On February 25, 2009, the U.S. FDA imposed on Ranbaxy what is akin to a death penalty if you are a pharmaceutical manufacturer: it invoked the Application Integrity Policy1. It cited numerous instances where the FDA said “These and other findings indicate a pattern and practice of submitting untrue statements of material fact and other wrongful conduct, which raise significant questions regarding the reliability of the data and information contained in applications (pending and approved) that your firm has filed with the Agency and which contain data developed at the Ranbaxy Laboratories, Paonta Sahib site.” Consequently, it banned the import of 30 drugs, which were manufactured at this site from entering the U.S. healthcare system2. However, if you look at the list of products that were manufactured at that site, one stood out, which was not banned from import into the U.S.: Ganciclovir Sodium.
The reason why the FDA exempted this antiviral drug, which is used to treat or prevent viral infections, was because Ranbaxy was the sole generic manufacturer of this drug sold it the U.S. It is used to prevent viral infections in patients who receive solid organ transplants among its other uses. If the FDA had included this drug in the import ban list, despite overwhelming evidence that the manufacturer’s systems and processes were violating cGMP and its application for marketing was most probably based on fraudulent data, it would have created a shortage of this drug in the US.
Over the last 10 years, there has been an increase in shortage of medications, which impact both acute and chronic care in the U.S. Data tracked by the University of Utah show that there were 267 cases of drug shortages in the U.S. in 2011, with the majority of the drugs falling into the following therapeutic areas: Oncology, anti-infectives, Cardiovascular and central nervous system. The common characteristics across all of these shortages are that they are mostly sterile injectables and generic drugs.
What causes drug shortages?
There are diverging opinions on what causes drug shortages. Potential reasons include lack of manufacturing capacity, lower profit margins leading to de-prioritization of their manufacture, price-gouging and overzealous regulations. FDA’s own data show that product quality-related issues are the primary drivers of drug shortages in 54% of the cases. In fact, if you look at the reasons behind the shortage of sterile injectable products in 2010, the lion’s share (>50%) of these were due to problems related to product quality.
This brings the focus back on effective cGMP inspections. Given that the majority of the drug shortages are for generic drugs, which are primarily manufactured overseas using active ingredients (API) which are also made overseas, it is critical that the inspectorate responsible for ensuring cGMP compliance at these overseas manufacturing facilities is provided with adequate resources to ensure that the largest source of these shortages, product quality is addressed effectively. One of the stated performance goal for the FDA in the Generic Drug User Fee Act (GDUFA) is to bring parity between domestic and foreign manufacturing plant inspections in five years. It is in our all our interest to advance this timeline significantly to close to two to three years.
How do we prevent drug shortages going forward?
It is in all our interests to have a list of “vulnerable” drugs, most of which are generic, that are susceptible to shortages. There needs to be continuity plans to ensure supply of these vulnerable drugs to protect public safety. The FDA sought input and comments on this topic by March 14, 20133.
While communications and information sharing are at the top of the agenda to address shortages, raw material sourcing and manufacturing issues also need to be highlighted in our comments to this request. Standard risk management techniques like the Failure Mode and Effects Analysis (FMEA) presented two recent articles4,5 focused on managing the risks caused by these shortages in hospitals could be extended to help identify steps of high risk within the overall supply chain. This will help us focus on large subsystems which drive such shortages, be it challenges within the distribution system, quality of raw material/manufacturing compliance, regulatory/legislative control or market factors dealing with business incentives for low margin products. The agency will then be in a better position to address these risks proactively.
3 FDA Docket Number: FDA-2013-N-0124, Federal Register, Volume 78, Number 29, Page 9928, 2-12-2013.
4Drug Shortages: Process for evaluating impact on safety, Elyse A. MacDonald et al., Hosp. Pharm 2011; 46(12): 943-951, Thomasland Publishers, Inc.
5Managing risks arising from medicine shortages in hospitals; David Cousins, Mary Evans & Kevan Wind, The Pharmaceutical Journal, 11th September 2012; 289:306