Nitrosamines in Drug Substance and Drug Product-A Regulatory Challenge

Nitrosamine is the class of synthetic compound which is a potent genotoxic agent and considered as probable plausible human cancer-causing agents by the International Agency for Research on Cancer (IARC).N nitroso mixes are known as the potent carcinogenic and a global worry according to the various authorities and also from ICH M7, Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. Before June 2018, the presence of nitrosamine in the drug substance and alsoproductwasnot known, however in June2018, USFDA identi ied thepresence of Nitrosamine impurities in one of the API producers of valsartanwhich is recognized as NDMA (N-Nitroso dimethylamine). Valsartan is a medication which is utilized for the treatment of hypertension, cardiovascular breakdown and diabetic kidney damage. From that point forward, FDA has discovered that different kinds of nitrosaminemixes, e.g., N-Nitrosodiethylamine (NDEA), are available at unsuitable levels in APIs from various API makers of valsartan and different medications in the ARB class. (Angiotensin receptor blocker). Then the Regulatory Authorities has stepped forward for educating the health care professional, manufacturers and also public about the adverse effect(carcinogenic)of the NDMA and NDEA consumption.


INTRODUCTION
Nitrosamines, or all the more accurately Nnitrosamines, allude to any particle containing the nitroso practical gathering. These particles are of concern in light of the fact that nitrosamine contaminations are plausible human cancer-causing agents. In spite of the fact that they are likewise present in certain nourishments and drinking water supplies, their quality prescriptions is, in any case, thought about unsuitable.
Objective 1. To understand the nitrosamine impurities.
2. To understand how the impurities came to the drug.
3. To understand the limit set by the regulatory authorities for nitrosamine impurities and the prescribed test methods.
4. To know how the authorities handled the challenge and resolved them.   USFDA irst became aware of the NDMA and MDEA impurities present in valsartan in July 2018, also Medicine Regulatory Authorities got an awareness of the problem. Then various Regulatory authorities like USFDA, EMA, WHO and many more has taken serious action to battle the nitrosamine impurities reaching the public. More recently, nitrosamine impurities have been reported in pioglitazone and ranitidine containing products as well as Health Singapore Authority has recalled Three metformin medicines which had NDMA level which is above the internationally acceptable limits on December 2019 (FDA, 2019). On account of the sartan mixes, most contain a tetrazole ring and the development of this tetrazole ring utilizes the utilization of sodium nitrite. Coincidently the solvents utilized either were amines or contained hints of amines, and this conceivable managed the watched NDMA and NDEA. The beginnings of NDMA content in bunches of ranitidine as of now stays indistinct. Regardless, during ongoing assessments, it was furthermore gathered that the probability for nitrosamine contamination content was more broad than basically the concurrent closeness of nitrites and amines in the association of the dynamic pharmaceutical ixing (API). Proof prescribes that wellsprings of nitrites or amines as coincidental contaminants of starting materials, reagents and solvents -,for instance, dimethylamine in the ordinary dissolvable dimethylformamide (DMF) -may similarly give conditions in which nitrosamines may outline. The remnant of nitrites or amines from coming about advances may moreover bear the expense of chances for course of action. Noticeably, contamination from outside sources has been perceived as a wellspring of nitrosamine content. In particular, sullying from the usage of reused materials and solvents that starting at now contain levels of nitrosamines. A referred to an instance of this incorporates the use of reused DMF, which is quenched with sodium nitrite to wreck remaining azide as a signi icant part of the recovery method. Materials and solvents can become cross-spoiled with nitrosamines or with contaminating impacts that could react downstream to shape nitrosamines if the equipment isn't agreeably cleaned between clients. Fundamentally, these additional segments, explicitly cross-sullying, are to moving degrees things obscure and may impact things that would some way or another or another not be depended upon to be in peril of nitrosamine advancement. These progressively broad concerns have induced the European Medicines Agency (EMA) to request that Marketing Authorisation Holders (MAHs) of all Finished Pharmaceutical Products (FPPs) direct risk evaluation to choose the peril of nitrosamine content (WHO, 2019).
NDMA and NDEA have a place with the supposed "companion of concern", which is a gathering of exceptionally strong mutagenic cancer-causing agents that have been grouped by the WHO's International Agency for Research on Cancer as most likely human cancer-causing agents. In spite of the strength of these polluting in luences, there is as yet a generally safe that nitrosamine contaminations at the levels found could cause malignancy in people.       Informing patients and the public as well as health care providers was the priority. FDA has provided a path for manufacturers to distribute risk assessments that can be used by manufacturers to determine the proximity of genotoxic emissions. This is a course that has been accepted by the two controllers and industry globally. In order to carry out the risk assessment for any genotoxic degradation, it must be accepted by the manufacturing process. FDA initiated the process of inspecting the manufacturing sites across the world for the impurities and cGMP and made the review of the manufacturers record pertaining the tests and the methods carried out during the impurities. Based on the FDA's analysis of the manufacturing process, it has testing all the products which come under the angiotensin receptor blocker to determine if it contains nitrosamine impurities because steps involved in the synthesis of other ARB might be similar to the valsartan. On November 1, 2019, CDER has said that Ranitidine is safe and NDMA levels found in this drug is the same as that of the levels which are found in the meat (USFDA, 2018) In the European Union (EU), following an Article 31 audit of sartans in danger of containing nitrosamine debasements (those containing a tetrazole ring),9 makers were approached to survey and make changes to their assembling procedures to limit nitrosamine pollutions to the degree for all intents and purposes conceivable. A progress time of two years has been permitted to roll out these improvements. During this progress period, between time constraints as sketched out in table 1 are being applied to items. Groups of items surpassing these cut-off points for an individual polluting in luence, or clusters containing both NDMA and NDEA are not permitted in the EU. Amendments are being made to the European Pharmacopeia to the medication substances monographs for the sartan arrangement to incorporate testing for nitrosamines. Furthermore, the general monograph for APIs (General monograph 2034) is under update and will likewise incorporate proper tests. Because of these measures, numerous sartan items were brie ly reviewed from the EU showcase. Many have now come back to showcase; in any case, EU guidance to patients was not to stop their medications except if they have been encouraged to do as such by their drug specialist or specialist. Along these lines, the USFDA attempted to recognize and review medications with levels above interval adequate cut-off points. The USFDA distributes a rundown of ARB items and their status regarding nitrosamine content. Like the EMA, the USFDA accentuated that the dangers, (for example, stroke) of unexpectedly suspending these medications far exceed the okay connected with proceeding with the drugs with these contaminations. All the more as of late degrees of the contamination NDMA has been distinguished in clumps of ranitidine and nizatidine items. Ranitidine medications are utilized broadly to decrease the creation of stomach corrosive in patients with conditions, for example, indigestion and stomach ulcers. They are accessible over-the-counter and on a solution. Administrative of ice responses have shifted. Some individual European national controllers, just as Swiss medic and Health Canada, took prudent steps to either review or suspend dispersion of all ranitidine items until the examination of clumps showed NDMA was underneath satisfactory levels. The EMA is presently assessing accessible information to evaluate whether patients utilizing ranitidine are at any hazard from NDMA. Different specialists, for example, the USFDA, have mentioned an intentional review of items just if test results show levels of NDMA over the interval levels.12 The USFDA has con irmed that the degrees of NDMA saw in most ranitidine and nizatidine items are like levels expected on the off chance that you ate basic nourishments like lame-broiled or smoked meats. Many companies have initiated voluntary recalls of their ranitidine products as preventative measures. As a general measure, the EMA has requested that the MAHs of all FPPs evaluate the possibility of nitrosamines being present in all products containing chemically-synthesize active ingredients. Although nitrosamines are not expected to form during the manufacture of the vast majority of medicines, the possibility of cross-contamination or unintentional introduction of amines and nitrites has prompted the request for companies to undertake this precautionary review. These reviews are expected to be broad in scope and to consider all aspects of the manufacturing process including Finished Pharmaceutical Product manufacture. The EMA has requested that MAHs complete this review within 6 months (EMA, 2019) The Council of Europe had also taken the measures and reviewed Site Master File and Marketing Authorization Applications by EU authorities. Sampling and testing of API and Medical Products. They also conducted GMP inspection and decision has taken on contaminated products which are in the market. Update of the Ph. Eur monographs for sartans with tetrazole ring and Development, validation of a general method that may be used as a reference has been initiated. The decision has taken that the solvents are being used which is free of nitrosamine impurities and manufacturing pro-cesses can be changed (EDQM, 2019) .
CDSCO also has taken action on ranitidine impurities-it has ordered its of icials to check for the nitrosamine impurities (The Indian Express, 2018).

Test Methods
The low levels at which the nitrosamine impurities occur creates challenges for testing. To assist in the testing of samples the USFDA has published several test methods that may be considered when determining nitrosamine content in the API or FPP. The USFDA has recommended the use of an LC-HRMS method when testing ranitidine due to the lower temperate conditions of the method; higher temperature conditions of some test methods may cause the sample to generate NDMA. Similarly, the Of icial Medicines Control Laboratories (OMCLs) Network of the Council of Europe has also published several methods that may be used when testing for nitrosamines The following are the methods used for determining nitrosamine in valsartan shown in Figure 4. (EDQM, 2019), Table 4 represent the regulation laid by European union for limits of NDMA and NDEA (EMA, 2019).

Figure 4: Various methods of determining nitrosamine in valsartan
LGL Method It's an LC-MS/MSmethod (AB SciexQtrap) a qualitative assurance method for NMBA for determining losartan drugs impurity. for reaching to the public and health care professionals. The challenge was to set out the rules and limits and various authorities across the globe have done the job perfectly. The limits set are 0.09% microgram or 0.32ppm of NDMA per day is considered safe for daily intake. This is based on the 2018 ICH guidelines M7(R1). there will be a probability of 1/100000 cancer occurrence. If the NDMA limits found above safe limit then the drug has to be withdrawn from the market. On December 4 Health Singapore Authority has withdrawn 'metformin' drug from the market and cancer risk from an additional 6-month exposure is estimated to be less than 0.00002%.and it is working on it. From all these cases we can observe the challenges faced by Regulatory Authorities in day to day life.