug Shortage Assessment and Prevention Tool in 2015. The DSPP informed ISPE’s contribution to a multi-association response to the European Medicines Agency’s request for an actionable plan to address drug shortages caused by manufacturing and quality issues. ISPE also offered a Drug Shortages Introductory Webinar in early 2016. Additionally, drug shortages prevention recognition is now included in the association’s flagship Facility of the Year Awards program.

“The data collected points towards a need for greater collaboration among all parties, at all levels,” stated Bournas. “ISPE is well positioned to enable this collaboration, as it is the cornerstone of ISPE’s philosophy and its raison d’etre. We look forward to continuing our relationship with Pew Charitable Trusts.”

As both organizations move forward sharing the survey results within industry, Pew/ISPE will assess whether follow-up surveys will be required, or the scope broadened to include other products and geographies.

“We will be presenting the study results and conclusions at the 2017 ISPE Aseptic Conference, this coming March 7-8,” stated Dr. Kourti.

FDA Issues Revised Draft Guidance On Quality Metrics

On 23 November 2016, the US Food and Drug Administration (FDA) released a much-anticipated revision of its draft guidance on the collection of quality metrics. The revised “Submission of Quality Metrics Data Guidance for Industry” is a response to industry concerns that the original guidance was too demanding.

In a Federal Register notice published two days later, FDA identified the revisions:

The revised draft guidance includes the following changes from the earlier draft guidance: Adoption of a phased-in (voluntary) approach, reduction in the number of data elements requested (i.e., reduction in reporting burden), support for both product reports and site reports, modifications to the quality metrics data definitions, addition of clarifying examples for the definitions, addition of comment fields, and clarification of special considerations for non-application and OTC [over-the-counter] product reporting.

Both the revised “Submission of Quality Metrics Data” Guidance for Industry and an explanatory webinar are available online. Links to both of ISPE’s Quality Metrics reports are also available on the FDA website.

ISPE 2017 Conference On Quality Culture

The first ISPE Conference on Quality Culture and Quality Metrics will be held in Bethesda, Maryland, 25–26 April 2017. The conference will coincide with the publication of the ISPE Cultural Excellence report, a collection of practical, powerful tools that outlines a comprehensive behavior-based approach to improving quality culture as a means of delivering enhanced quality outcomes.

Conference attendees will learn from industry peers through case studies and the sharing of best practice:

  • How to implement the practical approaches and tools compiled in the Cultural Excellence report
  • How industry leaders can help shape and contribute to quality culture
  • Which best practices enable a collective mindset to drive toward improving quality
  • Gemba’s key role in coaching and mentoring desired attitudes and behaviors
  • How to use a practical new tool to target and measure behaviors that matter
  • Which best practices are required for effective management oversight and review
  • What critical enablers are necessary to build and sustain a culture of excellence.

For more information on the conference, see the Quarterly Report on Quality Culture in the November/December 2016 issue of Pharmaceutical Engineering.

Quality Culture In Action At Ispe 2016 Annual Meeting

The well-attended Quality Metrics session at the 2016 ISPE Annual Meeting & Expo in Atlanta, Georgia, on 21 September featured excellent thought-provoking and informative presentations followed by a lively Q&A discussion. Session themes were understanding quality metrics applied to assess quality performance and the underpinning importance of a quality culture. Presenters were Marie Mathews, Compliance Officer, CDER/OC/OMQ, FDA, and Dr. Nuala Calnan, Research Fellow, Dublin Institute of Technology, Ireland. In a separate, related session, Mairead Goetz, Global Head Analytical Science and Technology, Novartis, provided a company perspective.

Counting the hard to count

Marie Mathews presented an FDA field perspective on quality metrics and culture. Building upon the maxim “Not everything that can be counted counts, and not everything that counts can be counted,” she reflected that a traditional approach to quality metrics may capture out-of-specification results, deviations, trends, rejects, complaints, and recalls, among others, but the values can be rendered useless unless the correct information is used and the appropriate action is taken promptly. “At first glance, some of the more out-of-control companies I’ve seen look pretty good with these metrics,” she said. It may not be until the FDA (or another agency) steps in that gaps are revealed. By then, the company will have already lost control and an extraordinary amount of effort will be required to get it back on track.

Many companies are good at creating mission or value statements but not so good at assessing their culture. Mathews cited an example of a very out-of-control plant that had a laboratory with 100% turnover of staff in two years. The plant had not recognized this huge red flag.

Mathews cited four “misconceptions about quality culture”:

  1. If an employee sees something objectionable, they will let someone know.
  2. We have an internal whistle-blower line, so employees will use it.
  3. We would know if one of our employees contacted the FDA.
  4. If I find out about a problem, it makes me personally responsible.

What does work, she said, are actions such as conducting a survey of all employees on culture,

with guaranteed anonymity, and a review of employee incentives, both monetary and nonmonetary, to encourage wanted behaviors and discourage unwanted behaviors. She closed by discussing the issues of empowerment and transparency as quality culture enablers.

ISPE cultural excellence

Dr. Calnan gave an update on the ISPE Cultural Excellence Program. She explained that the program is aimed at promoting, coaching, and leading specific desired behaviors while identifying and preventing specific undesired behaviors.

Over a period of 2 years, 35 members from 28 companies in six subteams are collaborating to produce a series of deliverables, which will be completed by the end of 2016. Each subteam is working on one of the dimensions in the outer circle of the diagram.

Dr. Calnan described these deliverables as tools that companies, sites, and individuals can use to move toward cultural excellence.

Quality culture and performance: A Novartis perspective

Mairead Goetz described Novartis’s challenge following several acquisitions that have combined different business models, cultures, and standards across 67 plants employing more than 6,600 people. The goal is to evolve a strong, consistent, and sustainable quality culture throughout Novartis, with sites having ownership and commitment from the top down.

The company chose 15 basic culture actions to inform specifically tailored site change plans.

Even within a large organization committed to quality improvement, each site has its own culture, requiring specific initiatives to improve its individual culture maturity.

Progress is assessed biannually, using a 12-question company-wide survey. Results are summarized using a scorecard matrix of survey findings, key performance indicators (KPIs), and key quality indicators. To approach these goals, Novartis has one quality standard for the whole network, uses KPIs constantly, and has a strong foundation of values and behaviors sponsored by senior management.

Goetz stressed that movement of quality performance requires more than just numbers. Quality culture change is a long journey and requires perseverance. Sites tend to initially overestimate their quality maturity, which is a subjective assessment. Management has the critical responsibility of fostering and enabling the change journey, and the ongoing surveys are an extremely important tool to provide visibility about each site’s progress.