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ICH M7 Industry Perspective
AAPS Short Course
25Oct2015
David DeAntonis – Pfizer Inc.
• High level perspectives on overall guidance –
• Focus on Section 8 – Control Options
– Overview of each control option
– Impurity Purge Tool and Importance of Option 4
• Focus on Section 5
– ICH Q3 vs. M7
– Selection of impurities to assess
– Data Mining of Recent Projects
• ICH M7 Appendix 2: Case Examples
• Summary
Outline
• High level perspectives on overall guidance –
• Focus on Section 8 – Control Options
– Overview of each control option
– Impurity Purge Tool and Importance of Option 4
• Focus on Section 5
– ICH Q3 vs. M7
– Selection of impurities to assess
– Data Mining of Recent Projects
• ICH M7 Appendix 2: Case Examples
• Summary
Outline
ICH M7 Overview
Assessment and Control of DNA Reactive (Mutagenic) Impurities in
Pharmaceuticals to Limit Potential Carcinogenic Risk
1. Introduction
2. Scope of Guideline
3. General Principles
4. Considerations for Marketed Products
5. Drug Substance and Drug Product Impurity Assessment
6. Hazard Assessment Elements
7. Risk Characterization
8. Control
9. Documentation
Notes
Glossary
References
Appendices
ICH M7 – Scope and Marketed Products
Assessment and Control of DNA Reactive
(Mutagenic) Impurities in Pharmaceuticals to
Limit Potential Carcinogenic Risk
1. Introduction
2. Scope of Guideline
3. General Principles
4. Considerations for Marketed Products
5. Drug Substance and Drug Product
Impurity Assessment
6. Hazard Assessment Elements
7. Risk Characterization
8. Control
9. Documentation
Notes
Glossary
References
Appendices
M7 Scope: “This document is intended to provide guidance for new drug
substances and new drug products during their clinical development and
subsequent applications for marketing. It also applies to post-approval
submissions of marketed products, and to new marketing applications for
products with a drug substance that is present in a previously approved product,
in both cases only where” • Changes to the drug substance synthesis
• Changes to the formulations, composition, or
manufacturing process….
• Changes in indication or dosing regimen….
Section 4 and Appendix 1 provides details on the
above
M7 is the first ICH guidance to provide clarity on
application to marketed products; however early
regulatory experiences indicate expectation for
application of M7 even when there is no change to
the marketed product – continues to be a
challenging area
ICH M7 – Clinical Development Considerations
Assessment and Control of DNA Reactive
(Mutagenic) Impurities in Pharmaceuticals to
Limit Potential Carcinogenic Risk
1. Introduction
2. Scope of Guideline
3. General Principles
4. Considerations for Marketed Products
5. Drug Substance and Drug Product
Impurity Assessment
6. Hazard Assessment Elements
7. Risk Characterization
8. Control
9. Documentation
Notes
Glossary
References
Appendices
Section 3: “ During clinical development, it is expected that control
strategies and approaches will be less developed in earlier phases
where overall development experience is limited”
Section 5: Recognition that ICH Q3A/B thresholds do not apply to
products in clinical development
Section 7: Phase I clinical studies 14 days or less – only need to
control known mutagens (class 1 or 2) or class 3 cohort of concern
Section 8: Recognition that limited data would be available to support
control options; focus efforts on the highest risk areas; greater
acceptance of purge arguments in-lieu of data
Section 9: Limited documentation requirements in regulatory filings in
early development; increases with phase
Recognition throughout the M7 guidance for alternative approaches for products in
clinical development
ICH M7 – Hazard Assessment
Assessment and Control of DNA Reactive
(Mutagenic) Impurities in Pharmaceuticals to
Limit Potential Carcinogenic Risk
1. Introduction
2. Scope of Guideline
3. General Principles
4. Considerations for Marketed Products
5. Drug Substance and Drug Product
Impurity Assessment
6. Hazard Assessment Elements
7. Risk Characterization
8. Control
9. Documentation
Notes
Glossary
References
Appendices
• Requirement in M7 for two QSAR system analysis
• Challenges associated with conflicting results or out of domain result
• Importance of expert review
• Challenges in keeping assessments up to date over the course of a
development program
• Negative two system QSAR in-lieu of Ames testing generally supported by
ICHM7 – see note 1
Note 1 The ICH M7 Guideline recommendations
provide a state-of-the-art approach for assessing the
potential of impurities to induce point mutations and
ensure that such impurities are controlled to safe levels
so that below or above the ICH Q3A/B qualification
threshold no further qualification for mutagenic
potential is required. This includes the initial use of
(Q)SAR tools to predict bacterial mutagenicity. In cases
where the amount of the impurity exceeds 1 mg daily
dose for chronic administration, evaluation of genotoxic
potential as recommended in ICH Q3A/B could be
considered. In cases where the amount of the impurity
is less than 1 mg, no further genotoxicity testing is
required regardless of other qualification thresholds.
ICH M7 – Risk Characterization – setting limits
Assessment and Control of DNA Reactive
(Mutagenic) Impurities in Pharmaceuticals to
Limit Potential Carcinogenic Risk
1. Introduction
2. Scope of Guideline
3. General Principles
4. Considerations for Marketed Products
5. Drug Substance and Drug Product
Impurity Assessment
6. Hazard Assessment Elements
7. Risk Characterization
8. Control
9. Documentation
Notes
Glossary
References
Appendices
• Several approaches outlined for establishing limits
• Less than lifetime (staged TTC) limit concept extended to marketed products
• Single table for both clinical development and marketed products
• Order of magnitude higher limit for mono-functional alkyl chlorides
Determination of what LTL category a
particular drug is in and then gaining
worldwide regulatory agreement needs
consideration
Examples provided in ICHM7 Note 7
ICH M7 – Documentation
Phase Documentation Elements
Clinical Trial Applications (9.1)
• Ph 1 < 14 days: Report Class 1 and 2 impurities, and those in CoC along with control plans or chemistry arguments
• Ph 1 > 14 days, Ph 2a: Report class 1, 2 and 3 impurities that require analytical control
• Ph 2b, Ph 3: Report impurities assessed by (Q)SAR and in silico systems described, control plans or chemistry arguments for Class 1, 2 or 3 actual and potential impurities, bacterial mutagenicity results
CTD (9.2) • (Q)SAR assessments and classifications (including supporting rationale) for actual and potential impurities/degradation products (all Classes); in silico systems described; supporting bacterial mutagenicity reports
• Justification for proposed specifications and approaches to control
• High level perspectives on overall guidance –
• Focus on Section 8 – Control Options
– Overview of each control option
– Impurity Purge Tool and Importance of Option 4
• Focus on Section 5
– ICH Q3 vs. M7
– Selection of impurities to assess
– Data Mining of Recent Projects
• ICH M7 Appendix 2: Case Examples
• Summary
Outline
Section 8: Control
Four options outlined for impurity control
Pfizer
Confidential │ 11
Option 4: No testing, control assured via chemistry and process understanding
Option 3: Include impurity on a starting material, intermediate or in-process control specification with an acceptance criteria above the acceptable limit coupled with well understood purge
“If option 4 or 3 cannot be justified, then”…..
Option 2: Monitor the impurity in intermediate, starting material or in-process control with acceptance criteria < acceptable limit
Option 1: Monitor the impurity in the drug substance at the with an acceptance criteria < acceptable limit
Option 4
• Option 4 approaches “can be appropriate if the process chemistry and
process parameters that impact levels of mutagenic impurities are
understood and risk of an impurity residing in the final drug substance above
the acceptable limit is determined to be negligible”1
• ..”especially useful for those impurities that are inherently unstable…or for
those impurities that are introduced early in the synthesis and are effectively
purged” 1
• “In many cases, justification of this control approach based on scientific
principles alone is sufficient” 1
• Reference 11 in ICH M7: Teasdale A., Elder D., Chang S-J, Wang S,
Thompson R, Benz N, Sanchez Flores I, (2013). Risk assessment of
genotoxic impurities in new chemical entities: strategies to demonstrate
control. Org. Process Res. Dev. 17:221-230.
1. ICH M7 Section 8.1
Mutagenic Impurity Purge Tool
Pfizer Confidential │ 13
• Approach introduced by A.
Teasdale et al. to assess potential
carryover of a mutagenic impurity
(MI) in a synthetic process through
to API
• Each impurity is assessed on the
basis of its physicochemical
properties & reactivity under
specific processing conditions in
the synthetic pathway to establish a
predicted purge factor
• Risk assessment tool used to
identify risk.
• Calculations are quick and simple
• Focus effort on those MIs that pose
an actual risk.
Purge Factor Calculations – Basic Principles
14
Physicochemical Parameters Purge Factor
Reactivity Highly Reactive = 100
Moderately reactive = 10
Low Reactivity / un-reactive = 1
Solubility Freely Soluble = 10
Moderately soluble = 3
Sparingly Soluble = 1
Volatility Boiling point >200C below that of the reaction/
process solvent = 10
Boiling point +/- 100C that of the reaction/
process solvent. = 3
Boiling point >200C above that of the reaction/
process solvent = 1
Ionizability Ionisation potential of GI significantly different
to that of the desired product 2
Physical Processes – chromatography Chromatography – GI elutes prior to desired
product = 100
Chromatography – GI elutes after desired
product = 10
Others evaluated on an individual basis.
Purge Factor Calculations: Example
Pfizer Confidential │ 15
Stage Details
Reactivity
(100, 10, 1)
Solubility
(10, 3, 1)
Volatility
(10, 3, 1) Ionisability
Physical
Processes
Total multiple
per stage
Measured
purge factor
Step 2/3 100 10 1 1 1 1000 >500
Step 3R 1 10 1 1 1 10
Step 4 1 10 1 1 1 10
Step 5 1 3 1 1 1 3
Overall 300,000
• TTC = 60 ppm (based on max daily dose of 25 mg)
• Starting Point: Level in Step 1 product <0.1% (1000 ppm) based on batch
history data
• Required purge to meet TTC 17x
• Predicted purge 300,000x
• Maximum predicted impurity at API level = 1000 ppm/300,000 = 0.003 ppm
• Recommendation: No need to test for this MI. Supporting purge data gathered
for Step 2/3 purge.
16
The Purge Tool: Industry Consortium
Lhasa Limited + 9 participating companies working to
develop a software purge tool (Mirabilis)
Work focused on:
• Standardisation of how purge factors are calculated
• Identification of knowledge gaps
• Data generation
• Development and Testing
• Software prototypes
Building a rxn grid for classes of MI under specific rxn conditions
Based on consensus expert opinion
Reaction Type Reagent Solvent Reactive?
1 Reduction H2 Pd/C Dioxane No
2 NaBH4 MeOH, THF, DCM No
3 LiAlH4 THF No
4 DIBAL-H THF, DCM No
5 Oxidation H2O2 DCE, DCM, CH3CN Yes
6 Peracetic Acid DCM Yes*
7 Oxone CH3CN, H2O, H2O:CH3CN Yes**
8 TEMPO DCM Yes***
9 Acids Aq HCl CH3CN, THF No
10 Conc. H2SO4 H2O No
11 Aq H2SO4 H2O, Dioxane, CH3CN No
12 HBr/HOAc DCM No
13 Bases Aqueous NaHCO3 CH3CN No
14 10% NaOH CH3CN, Dioxane, H2O No
15 50% NaOH H2O Yes
16 DBU CH3CN, DCE No
17 Amide Bond Formation CDI (with benzoic acid) DCM No
18 EDAc/HOPO (with benzoic acid) DMF No
19 Benzoyl chloride THF No
20 Nucleophiles MeOH THF No
21 Benzyl amine THF No
22 Other Reagents SOCl2 DCE No
23 NCS DCE No
24 NCS/TEA DCE No
25 NBS DCE Yes****
26 Boc2O/TEA THF No
27 TMSCl/TEA THF No
28 Cross-Coupling RuPhos-Pd complex (25 mol%), K2CO3, THF/H2O ?
29 Pd2dba3 (12.5 mol%), PtBu3HBF4 (25 mol%), TEA, THF ?
Knowledge gaps (– e.g. arylboronic acids,
aromatic amines, hydrazines) identified
and experimental plans in place to fill
Example – Reaction of phenylboronic acid
under various reaction conditions
Next Steps:
• Further development of
software tool
• Database development
• Investigation into
modelling of other
parameters
• High level perspectives on overall guidance –
• Focus on Section 8 – Control Options
– Overview of each control option
– Impurity Purge Tool and Importance of Option 4
• Focus on Section 5
– ICH Q3 vs. M7
– Selection of impurities to assess
– Data Mining of Recent Projects
• ICH M7 Appendix 2: Case Examples
• Summary
Outline
ICHQ3 vs. ICHM7
0.10% ID Threshold
0.15% qualification threshold
Or higher if qualified….
ppms, TTC, staged TTC
• Risk Based Approaches
• Synthetic Route Assessments
• In-Silico Tools
• Targeted low level control
-“Lower thresholds may be appropriate for unusually toxic impurities”
18
Section 5: Impurity Assessment
• Very important part of ICH M7
• Provides guidance on impurities that need to be assessed
• Actual impurities based on ICH Q3A/B and include impurities in
the drug substance or drug product that have been identified.
• Potential can include starting materials, reagents and
intermediates downstream of the starting material, in addition
to other identified impurities
Section 5.1: Word by Word
5.1 Synthetic Impurities
Actual impurities include those observed in the drug substance above the ICH Q3A reporting thresholds.
Identification of actual impurities is expected when the levels exceed the identification thresholds outlined
by ICH Q3A. It is acknowledged that some impurities below the identification threshold may also have
been identified.
Potential impurities in the drug substance can include starting materials, reagents and intermediates in
the route of synthesis from the starting material to the drug substance.
The risk of carryover into the drug substance should be assessed for identified impurities that are present
in starting materials and intermediates, and impurities that are reasonably expected by-products in the
route of synthesis from the starting material to the drug substance. As the risk of carryover may be
negligible for some impurities (e.g., those impurities in early synthetic steps of long routes of synthesis), a
risk-based justification could be provided for the point in the synthesis after which these types of
impurities should be evaluated for mutagenic potential.
For starting materials that are introduced late in the synthesis of the drug substance (and where the
synthetic route of the starting material is known) the final steps of the starting material synthesis should
be evaluated for potential mutagenic impurities.
Actual impurities where the structures are known and potential impurities as defined above should be
evaluated for mutagenic potential as described in Section 6.
Section 5.1: Key Points
• ICH M7 focuses efforts from starting materials to the drug substance
• ICH M7 does not advise to assess starting material route of synthesis
unless..
– The starting material is introduced late in the synthesis
– The synthesis of the starting material is known
– And in this case, assess only the final steps of the SM synthesis
• What do late and final equate to? Not specified in the guidance but
generally late equates to within 3 steps from the API and final equates
to the last 2 steps of the synthesis -- this was overall intent I believe
• Important to monitor this area (selection of potential impurities)
carefully to focus efforts on significant risk activities
Experiences on Identification and Control
• Data mining of the past 10 years
• Wealth of experiences and projects
• Objective of effort
– Understand and quantitate efforts to identify, assess risk, and
control mutagenic impurities
– Understand and share learnings across project teams
– Assess frequency of use of various control approaches
– Understand how many structures assessed vs. QSAR results
– Monitor trends
– Assess impurity risk from the perspective of # of steps from API
• Work in progress
Data Mining of Past Projects – Progress To Date
23
• 19 total projects from the last 10 years
• Late stage Phase 2, Phase 3 and
commercial – all commercial or proposed
commercial synthetic routes
• Phase I and early phase II excluded from
initial analysis
• Approx. 800 compounds submitted for
mutagenicity assessment, ~ 100 category
2/3
• Option 1 used in 5 cases
• only 1 instance actually involved a
detectable level of the impurity > 30% of
TTC -- other 4 instances were put in
place based on actual or expected
regulatory queries
• Option 2 not used
• Option 3 used often (~25 %)
• Option 4 is used most frequently
Class 4/5
Class 2/3
0
2
4
6
8
10
12
14
16
18
20#
MIs
Option 1
Option 3
Option 4
Data Mining Past Products -- Distribution of
Control Options
24
• In most cases, option 4 control strategies were supported by data
• A mix of
– Data from commercial scale batches
– Data from pilot scale batches
– Data from laboratory spiking studies
• In some cases, option 4 control was justified based on scientific principles alone when
purge was obvious
Number of Bond Forming Steps from API
0 1 2 3 4 5 6 7 8 9 10
• High level perspectives on overall guidance –
• Focus on Section 8 – Control Options
– Overview of each control option
– Impurity Purge Tool and Importance of Option 4
• Focus on Section 5
– ICH Q3 vs. M7
– Selection of impurities to assess
– Data Mining of Recent Projects
• ICH M7 Appendix 2: Case Examples
• Summary
Outline
What Data is Required to Support Option 3/4?
Appendix 2: Case Examples to Illustrate Potential Control Approaches
Case 1: Example of an Option 3 Control Strategy
An intermediate X is formed two steps away from the drug substance and impurity A is routinely detected in intermediate
X. The impurity A is a stable compound and carries over to the drug substance. A spike study of the impurity A at different
concentration levels in intermediate X was performed at laboratory scale. As a result of these studies, impurity A was
consistently removed to less than 30% of the TTC-based limit in the drug substance even when impurity A was present at
1% in intermediate X. Since this intermediate X is formed only two steps away from the drug substance and the impurity A
level in the intermediate X is relatively high, the purging ability of the process has additionally been confirmed by
determination of impurity A in the drug substance in multiple pilot-scale batches and results were below 30% of the TTC-
based limit. Therefore, control of the impurity A in the intermediate X with an acceptance limit of 1.0% is justified and no
test is warranted for this impurity in the drug substance specification.
Case 2: Example of an Option 3 Control Strategy: Based on Predicted Purge from a Spiking Study Using
Standard Analytical Methods
A starting material Y is introduced in step 3 of a 5-step synthesis and an impurity B is routinely detected in the starting
material Y at less than 0.1% using standard analytical methods. In order to determine if the 0.1% specification in the
starting material is acceptable, a purge study was conducted at laboratory scale where impurity B was spiked into starting
material Y with different concentration levels up to 10% and a purge factor of > 500-fold was determined across the final
three processing steps. This purge factor applied to a 0.1% specification in starting material Y would result in a predicted
level of impurity B in the drug substance of less than 2 ppm. As this is below the TTC based limit of 50 ppm for this
impurity in the drug substance, the 0.1% specification of impurity B in starting material Y is justified without the need for
providing drug substance batch data on pilot scale or commercial scale batches.
“It Depends”
ICH M7 Case Examples (continued)
Case 3: Example of an Option 2 and 4 Control Strategy: Control of Structurally Similar Mutagenic
Impurities
The step 1 intermediate of a 5-step synthesis is a nitroaromatic compound that may contain low levels of
impurity C, a positional isomer of the step 1 intermediate and also a nitroaromatic compound. The amount
of impurity C in the step 1 intermediate has not been detected by ordinary analytical methods, but it may be
present at lower levels. The step 1 intermediate is positive in the bacterial mutagenicity assay. The step 2
hydrogenation reaction results in a 99% conversion of the step 1 intermediate to the corresponding
aromatic amine. This is confirmed via in-process testing. An assessment of purge of the remaining step 1
nitroaromatic intermediate was conducted and a high purge factor was predicted based on purge points in
the subsequent step 3 and 4 processing steps. Purge across the step 5 processing step is not expected
and a specification for the step 1 intermediate at the TTC-based limit was established at the step 4
intermediate (Option 2 control approach). The positional isomer impurity C would be expected to purge via
the same purge points as the step 1 intermediate and therefore will always be much lower than the step 1
intermediate itself and therefore no testing is required and an Option 4 control strategy for impurity C can be
supported without the need for any additional laboratory or pilot scale data.
Case 4: Example of an Option 4 Control Strategy: Highly Reactive Impurity
Thionyl chloride is a highly reactive compound that is mutagenic. This reagent is introduced in step 1 of a 5-
step synthesis. At multiple points in the synthesis, significant amounts of water are used. Since thionyl
chloride reacts instantaneously with water, there is no chance of any residual thionyl chloride to be present
in the drug substance. An Option 4 control approach is suitable without the need for any laboratory or pilot
scale data.
Summary
• ICHM7 is a comprehensive guidance for assessment and control of mutagenic
impurities
• ICHM7 is a complex guidance and regulatory interpretation can be variable, especially
in the area of application to marketed products
• Flexibility during clinical development is appropriately recognized in the guidance and
alternative approaches suggested
• Option 3 and Option 4 control approaches should be encouraged and expected as they
reflect synthetic routes with quality built in
• Option 1 and 2 control approaches can be used if necessary, in particular for very late
entry impurities when purge cannot be assured
• Option 4 control strategies based on scientific principles alone is often appropriate and
current industry efforts should continue to develop an impurity purge tool that is broadly
recognized
• The overall risk of a mutagenic impurity originating from a synthetic route residing in
the API is generally low and often negligible, especially for impurities that arise in
early synthetics steps
• ICHM7 allows flexibility to focus efforts on the later synthetic steps; this is an important
area to monitor for the future to ensure industry and regulatory resources are focused
on the right areas
28
Acknowledgements
• Greg Sluggett
• Frank R. Busch
• Andy Teasdale
• Ron Ogilvie
• John Ragan
Reaction Grid Expanded from Slide 16
Reaction Grid Expanded from Slide 16