SMS Lifesciences India Limited Registered & Corporate Office Plot No, 19-11, Road No, 71, m Opp, Bharatiya Vidya Bhavan Public School, Jubilee Hills, Hyderabad, Telangana - S00 096, INDIA LifeSciences Tel : +91-40-6628 B88, Fax : +91-40-2355 1401 Website : wwwsmsie.in NDMA (N-NITROSODIMETHYLAMINE) RISK ASSESSMENT REPORT Strictly Confidential NDMA (N-NITROSODIMETHYLAMINE) RISK ASSESSMENT REPORT WITH TECHNICAL EVALUATION IN RANITIDINE HYDROCHLORIDE ROS OF SMS LIFESCIENCES INDIA LIMITED DRUG SUBSTANCE NAME RANITIDINE HYDROCHLORIDE SMS LIFESCIENCES INDIA LIMITED, Unit-L, Sy No. 180/2, Kazipalli (V), Tinnaram (M), Sangareddy District, ‘Telangana ~ 502 319, INDIA. Date : 30/09/2019 Page | of 13 Factory : Unit - I, Sy No. 180/2, Kazipali (V), Jinnaram (M), Sangareddy District, Telangana - 502 319, INDIA. Tel : +91-8458-277067 / 277068 / +91-8374455598, E-mail : qa_unitl @smsife.inc sms LifeSciences SMS Lifesciences India Limited Registered & Corporate Office: Plot No. 19-11, Road No. 71, (Opp. Bharatiya Vidya Bhavan Public School, Sublee Hlls, Hyderabad, Telangana ~ 500 096, INDIA Tel: +91-40-6628 8888, Fax : +91-40-2355 1401 ‘Website: wwav.smsife.in NDMA (N-NITROSODIMETHYLAMINE) RISK ASSESSMENT REPORT Strictly Confidential TABLE OF CONTENTS S.No. Content Page No. Cover Page (Title of Document) 1 Table of Contents 2 1.0 | Brief introduction of Ranitidine Hydrochloride and NDMA 3 20 | Objective 5 3.0. | Scope of study 5 40 i 5.0. | NDMA Analysis Results in Ranitidine Hydrochloride 7 | go | St#ge wise Route of synthesis of Ranitidine HCL & Stage wise ROS i Process evaluation 7.9 | Manufacturing Facilities Assessment Highlights i 80 Conclusion 12 90 Further Action Plan 12 10.0 | Literature Rees 13 11.0 | Report approval i Het ; 1B - Page 2 of 13 Factory : Unit- I, Sy No. 180/2, Kazipalli (V), Jinnaram (M), Sangareddy District, Telangana - 502 319, INDIA. Tel : +91-8458-277067 | 277068 / +91-8374455598, E-mail : qa_unit1@smsife.in6% sms SMS Lifesciences India Limited Registered & Corporate Office Plot No, 19-UL, Road No, 71, pp. Bharatiya Vidya Bhavan Public School, Jubilee Hills, Hyderabad, Telangana ~ $00 096, INDIA LifeSciences Tel : +91-40-6628 8888, Fax : +91-40-2355 1401 Website: waw.smsif.in NDMA (N-NITROSODIMETHYLAMINE) RISK ASSESSMENT REPORT Strictly Confidential 1.0 BRIEF INTRODUCTION OF RANITIDINE HYDROCHLORIDE AND NDMA: L.1 Ranitidine Hydrochloride: A medication which decreases stomach acid production was discovered in 1976 and came into commercial use in 1981. It is a known, strongly acting selective histamine H2 antagonist which especially is an important agent against gastric and duodenal ulcers. The first FDA approval for this drug was provided on 6/9/1983 and has been sold as an effective drug for the last 38 years. In fact, it is on the World Health Organization's List of Essential Medicines, and is generally considered as the most effective and safe medicines needed in a health system. Ranitidine Hydrochloride Chemical Name: N-[2-{[[5-{(imethylamino)methyl]-2-furanyl]methy[[thiojethyl}-= N'-methyl-2-nitro-1,l-ethenediamine Chemical Structures [8 Se OL ve o NA A~ory tee Molecular formula: | CistiN.O,SHCI Molecular weight: “) 350.9 CAS Number: [66357-59-3] 1 1.2 N-Nitrosodimethylamine (NDMA), is a semi-volatile organic chemical, which is a yellow, oily liquid with a fai i, characteristic odour and a sweet taste. It is a member of N- Nitrosoamines, a family of potent carcinogens. Synonyms include dimethylnitrosamine (DMN), nitrosodimethylamine, N-methyl-N-nitrosomethanamine and N.N-dimethy! nitrosamine/EPA IRIS 1993) Page 3 of 13 Factory : Unit - I, Sy No. 180/2, Kazipalli (V), Jinnaram (M), Sangareddy District, Telangana - 502 319, INDIA. Tel: +91-8458-277067 | 277068 / +91-8374455598, E-mail: qa_unit1@smsiife.inSe sms LifeSciences NDMA (N-NITROSODIMETHYLAMINE) RISK ASSESSM: Strictly Confidential ‘SMS Lifesciences India Limited Rogistored & Corporate Office Pot No, 19-1, Rood No. 71, Opp. Bharatiya Vidya Bhavan Public School, Jubilee Hills, Hyderabad, Telangana - 500 096, INDIA Tel : 491-40-6628 888, Fax : +91-40-2355 1401 Website : wwwsmstife.in REPORT. NDMA is not currently produced in pure form or commercially used except for research purposes. Itis formerly used in production of liquid rocket fuel, antioxidants, and additives for lubricants and softeners for copolymers (ATSDR 1989; HSDB 2012). Potential industrial sources include byproducts from tanneries, pesticide ‘manufacturing plants, rubber and tyre manufacturers, alkyl amine manufacture and use sites, fish processing facilities, foundries and dye manufacturers (ATSDR 1989) w It is also an unintended by-product of the chlorination of wastewater and drinking water at treatment plants that use chloramines for disinfection, (Bradley and others 2005; Mitch and others 2003). NDMA can be unintentionally produced in and released from industrial sources through chemical reactions, such as those that involve alkyl amines with nitrogen oxides, nitrous acid or nitrite salts of human consumption like meat, dairy product NDMA isa general environmental contaminant found at low levels in numerous items and vegetables, especially those foods which are cooked, smoked, or cured. It is, however, unlikely to bioaccumulate. (Najm, 1; Trussell, R. R, 2001) ‘Chemical Name: N-methyl-N-nitrosomethanamine Chemical Structure: mes om Molecular formula: Molecular Weight: CAS No: 7 Chemical properties of | - NDMA: Freely soluble in water and solvents like Solubil Methanol, Chloroform, Toluene, DMSO, Isopropyl Alcohol Description: Yellow, oily liquid Boiling point: 153.1°C Page 4 of 13, Factory : Unit - I, Sy No. 180/2, Kazipalli (V), Jinnaram (M), Sangareddy District, Telangana - 502 319, INDIA. Tel : +91-8458-277067 / 277068 / +91-8374455598, E-mail : ga_uniti@smeife.inSMS Lifesciences India Limited Registered & Corporate Office Plat No, 19-11, Road No. 71, Opp. Bharatiya Vidya Bhavan Public School, sms leis se, tans 5006 IDX ieee Trott ns Foc e-0285 10 Website: wiw.smsife.in NDMA (N-NITROSODIMETHYLAMINE) RISK ASSESSMENT REPORT Strictly Confidential NDMA freely available in natural sources other than chemical reactions they are AIR (0.98 ng/L) Ground water (310-370 ng/L) Drinking water (180 ng/L, Albert, Canada) Bakery items (0.12 ng/Kg) Meat/Lamb (0.04 n9/Kg) Milk (0.03n9/Kg) Rice (0.11.g/Kg) , TEA, coffee, vegetables ete., vvvvyy v Ref: 1 Environmental science and technology;vol.38; 18; (2004); P. 4835-4841 2.Environmental sci nce and technology;vol.42; 17; (2008); P. 6340-6346 2.0 Objective : The main objectives of this review/Report on Ranitidine Hydrochloride is > To address the possibilities for formation of NDMA in Ranitidine hydrochloride as per selected route of synthesis with supporting literature and technical evaluation > To identify the areas which can be extended part of review To make the action plan based on this review 3.0 Scope of study: This study involves NDMA Risk assessment in selected route of synthesis of Ranitidine Hydrochloride manufacturing and further action plan. 4.0 NDMA Formation Pathways: 4.1 Reaction mechanism of NDMA formation The formation of N-nitrosamines is possible in the presence of amine and nittite, usually under acidic reaction conditions, For the formation of NDMA, the presence of an amine such as dimethylamine (DMA) is important. The secondary amine along Page 5 of 13 Factory : Unit - I, Sy No. 180/2, Kazipalli (V), Jinnaram (M), Sangareddy District, Telangana - 502 319, INDIA. ‘Tel : +91-8458-277067 / 277068 / +91-8374455598, E-mail : qa_unit! @smsiiSMS Lifesciences India Limited Registered & Corporate Office Pot No, 19-11, Road No. 71, Opp. Bharatiya Vida Bhavan Publ Schoo, sms Nile Hyderabad, Teanga» 500096, INDIA i Tel: 91-40-6628 BBB, Fax +1-40-2355 1401 LifeSciences Website : www.smslife.in NDMA (N-NITROSODIMETHYLAMINE) RISK ASSE! Strictly Confidential MENT REPORT. with nitrous acid/Sodium nitrite in presence of strong acid generates N-nitrous derivative NDMA or substituted NDMA. NeNO2+ H" (acid) V Hc cH HyC__CHs nei + HNO? eee " ho ee (NDMA) 4.2 Possible ways to NDMA formation ey ay 1 4 wey, eater mm ni (amine Phosphate puter ~doE CN eee u al, yo eu, Anes bh, NMA eo Water contamination Air contamination / aereal oxidation Page 6 of 13 Factory : Unit - I, Sy No. 180/2, Kazipalli (V), Jinnaram (M), Sangareddy District, Telangana - 502 319, INDIA. Tel : +91-8458-277067 / 277068 / +91-8374455598, E-mail : qa_unitt@smslife.in6% sms SMS Lifesciences India Limited Registered & Corporate Offic Plot No. 19-1, Road No, 71, (Opp. Bharatiya Vidya Bhavan Public Schoo, Dubilee His, Hyderabad, Telangana ~ 500 096, INDIA LifeSciences Tel : +91-40-6628 8888, Fax : +91-40-2355 1401 Website: wow.smstfe.in NDMA (N-NITROSODIM HYLAMINE) RISK ASSESSMENT REPORT, Strictly Confidential 5.0 NDMA Analysis Results in Ranitidine Hydrochloride: Analysed 4 batches of Ranitidine Hydrochloride as per validated methods using LC- MS/MS. The details of instruments used, standards, chemicals and reagents used for analysis and the results obtained are tabulated below for reference. Results of NDMA content in Raniti 1¢ Hydrochloride by LC MS/MS Analysed by External Laboratory: SMS Pharmaceuticals Limited (Central Laboratory Analytical Services), Approved by Local Regulatory Authorities Instrument Details: Name of the equipment used ‘Make and Model Liquid Chromatography with Mass Agilent Technologies LC-MS/MS, Model Spectrometer 6470 A Standards, Chemicals and Reagents Used: N-methyl-N-nitrosomethanamine (NDMA) standard Formic acid, Methanol and water Results of NDMA content in Ranitidine HCL: Batch Number | Manufacturing | NDMA Content. | NDMA TTC limit * date (ppm) (ppm) 7 | 300 mg_| 600 mg RH/19/690_ Sep -2019 0.029 5.0 25 RH/19/691 Sep -2019) 0.044 5.0 25 RIH/19/692 Sep -2019 0.056 BO Hr ease H(PM)/19/041 Aug-2019 0.042 5.0 25 | LOD (Limit of Detection) 0.0055 ppm - 0.0166 ppm eee * Threshold of Toxicological Concern (TTC) limits in Ranitidine Hydrochloride are calculated as per ICH M7 guidance for genotoxic impurities. Note: Based on above established results, in future we shall follow any one of the equivalent and validated methods (LC-MS/MS / GG-MS / HPLC) for Analysis of NDMA content in Ranitidine Hydrochloride, Page 7 of 13 Factory : Unit - I, Sy No. 180/2, Kazipalli (V), Jinnaram (M), Sangareddy District, Telangana - 502 319, INDIA Tel: +91-8458-277067 | 277068 / +91-8374455598, E-mail : qa_unit1@smsiife.inSMS Lifesciences India Limited Registered & Corporate Office Pot No. 19-11, Road No. 71, Opp. Bharata Vie Bhavan Pubic S20, sms Nie ile ead, aga 500 036, INDA i Sa +9140 628 898, Fx 49-40-7355 1401 reseences Website : www.smslife.in. NDMA (N-NITROSODIMETHYLAMINE) RISK ASSESSMENT REPORT Strictly Confidential 6.0 Stage wise Route of synthesis of Ranitidine HCL & Stage wise ROS Process evaluation Stage-I: Synthesis of Cystofer We use Furfuryl Alcohol, Di-Methyl Amine HCL and Formaldehyde as raw materials and condense with Cysteamine Hydrochloride to produce Cystofer (Crude) ‘The Cystofer (Crude) is subjected to extreme high vacuum distillation (HVD) to get Cystofer(Pure). war Stage-Il: Synthesis of NSM NMSM (Crude) is synthesised using nitromethane, methy! iso thiocyanate, potassium hydroxide and dimethy! sulfate as reactants, Icon eH oe ee OO we, OD Page 8 of 13 Factory : Unit - I, Sy No. 180/2, Kazipalli(V),Jinnaram (M), Sangareddy District, Telangana - 502 319, INDIA Tel : +91-8458-277067 / 277068 / +91-8374455598, E-mail : a_unit1 @smsiife.in‘SMS Lifesciences India Limited Registered & Corporate Office Pot No. 19-11, Road No. 71, Op ht atone ub chs, sms Stes dba, Trgae 300035, ROA LifeScences Tas S314 25 8, ox 91402385101 Website : vnw.smsife.in NDMA (N-NITROSODIMETHYLAMINE) RISK ASSESSMENT REPORT. Strictly Confidential The NMSM (crude) is further purified with activated charcoal in the presence of water/methanol O2N O2N Hae fy activated carbon Hse fy NH: ———— ae NH: 5 water,Methanol 's Hc” Hye’ Molecular Formula: C,H,N,O,S pure NMSM Stage-IIL: Synthesis of Ranitidine Base Cystofer is condensed with NMSM in presence of water and extracted with chloroform and crystallization with Methyl isobutyl ketone to form Ranitidine Base. pi LY. 4 \ ainsi aetna vs oem Ronin base Stage-IV: Synthesis of Ranitidine Hydrochloride Ranitidine base is treated with IPA-HCI in the presence of Isopropyl alcohol, methanol and water to form Ranitidine Hydrochloride (Form — 2) wt wt pape rh a Matas Joyo LY Dey 2 ma Nee ‘ ian DL ng, WA Weer? on ww Ramtcine tytectioade ye" Page 9 of 13 Factory : Unit - I, Sy No. 180/2, Kazipalli (V), Jinnaram (M), Sangareddy District, Telangana - 502 319, INDIA. ‘Tel : +91-8458-277067 / 277068 / +91-8374455598, E-mail : qa_uniti @smslifein4 sms LifeSciences ‘SMS Lifesciences India Limited Registered & Corporate Office Pot No, 19-11, Road No. 71, ‘Opp. Bharatiya Vidya Bhavan Public School, Aubilee His, Hycerabad, Telangana - 500 096, INDIA Tel: 491-40-6628 8888, Fax : +91-40-2355 1401, Website : vavw.smsife.in NDMA (N-NITROSODIMETHYLAMINE) RISK ASSESSMENT REPORT Stage wise ROS Process evalu; Strictly Confidential Stage I Cystofer ‘Although we are having a secondary amine (dimethyl amine-DMA) in this stage, it is improbable to form NDMA in this stage, since there is no source of nitrous acid / nitrite ion source for the formation of NDMA. NDMA, if any, formed may be washed out in highly soluble solvents used in the process like water, methanol and toluene. We are isolating highly pure Cystofer using high vacuum distillation at extremely high temperature (< | torr vacuum ; 120-140°C temperature). Excess DMA if any should be removed by the HVD due to its extremely low boiling point (7°C at atmospheric pressure). Stage II NMSM In this reaction there is no source of amines (such as DMA) from raw materials used, hence there is no chance of NDMA formation in this stage. Due to lack of Nitrous acid/Nitrite ion source, NDMA impurity formation may not be possible NDMA, if any, formed may be washed out in highly soluble solvents used in the process like water, methanol and DMSO. Stage IIT Ranitidine Base Ranitidine Base is formed with water as a medium and immediately extracted into chloroform, The scrubbers installed and continuous nitrogen bubbling provided to continuously remove mercaptan gas also ensures that there is no/minimal scope of any oxidation as the reactors are mostly operated under low atmospheric pressures. ‘The material is most of the time alkaline in nature, which further significantly reduces the Ranitidine decomposition rate if any. NDMA, if any, formed may be washed out in highly soluble solvents used in the process like water, chloroform and MIBK "Page 10 of 13 Factory : Unit - I, Sy No. 180/2, Kazipall(V), Jinnaram (M), Sangareddy District, Telangana - $02 319, INDIA. Tel : +91-8458-277067 / 277068 / +91-8374455596, E-mail: qa_unitl @smsiif.inSe) sms LifeSciences Note: SMS Lifesciences India Limited Registered & Corporate Office: Plot No. 19-11, Road No. 71, (Opp. Bharatiya Vidya Bhavan Pubic School, Jubilee Hills, Hyderabad, Telangana - 500 096, INDIA Tel : +91-40-6628 8888, Fax : +91-40-2355 1401 Website : wuwsmife.in NDMA (N-NITROSODIMETHYLAMINE) RISK ASSESSMENT REPORT Strictly Confidential idine + The material is most of the time alkaline in nature, which significantly reduces the Ranitidine decomposition rate if any in IPA HCL. + NDMA, if any, formed may be washed out in highly soluble solvents used in the process like water, methanol and IPA. NDEA and other Nitrosoamine impurities: As per route of synthesis, N,N diethyl amine or any ethyl substitution function group reagents are not used during manufacturing of the product hence we believe that NDEA is not likely to be presen in Ranitidine Hydrochloride. 7.0 Manufacturing Facilities Assessment Highligh > x a v ‘The manufacturing facilities for Ranitidine are not only dedicated for the product but also for each of the four stages. All these manufacturing blocks are well segregated and dedicated. RO water is used in the manufacturing process of Ranitidine Hydrochloride and Process water is used in its intermediate stages are well treated and ensured that it is of the highest quality All serving utilities, storage tanks and process pipelines are well segregated, demarcated and dedicated only for Ranitidine manufacturing blocks All the solvents are recovered using dedicated and highly efficient fractional columns. Even all the manufacturing personnel operating in the plants are dedicated only for Ranitidine production Page 11 of 13 Factory : Unit - I, Sy No. 180/2, Kazipalii (V), Jinnaram (M), Sangareddy District, Telangana - 502 319, INDIA. Tel | +91-8458-277067 / 277068 / +91-8374455598, E-mail : qa_unit1@smslifeinSMS Lifesciences India Limited Registered & Corporat Office : Plot No. 19-1, Road No. 71, Opp. ht Via bh Pb Sod, sms Sb ts Fs Tezogan 500%, INIA LifeSdences Ta 1014 08 0, fox! 9140233510 Website: wiv mehifein NDMA (N-NITROSODIMETHYLAMINE) RISK ASSESSMENT REPORT Strictly Confidential 8.0 Conclusion: > After reviewing all the available literature of NDMA, our Raniti process has been evaluated and found that the chances of formation of NDMA in Ranitidine Hydrochloride with respect to the selected route of synthesis & reaction parameters is very low and also proved in our above analysis results so far. > However, SMS is anticipating mild content of NDMA in Ranitidine Hydrochloride based ‘on Charois Jeffery W.A etal” literature reference those who have identified NDMA content in Drinking water (Alberta, Canada) about 180ng/L and Schmidt, Carsten K etal”® also identified 310ng/L in ground water > Based on fiteratures and our analytical results SMS confirms presence of trace levels of NDMA content (below the acceptable daily exposure limit) in regular manufacturing batches of Ranitidine Hydrochloride. We anticipate that the obtained NDMA content results may be because of Process Water, Air, Equipment or other sources which we plan to investigate further. > Based on the Risk assessment report and obtained results, SMS Lifesciences India Limited is willing to adopt the limits, if any, recommended by the Regulatory Authorities for controlling/monitoring NDMA and other Nitrosamines along with other possible genotoxic impurities, 9,0 Further Action Plan: > Develop and validate new analytical procedures, that are currently not available, to evaluate the precursors of NDMA impurities in raw materials, intermediates, KSMs and solvents used > Evaluate the formation potential of these nitrosamine derivatives in all intermediates, key starting materials and recovered solvents > SMS will take precautionary actions for upcoming batches by introducing preventive measures, control strategies and avoid NDMA risk in SMS’s Ranitidine Hydrochloride before releasing the API Page 12 of 13 Factory : Unit - I, Sy No, 180/2, Kazipalli (V), Jinnaram (M), Sangareddy District, Telangana - 502 319, INDIA. Tel : +91-8458-277067 / 277068 / +91-8374455598, E-mail : qa_unit1 @smsiife.inSMS Lifesciences India Limited Registered & Corporat Oe Pot No 19, oad No.7, Opp arate Vea Bhavan Pub Schoo sms ile His, deat, Telangana - 500096, INDIA j Tel 1910-6608 889, fax 69140-2355 100) LifeSciences Website : www.smsiife.in NDMA (N-NITROSODIMETHYLAMINE) RISK ASSESSMENT REPORT Strictly Confidential 10.0 Literature References: Synthetic communications vol. 30,nb11 (2000) p 2087-2060 Chemical and pharmaceutical bulletin Vol 30,nb 9 (1982); P.3399-3404 Journal of physical chemistry A; Vol.120: nb 35 (2016); P.6970-6977. Journal of Labelled compounds and radio pharmaceuticals; Vol 62:nb.2 (2019), P.62-66. Environmental science and technology;vol.38; 18; (2004), P. 4835-4841 Environmental science and technology;vol.42; 17; (2008); P. 6340-6346 11.0 Report Approval # Name Designation Sign & date Prepared by | SK. Mastan Dy. Manager-QA esti iti Mores — clon Reviewed by | S. Naresh Manager-R&D —s Now Ee ss9 Approved by P.D.Varna AGM-Qualit aie amt | Ne atoal Page 13 of 13 Factory : Unit - I, Sy No. 180/2, Kazipall (V), Jinnaramn (M), Sangareddy District, Telangana - 502 319, INDIA. Tel : +91-8458-277067 / 277068 / +91-8374455598, E-mail: qa_unit1@smsife.in