Risk Assessment Best Practice - Development of a Cross ...
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Risk Assessment Best Practice - Development of a Cross Pharma Work-flow for DP Nitrosamine Risk Assessment
Lhasa Brazil Webinar: 14th July 2021
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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
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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
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Nitrosamines – how they form and areas of focus?
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Drug Substance
Science
Reagent
Impurity / by-product
Part of DS scaffold
Quality
“Cross contamination”
Recycled solvents,
reagents or catalysts
Multipurpose equipment
Quality
“Cross contamination”
Recycled solvents,
reagents or catalysts
Multipurpose equipment
Science
Reagent
Impurity / by-product
Part of DS scaffold
Science
Reagent
Impurity / by-product
– 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
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
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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.
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Nitrosamines – how they form and areas of focus?
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Drug Product
Science (DS)
Part of DS scaffold
“Higher Potential”
Science (DP)
Impurity within excipients
“Higher Potential”
Science (DP)
Impurity in API / excipient
Amine excipient(?)
“Lower Potential”
Science (DS)
Impurity in DS
Part of DS scaffold
“Lower Potential”
Science (DS)
Impurity
in DS
Impurity derived from
packaging
– 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)
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?
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IQ / EFPIA Drug product (DP) Workflow 1
Critique conditions of formulation for likelihood of nitrosation (e.g. pH, Temp, solution). Is nitrosation expected? (Y/N)
Guidance Note 4
Y
Risk identifiedTest DP for potential nitrosamine of concern
Present at ≥ agreed level (Y/N)Guidance Note 2
Y
Risk ConfirmedDocument / Report findings
Initiate change control (process and processing
materials)Verify change effectiveness
Guidance Note 10
Does the DS, or do the DP excipients, contain tertiary or secondary amines that could react with a nitrosating agent leading to a nitrosamine(s)? (Y/N)
Guidance Note 2
No risk identifiedProceed to packaging assessment
DP workflow 2
Y
N
N
Y
Does the DS, or do the DP excipients, contain a source of nitrosating agent e.g. nitrite? (Y/N)Guidance Note 3
Y
Seek guidance from safety group – extent of risk and levels for controlIs nitrosamine a potential mutagen? (Y/N)
Guidance Note 5
Calculate potential level of nitrosamine which could form. Is nitrosamine level ≥ agreed level? (Y/N)
Guidance Notes 6 and 8
Y
Consider Ames testing nitrosamine of concern. Is nitrosamine mutagenic / assumed to be mutagenic (Y/N)
Guidance Note 7
Y
N
N
N
N
N
Proceed to packaging assessmentDP workflow 2
Is there a risk for the DS or excipients to contain nitrosamines? (Y/N)
Guidance Note 1
Risk Confirmed
Proceed to DP workflow 3
N
Y
IQ / EFPIA Drug product (DP) Workflow 2
Risk identifiedTest DP for potential nitrosamine of concern
Present at ≥ agreed level (Y/N)Guidance Note 8
Risk ConfirmedDocument / Report findings
Initiate change control (process and processing materials)
Verify change effectivenessGuidance Note 10
N
Risk identifiedSeek guidance from safety group – extent of risk and
levels for control
(Is nitrosamine a potential mutagen and predicted to be above level of concern? (Y/N)
Guidance Note 5
Y
N
Y
Does packaging contain materials of concern? Is potential nitrosamine likely to be ≥ agreed levels (Y/N)
Guidance Note 9
N
Y
No risk identified
Document risk assessment output
IQ / EFPIA Drug product (DP) Workflow 3
Risk identifiedTest DS &/or excipients for potential nitrosamine
of concernPresent at ≥ agreed level (Y/N)
Guidance Note 8
Risk ConfirmedDocument / Report findings
Initiate change control (process and processing materials)
Verify change effectivenessGuidance Note 10
No risk identified
Proceed to DP workflow 1
Is there a risk for the DS or excipients to contain nitrosamines? (Y/N)
Guidance Note 1
Risk identifiedSeek guidance from safety group –extent of risk and levels for control
Is nitrosamine a potential mutagen (Y/N)
Guidance Note 5
N
Y
Y
N
N
Y
Proceed to DP workflow 1 box 2 (guidance note 2)
Accompanying Guidance notes
1. Is there a potential nitrosamine from the API or excipient?
2. Is there a source of amine within the API or excipient?
– Low level impurities are considered low potential for nitrosation
– Not all secondary amines are reactive toward nitrosation
– Tertiary amines are lower reactivity
3. Potential for containing a nitrosating agent?
– Excipients can contain trace nitrite
– Water for formulation generally no potential for formation
4. Could formulation process lead to potential nitrosation?
– Low pH (3 to 4) higher potential, pH > 7 “No potential”
– API aqueous solubility, water content of formulation
5. Understand safety limits for potential nitrosamine
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DP assessment for the potential of nitrosamines is complex
Guidance notes are provided offering cross pharma advice as how to best to move forward and includes both literature and scientific rationale
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 <ADI
8. Manufacture of a nitrosated marker of DP:
– Inability to manufacture a stable marker can justify no further action
– Use of literature to confirm whether nitrosation is likely / product stable
– Sample can be Ames tested to understand potential mutagenicity (Note 7)
– Testing DP with highest risk of NA formation should be the focus (formulation
and samples from manufacture through to end of shelf life)
9. Consider impact from packaging (nitrocellulose which could react from
amines within printing ink during heating sealing process):
– Generally considered to be very low
– Should consider multiple daily dosing
10. Mitigation to take should a nitrosamine be confirmed through testing:
– Could lead to re-formulation activities
– Any new product would need to be reassessed
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DP assessment for the potential of nitrosamines is complex
Guidance notes are provided offering cross pharma advice as how to best to move forward and includes both literature and scientific rationale
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
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GSK Experiences – Inform the Risk
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Likelihood of nitrosamine
formation in potential formulation
(reaction conditions)
Nitrite source
in formulation
In silico predictions
of toxicity Ames assayMarker synthesis & relevant
chemistry experiments to
understand formation
In vivo studyAnalysis in the
drug product
No risk if not present !
How much ?
Inform the risk
Iterative Process
Could lead to:
Substitution
Reformulation
Additives
Risk assessment
pH of formulation
API aq. solubility
Water content
Calculate potential levels
Versus daily dose
Justification
Expert knowledge
‘Read across’
Justification
Expert assessmentProvides ADI
Ease of synthesis
Reaction conditions used
Link to micro-reaction
conditions in formulation
Stability
Justification
Outcome &context
CoC nitrosamine, ICH M7 mutagen or non mutagenic
Confirm mutagenicity
Potential control limits (e.g. control to
ADI or ICH Q3B)
Method capability
Understanding throughout shelf life
Batch selection
Levels observed
Safety justification
GSK Experiences – Inform the Risk
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Likelihood of nitrosamine
formation in potential formulation
(reaction conditions)
Nitrite source
in formulation
In silico predictions
of toxicity Ames assayMarker synthesis & relevant
chemistry experiments to
understand formation
In vivo studyAnalysis in the
drug product
No risk if not present !
How much ?
Inform the risk
Iterative Process
Could lead to:
Substitution
Reformulation
Additives
Risk assessment
pH of formulation
API aq. solubility
Water content
Calculate potential levels
Versus daily dose
Justification
Expert knowledge
‘Read across’
Justification
Expert assessmentProvides ADI
Ease of synthesis
Reaction conditions used
Link to micro-reaction
conditions in formulation
Stability
Justification
Outcome &context
CoC nitrosamine, ICH M7 mutagen or non mutagenic
Confirm mutagenicity
Potential control limits (e.g. control to
ADI or ICH Q3B)
Method capability
Understanding throughout shelf life
Batch selection
Levels observed
Safety justification
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
Nitrites in Excipients Data Sharing Initiative
• Nitrates 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.
2020.1 2020.2 2020.1 2020.2N
um
ber
of
stu
die
s
Num
ber
of
excip
ients
Database updates
130
277
440
0
50
100
150
200
250
300
350
400
450
500
2021.1
23
54
64
0
10
20
30
40
50
60
70
2021.1
Database updates
• Vitic is the platform used to host the data
sharing initiative.
• Third database update was 5th March
2021 and data collection is ongoing.
• The database contains 440 studies for
64 excipients.
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
Ingredient mg %ppm
(Lhasa Vitic DB)Wt (mcg) in single dose (50
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
– 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
Current status – High Level
1. S.S Mirvish; “Kinetics of dimethylamine nitrosation in relation to nitrosamine carcinogenesis” J. Nat. Cancer Inst.; 1970, 44 (3), 633 to 639
– 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)
Confirmatory testing at GSK
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
Output science based assessment – potentially reactive amine present
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)
Experiences related to regulatory interactions
Future State
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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 mutagens 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),
101 to 7 (doi: 10.1016/j.mrgentox.2009.04.005)
Conclusions and Acknowledgements
Summary
– 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 ✓
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Acknowledgements
Andrew Lennard Amgen David Hobbs Lilly
Heather Akehurst AZ Justin Moser MSD
Ian Ashworth AZ Thomas Storm Novartis
Dawn Sievwright AZ Laurence Harris Pfizer
Fiona King GSK Ron Ogilvie Pfizer
Paul Trusty GSK Alain Sirvain Sanofi
Mike O'Sullivan GSK Nigel Hamilton Sanofi
Steve Hermitage GSK Rajesh Kamat Sanofi
Jim Harvey GSK Philip Lienbacher Takeda
Matt Popkin GSK Valeria Coscia Takeda
Mat Whiting GSK Tim Curran Vertex
Andy Whitehead GSK
Many thanks to Lhasa for the invitation and to you for your attention