<<

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- impurities in sartan medications after NMDA and NDEA were detected in some 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 (secondary or tertiary) with a nitrosating agent (e.g. , / H+, 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 , 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 (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 ? (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 trace nitrite provided offering cross – Water for formulation generally no potential for formation pharma advice as how to 4. Could formulation process lead to potential nitrosation? best to move forward and – Low pH (3 to 4) higher potential, pH > 7 “No potential” includes both literature – API aqueous solubility, water content of formulation and scientific rationale

5. Understand safety limits for potential nitrosamine

13 https://efpia.eu/media/580594/workflows-for-quality-risk-management-of-nitrosamine-risks-in-medicines.pdf Accompanying Guidance notes (Continued)

6. Calculation of potential nitrosamine that could form versus provided ADI: – No further action required if estimated level

10. Mitigation to take should a nitrosamine be confirmed through testing: and scientific rationale – Could lead to re-formulation activities – Any new product would need to be reassessed

14 https://efpia.eu/media/580594/workflows-for-quality-risk-management-of-nitrosamine-risks-in-medicines.pdf GSK Experiences – Practicalities

– DP workflow is a simple but robust approach to quickly understanding likely potential for nitrosamines

– Identifying presence of amines is key focus: – Output from API risk assessment highlights potential amines for further assessment – Understanding likelihood of presence of amines within excipients similarly important

– GSK have reviewed excipients from ~3000 suppliers: – Created internal Excel database with output information – Identified a limited number of excipients which have the potential presence of amines

– Reinforced excipient assessment by consideration of relevant monograph in Handbook of Pharmaceutical Excipients

15 GSK Experiences – Inform the Risk

Likelihood of nitrosamine In silico predictions Marker synthesis & relevant In vivo study Analysis in the Nitrite source formation in potential formulation of toxicity chemistry experiments to Ames assay drug product in formulation (reaction conditions) understand formation

No risk if not How much ? Risk assessment Expert knowledge Ease of synthesis Outcome & Method capability Confirm present ! context mutagenicity Inform the risk pH of formulation ‘Read across’ Reaction conditions Understanding used CoC nitrosamine, throughout shelf life Potential control Iterative Process API aq. solubility Justification ICH M7 mutagen limits (e.g. control to Link to or non mutagenic Batch selection ADI or ICH Q3B) Could lead to: Water content micro-reaction conditions Levels observed Substitution Calculate potential Expert assessment in formulation levels Provides ADI Safety justification Reformulation Versus daily dose Stability

Additives Justification Justification 16 GSK Experiences – Inform the Risk

Likelihood of nitrosamine In silico predictions Marker synthesis & relevant In vivo study Analysis in the Nitrite source formation in potential formulation of toxicity chemistry experiments to Ames assay drug product in formulation (reaction conditions) understand formation

No risk if not How much ? Risk assessment Expert knowledge Ease of synthesis Outcome & Method capability Confirm present ! context mutagenicity Inform the risk pH of formulation ‘Read across’ Reaction conditions Understanding used CoC nitrosamine, throughout shelf life Potential control Iterative Process API aq. solubility Justification ICH M7 mutagen limits (e.g. control to Link to or non mutagenic Batch selection ADI or ICH Q3B) Could lead to: Water content micro-reaction conditions Levels observed Substitution Calculate potential Expert assessment in formulation levels Provides ADI Safety justification Reformulation Versus daily dose Stability

Additives Justification Justification 17 Potential risk identified – estimation of likely levels of nitrite in excipients

– Use excipient specification detail for nitrite levels where available: – Not generally captured within excipient specification

– Vitic Nitrite in excipients database: – Provides a range of data for individual excipients – To ensure a suitably conservative assessment the highest recorded level for nitrite is used for predictive purposes

– Where no excipient data is available a generic 5 ppm figure is used

– Testing of relevant excipient batches where a decision to progress to testing has been made: – Output results can be used to understand potential factors for formation i.e. available nitrite versus observed nitrosamine (if detected) – Provide any excipient testing results to Lhasa to build capability of the Vitic Nitrite in excipient database in Excipients Data Sharing Initiative

and nitrites are common nitrosating impurities that can be found in excipients, and therefore the level of risk posed by these impurities needs to be established.

• Working closely together, Pharmaceutical industry and Lhasa Limited have established a database to help support the assessment of the level nitrosamine risk.

• The aim is to develop a comprehensive and robust dataset of the shared analytical data, on level of nitrates and nitrites in a broad range of excipients. 500 70 64 440 450 • Vitic is the platform used to host the data 60 54 400 sharing initiative. 350 50 277 300 40 250 • Third database update was 5th March 30 200 23 130 2021 and data collection is ongoing. 150 20 100

Number Number studies of 10 • The database contains 440 studies for 50 Number excipients of 0 0 64 excipients. 2020.1 2020.2 2021.1 2020.1 2020.2 2021.1 Database updates Database updates Potential risk identified – calculation for potential NDMA presence 50 mg tablet for a product with a 300 mg daily dose

50 mg tablets Potential Nitrite ppm Wt (mcg) in single dose (50 Ingredient mg % (Lhasa Vitic DB) mg)

API 70.0 23.4 0 0

Lactose monohydrate 70.0 23.4 1.7 0.12

Lactose anhydrous 140 46.7 <0.5 0.07

Microcrystalline Cellulose 15.5 5.2 2.38 0.04

Croscarmellose sodium 3 1.0 <0.5 0.001

Magnesium Stearate 1.5 0.5 4.6 0.01 Total 300 100.00 0.241 Safety limit for nitrosamine of concern (Computational Toxicology) = 96 ng per day Estimated weight of nitrite in 300 mg daily dose = 0.241 x 6 = 1.45 mcg (0.0315 micromole) Molecular weight of nitrite = 46 Molecular weight of NDMA = 74 Highest level of nitrosamine which could form from daily dose is 74/46 x 1.45 = 2.33 mcg (100% conversion) Formulation “conversion factor” could be applied – NDMA level > 10% ADI even assuming only 1% conversion Identified potential for nitrosamine formation at > ADI therefore testing recommended Current status – High Level

– Step 2 confirmatory testing in progress

– Markers of nitrosated API being prepared where RA highlighted potential for nitrosamine formation

– Activated tertiary amine APIs which could potentially release low molecular weight nitrosamine if nitrosated generally appear low potential for oral solid dose type formulations

– Activated amines include those with proximal aromatic and heteroaromatic rings or other functionality which would facilitate loss of a nitrosamine if nitrosation was to occur

– Observation aligned with literature1 confirming tertiary amines are at least 1000 fold less reactive than secondary amines

1. S.S Mirvish; “Kinetics of dimethylamine nitrosation in relation to nitrosamine carcinogenesis” J. Nat. Inst.; 1970, 44 (3), 633 to 639 Confirmatory testing at GSK

– Quantitative analysis (LC-MS/MS) of nitrosamine capabilities within GSK UK and US: – Additionally using CROs for trace level analysis

– Ion chromatography systems also being used for nitrite analysis

– GSK experience that it takes typically 6-8 weeks to develop quantitative trace (ng/g) nitrosamine methods, plus validation and testing

Learning: – Analysis to such trace levels has significant difficulties with potential false positives: – Trace DMF can give rise to a false positive for NDMA (use of second derivative to confirm peak): – Can be other formamides from other dialkylamines – Co-eluting impurity peaks at such low levels are an observed issue – Potential for forming nitrosamine during the analytical preparation / on the column in low pH especially in presence of acetonitrile – Overall analysis at such low levels in complex matrices brings difficulties per product.

– Important to understand analysis prior to reporting (Aligns with Health Canada Q&A) Output science based assessment – potentially reactive amine present

Where a potentially reactive amine is present within the formulation then discussion is required to inform the assessment reviewer of the nature of the potential and provide a science based rationale why a conclusion of “there is, or isn’t” an identified potential for nitrosamines can be made. The discussion includes:

– Relevance of the amine – likelihood of nitrosation? – Potential pH of the DS / DP – Solubility of the DS within the formulation – Levels of water within the formulation (heterogeneity) – Projection of levels of corresponding nitrosamine of concern from available levels of nitrite (Lhasa Vitic) if applicable – Assessment conclusion – Where potential for nitrosamine is identified, the RA would be updated with results from confirmatory testing once available

Assessment conclusions further reinforced by including supporting references to scientific literature

Important that an “unfamiliar” reviewer can follow the science based rationales which lead to the RA conclusion Where there is no amine or nitrosating agent identified, it is appropriate to conclude no identified potential with limited discussion Experiences related to regulatory interactions

Regulatory activity (Commercial): – Experience suggests that DP assessment with clear rationale is key – Important to explain i) why it’s clear there is no risk or ii) if there is a risk then why is this – Provide assessments for where potential for presence of nitrosamines has been identified – Likely that stage 2 (Confirmatory testing) will lead to more regulatory interaction (understanding contributing factors) – Look to provide a root cause when nitrosamines are detected

Regulatory activity (R&D): – Recent marketing applications have included position for nitrosamine assessment: – Acceptable to some authorities, others request provision of full assessment – Assessment reports were requested for two products; and day 180 major objection raised which was later resolved through provision of the assessment and accompanying discussion. – Going forward and aligned with industry positioning, summary outcomes will be provided in Module 3, and the assessment report will be attached to Module 1 for certain markets (e.g., EU, UK) Future State

CMC and Quality – Continue to refine the assessment process and share knowledge of what constitutes a risk: – GSK testing suggests tertiary amine API within an OSD is not generally a concern – Follow the science – Use of further testing to understand risks associated with future APIs i.e. data on one API and DP should be used to understand the risk associated with a different API and DP – Where risks are identified, share outcome from root cause analysis with industry / regulators to better understand risk factors

Safety – Chemistry: Structural basis of cohort of concern nitrosamines is well established – Biology: An OECD compliant Ames test (where the experimental design has been tailored according to the chemical class) is appropriate to understand mutagenicity without in vivo studies: – Strong correlation of mutagenicity within the Ames test to observed rodent carcinogenicity (supports framework in ICH M7) – Use of Ames test profile to understand potential mutagenicity i.e. confirmed CoC versus likely ICH M7 standard mutagen – Thresholds of toxicological concern: Move to a safety and control position aligned with ICH M7: – Is 18 ng per day an appropriate control for a potential nitrosated API or could a “still conservative” figure of 50 ng be considered? – Nitrosamines are therefore use of less than life time approaches should be appropriate – Follow the science – where an in vivo study is conducted, use of output data to assign an ADI1

1. E. Gocke & L. Muller; “In vivo studies in the mouse to define a threshold for the genotoxicity of EMS and ENU”; Mutat Res.; 2009, 678(2), 25 101 to 7 (doi: 10.1016/j.mrgentox.2009.04.005) Conclusions and Acknowledgements

Summary Acknowledgements Andrew Lennard Amgen David Hobbs Lilly – Background to nitrosamines ✓ Heather Akehurst AZ Justin Moser MSD Ian Ashworth AZ Thomas Storm Novartis – Development of a cross industry aligned approach to the nitrosamine assessment of drug products ✓ Dawn Sievwright AZ Laurence Harris Pfizer Fiona King GSK Ron Ogilvie Pfizer – GSK experiences of using this workflow to perform drug Paul Trusty GSK Alain Sirvain Sanofi product assessments ✓ Mike O'Sullivan GSK Nigel Hamilton Sanofi Steve Hermitage GSK Rajesh Kamat Sanofi – Experiences relating to regulatory submissions ✓ Jim Harvey GSK Philip Lienbacher Takeda Matt Popkin GSK Valeria Coscia Takeda – Forward looking – potential alignment with ICH M7 ✓ Mat Whiting GSK Tim Curran Vertex Andy Whitehead GSK

Many thanks to Lhasa for the invitation and to you for your attention

26 Questions?

27