Using CGMP Site Risk Scores to Predict Drug Shortages

Author: Katie Henchir Terry

In 2011, drug shortages captivated the United States' attention as an emerging public health crisis, as the number of reported shortages tripled between 2005 and 2011.1? With this alarming data, the Obama Administration took action to protect the public against worsening drug shortage conditions.? On 31 Oct 2011, Executive Order 13588 - Reducing Prescription Drug Shortages - was signed into effect.1? The aim of the Order was not only a call to action for the many stakeholders; it empowered the FDA to exercise its full authority and resources to combat this emerging public health threat.1?

Aspects of the Order were codified into law, becoming the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA).? Of significance to drug shortages, Title X – Drug Shortages – enhanced the early supply interruption notification mandate to include specific, medically necessary prescriptions, authorized the FDA to issue letters of non-compliance to manufacturers failing to satisfy the notification requirements, promoted public transparency through a drug shortage listing, and was the basis for an initial strategic assessment of drug shortages.2? The primary focus was to evaluate and enhance the Agency’s prevention and response capabilities for drug shortages, culminating in a strategic plan. Moreover, the FDA was directed to report annually on drug shortage data, such as the number of notifications, while assessing the impact on public health.?

The strengthened regulatory framework offered great promise in combating drug shortages in the United States.? It served as a foundation for future regulatory innovations, such as the 21st Century Cures Act, the 2018 FDA Drug Shortage Task Force, and the creation of the U.S. Essential Medicines List.? This movement also yielded seminal reports, including the 2019 FDA Drug Shortage Task Force report titled “Drug Shortages: Root Causes and Potential Solutions” and “Short Supply: The Health and National Security Risk of Drug Shortages”? prepared by the Majority Committee Staff, Homeland Security, and Governmental Affairs Committee in 2023.

The 2019 FDA Drug Shortage Task Force report analyzed 163 prescription medications that met the definition of a shortage between 2013 and 2017.3? The sample breakdown is as follows: 63% were “sterile injectables” and 67% were drugs with a generic version commercially available.3? The sample prescription medication also included aged products (i.e., 35 years post initial approval) and retailed at minimal prices, much less than $10 per unit before entering a drug shortage.3? The FDA described three root causes for drug shortages in the United States based on their survey:3

1. “Lack of incentives to produce less profitable drugs.” When market conditions reduce profitability, manufacturers have less incentive to produce older prescription drugs or invest in manufacturing quality and capacity. Generic drug makers, in particular, face pricing competition, unreliable revenues, and lofty investment requirements, limiting their potential returns.
2. “Market does not recognize and reward manufacturers for mature Quality Management Systems.” While all manufacturers must meet regulatory standards for Current Good Manufacturing Practices (CGMPs), mature quality management systems go beyond these minimums, incorporating technology and processes that ensure a reliable drug supply. However, purchasers have limited information about the quality management of manufacturing facilities, and the market does not reward manufacturers for investing in higher quality or penalize those who fail to modernize. As a result, manufacturers tend to minimize investments in manufacturing quality, leading to quality issues, supply disruptions, and shortages.
3. “Logistical and Regulatory Challenges make it difficult for the market to recover after a disruption.” Over the past two decades, the drug supply chain has become longer, more complex, and fragmented due to increased overseas production and reliance on contract manufacturers. Regulatory and logistical challenges, particularly supply chain complexity, can hinder manufacturers' ability to quickly increase production during shortages, as they must navigate approvals from various national regulatory bodies and secure new sources of active pharmaceutical ingredients (APIs).

Within the 2019 report, FDA also supplied solutions of varying complexity, such as improved analytics to characterize shortages better, increased transparency in contracting practices, Quality Management System rating capabilities, and other market-driven recommendations.3?

In 2023, the Homeland Security and Government Affairs report issuance titled “Short Supply: The Health and National Security Risks of Drug Shortages” was published.4 ?The report credits efforts to curb the shortages in 2021, but by the end of 2022, the United States experienced a “peak” of shortages, reaching 295 prescription drugs in short supply or a 30% increase between 2021 and 2022.4? Given the persistent nature of this public health crisis, it comes as no surprise that many of the 2023 report findings mirror learnings from the years before. ? The report re-emphasized the importance of supply chain visibility and Quality Management Systems as an indicator for product quality.4? Furthermore, the 2023 report characterized additional supply chain vulnerabilities contributing to drug shortages, illuminating the over-reliance on ex-US manufacturers for raw materials, API, and generics.4

A recent example of a drug shortage underscores the importance of understanding supply chain vulnerabilities and how quality systems can affect product quality: the 2023 shortage of generic carboplatin and cisplatin.5 ?Both carboplatin and cisplatin are approved as a chemotherapeutic agent supplied as a sterile aqueous solution administered under the care of a qualified physician.6,7? Cisplatin was an early discovery and marketed by Bristol Myers Squibb in 1978 as Platinol? after securing FDA approval.8? A little over a decade later, in 1989, carboplatin was marketed again by Bristol Myers Squibb as Paraplatin?.8 ?The chemotherapeutic agents are now manufactured globally as generics, and the cost for each dose, depending on concentration, can be as little as $15.9,10 ?Using Redica Systems data, Figure 1 maps parts of the supply chain of these two agents, showing the applicants and manufacturers of cisplatin and carboplatin products.

Figure 1. Number of distinct carboplatin and cisplatin national drug codes (NDCs) by applicant (left) and manufacturer (right).?

A review of fifteen sites was performed to understand better the relationship between a robust quality management system, a known root cause of drug shortages, and the shortage associated with these two oncology medicines.? Utilizing Redica Systems, a vendor group was created for the available manufacturers of carboplatin and cisplatin.? As illustrated below in Table 1, the Redica Systems Site Risk Score categorizes facilities based on inspection performance over a set period of 5 years and 10 years.? Of particular interest, Intas Pharmaceuticals Limited manufactured carboplatin and cisplatin on behalf of Accord Healthcare and is ranked by Redica Systems as having a “very poor” compliance position.??

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Table 1. Redica Systems Site Risk Score of cisplatin and carboplatin manufacturers.

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Redica Systems data on this facility provides meaningful insight into the compliance position and the areas where the facility has repeat observations.? Inspection data is available from the FDA, Health Canada, MHRA, and EMA (Figure 2).??

Figure 2. Inspections by agency.

Between November 22 and December 2, 2022, the FDA conducted an inspection that culminated in a 36-page Form 483 (https://platform.redica.com/documents/100149798). The observations highlighted issues across the Quality Unit, Laboratory, and Production systems, including several data integrity concerns. Following the inspection, Intas Pharmaceuticals halted the manufacturing and distribution of cisplatin.12 This decision triggered a chain reaction, prompting healthcare providers to substitute carboplatin for cisplatin and other manufacturers to address the rising demand for both agents.12?

Figure 3. Redica Systems Site Risk Score over time for Intas Pharmaceuticals Limited (FEI: 3004011473)

The Redica Systems data reviewed for the case of cisplatin and carboplatin drug shortage demonstrates a link between a robust quality management system and uninterrupted supply. By analyzing compliance data, we see a correlation between poor regulatory inspection history and drug shortages.? Though the FDA allowed the importation of both oncology therapeutics from Intas Pharmaceuticals, the firm was placed on Import Alert 66-40, which was issued on 01 June 2023.11 ? The FDA's import alert and subsequent warning letter to Intas Pharmaceuticals reflect how lapses in quality control and data integrity directly impact product availability. This scenario demonstrates that a resilient supply chain, supported by reliable data-sharing and stringent quality systems, is essential for ensuring that patients have consistent access to safe and effective medications.

As of today, the shortage for cisplatin is deemed resolved with a shortage duration of approximately 16 months (10 Feb 2023 - 27 Jun 2024).13 ? Meanwhile, carboplatin remains in short supply.13??

The Intas example for cisplatin and carboplatin demonstrates that a manufacturing site’s recent CGMP inspection history can serve as a powerful indicator of drug shortage vulnerability. We can systematically analyze the relative risk of supply disruption to any product line using this data.?

References

1. Executive Order 13588 -- Reducing prescription drug shortages. whitehouse.gov. Published December 8, 2011. https://obamawhitehouse.archives.gov/the-press-office/2011/10/31/executive-order-13588-reducing-prescription-drug-shortages
2. Office of the Commissioner. Fact Sheet: Drug products in shortage in the United States. U.S. Food And Drug Administration. Published March 28, 2018. https://www.fda.gov/regulatory-information/food-and-drug-administration-safety-and-innovation-act-fdasia/fact-sheet-drug-products-shortage-united-states
3. FDA drug shortages: Current and Resolved Drug Shortages and Discontinuations Reported to FDA. U.S. Food And Drug Administration.. https://www.accessdata.fda.gov/scripts/drugshortages/default.cfm

1. Peters G. Short Supply:? The Health and National Security Risks of Drug Shortages. United States Senate Committee on Homeland Security and Governmental Affairs; 2023. https://www.hsgac.senate.gov/wp-content/uploads/2023-06-06-HSGAC-Majority-Draft-Drug-Shortages-Report.-FINAL-CORRECTED.pdf
2. Nelson B, Faquin W. Generic cancer drugs are still in short supply. Cancer Cytopathology. 2024;132(1):5-6. doi:10.1002/cncy.22788
3. DailyMed - CARBOPLATIN injection. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=48aa7ef3-9f44-2a08-e054-00144ff88e88&audience=consumer

1. DailyMed - CISPLATIN- cisplatin injection, solution. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=de6302d5-85f0-4116-a709-57826c2c84fe

1. Monneret C. Platinum anticancer drugs. From serendipity to rational design. Ann Pharm Fr. 2011;69(6):286-295. doi:10.1016/j.pharma.2011.10.001
2. Carboplatin Prices, Coupons, Copay Cards & Patient Assistance. Drugs.com. https://www.drugs.com/price-guide/carboplatin
3. Cisplatin Prices, Coupons, Copay Cards & Patient Assistance. Drugs.com. https://www.drugs.com/price-guide/cisplatin
4. Import Alert 66-40. FDA. https://www.accessdata.fda.gov/cms_ia/importalert_189.html

1. Goldberg P. Richard Pazdur discusses root causes of cisplatin and carboplatin shortage and what can be done to alleviate it. The Cancer Letter. Published May 31, 2023. https://cancerletter.com/conversation-with-the-cancer-letter/20230530_1/
2. Drug shortages | FDA. https://dps.fda.gov/drugshortages