Risk Assessment Best Practice - Development of a Cross Pharma Work-flow for DP Nitrosamine Risk Assessment Lhasa Brazil Webinar: 14th July 2021 1 Mike Urquhart Today’s Presentation – Background to nitrosamines – Development of a cross industry aligned approach to the nitrosamine assessment of drug products – GSK experiences of using this workflow to perform drug product assessments – Experiences relating to regulatory submissions – Forward looking – potential alignment with ICH M7 Background 2017-2018 Valsartans (and Sartans) – 2018 concerns were raised around the presence of N-nitroso impurities in sartan medications after NMDA and NDEA were detected in some valsartan products – Root causes: low level impurities formed during manufacture and not identified as risk during M7 RA – Contamination traced to recycled solvents – All sartans to be reviewed as considered high risk due to potential use of nitrosamine-generating chemistry in the synthesis – EMA published new limits for common nitrosamines in sartans and agencies globally began testing sartan batches and publishing results 2019 General Requests for Nitrosamine Risk Assessments – Companies to address risks of nitrosamines in all products, via a 3 step process – Step 1: Risk assessment of all commercial products to define where there is risk – Step 2: Confirmatory testing of drug products where risk is identified – Step 3: Remediate (e.g. via controls or product/process changes) where a nitrosamine risk is confirmed – Initially in EU, Switzerland and HC then requirements mirrored in US, China, S Korea, Brazil, Japan, Turkey…… – Tens of thousands of products (API and finished product) in scope 3 Nitrosamines – how they form and areas of focus? – Reaction of a vulnerable amine (secondary or tertiary) with a nitrosating agent (e.g. nitrous acid, nitrite / H+, alkyl nitrite) – DS the main focus but there is a risk for the DP and assessment needs to involve both “science” and “quality”: – Assessment of route and processes required as well as potential for cross contamination 4 Nitrosamines – how they form and areas of focus? Science Drug Substance Reagent Impurity / by-product Part of DS scaffold Science Science Reagent Reagent Impurity / by-product Impurity / by-product Part of DS scaffold Quality Quality “Cross contamination” “Cross contamination” Recycled solvents, Recycled solvents, reagents or catalysts reagents or catalysts Multipurpose equipment Multipurpose equipment – Need to ensure all materials / reagent, impurities, and potential contaminants are included in assessment – Note, nitrite is a known contaminant of potable water and so use of water can potentially be a source reagent if present with a secondary amine under acidic conditions (OPRD paper written through pharma IQ consortium describes when further assessment is required) – If formation is identified then need to consider downstream purge 5 Nitrosamine potential from nitrite present within water Manuscript published in 2020 in OPRD – Org. Process Res. Dev. 2020, 24, 1629−1646 Key messages: – Levels of nitrite in water used in manufacture of APIs are typically very low (<0.01 mg/L) – This level of nitrite will not generally give rise to significant levels of N-nitrosamines from basic amines, such as dimethylamine, under typical processing conditions – Use of less basic amines, elevated temperature or low pH conditions with “elevated” levels of nitrite could lead to higher levels of N-nitrosamines: – Greater impact if formed close to final API stage – Tertiary alkyl amines generally not considered likely to form nitrosamines from trace nitrite – No identified potential if purified water is used as nitrite levels are expected to be extremely low 6 API Nitrosamine Assessment workflow developed GSK a major contributor and published on the EFPIA Website as best practice guide. https://efpia.eu/media/580594/workflows-for-quality-risk-management-of-nitrosamine-risks-in-medicines.pdf Assessment focusses on: 1. Have any sources of N-nitrosamines or nitrosating agents been identified in the manufacturing processes or the API itself? 2. Have any sources of secondary or tertiary amines been identified in the manufacturing processes or the API itself, if they have then describe any accompanying risk of N-nitrosamine formation? (Assessment only required if a source of nitrosating agent was identified in 1.) 3. Have any recovered / recycled materials or solvents been used during the registered manufacturing process? 4. Do the recovered / recycled materials or solvents that have been used during the registered manufacturing process pose a cause for concern due to the potential for contamination with N-nitrosamines, nitrosating agents or secondary / tertiary amines? Any identified potential for formation leads to testing of API for nitrosamine of concern which could lead to manufacturing process changes. 7 Nitrosamines – how they form and areas of focus? Drug Product Science (DP) Impurity within excipients “Higher Potential” Science (DS) Part of DS scaffold “Higher Potential” Science (DS) Impurity in DS Impurity derived from packaging Science (DP) Science (DS) Impurity in API / excipient Impurity in DS Amine excipient(?) Part of DS scaffold “Lower Potential” “Lower Potential” – Factors for formation of nitrosamines in the DP are not well understood at this time: – Excipients may contain nitrite (assume 5 ppm) – unusual for excipients to contain reactive amines – Formulations range from dry and heterogenous to solution – Potential formation from formulation, process and stability needs to be assessed as well as packaging (e.g. nitrocellulose) 8 Benefits of developing an industry aligned DP risk assessment work-flow – Factors for the potential of nitrosamines within DP were not well understood – Opportunity to learn from other scientists, company experiences as well as share literature knowledge – Provide a robust process for risk assessment accessible for everyone – Builds consistency of assessment across companies which gives assurance that appropriate rigour has been adopted – The final risk assessment was reviewed across both EFPIA and IQ consortia – each company had a voice / was listened to – Resulted in “best practice” guidance to DP risk assessment being published for all to use: – https://efpia.eu/media/580594/workflows-for-quality-risk-management-of-nitrosamine-risks-in-medicines.pdf What does the DP assessment process look like? 9 IQ / EFPIA Drug product (DP) Workflow 1 Is there a risk for the DS or excipients to N Does the DS, or do the DP excipients, contain tertiary or secondary amines N contain nitrosamines? (Y/N) that could react with a nitrosating agent leading to a nitrosamine(s)? (Y/N) Guidance Note 1 Guidance Note 2 Y Y Risk Confirmed Does the DS, or do the DP excipients, contain a source of nitrosating agent N No risk identified e.g. nitrite? (Y/N) Proceed to packaging assessment Proceed to DP workflow 3 Guidance Note 3 DP workflow 2 Y Critique conditions of formulation for likelihood of nitrosation (e.g. pH, Temp, N solution). Is nitrosation expected? (Y/N) Guidance Note 4 Y Proceed to packaging assessment Seek guidance from safety group – extent of risk and levels for control N DP workflow 2 Is nitrosamine a potential mutagen? (Y/N) Guidance Note 5 Y Risk Confirmed Calculate potential level of nitrosamine which could form. Is N Document / Report findings nitrosamine level ≥ agreed level? (Y/N) Initiate change control Guidance Notes 6 and 8 (process and processing materials) Y Verify change effectiveness Guidance Note 10 Consider Ames testing nitrosamine of concern. Is nitrosamine mutagenic / N assumed to be mutagenic (Y/N) Guidance Note 7 Y Risk identified Y Test DP for potential nitrosamine of concern N Present at ≥ agreed level (Y/N) Guidance Note 2 IQ / EFPIA Drug product (DP) Workflow 2 Does packaging contain materials of concern? Is N potential nitrosamine likely to be ≥ agreed levels (Y/N) Guidance Note 9 Y Risk identified Seek guidance from safety group – extent of risk and No risk identified levels for control N (Is nitrosamine a potential mutagen and predicted to be above level of concern? (Y/N) Document risk assessment output Guidance Note 5 Y Risk identified Test DP for potential nitrosamine of concern N Present at ≥ agreed level (Y/N) Guidance Note 8 Y Risk Confirmed Document / Report findings Initiate change control (process and processing materials) Verify change effectiveness Guidance Note 10 IQ / EFPIA Drug product (DP) Workflow 3 Is there a risk for the DS or excipients to N contain nitrosamines? (Y/N) Guidance Note 1 Y Risk identified Seek guidance from safety group – No risk identified extent of risk and levels for control N Is nitrosamine a potential mutagen Proceed to DP workflow 1 (Y/N) Guidance Note 5 Y Risk identified Test DS &/or excipients for potential nitrosamine N of concern Present at ≥ agreed level (Y/N) Guidance Note 8 Y Risk Confirmed Document / Report findings Initiate change control (process and processing materials) Verify change effectiveness Guidance Note 10 Proceed to DP workflow 1 box 2 (guidance note 2) Accompanying Guidance notes 1. Is there a potential nitrosamine from the API or excipient? DP assessment for the 2. Is there a source of amine within the API or excipient? potential of nitrosamines is – Low level impurities are considered low potential for nitrosation – Not all secondary amines are reactive toward nitrosation complex – Tertiary amines are lower reactivity 3. Potential for containing a nitrosating agent? Guidance notes are – Excipients can contain