The valsartan API debacle – the way forward

In a world where globalism has allowed ideas to spread at phenomenal rates, novel drugs are becoming a rarity. Generics are rapidly filing our local pharmacy shelves – and while this is an auspicious development, providing high quality drugs at a lower cost – it is not without its pitfalls. The recent recall of many versions of valsartan formulations from many European countries by the European Medical Agency (EMA) and FDA is a testament to this, as is the similar action by Drug Regulatory Authority of Pakistan for the same issue. The valsartan versions in question were dispensed to patients to control blood pressure, but an unprecedented carcinogenic chemical impurity caused havoc. Patients soon found themselves potentially at risk of cancer. In Pakistan, there are 300,000 new cases of various forms of cancer every year- but with use of tainted medicine with potentially carcinogenic impurity, this figure may rise to unforeseeable rates. Such an incident divulges the severity of the issue- and causes one to question: who is at fault for subjecting innocent patients to such portentous effects? Is it the API manufacturers who manufactured the active drug with a change in their manufacturing process? Did the drug companies who sourced the API from Zhejiang Huahai of China had an agreement for exchange of information related to process change? If they had the knowledge of process change, was it communicated and approved by the regulatory authorities (DRAP)? Does DRAP have a vigilant system to question manufacturers for sourcing of API, testing and process change? The answer to all these questions lies in streamlining the process of any change in the manufacturing process with discussion and consultation between the parties, communication of the change to regulatory authorities and most importantly establishing a process of analytical review by the regulatory authorities (DRAP) that includes validation of the manufacturing process and analysis of any product and/or process related impurities. This analysis should be carried out by independent third parties/laboratories that are accredited/approved by authorities such as WHO, FDA or EMA. Moreover there should also be accredited centers that can perform BA/BE studies on API from new sources. The BA/BE studies are also important in relation to the CTD process that is in the process of being implemented. Specifications for API are essential for product quality, efficacy and safety.  Establishing specifications to achieve desired standards and meet regulatory requirements are now being driven by Quality Systems such as Quality by Design, Quality Risk Management and Pharmaceutical Quality Systems. The manufacturing process must take into account critical quality attributes (CQA) and critical material attributes (CMA) of the API that can have an impact on the quality of the drug. These include the physical, chemical, biological and/or the microbiological characteristics within a defined range. Impurities are also an important component of critical quality attributes as they have the potential to affect product safety. Thus the sourcing of APIs is critical to the overall quality, efficacy and safety of a drug. The manufacturers must ensure consistency of CQA and CMA and even enter into change control agreements with the suppliers of API so that consultations must take place before any changes are made by the suppliers of APIs. The recall referred to above was mandated as an impurity N-nitrosodimethylamine (NDMA) was detected in the API of valsartan supplied to various manufacturers throughout Europe. NDMA is regarded as a probable carcinogen and its presence in the API is suspected to be a result of changes in the manufacturing process. The debacle has also affected Pakistan and DRAP has also issued an alert for recall by nine companies who were being supplied the API of valsartan from Zhejiang Huahai. Although Drug Regulatory Authority of Pakistan (DRAP) has asked for a recall of the valsartan containing medicines by the affected manufacturers, a more aggressive recall plan was needed for the safety of patients. This may include measures by affected manufacturers such as a press release specifying the batch numbers of drug produced with API from Zhejiang and confirmation of their destruction so as to avoid any mix-up with future batches and asking patients to stop using their drug and switch to alternate brands. The healthcare professionals also need to provide information about alternate brands or other treatment options to their patients. This fiasco has highlighted the importance not only of rigorous testing and validation of all processes and finished products but also establishing safety standards and pharmacovigilance procedures in letter and spirit. Ultimately it is the responsibility of DRAP to demand and enforce such testing in centers that can provide accurate and reliable data.