Valsartan
Between 2012 and 2018, several antihypertensive drugs from the group of sartans containing an impurity classified as potentially carcinogenic, nitrosamines, were consumed worldwide1.
To briefly summarize the facts:
In 2012, a Chinese company made a change in the synthesis of the active pharmaceutical ingredient (API) valsartan. This change led to the formation of nitrosamines, which remained as an impurity in the final API and consequently in the medicinal product.
This impurity was discovered more or less by chance in 2018. The German Federal Health Agency (BfArM) was informed by a governmental surveillance authority of another country that the impurity N-nitrosodimethylamine was discovered in the active substance valsartan produced by the Chinese active substance manufacturer "ZHP Co LTD". The notification is based on the test results of the active substance manufacturer, which were carried out in the course of production for a finished medicinal product manufacturer from Spain. (BfArM on “Valsartan; Questions and answers on the background”).
This was the reason that such impurities appeared in a generic drug, but not the reason that they were not detected for years. Both types of active ingredient, before and after the change in synthesis, complied with the regulations. Both met the requirements of the Ph.Eur. monograph in force at the time, a new CEP was issued after the change, thousands of API CoAs and Annex 16 batch certificates were issued between 2012 and 2018 confirming the GMP compliance of the products. The Chinese manufacturer could have started from the beginning with the synthesis route applied in 2012. The situation would have been the same.
The requirements for impurities according to Ph.Eur. General monograph "Substances for pharmaceutical use", No 2034 are:
Related substances
Unless otherwise specified or justified and approved, organic impurities in active substances shall be disclosed, identified where possible, and labeled as indicated ...
... Identification threshold (human use) > 0.1%.
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That is, if the impurity content is less than 1%, it does not need to be identified. How this works was clearly explained, for example, in 2019 by
Impurity Control in the European Pharmacopoeia 2019 Training Session “The European Pharmacopoeia” 10-11 September 2019, Iselin, New Jersey, USA
European Directorate for the Quality of Medicines and Healthcare (edqm) paper, page 25.
But do not forget that according to Option 2 the substances to be detected and evaluated (% content) must present similar behavior toward the detection system, response factors should be identical. Only under this condition it can be assumed that a certain value of a peak area corresponds to a w/w concentration. Thus, if the % value is below 0.1%, the requirements are fulfilled, but there remains an uncertainty about the criticality of the (unidentified) impurity and the real content.
This could explain why the nitrosamine contamination remained undetected when the synthesis of the active ingredient was changed.
Who can assure that a case similar to the so-called Valsartan scandal will not happen again?
On the other hand, a change in the manufacturing process of ingredients, bulk material or final product is nothing unusual. The change control (CC) policy is one of the most important chapters in a marketing authorisation holder's pharmaceutical quality management system (MAH is also the holder of a Manufacturing Authorisation as indicated in the hypothetical example below).
In this case, was the change in active ingredient synthesis carried out thoroughly and correctly in accordance with the CC policy and all other rules and guidelines designed to ensure the safety, efficacy, and quality of the marketed pharmaceutical products? In other words, were there no indications or clues between 2012 and 2018 that would have suggested further investigation?
To answer this question, one has to analyse all the steps of the supply chain in detail.
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Nowadays, supply chains can be quite complicated and involve more than one responsible party or person (QP).
For example, an EU marketing authorisation holder (MAH) and distributor of valsartan tablets imports the active substance from a Chinese company. The marketing authorisation holder supplies the active substance to a manufacturing authorisation holder (CMO) in the EU who manufactures the final medicinal product and issues the QP certification for each batch of product according to Annex 16.
Flow Chart Supply Chain Example
*) MAH possesses a MIAH limited to batch certification/release
In the valsartan case, the main issue is the supply and quality of the active substance, so the following questions need to be clearly answered:
- Has the Chinese company been properly qualified by or on behalf of the MAH/MIAH?
--> Check audit report and whether the QA system and change control SOP items are in place and properly implemented. - Was the Chinese company routinely audited by or on behalf of the MAH/MIAH?2
--> Review of the QP declarations ("Declaration of Compliance with Good Manufacturing Practice in the Production of Active Substances"), Check the audit reports; frequency, findings, CAPA plans and last but not least the main changes since the last audit. - How did MAH deal with the new CEP after the change in 2012? Was the document evaluated or simply filed?
--> Check the information flow in the company - Regulatory Affairs, QA, QP - and the completion of the process. - Are all relevant QP statements properly documented and signed by the MAH/MIAH's QP?
--> Review audit records and ensure that they have been carried out in a timely manner and that the change control policy has been taken into account, especially in the first audit after 2012. - Are the Product Quality Reports (PQR) for the periods 2011, 2012 and 2013 properly signed and available?
--> Review according to "EudraLex Volume 4 EU Guidelines on GMP Chapter 1"; such reviews should normally be carried out and documented annually, taking into account previous assessments, and should include at least:
Paragraph(i)
A review of source materials, including packaging materials used in the product, in particular those from new sources. A review of the traceability of the supply chain of active substances and any changes made to the procedures or methods of analysis is also relevant.
Other aspects such as the ongoing stability data could also have given an indication of differences between the two drug quality properties, namely the impurity profile in the HPLC chromatograms, something that should be followed in any stability testing.
A single analytical study was more effective than six years of supplier evaluation.
The outcome of such a study on a real case should show whether the GMP framework is so comprehensive that no new guideline needs to be developed. If so, attention must be paid to how, where and under which QP responsibility the rule in question was not correctly applied.
However, in January 2022 the edqm published a public document (PA/PH/CEP (21) 57) entitled "CEP ... Responsibility of CEP holders towards their customers" and on 08. March 2023 the supplement 11.2 to the European Pharmacopoeia. This supplement edition lists several (24) updated monographs which were supposed to enter into force on 01. July 2023.
But why not intensify experimental control in parallel? It was not that difficult to identify a few ppm nitrosamines (limit test Ph.Eur. 11.0 01/2022:20542; 30ppb). It is relatively easy to stop analysing impurities at 0.1% peak area and disregard LT 0.05% (500 ppm) and not worry about it any further. The analytical procedure can be improved if the impurity level is low. For example, the sensitivity of the HPLC method can be improved, also combined with other methods such as MS and MS/MS, improve preparative HPLC, etc.. But also optimising sample preparation, which should focus on the impurities and not only on the main substance, possibly by sampling in earlier synthesis steps. If necessary, experiments should be carried out with modified reaction conditions to increase the yield of impurities. Such experimental work should be submitted when applying for a CEP, which was probably not the case with the valsartan scandal. ICH Q3A (R2) (last update 2006) refers to "impurities in new drug substances". If an API chemical synthesis of an already approved product is changed, it is only logical to follow this guide line again.
Finally, a reminder recently published in an ECA newsletter (30. May 3023; "What does FDA actually mean by CGMP?):
The FDA emphasises that CGMP are minimum requirements. Modern, comprehensive quality systems and risk management concepts can also go beyond these requirements.
About the Author
Dr Jaime Guardiola is owner of DocJaGuar Consulting and has over 40 years of industrial experience in production, development, regulatory affairs, quality control and quality management.
Notes:
1 Note: Care has been taken to indicate the criticality of the impurities. The nitrosamines are mostly classified as "potentially" carcinogenic. Carcinogenicity has been demonstrated for some animals, but the available data do not appear to be sufficient to classify them as "carcinogenic" to humans.
2 Note: It is common practice to outsource activities such as conducting audits. Of course, this must be done in compliance with the rules of good contract manufacturing. In such cases, it is common to engage a third party inspection body. This is a supplier that has to be qualified and audited like the others, e.g. laboratory, pest control service, primary packaging material manufacturer, etc.
