Carcinogens under the scan

As trace amounts of cancer causing contaminants continue to crop up in certain medicines, pharma companies are upgrading their testing methods and equipment to meet increased regulatory scrutiny. The result? Safer medicines but even thinner margins By Viveka Roychowdhury

It is now one and a half years since the carcinogenic contaminant N-nitrosodimethylamine (NDMA) was first detected in sartans in June 2018. The fact that high blood pressure medicines are prescribed for long time use, on a daily basis added to the risk that life long use of NDMA, even in trace amounts, was definitely more harmful than the occasional exposure to the carcinogen from certain food and environmental sources.

While global regulators alerted companies and distributors, pharma companies withdrew their stocks from circulation. Once tests confirmed the presence, batches were recalled. The presence was found to be an impurity in API supplied by a Chinese API manufacturer, Zhejiang Huahai and linked to a change in the process of synthesis.

It was almost action replay in September 2019, when trace amounts of NDMA were found in rantidine, an anti-ulcerant, commonly prescribed and available as OTC brands as well. Unlike sartans, ranitidine is not prescribed for long term use. And unlike sartans, the contaminant is not part of the medicine but thought to have been formed during the testing process, when the high temperature required for gas chromatography-mass spectrometry (GC-MS) caused ranitidine to react with itself and form nitrosamines.

Though the US online pharmacy Valisure which detected this felt that there was evidence to suggest NDMA formation under these conditions in the human body, the US FDA did not believe this was the case. The agency said that GC-MS was the suggested testing procedure for nitrosamine impurities in sartans, not in ranitidine. For the latter, the US FDA prescribed an alternative liquid chromatography-high resolution mass spectrometry (LC-HRMS) method, which showed much lower levels of nitrosamine impurities than Valisure. NDMA and N-nitrosodiethylamine (NDEA) have also been found in pioglitazone, used to treat type 2 diabetes mellitus.

The aftermath
A lot has changed since June 2018. Today, the understanding is that nitrosamines are expected to be formed during the manufacture of sartans, under certain conditions with certain solvents, reagents and raw materials. They could also form due to contaminated equipment or reagents, either present as contamination from previously used equipment or reagents. Thus the onus is on manufacturers to control and remove these impurities during the manufacturing process itself.

Voluntary recalls continue, the latest being Mylan’s voluntary recall of prescription nizatidine capsules on January 8 due to possible contamination with NDMA.

While regulators seek to diffuse patient fears, they are raising the bar for manufacturers. For example, the European Medicine Agency (EMA) has given companies six months (on or before June 19 2020) for the risk evaluation and three years (on or before December 20, 2022) for remediation, if any.

In turn, formulation companies as well as API manufacturers have changed their processes to be in sync. Thus the next two years will be about testing all samples for the presence of such impurities. How are companies in India coping with these evolving standards and increased risk mitigation?

In December 2019, the sartan market in India was worth approximately Rs 5069 crore, while the ranitidine market was worth approximately Rs 662 crore, according to data from AIOCD Pharmasofttech AWACS. Glenmark Pharma’s Telma was the market leader among sartans, followed by Mankind Pharma’s Telmikind and USV’s Tazloc. Among ranitidine brands, Cadila Pharma’s Aciloc was the market leader, followed by GSK’s Zinetac and J B Chemicals & Pharmaceuticals’ Rantac.

According to Dr Milind Joshi, President-Global Regulatory Management, J B Chemicals & Pharmaceuticals, “Most API manufacturers have taken steps recommended by the US FDA to bring down NDMA levels considerably below the prescribed level. Similarly, formulation manufacturers have also adapted their process to ensure that NDMA presence, if any, does not increase during the formulation manufacture and hence are able to comply with the limits that have been set by regulators internationally.”

Dr Joshi emphasises that the company has taken all required measures to comply with regulations for the safety of Rantac, stressing that it was not banned by the regulatory authorities, and has been deemed safe by the standards applicable to ranitidine, set by the regulatory authorities in India and US.

Referring to the new standards, he points out that on December 20, the EMA announced that they are reviewing the limit that was earlier set for NDMA in ranitidine formulations based on the dosage and the duration of treatment.

He estimates that the permissible levels are likely to change (increase) significantly based on the duration of the treatment. Based on a daily dose of ranitidine product for a year, the level of NDMA may be 4.256 ppm against 0.32ppm followed currently. The US FDA’s permissible limit of NDMA in ranitidine at 0.32 ppm means is that if a patient takes ranitidine daily recommended dose for 70 years, then 1 out of 1,00,000 patients have the probability of getting cancer.

The NDMA issue seems to add to the perception that industry has been cutting corners and regulators have been caught unawares, yet again. As Khushbu Jain, Industry Analyst, Transformational Health Practice, Frost & Sullivan analyses, “Unfortunately the NDMA contamination issue which first came to light in 2018 continues to trouble us in 2020 and has led to recall of several sartans and some antacids. FDA suspects the origin of the problem to be the reuse of solvent and/or change in materials used during the manufacturing process of the drug and/or change in synthesis route to a cheaper and higher-yielding route, but a more toxic one. Intensifying competition and thinning profit margins in generics prompts manufacturers to introduce these changes.”

Referring to regulators changing the goalposts, she says, “Even though there are regulations in place to monitor the safety of these changes, often, analytical methods used by manufacturers are not adequate to accurately measure impurities/toxicity (especially when present in lower concentration). To compound the problem, Indian pharma is infamous for data integrity and data reporting which can, in theory, bring such issues to light before they create public health havoc.”

Long-term impact
Jain points out that there are micro and macro bearings of this incident. In the micro sense, some companies have faced a setback in their product sales because of drug recalls across North America and Europe but some others have enjoyed opportunistic price increase. For example, Lupin, Aurobindo, and Macleods have taken a hit and saw stock price decline immediately after the recall (but recovered later as these companies enjoy a wide product portfolio insulating them from episodes linked to singular drugs), but companies like Alembic increased the prices of their sartans fivefold.

But in the larger scheme of things, Jain expects, “The quality of drugs manufactured in India will come into greater scrutiny. This will potentially bring in a slew of new regulations, which will make it even more costly for Indian generic pharma companies to comply with rigorous monitoring, testing and reporting regulations, ultimately squeezing profit margins.”

Equipment manufacturers have responded to the situation by partnering with clients to ease their pain points. For example, Shripad Joshi, Director – India & South Asia, PerkinElmer India informs that their team of expert

application specialists have developed robust analytical methods in collaboration with customers to address the challenging need of NDMA testing and analysis. “For example, we have a method that offers a readymade seven minutes run time with high sensitivity and reproducibility, while adhering to all the regulatory compliance requirements of pharma.”

The PerkinElmer QSight 120 UHPLC-LCMS/MS provides a comprehensive solution to quantify the presence of NDMA impurity in ranitidine and meets the limits set by USFDA of 96 ng/day. In addition, Joshi says that the PerkinElmer Clarus GCMS with Turbomatrix Headspace and Autosampler is also a proven technique for determination of NDMA in sartans and other drug products.

Other solution providers too ahve stepped up to the challenge. V Umasankar, General Manager – Pharma, Waters Corporation says that his company has developed an LCMS/MS method to investigate the final API and formulated products for the presence of all listed nitrosamines (nine compounds) in a single method.

Beyond sartans and ranitidine
As regulators are concerned that nitrosamine and other impurities might be found/formed in other medicines as well, they have expanded the search to all medicines. The attitude seems to be, ‘Let’s check all corners and clean out all cobwebs once and for all.’

But these efforts obviously come at a cost. The risk mitigation strategy has forced manufacturers, both API and formulators, to re-look and change the manufacturing process to bring down NDMA levels below the prescribed level. These changes, and increased testing have added to the cost, the timeline of the manufacturer, and also required the purchase of new equipment.

According to Dr Joshi of J B Chemicals & Pharmaceuticals, most companies in India use the LCMS to check for NDMA since LCHRMS testing devices are not easily available. As he explains, “The control strategy for NDMA involves various process parameters like temperature, humidity and extra purification, additional time cycles and such, during API manufacturing and similar stringent controls during formulation manufacturing.”

He agrees that this is an expensive process but they want to ensure quality medicines for their patients and do not compromise on the quality and patient safety.

Similarly, on the analytical front, Dr Joshi estimates that most manufacturers have procured LCMS systems to detect NDMA, which cost “around few crore rupees” and ensure that each batch is tested for NDMA before releasing the batch to the market so that the quality of the final product reaching patient is assured.

The cost of compliance
The nitrosamine scare has also put the spotlight on API manufacturers, and the push back from regulators and clients has forced them to clean up their act. Hyderabad-headquartered SMS Lifesciences India is one such API manufacturer, which undertakes contract manufacturing of APIs, and advanced or basic intermediates. Praveen V Talluri, Senior Vice President, SMS Lifesciences India explains that there are are two possibilities to explain the presence of NDMA in the product. First, the route of synthesis (or manufacturing process and raw materials used). And second, the possibility of contamination. According to Talluri, SMS Lifesciences India uses validated methods published by US FDA, LC MS/MS instruments to check levels of NDMA in the final product, intermediates and raw materials.

He specifies that his company has been manufacturing ranitidine in dedicated equipment for the last 30 years in a robust process which was capable of controlling NDMA within limits. “With controls and few modifications, we are able to consistently release material with NDMA less than 0.02 ppm (US FDA limit of 0.32 ppm) for the majority of the batches.” He too concurs that new expensive equipment like LC MS/MS, increase in the cost of analysis and other controls have increased cost of production.

Saraca Laboratories, another Hyderabad-headquartered API manufacturer, too adopted the prescribed LC-MS/MS method for estimation of NDMA in ranitidine hydrochloride and is hence investing in new equipment. According to T S Prasad, General Manager – TS, Saraca Laboratories, the company is procuring AB SCIEX 4500 Qtrap model LC-MS/MS equipment for this analysis, which costs approximately Rs 1.80 crores.

As procurement of instruments and establishing new methods takes time, to avoid delay in analysis, Prasad reveals that the company has hired the services of an external laboratory, which is an added cost of Rs 1.20 crores.

Commenting on how much the increased risk evaluation and testing will cost API and formulation companies Joshi of PerkinElmer India said it largely depends on the range of products offered by the API companies who may have to take the precautionary measure to mitigate the risk of nitrosamine formation or presence during the manufacture of all medicinal products containing chemically synthesised APIs.

Estimating a price to these measures, he says, “While LC MS/MS itself – a highly sensitive high throughout an instrument – typically requires an initial capital investment in the range of $ 200,000-250,000, the total investment would vary depending on various factors at the customer’s lab. A typical GCMS with headspace sampler and auto sampler could cost around $100,000-150,000.”

Confirming the same, Umasankar of Waters also points out that these high sensitivity instruments need proper regular maintenance and trained man power to operate the systems. This adds around $25000 every year towards regular complete maintenance and analytical method life cycle management.

Learnings from the NDMA episode 
Talluri of SMS Lifesciences India says, “There is a possibility of NDMA impurity (which is commonly present in foods, beverages) to be present in many more drugs in future and the limits are based on extreme caution based on lifetime exposure. Hence manufacturing products well within limits ensures patient safety. An NDMA limit of 0.32 ppm (0.000032 per cent) is control of impurities at extremely low level which has ensured we investigate the entire process in great detail and deliver a product with the highest quality than ever.”

He also believes that constant process, quality and compliance improvements are important to meet any new guidelines that can be implemented in future.

Commenting on the perception battle, he opines that effective control strategy in all products related to NDMA impurity can be reasonably implemented and hence negative perception of products and the industry is not prudent. He also mentions that there is an opinion that in general, the benefits of the medicine outweigh any theoretical risk associated with nitrosamine impurities.

Prasad of Saraca Laboratories too refers to the negligible risk. Quoting from the 2018 ICH Guidance M7 (R1), according to which if people consume 96 nanograms of NDMA daily for 70 years, the probable risk of cancer would be 1 in 100,000 patients. He points out that the risk factor in consuming ranitidine is negligible, as a peptic ulcer drug is normally used for a few days/weeks/months and not lifelong.
As for other learnings, Prasad says, “As of now, pharma companies are not identifying unknown impurities of less than 0.1 per cent by considering ICH Q3A. However, to understand impurities like NDMA, we have to seriously look at all these impurities, irrespective of the guidance.”

Second, ICH M7 principles on mutagenic impurities do not seem to be sufficient for nitrosamines. Third, routine traditional methods for estimation of impurities by HPLC or residual solvents by GC are not sufficient to estimate impurities like NDMA and it needs new methods like LC-MS/MS etc. Quoting from an EDQM release, Prasad says that NDMA levels should be fixed based on importance/usage/dosage of individual medicines.

In the long run, Jain of Frost & Sullivan believes the solution lies in the digitisation of operations, tamper-free handling of data (employing blockchain for example) and adoption of best practices in the supply chain will become the mandate and a key differentiator. “This will allow continuous monitoring of every process, easier compliance with regulations and restore stakeholder confidence (regulatory agencies, providers and patients) in the Indian industry,” she says.

It is clear that an increase in testing and tighter controls is the new normal. As Joshi of PerkinElmer India predicts, “The NDMA issue will push pharma companies to bring even tighter controls around their processes. This is applicable not only for the API manufacturers and the finished pharma products (FPPs) but also to the third-party service providers who work with pharma companies. Even the slightest possibility of NDMA contamination should be ruled out by appropriate tests during the process itself. The EMA has requested that all the FPPs should be evaluated for the possibility of NDMA being present in all products containing chemically synthesised active ingredients. The testing processes will only become more strict.”

Umasankar of Waters points out that the NDMA issue has led to stringent regulatory guidelines and audits on all genotoxic impurities (GIs) and probable genotoxic impurities (PGIs) based on functional group. Besides testing the final product upto the trace level, he advises that the QC department of API manufacturers should now develop GC /HPLC methods for routine monitoring of GIs and PGIs during synthesis and prove how these impurities are purged out from the synthetic process.

These efforts will also have to meet data integrity norms. For instance, the UPLC system from Waters, with single quadrupole mass detector, reportedly creates data with 21CFR11 compliance, with strict audit trails to ensure data integrity.

Concluding on a positive note, Joshi of PerkinElmer India says, “The good news for pharma companies today is the availability of many innovative technologies that can detect and quantify the impurities/carcinogens at very low levels. It is to their advantage and to the advantage of consumers globally that these new and advanced technologies are utilised to help drive better health quality and safety.”

Thus while compliance with the new diktats comes at a cost, the nitrosamine contamination episodes have proved that the cost of non-compliance is even higher in the long run.

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