Cardiovascular disease is a widespread health problem. About 25 percent of the Swiss population suffers from high blood pressure, which significantly increases the risk of heart attacks, strokes and other cardiovascular disease. The drugs used to control high blood pressure include so-called sartans (also AT1-antagonists, angiotensin receptor blockers). They block the binding sites via which angiotensin II constricts the blood vessels. In the worst case scenario, a shortage of medication may be caused if a class of drugs, such as sartans, is contaminated. This article talks about the effects of the “sartan case” on Siegfried, how the company responded and what lessons can be learned from this.
In the early part of summer 2018 the contamination N-nitrosodimethylamine (NDMA) was first found in the substance valsartan. The contaminant is considered to be a potential human carcinogen. It occurred due to a change in the synthesis during the production of the API by Chinese manufacturer Zheijang Huahai. In the course of the year, both the contaminant NDMA and the structurally related N-nitrosodiethylamine (NDEA) were detected in other sartan APIs produced by various manufacturers. Meanwhile, other structurally related nitrosamine contaminants have become known and the manufacturers have to check whether these may possibly occur in the APIs they produce. These contaminants may develop in the formation of a tetrazole ring, which is part of the structure of some of the sartan drugs (see box).
Regulatory authorities for pharmaceutical products worldwide responded to this case with the largest recall of high blood pressure medication known to date. Other than the recall of various drugs, this included inspections of the manufacturers concerned, the request for risk assessments, the development of analysis methods, and the examination of samples.
The European Directorate for the Quality of Medicines and Healthcare (EDQM) inspected more than 120 Certificates of Suitability (CEPs) of the various sartan derivatives from all manufacturers and requested the certificate holders to comment with respect to the contamination of their APIs. Zheijang Huahai’s CEP for valsartan and the CEPs of other affected sartans have been suspended. The European Medicines Agency (EMA) initiated an inspection procedure and required the presentation of risk assessments and the introduction of routine tests, starting in late 2018. The Swiss regulatory agency, Swissmedic, conducted analyses and required a routine test based on a method with a low detection limit as early as 1 March 2019. The American FDA and Health Canada took similar steps.
For a transition period of two years, limits were set of 3.000 ppm (parts per million)and 0.820 ppm for NDMA and NDEA. Thereafter, the manufacturers were obliged to implement changes in their manufacturing process to ensure that the sartan preparations are “free of nitrosamines” (detection limit 0.03 ppm).
Siegfried and candesartan
Siegfried is a major supplier of candesartan tablets which are produced in Malta for the European market. The company was involved in the events from the outset. To respond to the situation the matter was immediately assigned to the Candesartan Lifecycle Team. In addition, a Candesartan Action Team was established, headed by Beatrice Harder. A routine audit of the supplier in China had previously been scheduled for August 2018. Siegfried took this opportunity to look into the situation on site immediately.
The Candesartan Action Team was faced with a number of challenges:
- ensuring quality and safety of the substance manufactured by Siegfried
- implementing and complying with authorities' requirements
- maintaining contact with the authorities
- handling customer inquiries concerning the case
- providing proof of the absence of nitrosamines in the candesartan API used by Siegfried.
As a result of the project team’s proactive and anticipating course of action, the test methods required by the authorities were quickly achieved. Siegfried had no problem conducting the routine tests for candesartan cilexetil after 15 December 2018, the date when testing the substance became mandatory. So far, about 400 of the approximately 1000 API batches used since 2012 have been retrospectively tested. This allowed us to confirm that all batches of medical products for which the authorities or customers requested implementation of tests are free of nitrosamines.
The problems with contaminated valsartan and the fact that Siegfried was able to successfully prove the absence of contamination in the candesartan it used led to a significant upsurge in the demand for candesartan tablets. They are also used to control blood pressure and may replace treatment with valsartan tablets under medical supervision.
The project included a number of challenges for Siegfried and will continue to occupy the organization for at least another two years.
Successfully managed challenges included keeping a consistent overview of the rapidly changing requirements from the various authorities. Siegfried’s Analytical Development team and QC were able to quickly perform the additionally needed analyses on account of a sophisticated analytical method.
Future challenges for Siegfried will include managing the higher level of incoming orders. One of the solutions to handle the situation is by implementing our dual sourcing strategy, in other words, the product will be manufactured by two sites, namely Siegfried Malta and Siegfried Pharma in Zofingen.
Teamwork of the project team and lessons learned
The project is an example of the successful teamwork between the Malta and Zofingen sites and between the Corporate Compliance, Quality Assurance, Analytical Development, Quality Control, Regulatory Affairs, Sourcing, Customer Service, Business Development and Legal/IP Management departments. Not only did cooperation work well at all times, it also showed the importance of consistent proactive analysis of a situation. Additionally, we also recognized that other substances also need to be assessed with regard to contamination or cross-contamination. For example, Siegfried has already received a request from a local authority in Germany for a risk assessment of caffeine and theophylline. Similar demands for other substances are expected.
This is what Beatrice Harder, Head of the Candesartan Action Team, had to say: “Siegfried has demonstrated that the company is up to managing such exceptional and highly dynamic situations and is capable of responding to the rapidly changing requirements by authorities and customers. The interdisciplinary teamwork was seamless and the ComCom (Compliance Committee) provided the necessary support.”
What are sartans?
Substances of the sartan group are used for treatment of cardiovascular disease, such as high blood pressure, either as a single drug or in combination with other substances. Not all sartan products are affected by nitrosamine contamination. Patients are urged to discuss their treatment with a medical professional.
Examples of Sartan APIs with tetrazole structure with the potential of nitrosamine formation: