HETERO LABS LIMITED (UNIT-I1) Assessm ‘Nitrosamine Impurities for Losartan Potassium (LS) APL Background: Risk assessment is conducted to find out Risk of Genotoxie Niosamine impurities in the product Losartan Potassium API manufactured at Heto Labs Limited (Unit) N-Nitrosamine impurities are carcinogenic agents in animals and is elesiied as probably cattinogenic to humans (class 2 A estcinogen) by the intemational agency for Research on cancer (ARC, WHO). Risk assessment evaluation is conducted as per ICH M7(R1) guideline ‘and per CMdH405/2019, Questions and answers on Information on Nitrosamine for marketing authorisation holders", Assessment report EMA/217§23/2019 from committe for Meslcinal products for Human (CHMP) [As & part of comprehensive assessment to identify the formation of NDMA, NDEA, NDIPA, NIPEA, NIDBA, NMBA and/or other Nittosmine impurities in Losartan Potassium API ‘manufactured at Hetero, the ROS of API starting milerals and Active Pharmaceutical Ingredient (API) manufacturing processes were assessed forthe following, The combined sage of ‘+ Sodium ntite (NaNO) or Source of NaNOr such as Sodium Azide (NAY). ‘Source of Secondary or Tetiary or Quaternary amine base (Eesh andor recovered) such as Dimethyl formamide (DMF) / Dimethyl Amine (DMA), Triethyl amine (TEA) / Diethyl Amine (DEA) Di-sopropy! ethylamine (DIPEA? /Tetra Buty! ‘Ammonium Bromide (TBAB) / N-Methy-2-Pyrrolidane (NMP) any other Secondary or ‘Tertiary or Quaternary amine base in the process which ean lead tothe formation of NDMA, NDEA, NDIPA, NIPEA, NDBA, NMBA andlor other Nitrosamine impurities, Abbreviations: NDMA: N-Nitoso dimethyl amine DEA: N-Nitvoso diethyl amine NDIPA: N-Nitros disopropy| amine \NIPEA: N-Nitosoisopropylthyl amine DBA: N-Nitrosoi-n-butyl amine NMBA: N-IMethyl-N-niteoto-4-amino butyric acid Page 1of 4HETERO LABS LIMITED (UNIT-I1) 1. Materials Evaluation: “The materials considered for tis assessment areas mentioned in below table, S.No. Category ‘Material Name 2-BUTYL-4-CHLORO-5-FORMYL IMIDAZOLE 1. | API Stating Material ‘4 BROMO METHYL 2-CYANO-1,1 BPHENYL intermediate ‘Stage-1 (LSR) Tne Stage SR) 2 Sige SRI) 3 [APT — 6 |SQRBSREO ET | ssn, Metal TEA yl Ace PA end Aosone 7._| Cleaning solvents ‘Methanol : - 1.1 All General materials, fresh solvents used in the process are evaluated and found there are no sourees containing Sodium nitrite (Example: Sodium Azide ets), 1.2 Based on the assessment nitrite source (Example Sodium Azide) was not used, only DMF is used ‘in the manufacturing process ofthe API starting material, Hence no significant Risk associated ‘with Nitcosamine impurities in Losartan Potassium APL from either ofthe starting materials. 1.3 Based on the manufacturing proces review itis concluded that Sodium Azide, Triethyl amine and ‘TBAB is used, DMF possible from API staring material and hence potenial formation for \Nitrsamine impurities NDMA, NDEA and NDBA are considered ‘Unlikely’ in the ‘manufacturing process and other Nitrosamine impurities NMBA, NDIPA and NIPEA ate not possible in the manufacturing process, 1.4 Formation of Nittosamine impurities ate nt possible from the degradation of Losartan Potassium APL 1S Process related impurities Potential impurities are identified inthe API and established routine contol as part of APL release specifications. Fach manufactured batch is tested in accordance with the established specifications. 1.6 Packing materials: Losartan Potassium API is packed in double layered polythene LDPE bags, followed by secondary packing of HDPE Drums. The product contact transparent LDPE bagis made with food trade pramules which is compatible with Losartan Potassium API Page 2 0f4HETERO LABS LIMITED (UNIT-I11) 2.0 Confirmatory esting: ‘Three batches of Losartan Potasium API samples are tested wih a validated text method and the resulls for Nitrosamine Impurities (NDMA, NDEA, NDBA, NMBA, NIPEA and NDIPA) are found not detected, The results are tabulated below. Batch No. NDMA Results [NDEA Results NDBA Results HLLS20010001 | Not Deteced Not Detected Not Detected HL/LS20010002 Not Detected ‘Not Detected NowDeteced | HL/LS20010003, Not Deteied ‘Not Deeced Not Detected Batch No. NMBA Results| NIPEA Results Npira Rett | HLILS20010001| Not Detected Not Detected ‘Not Detected HUULS20010002 Not Detected Not Detected Not Detected HLILS20010005, Not Detected Not Deteced NotDetcied | 30 Machine 3.1 Manufacturing equipment ‘Manufacturing equipment is compatible throughout manufietuing process. No possibility for ‘contamination ot lesching of primary / secondary amines or NO, NO) compounds from any of ‘the equipment used in the process of Losartan Potassium. It can be eonchided that equipment cannot contribute in the formation of Nitwosamine impurities during processing. 32 Cleaning of equipment ‘Equipment cleaning procedures are established and cleaned a per respective cleaning procedures and details are documented. Cleaning activity is conducted after each product change over for ‘ulti products manufacturing and recovery solvents equipment. During product change over leaning (thorough rinse with water followed by Reflux with suitable solvent) fal rinse is tested {or previous product content, Fresh solvents are only used for equipment cleaning. During leaning. activity there is no possibility of contamination or formation of Nitrosamine impurities, Page 3 of 4HETERO LABS LIMITED (UNIT-II1) 3.3 Equipment contamination Assessment detils with respect to formation of Nitosamine impurities, all te ARBs products fre manufecured ina dedicated block, no other products are manufietured in ARBS manufacturing block Losartan Potassium product is manufactured in dedicated equipment, all the manufactured batches of Losartan Potassium are tested for Nitrsamine Impurities (NDMA, NDEA, NMBA, NDBA, NDIPA and NIPEA). Cleaning samples ate als tested for Nitrosamine Impurities (NDMA, NDEA, NMBA, NDBA, NDIPA and NIPEA) were found Not Detected, The formation of Nitrosamine impurities NDMA, NDEA and NDBA are considersd “Unlikely” and other Nitrosamine impurities NMBA, NDIPA and NIPEA are not posible inthe manufacturing process. Henge, no risk for formation /eanyover / contamination of Nitosamine impurities in Losartan Potassium from manufacturing process. No recovered solvents are used inthe manufacturing process of Losartan Potisium, Hence no potential for contamination or cross contamination of recovered solvents manufacturing lines, 344 In Losartan Potassium manufeeturing process, Toluene, Methanol, TEA, Ethyl Acetate, IPA and 50 Acetone solvents are used, Men Exiablished systems are followed by trsined personne! during Cleaning, manuficturing, Packing, and testing. Conclusion of Risk assessment: In Losartan Potassium manufacturing process and its components, the formation of Nitrosamine ‘impurities NDMA, NDEA and NDBA are considered “Unlkely* and other Nitrosamine impurities NMBA, NDIPA and NIPEA are not possible in the manufacturing process. The same Is concluded by testing of representative batches, ‘Based on overall assessment, itis concluded that there is no Risk identified due to Nitrosamine impurities in Losartan Potassium manufactured st M's, Hetero Labs Limited (Unit, For Hetero Labs Limited (Unit-I1) BYS. AGM-QA Page 4 of 4