ICH M7 Industry Perspective - Amazon Web Services...ICH M7 Industry Perspective AAPS Short Course...

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






– ICH Q3 vs. M7




• 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




5. Drug Substance and Drug Product

Impurity Assessment



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




1. Introduction





Impurity Assessment



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




1. Introduction





Impurity Assessment



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




1. Introduction





Impurity Assessment



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






– ICH Q3 vs. M7




• 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






– ICH Q3 vs. M7




• 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






– ICH Q3 vs. M7




• 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

Date post:	25-Jul-2020
Category:	Documents
Upload:	others
View:	1 times
Download:	0 times

ICH M7 Industry Perspective - Amazon Web Services...ICH M7 Industry Perspective AAPS Short Course...

Documents