By Peter H. Calcott, Ph.D., president and CEO, Calcott Consulting LLC
Patients’ health can be severely impacted by poor-quality medicines in the marketplace, but people’s health can also be similarly impacted by lack of access to drugs brought on by drug shortages. There are many reasons drug shortages occur. For instance, manufacturers can choose to not manufacture drugs that become less profitable; in other words, they exit the market. In a similar fashion, the supply can be impacted by disruptions in the supply chain caused by a multitude of factors, including raw materials supply, manufacturing difficulties, and natural disasters, to name just a few. Our present COVID-19 pandemic is an example of the last category.
Passage of the Food and Drug Administration Safety and Innovation Act (FDASIA)1 gave FDA the authority to pursue effective measures to combat this challenge. One such measure was the guidance to industry, Notifying FDA of a Permanent Discontinuance or Interruption in Manufacturing under Section 506C of the FD&C Act.2 This guidance lays out the requirement to notify the agency well in advance if a supplier intends to stop production. With this information, the FDA can notify other manufacturers to increase production and the agency can prioritize review of applications for replacement therapies. In a similar fashion, the agency requires manufacturers to notify it if they are experiencing significant supply chain disruptions that could disrupt drug availability. Priorities were set for life saving drugs and those that are critical for public health.
FDA Task Force Report On Drug Shortages
A complete analysis of the situation and the measures that FDA intends to implement in the near future are described in “Drug Shortages: Root causes and potential solutions: A Report by the Drug Shortages Task Force.3. In this report, the agency presents persuasive evidence to indicate that drug shortages are most often caused by quality issues in the production plants (almost two-thirds) versus other causes such as planned discontinuation. These quality issues include manufacturing process problems, equipment reliability issues, and raw material and API availability, to name a few. These shortages appear to occur more often in drugs that tend to be lower in price and that have been on the market longer. The report describes several factors that contribute to this pattern, including a lack of incentives for companies to produce less profitable drugs, to invest in their infrastructures, and to implement superior quality systems and difficulty recovering after a disruption. In many cases, the companies never fully recover to the same output levels as before the disruption. The report also includes an action plan of other measures recommended and planned for.
New FDA Guidance: Risk Management Plans To Mitigate The Potential For Drug Shortages
The reporting guidance discussed above is one measure, while another is the main focus of this article, the new FDA Guidance to industry, Risk Management Plans to Mitigate the Potential for Drug Shortages.4 The steps in this guidance are clearly more prospective in tackling potential drug shortages than the other actions described above.
The mitigation guidance can be divided into two major areas. The first is a discussion of what is referred to as a Risk Management Plan (RMP) and when it is applicable. The second is how to put together an RMP, the tools to use, and how to interface with the agency.
The purpose of the RMP is for the stakeholders to take an active role in analyzing their supply chain, identifying potential weaknesses and vulnerabilities, and developing remediation plans to combat or minimize impact before a shortage occurs. The guidance applies to human medicines, including biologics and drugs regulated by both CDER and CBER as well as devices used in combination products, where the drug or biologic is the primary mode of action of the product. Of course, the principles can be applied to devices in their own stead. The FDA focuses on the use of quality risk management techniques described in ICH Q9,5 stating that the assessment of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient and the level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk. But more about that later.
The guidance identifies stakeholders who are charged with development of the RMPs. Primary stakeholders are those who are directly responsible for the drugs on the market. They drive the supply chain and include NDA, BLA, and ANDA holders and OTC manufacturers. Secondary stakeholders are contract manufacturing organizations (CMOs) and active pharmaceutical ingredient (API) manufacturers. The guidance also identifies “other” stakeholders, including packagers, labelers, distributors, etc.
Not all products require an RMP. Those that require one include prescription drugs that are life supporting, life sustaining, and those that are to prevent or treat a debilitating disease or condition in emergency care and surgery, or drugs defined by the Secretary of Health and Human Services under the Public Health Services Act. They also include APIs needed for the above-mentioned drugs and devices used in conjunction with them. Primary and secondary stakeholders are charged with this requirement.
The FDA also describes drugs for which an RMP is recommended. These drugs include those to treat rare diseases and conditions, drugs with no alternatives, potential public health countermeasures to terrorist attacks, sole source products, products with only one API and/or drug product manufacturing site available, and drugs made in a facility where an OAI (official action indicated) has been issued in the last five years. It seems clear that the RMP would be an excellent tool to help those in the last category to build a more robust and compliant quality program.
Drugs that do not fall into these two categories are exempt but it would appear that these tools and plans would and should aid every manufacturer to strengthen their operations.
The RMP helps to identify risk in the supply chain, assess or quantify the risk, and mitigate those risks that are significant. The primary stakeholders should take the lead in analysis of their supply chain and work with secondary and other stakeholders, sharing information and analyses. The principles of ICH Q9 should be used in a proactive manner before a disruption occurs, as they would be for other analyses the company makes. Analyses should include as broad a basis as possible and include:
- historical data analysis;
- theoretical analysis;
- informed opinions;
- relationships with suppliers, vendors, and contractors;
- market forces that may affect the availability or reliability of raw materials; and
- overall manufacturing process stability and reliability, to name a few factors.
Analyses should consider location of manufacturing, source of components, and historical information, such as if there were one or more near-miss situations where a shortage was narrowly avoided. Mitigation should be comprehensive and include building redundancy into manufacturing operations, establishing adequate controls on the supply chain, strengthening relationships with suppliers (e.g., contract manufacturers, ingredient suppliers), and/or identifying alternative suppliers. As with any risk analysis, a report should be generated including all assumptions and it should be periodically reassessed as situations may change. For a review of implementation and challenges of quality risk management, check out my previous articles, How To Set Up An Effective Quality Risk Management Program and What's The Role Of Intuition When Making QRM Decisions?.6,7
Risk communication is critical. FDA recommends that primary stakeholders work closely with their secondary and other stakeholders, so their efforts are complementary. It also describes what needs to be reported to the FDA and provides a Q&A to aid the industry.2 There is a very comprehensive appendix to the guidance to help in the analysis process and development of the RMP for both primary and secondary stakeholders, posing many factors to consider.
Based on my analysis of the 2019/2020 task force report and the new guidance, I expect to see further guidances on this topic to be issued. These might include guidances for extension of shelf lives for products and implementation of ICH Q12.8 All of these measures are very compatible with the FDA’s drive for institutionalized quality management maturity.3 With the continued COVID pandemic and counterfeit drugs on the market and other geopolitical events, I cannot see drug shortages going away on their own.
- Food and Drug Administration Safety and Innovation Act (FDASIA) July 2012
- Notifying FDA of a Permanent Discontinuance or Interruption in Manufacturing under Section 506C of the FD&C Act. Guidance for Industry March 2020
- Drug Shortages: Root causes and potential solutions A Report by the Drug Shortages Task Force. June 2019, updated February 2020
- Risk Management Plans to Mitigate the Potential for Drug Shortages Guidance for Industry May 2022
- ICH Q9 Pharmaceutical Quality Risk Management June 2006 and November 2021
- Calcott, P. How to set up an Effective Quality Risk Management Program Outsourced Pharma February 2022
- Calcott, P. What’s the Role of Intuition when making QRM decisions Outsourced Pharma? February 2022.
- ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. November 2019
About The Author:
Peter H. Calcott, D.Phil., is president and CEO of Calcott Consulting LLC, which delivers solutions to pharmaceutical and biotechnology companies in the areas of corporate strategy, supply chain, quality, clinical development, regulatory affairs, corporate compliance, and enterprise e-solutions. He has also served as an expert witness. He also teaches at the University of California, Berkeley in the biotechnology and pharmaceutics postgraduate programs. Previously, he was executive VP at PDL BioPharma, chief quality officer at Chiron and Immunex Corporations, and director of quality assurance for SmithKline Beecham and for Bayer. He has also held positions in R&D, regulatory affairs, process development, and manufacturing at other major pharmaceutical companies. He has successfully licensed products in the biologics, drugs, and device sectors on all six continents. Calcott holds a doctorate in microbial physiology and biochemistry from the University of Sussex in England. He has been a consultant for more than 20 years to government, industry, and academia.