ISPE Set To Address Drug Shortages At Annual Meeting

By Ed Miseta, Chief Editor, Clinical Leader

Drug shortages continue to plague the pharmaceutical industry. According to a GAO report on shortages, dated February 2014, the number of shortages continues to increase in the U.S., as well as around the world. In 2007 there were 154 shortages, 114 new shortages and 40 ongoing from a prior year. In 2012, there were 456 shortages, 195 news ones and 261 ongoing. As of June 30, 2013, there were already 73 new shortages and 288 ongoing.

The public health importance of these shortages cannot be overemphasized. Shortage situations have included zinc for parenteral nutrition in neonates and premature infants, doxorubicin for ovarian and other cancers, and Propofol for anesthesia.

Clearly something needs to be done. “ISPE believes efforts to address this complex and multi-faceted problem of drug shortages requires close collaboration and clear communication between the pharma industry and global health authorities,” says Francois Sallans, VP and chief quality officer for Johnson & Johnson, and presenter at the 2014 ISPE-FDA CGMP Conference. “We believe The Drug Shortages Prevention Plan being assembled by ISPE will provide guidance to pharma and global health authorities to manage drug shortages more effectively. But more importantly we are looking into ways for the two groups to manage these shortages more proactively as well. That is an important component that we need to have in place in order to make these shortages rare, but short-lived.”

The ISPE Drug Shortages Prevention Plan will consist of six dimensions: corporate culture, robust quality systems, metrics, business continuity planning, communication with authorities, and building capability. All will need to work together in one cohesive unit for the plan to be successful.

Many Sources, Same Results

Francois Sallans, VP and chief quality officer for Johnson & Johnson

There are many sources of issues that can arise in the manufacture of pharmaceuticals, any of which can end in a drug shortage. In looking at just one product class, sterile injectables, Sallans was able to rattle off four distinct sources for a shortage.

The first is the state of the industry. Sallans notes with sterile injectables, there are a small number of manufacturers that make up most of the market. Add to that the fact that this industry segment has contract manufacturers acting as both contract manufacturers as well as firms contracting out manufacturing, and the possibility of a shortage becomes all too real.

Second is a lack of redundant manufacturing in the industry. “In many companies we have multiple products made on the same manufacturing line,” says Sallans. “Many of these lines run 24/7 with no cushions for downtime or maintenance. If an issue arises, production will be halted for multiple products.”

Third are complex manufacturing processes, where a manufacturing problem can again affect multiple products at once. Finally, Sallans cites the investment economics question: if one 20 ml vial of propofol sells for 48 cents, is there enough profit to be made in producing the product? If not, we should not be surprised if some companies opt out of manufacturing it. That situation will then contribute to the earlier problem of having a small number of manufacturers.   

Quality manufacturing issues will also have a huge impact in the prevalence of shortages. Quality issues can result in both product manufacturing issues as well as facility remediation issues. Other manufacturing issues affecting shortage situations include the discontinuation of a product or loss of a site, raw materials (API) and other component shortages, a sudden increase in demand, equipment breakdowns, natural disasters, and issues with sterility, particulates, crystallization, precipitation, degradants, and impurities.

What’s The Solution?

 When looking for a fix to the shortage problem, there are many possible solutions. One is a better early-warning notification system. This is an area where regulators have clearly placed an increased focus. If we know of a potential problem before it arrives, we have the opportunity to take corrective action to avoid the shortage. In October 2011 an executive order from President Obama directed FDA to use its authorities to encourage early notification of potential shortages. Just two months later, an Interim Final Rule was published to improve advance notification of potential shortages. Seven months after that, in July 2012, FDASIA broadened the scope of early notification requirements. It also required a strategic plan and annual report on drug shortage efforts. The result of these actions was close to 200 drug shortages prevented in 2011 and another 280 in 2012.

Once a shortage situation is reported, FDA now has a key role to play in the effort as well. The agency has been tasked with responding promptly and efficiently to notification of a shortage. Once a situation is reported, the agency will perform a risk analysis to determine proper ways to address the shortage. This includes:

• Determining if other manufacturers can increase production
• Expediting inspections and reviews of submissions
• Exercising temporary enforcement discretion for new sources of medically necessary drugs
• Working with manufacturers to ensure adequate investigation into the root cause of the shortage
• And reviewing possible risk mitigation measures for remaining inventory.

Finally, the agency has been tasked to communicate effectively with all stakeholders.

Of course these efforts will help to more quickly identify and ease a shortage situation. The long term goal is ultimately to prevent drug shortages altogether. ISPE identifies several measures that it believes will help in that regard.

The first is obviously a focus on the underlying causes of production disruptions. In this regard the industry needs to develop methods to incentivize and prioritize manufacturing quality. If we want to truly be proactive in preventing shortages, punishing companies after the fact will not be sufficient.        

We must make use of regulatory science to identify the early warning signals of shortages. The proposed Office of Pharmaceutical Quality is expected to assist in this endeavor. Finally the development of new strategies to address shortages will also be essential.

There needs to be an increased focus on cooperation. No one company, regulator, or industry group can solve this problem singlehandedly. For example, FDA can only prevent shortages if problems are correctly reported. International regulatory cooperation will be essential as well, since drugs and drug products can now cross multiple borders.

An increased focus must be placed on persistent drug shortages to analyze root causes for differences between these and other shortages that are resolved more quickly. New tools will also need to be developed to speed the resolution of persistent shortages.

Obviously the manufacturing industry must also commit to a culture of quality in manufacturing. Sallans notes there are many steps that must be taken to make this a reality. “Three things we are in immediate need of are better manufacturing practices/methods/quality testing, more production redundancy, and appropriate updates to facilities,” he notes. “Manufacturers must report and correct even small production and quality problems, since failing to do so will inevitably lead to larger production issues. And certainly continued discussions with FDA on ways to support quality manufacturing will be key.”

Working Towards A Solution

ISPE would like to be at the forefront of efforts to eliminate drug shortages. In 2013 the group conducted a Drug Shortages Survey to identify areas that contributed to drug shortages. The top three responses were less than robust pharmaceutical quality systems, limited governance and oversight at a cross-functional level, and the lack of supplier controls across the extended supply chain network. But identifying the issues is just the start. Solutions are still needed to overcome these challenges.

One thing the ISPE survey clearly showed is that drug shortage prevention will require commitment throughout the organization. This includes:

• A Clear corporate goal to avoid shortages
• Resources dedicated to preventing shortages
• Strong quality systems for regulatory compliance
• Metrics defined around drug shortages
• The ability to react quickly to drug shortages
• And strong relationships and communications with regulators.

The next step is producing a plan to make this happen. For that ISPE turned to its internal task force. The group was formed to collect additional information from its members and develop a plan for preventing drug shortages due to manufacturing and quality issues. The resulting ISPE Drug Shortages Prevention Plan will be unveiled at the ISPE Annual Meeting in Las Vegas in October. The Plan will include the following:

• Defining a robust quality system across the whole supply chain and how to implement it
• Improving the corporate culture
• The implementation of metrics  to serve as performance indicators
• Recommendations for improved communication with authorities to move from a culture of compliance to one of dialogue
• Business continuity planning to identify weaknesses and plan alternative solutions
• Capability building programs as a key enabler of a strong and sustainable quality system.
• And the publishing of journal articles, technical reports, and guidance documents, along with training workshops, to get the word out.

In 2015, ISPE’s Drug Shortages Initiative will enter its third phase, which will consist of delivering solutions based on the Plan’s recommendations in ISPE conferences, training programs, and publications. No plan can eliminate 100% of drug shortages, but by following the recommendations developed by ISPE the number of shortages can be reduced and the impact on patients can be lessened.

For more information on ISPE please visit the organization’s website www.ispe.org.