The Reaction To Valsartan Impurities: More Scrutiny, More Testing And Tighter Limits

In the months since US and EU authorities restricted Zhejiang Huahai’s market access over the discovery of nitrosamine impurities in its valsartan API, the broader regulatory consequences for drug manufacturers are coming into focus.

 

The regulatory consequences of last year’s discovery that carcinogenic impurities called nitrosamines tainted a major supplier’s active ingredient for a popular blood pressure medication are becoming clear.

There will be greater scrutiny, more testing and tighter limits not only for that medication, valsartan, but also for other similar blood pressure medications – and perhaps for other pharmaceuticals and their active ingredients.

The regulatory response to the valsartan crisis reinforces the idea that even when authorities acknowledge no one could have anticipated a serious risk, someone will take the blame for failing to anticipate it.

The case also highlights some limits of emerging science- and risk-based approaches to regulatory standard setting. It appears US and EU scientists diverge on how the impurities formed, one reason interim risk-based standards vary between the regions. But regulatory authorities in the two regions do agree that, given the significant but uncertain risk potent carcinogens like nitrosamines pose, they will transition as soon as possible from standards based on theoretical risk to standards based on detection limits.

It is the type of regulatory response that can increase general anxiety, possibly driving over-testing and over-tightening even of unrelated manufacturing processes for fear of unknown unknowns.

A Swift And Sure Initial Response

When Zhejiang Huahai Pharmaceuticals Co. Ltd. alerted regulatory authorities that a customer had found significant levels of a carcinogenic nitrosamine impurity while testing its valsartan API for residual solvents, the initial response was swift and sure.

After conducting separate for-cause inspections of Huahai’s API plant in Linhai, China, the US FDA and the European Medicines Agency on Sept. 28 banned the plant’s valsartan API from their respective markets – FDA by adding the facility to its drug GMP import alert, EMA by finding the firm out of compliance with its EU GMP certificate.

Recalls and shortages of valsartan and related drug products soon followed.

FDA dashed off a warning letter in November that spelled out the agency’s concerns and blamed Huahai for failing to detect a pair of nitrosamine impurities found in its valsartan API. (Also see "US FDA Warning Letter Hits Huahai For Failure To Prevent Valsartan Contamination" - Pink Sheet, 13 Dec, 2018.)

At the same time, FDA and the European Directorate for the Quality of Medicines developed methods for detecting the impurities, N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) – one set of methods for the US; another for the EU.

Additionally, FDA and EMA conducted root cause investigations that diverged on how the nitrosamines were generated.

A Widening Scope

US and EU authorities focused their root cause investigations initially on a manufacturing process change that Huahai carried out in 2012, which appears to have created the conditions for NDMA formation.

However, they soon found they would have to widen the scope of their investigations.

They found the two impurities in many other firms’ valsartan API and drug product, though at lower levels.

They also found the impurities in other blood pressure medications of the same class, angiotensin II receptor blockers, or ARBs.

EMA found a commonality among the ARBs of concern: it determined they all contain tetrazole rings.

The European agency said in a Feb. 1 report that the nitrosamine impurities can form during production of molecules that contain tetrazole rings under certain conditions and in the presence of certain solvents, reagents and other raw materials. Once formed, such impurities can contaminate equipment or reagents, thereby spreading to other drug products.

The EMA report stems from a review the European Commission had requested, and its conclusions are subject to the commission’s approval.

While FDA has been more circumspect about the process chemistry issues it has identified, it appears that agency does not believe tetrazole rings must be present for the impurities to occur.

All FDA Commissioner Scott Gottlieb and Center for Drug Evaluation and Research Director Janet Woodcock disclosed in a Jan. 25 statement was that through its ongoing investigation, FDA had identified certain risk factors for formation of the two impurities in manufacturing processes and is studying whether other manufacturing conditions might also contribute to formation of NDMA and NDEA or related impurities.

Of the eight ARBs for which FDA has set interim NDMA and NDEA limits, three were specifically excluded from EMA’s analysis because they lack tetrazole rings: azilsartan, eprosartan and telmisartan.

The divergence between the two premier regulatory agencies on root cause suggests the scope of the problem remains uncertain.

The Theoretical Risk To Patients

Both agencies have shared their analyses of patient risk.

FDA figures that at worst, NDMA would cause one extra cancer case for every 8,000 Americans who took the highest daily valsartan dose, 320 mg, for the four years that Huahai’s tainted valsartan had been on the US market.

That four-year excess cancer risk is 12.5 times the one-in-100,000 lifetime excess cancer risk that would normally be acceptable under international guidance. But it’s still far below the more than one-in-three lifetime cancer risk in the US.

FDA still is working on its cancer risk assessment for the other impurity, NDEA.

EMA’s review assessed the risk a little differently. It figured that daily exposure to NDEA during the six years the impurity was present in EU valsartan API from Huahai could add 22 cancer cases per 100,000 patients. In addition, the four years of such exposure seen in the EU with NDMA could add another eight cases per 100,000.

The agency noted that the estimated 30-per-100,000 excess cancer risk added in the EU by Huahai still is very low compared to the one-in-two lifetime cancer risk in the EU.

Two Stages Of New Limits

Both agencies took two-step approaches to limiting nitrosamine impurities in valsartan and other ARBs.

First, they set risk-based limits for an interim period. Later, both agencies will transition to stricter limits based on analytical process capability so that ARBs will contain no discernible nitrosamines.

Risk-Based Interim Limits

The risk-based approach used for the interim limits is outlined in international guidance that FDA and EMA helped develop.

The International Council on Harmonization adopted the multidisciplinary guideline on mutagenic impurities, called M7, in June 2014, and later revised it with an addendum listing 15 carcinogens and mutagens commonly used in pharmaceutical manufacturing. (Also see "Pharmaceutical Industry and FDA Preparing for ICH M7 Implementation" - Pink Sheet, 20 Nov, 2015.)

M7(R1) is a 29-page document with 101 pages of appendices that guides firms in assessing carcinogenicity during development as well as during commercial manufacture, for example when there are changes to drug substance synthesis.

There are carve-outs for advanced cancer substances and products already covered under another ICH guideline called S9, and for biotech products in general.

The M7 guideline aims to protect patients from a theoretical one-in-100,000 lifetime excess cancer risk, at least for impurities that exceed a 1.5 micrograms/day threshold of toxicological concern.

However, the guideline says that threshold won’t work for certain high potency carcinogens, including aflatoxin-like compounds, alkyl-azoxy compounds and N-nitroso- compounds such as nitrosamines. For such compounds, intakes below the TTC “would theoretically be associated with a potential for a significant carcinogenic risk,” M7(R1) says.

The guideline says it’s not intended to apply retrospectively to products marketed before its adoption, including any pre-adoption changes to manufacturing processes, as occurred with Huahai’s valsartan.

Even so, FDA and EMA are following the M7 approach in their response to the problem of nitrosamines in valsartan and other ARBs.

Both agencies started with interim limits based on acceptable daily intake values of 96 nanograms for NDMA and 26.5 nanograms for NDEA, which in turn were derived from animal studies.

These acceptable daily intake values give a theoretical one-in-100,000 cancer risk after 70 years of exposure (at maximum dosage) to the two high-potency carcinogens.

Both agencies converted the acceptable daily intake values from nanograms to parts per million based on maximum dosages.

A Complex Array Of Values

The daily intake values for NDMA are identical in the US and the EU for many ARBs: 0.3 ppm for valsartan, 0.32 ppm for irbesartan, 2.4 ppm for olmesartan and 3.0 ppm for candesartan.

However, the limit for NDMA in losartan is 0.96 ppm in the US but 0.64 ppm in the EU. That’s because the maximum daily dose differs in the two regions; it’s 100 mg in the US, 150 mg in the EU.

There also are US-only NDMA limits for the three ARBs that lack tetrazole rings: 1.2 ppm for azilsartan, 0.12 ppm for eprosartan and 1.2 ppm for telmisartan.

The picture for NDEA limits is similar, but with lower and slightly divergent limits: 0.083 ppm in the US and 0.082 ppm in the EU for valsartan, 0.088 ppm in the US and the EU for irbesartan, 0.66 ppm in the US and 0.663 in the EU for Olmesartan, and 0.83 ppm in the US and 0.82 in the EU for candesartan.

The NDEA limit for losartan is 0.27 ppm in the US and 0.177 ppm in the EU.

As with NDMA, only the US gives limits for NDEA in three ARBs: 0.33 ppm for azilsartan, 0.033 ppm for eprosartan and 0.33 ppm for telmisartan.

Non-Detectable Post-Transition Limits

Gottlieb and Woodcock said FDA expects manufacturers using at-risk processes to conduct testing “to ensure that active ingredients and finished products are free of detectable levels of nitrosamine impurities.”

However, they said they won’t impose the detection-limit-based standards until after shortages resolve. They noted that valsartan is in shortage and that they expect other ARBs also to fall into shortage in the US.

EMA gave a different rationale for establishing interim limits, saying that would give manufacturers time “to make the necessary changes to their manufacturing processes and to put into place testing regimes to be able to detect the smallest amounts of these impurities.”

EMA gives two years for the transition period. After that, manufacturers will have to reduce NDEA and NDMA each to less than 0.03 ppm in drug products marketed in the EU.

What The Future Holds

FDA’s Gottlieb and Woodcock raised a critical concern about the valsartan case in their Jan. 25 statement: “While we acted aggressively to address the issue once we became aware of it, we must also answer the critical question of, why weren’t these impurities detected earlier?”

They noted that the agency engages organic chemists to detect potential impurity risks during reviews of manufacturing processes, and that it has adopted the M7 guideline for assessing the risks of such impurities.

They noted that agency chemists review applications and change requests, as well as referenced information such as drug master files, with an eye to the possibility of a manufacturer inadvertently introducing genotoxic impurities into manufacturing processes.

They suggested that agency chemists overlooked the formation of nitrosamine impurities in ARBs because no one had recognized such a possibility.

But no more. “Now that we’ve uncovered the risk of nitrosamine impurities in the manufacturing steps involved in ARBs, we’ll incorporate the findings into ongoing policy development,” Gottlieb and Woodcock promised.

More Organic Chemistry

Gottlieb noted in a Jan. 30 twitter thread that the agency is “investing heavily in building a large cadre of organic chemists and other experts in our Office of Pharmaceutical Quality and throughout other parts of our drug program to safeguard against these rare but troubling risks.”

He added that in recent years, the agency has issued guidance to tighten oversight of process changes that could introduce impurities. “This is an area of very active oversight. There’s always concern that new processes could introduce hard-to-detect chemical reactions.”

After complimenting CDER staff on the “fabulous job” they’re doing on the valsartan contamination problem, Woodcock acknowledged in a Feb. 6 podcast that it’s going to take time to resolve. “I don't see this coming to an end for a while.”

When the valsartan case finally does reach closure, only one thing will be certain.

It will be one unknown unknown down, an unknown number to go.

From the editors of the Gold Sheet.