11

ICH M7 Overview: Predicting,

Assessing, and Controlling

Mutagenic Impurities from

Degradation

Steven W. Baertschi, Ph.D.

Baertschi Consulting, LLC

http://baertschiconsulting.com/

May 24-25, 2018

Lhasa 2018 Pharmaceutical Industry and

Regulators Symposium

Brasilia, Brazil

2

Acknowledgments

• PhRMA Limited Duration Key Initiative Team, ICH M7

• Stephen Miller, US-FDA

• Stephen Raillard, Xenoport

• Chris Riley, Riley and Rabel Consulting

• Bernard A. Olsen, Lilly-retired, currently a consultant

• Joel Bercu, Gilead

• Robert Jolly, Lilly

• Dave Elder (GSK), Mark Kleinman (GSK), Mark Mowery

(Merck); Andrew Teasdale (AstraZeneca), Dave DeAntonis

(Pfizer), Karen Alsante (Pfizer)

3

Introduction

• History / Background

• Definitions, Regulatory framework

• Short Overview of ICH M7

• Developing strategies / approaches to predict and

assess potential mutagenic deg products

• Predicting “actual” degradation products in a short

timeframe

• Structure alerts and Degradation pathways

• How likely will there be a “problem”?

• Expected Frequency

• Conclusions

4

Quote from ICH Q3A and Q3B

• Degradation products present at a level of not

more than (≤) the identification threshold

generally would not need to be identified.

However, analytical procedures should be

developed for those degradation products that

are suspected to be unusually potent, producing

toxic or significant pharmacological effects at

levels not more than (≤) the identification

threshold.

5

EMEA / CHMP “Guidelines on the limits of Genotoxic Impurities”,

CPMP/SWP/5199/02; EMEA/CHMP/QWP/251344/2006, London, UK, 28

June 2006.

• Quotation from EMEA guideline on GTI’s: “As stated in the Q3A guideline, actual and potential impurities most likely to arise during synthesis, purification, and storage of the new drug substance. This summary should be based sound scientific appraisal of the chemical reactions involved in the synthesis, impurities associated with raw materials…and possible degradation products. This discussion can be limited to those impurities that might reasonably be expected based on knowledge of the chemical reactions and conditions involved.”

• Guided by existing genotoxicity data or the presence of structural alerts, potential genotoxic impurities should be identified.”*

6

FAST FORWARD TO TODAY…

ICH M7

7

ICH M7 Guideline: Step 4 published July

2014; full implementation January 2016

• Title: “Assessment and Control of DNA Reactive

(Mutagenic) Impurities in Pharmaceuticals to

limit potential carcinogenic risk”

• Guideline Objective: This guideline outlines recommendations for assessment and control of mutagenic impurities (to levels that are expected to pose negligible carcinogenic risk) that reside or are reasonably expected to reside in final drug substance (DS) or product (DP), taking into consideration the intended conditions of human use.

8

Guideline General Framework

Sections 1-4Scope etc.

Section 5:Impurity

Assessment

Section 6:Hazard

Assessment

Section 7:Risk

Characterization

Section 8:Control

Section 9:Documentation

What impurities need

to be assessed? – actual,

potential, degradation products

Is the impurity

mutagenic?

QSAR + Ames

What is the

acceptable intake?

(TTC, compound

specific, less than

lifetime exposures)

Expectations, options

for impurity control,

lifecycle

Expectations

for regulatory

filings

Scope,

General Principles

Considerations for

Marketed Products

**Slide from Stephen Miller, US-FDA, presented at AAPS Short Course on

Assessment and Control of Mutagenic Impurities, Oct 25, 2015, Orlando, FL

9

Scope: Intended

• New drug substances and new drug products in clinical development and subsequent application for marketing

• Certain post approval submissions of marketed products and to new marketing applications (drug substance previously approved):• Changes to the drug substance

• Changes to the drug product

• Changes in clinical use

10

Scope: Not Intended

• Biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation products, herbal products, and crude products of animal or plant origin, excipients used in existing marketed products, flavoring agents, colorants, perfumes

• Drugs covered by ICH S9 (advanced cancer indications) or where the drug substance itself is genotoxic and exposure to a mutagenic impuritywould not significantly alter the overall cancer risk.

11

Considerations for Marketed Products

Category (Section) Guidance for Re-Evaluation

Changes to Drug Substance (4.1)

• Post approval submissions with changes in synthesis or process conditions after the starting material

• Not required for changing drug substance site of manufacture, raw materials supplier

Changes to Drug Product (4.2)

• New or higher levels of existing mutagenic degradation products when product submission involves change e.g., composition, manufacturing process, dosage form

• Not required for changing site of manufacture

Changes to Clinical Use (4.3)

• Changes in clinical dose or duration of use, change in indication e.g., life-threatening disease to non-life threatening disease or less serious condition

Other Considerations (4.4)

• (Q)SAR alert alone does not warrant re-evaluation, unless it is a structure of ‘cohort-of-concern’ (CoC)

• Cause for concern: 1) New mutagenicity or carcinogenicity data for impurity; 2) Newly discovered impurity that is a mutagenic carcinogen or mutagen

Lifecycle (8.5) • Newly identified impurities in products approved after issuance of M7 would be assessed for mutagenicity

**Slide from Stephen Miller, US-FDA, presented at AAPS Short Course on Assessment

and Control of Mutagenic Impurities, Oct 25, 2015, Orlando, FL

12

12

Table 2: Acceptable Daily Intakes for an Individual

Impurity (during clinical development and at

marketing)*

Duration of treatment

< 1 month>1 - 12

months>1 - 10 years

>10 years to lifetime

Daily intake[µg/day]

120 20 10 1.5

• Duration of treatment intended to apply to “great majority of patients” (Section 7.3.2.)

• Intermittent dosing – can be based on the total number of dosing days

• Compound-specific AI can be adjusted proportionally for shorter durations

13

13

Table 2: Acceptable Daily Intakes for an Individual

Impurity (during clinical development and at

marketing)*

Duration of treatment

< 1 month>1 - 12

months>1 - 10 years

>10 years to lifetime

Daily intake[µg/day]

120 20 10 1.5

• Duration of treatment intended to apply to “great majority of patients” (Section 7.3.2.)

• Intermittent dosing – can be based on the total number of dosing days

• Compound-specific AI can be adjusted proportionally for shorter durations

Maximum Daily Intake = 1.5 ug/day (Threshold of Toxicological Concern

(TTC))

Applicable to compounds if there is insufficient evidence for a

threshold-related mechanism

Original calculation assumes life-time exposure of 70 years

Based on potential cancer risk of 1 in 100,000

Compare with actual life-time cancer risk of ~40%*41% → 41.001%

*Based on rates from 2006-2008, 41.21% of men and women born today will

be diagnosed with some form of cancer at some time during their lifetime.

http://seer.cancer.gov/statfacts/html/all.html#risk

E. J. Delaney, “An impact analysis of the application of the threshold of toxicological concern

concept to pharmaceuticals”, Reg. Tox. Pharmacol., 49, 107-124 (2007)

The Cliff of

Regulatory

Concern!

14

14

Naked Eye vs Hubble TelescopeHubble Deep Field

Hubble Ultra-Deep Field

15

15

Naked Eye vs Hubble TelescopeHubble Deep Field

Hubble Ultra-Deep Field

Take home message: The more sensitive

the analytical technique / detector, the more

we will “see”.

16

16

Table 3: Acceptable Total Daily Intakes for

Multiple Impurities*

• *For 3 or more Class 2 and 3 impurities specified on the drug

substance specification (during clinical development and at

marketing).

• For combination products, each active ingredient should be

regulated separately.

• Impurities with compound-specific or class-related acceptable

intake limits (Class 1) should not be included in the total limits of

Class 2 and Class 3 impurities.

• Degradation products would be controlled individually and a

total limit would not be applied.

Duration of treatment

< 1 month >1 - 12 months >1 - 10 years>10 years to

lifetime

Total Daily Intake

[µg/day]120 60 30 5

17

17

Options for Control of Impurities

• Synthesis prior to SM will generally be managed under the applicant’s quality system

• Removal of impurity can be monitored through starting material, intermediate, or drug substance specifications, or assured by the manufacturing process controls themselves

Starting

Material

Synthetic

Intermediate

A

Synthetic

Intermediate

B

Drug

Substance

Etc.

**Slide from Stephen Miller, US-FDA, presented at AAPS Short Course on Assessment

and Control of Mutagenic Impurities, Oct 25, 2015, Orlando, FL

18

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Control Options (8.1)

Option 1: Monitor the impurity in the drug substanceAcceptance criterion at or below the TTC

Option 2: Monitor the impurity in intermediate, starting material or in-process control

Acceptance criterion at or below the TTC

Option 3: Monitor the impurity in intermediate, starting material or in-process control

Acceptance criterion above the TTC, with demonstrated understanding of fate and purge and associated process controls

Option 4: Design robust process controls to reduce the risk of impurity level above the TTC to negligible

“Especially useful for those impurities that are inherently unstable, or those impurities introduced early in the synthesis and are effectively purged”

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And now for the hardest part…!

Degradation

Products Process

Impurities

20

From ICH M7: 5. DRUG SUBSTANCE AND DRUG

PRODUCT IMPURITY ASSESSMENT

• Actual and potential impurities that are likely to arise

during the synthesis and storage of a new drug

substance, and during manufacturing and storage of a

new drug product should be assessed.

• The impurity assessment is a two-stage process:

• Actual impurities that have been identified should be

considered for their mutagenic potential.

• An assessment of potential impurities likely to be present

in the final drug substance is carried out to determine if

further evaluation of their mutagenic potential is required.

• The steps as applied to synthetic impurities and

degradation products are described in Sections 5.1 and

5.2, respectively.

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Questions

• What defines “potential”? “likely”, “reasonably

expected”?• Sound scientific appraisal and reasonable expectation

• Degradants produced via stress testing are considered, by

Q1A(R2) definition, “likely”

“Stress testing helps to determine the intrinsic stability of the molecule by

establishing degradation pathways in order to identify the likely

degradation products and to validate the stability-indicating power of the

analytical procedures used… Examining degradation products under stress

conditions is useful in establishing degradation pathways and developing and

validating suitable analytical procedures. However, such examination may not

be necessary for certain degradation products if it has been demonstrated that

they are not formed under accelerated or long-term storage conditions.

--ICH Stability Guideline Q1A(R2):

22

Questions

• What defines “actual”? • Degradation products formed under accelerated or long-term

storage conditions (see quote below)

“Stress testing helps to determine the intrinsic stability of the molecule

by establishing degradation pathways in order to identify the likely

degradation products and to validate the stability-indicating power of the

analytical procedures used… Examining degradation products under

stress conditions is useful in establishing degradation pathways and

developing and validating suitable analytical procedures. However,

such examination may not be necessary for certain degradation

products if it has been demonstrated that they are not formed

under accelerated or long-term storage conditions.”

--ICH Stability Guideline

Q1A(R2):

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ICH M7: 5.2 Degradation Products

• Actual degradation products: include those

observed above the ICH Q3A/B reporting

threshold during storage of the drug substance in

the proposed long-term storage conditions and

primary and secondary packaging.

• Potential degradation products: include those that

form above the ICH Q3A/B identification threshold

during accelerated stability studies (e.g.,

40°C/75% relative humidity for 6 months) and

confirmatory photo-stability studies as described

in ICH Q1B…yet to be confirmed…under long-

term storage…in the primary packaging.

24

ICH M7: 5.2 Degradation Products

• Knowledge of relevant degradation pathways

can be used to help guide decisions on the

selection of potential degradation products to be

evaluated for mutagenicity e.g., from

degradation chemistry principles, relevant stress

testing studies, and development stability

studies.

It is clear that ICH M7 is expecting MORE than just

looking at “actual” degradation products (Q3A/B

thresholds) and performing a mutagenicity

assessment.

25

Piecing Together What ICH

M7 says about “Potential”,

“Reasonably Expected”,

and “Likely to Arise”….

26

Proposed Process

Flow for Assessing

Degradants in API /

DP

Scheme 1 from “Strategies to

address mutagenic impurities

derived from degradation in drug

substances and drug products”,

Kleinman MH et al., Org. Proc.

R&D, Org. Process Res.

Dev. 19, 11, 1447-1457 Article

ASAP, DOI:

10.1021/acs.oprd.5b00091

27

Building Knowledge of Deg Pathways:

“Theoretical” / Hypothetical

• Proposed Construct:

• Chemistry principles = Theoretical (or “Hypothetical”)

• based on scientific principles (either personal

knowledge or from the literature).

• Theoretical / hypothetical would mean that it has

not been demonstrated with data.

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What is the state of our ability to predict

Degradation Pathways based on Chemical

Principles?

In Silico / Hypothetical

Real world Real world

In Silico / Hypothetical

In Silico / Hypothetical

Real world

In Silico / Hypothetical

Real world

30

• More chemistry- 445 transformations projected for 2016.1.0 knowledge base

• Excipients• ~120 “excipients” or counterions.

Continuing Improvements: Zeneth 7 and Knowledge Base (2016)

45 new and 47 improved transformations

Improved calc of “likelihood”

Separation of counterions and excipients

Compatibility upgrades

– Windows 10 and latest drawing packages

31

How well does Zeneth work?

Benchmarking Study in 2014

• “In silico prediction of pharmaceutical degradation pathways: a

benchmarking study”, Kleinman et al., Mol. Pharm., 11, 4179-4188

(2014).

• Involved GSK, Lilly, Pfizer, Amgen, Merck, and Lhasa.

• 27 Drug Substances, 191 known deg products (long-term, accelerated, and

stress)

• Also process against “historical” knowledge bases (2009.1, 2009.2, 2010.2, 2011.1, 2012.1.1, 2012.1.3/2012.2.0)

• Evaluation of coverage(positive predictions)

• Evaluation of overprediction(“unconfirmed positive” predictions)

• Evaluation of predictive progress in time

80 transformations →277 transformations

32

Summary of Benchmarking

0%

50%

100%

2009.1.0 2009.2.0 2011.1.0 2011.2.0 2012.1.1 2012.2.0

80 183 277

54%

33

Why we can’t rely on Theoretical / “Hypothetical”

Predictions…

• The relationship between Idealized and Realistic Degradation

Knowledge Landscapes: Hypothetical predictions can be

MUCH larger than “reality”…

• Hypothetical Predictions “miss” many real world degradation

pathways/products

Zeneth

See “In silico prediction of pharm

deg pathways: a benchmarking

study”, Mol. Pharm. (2014) 11(11),

4179-88.

34

How about Stress Testing as a

Predictive Tool?

35

For more details see Baertschi, S.W. “Pharmaceutical Stress Testing: Predicting Drug

Degradation”, Chapter 2, 2nd Edition, Informa Healthcare, 2011.

•Hydrolytic --> high humidity and solution stressing

Acid/Base: pH’s 1-13 at RT up to 70 C, 1-2 weeks

•Thermolytic --> heat / humidity

70 C, high (75%) and low (20%) humidity, 2-4 weeks (DP and API)

•Photolytic --> exposure to appropriate light source(s)

Expose solid and solutions to both visible and UV light in excess of ICH

minimum confirmatory exposure (2-5 fold excess recommended)

•Oxidative --> oxidative degradation can be complex.

Peroxides – 0.3% hydrogen peroxide, RT, 1-3 days.

Radical-initiator – e.g., VAZO 52, 2-3 days, 30C.

Cu(II) and Fe(III) – 1-2 mM, 1 day, RT – 40C.

Why we CAN rely on well-designed stress

testing…benchmarking data from 15 Lilly cmpds

Using Stress Testing to Predict Real World Degradation: Four

Main Pathways

36

Important Questions

1. Do we / should we elucidate structures of deg

products observed during stress testing?

--No clear regulatory mandate – up to individual company

--On what basis? “Major” or “Significant” deg products?

-- When in relation to the timeline?

2. How do we define “Major” in stress testing

studies?

3. How do we determine which stress testing-

derived deg. products are relevant to the drug

product?

37

Question 2. Defining “Major”

• Stress to end point or to 10-20% degradation

• Define “major” as 10% or more of total

degradation and >25% of largest individual

➢For more details or comparison, see:

➢Alsante et al., Adv. Drug Deliv. Rev. (2007) 59:29-37

➢Kleinman et al., Org. Process Res. Dev. 19, 11, 1447-1457;

DOI: 10.1021/acs.oprd.5b00091

• Typically, 6-12 degradation major deg products

are observed (average 8.2, Lilly benchmarking

data)

38

Question 2. Defining “Major”

➢Kleinman et al.,

Org. Process Res.

Dev. 19, 11, 1447-

1457; DOI:

10.1021/acs.oprd.

5b00091

39

Question 2. Defining “Major”

➢Kleinman et al.,

Org. Process Res.

Dev. 19, 11, 1447-

1457; DOI:

10.1021/acs.oprd.

5b00091

40

Predicting Degradation Profiles from Stress

Testing: Data from 15 Lilly Compounds

12445

“Knowledge

Space”“Control

Space”

“Design Space”

▪Observations:

➢ 36% of Major Stress Degradants formed under “real world”

conditions (45/124 = 36%)

➢8.2 Major Stress Degradants per API

➢No Surprise Degradants outside of Knowledge Space!!

What DOES FORM in final DP

under proper packaged

conditions, long term stability

What CAN FORM in the DP (40/75

or 25/60, no special packaging /

open conditions)ALL STRESS TESTING

results, including Excip.

Compat. and Formulation Stress

Testing

39

Dow LK,* Pack BW, Hansen MM, and Baertschi SW,

J. Pharm.Sci.,102(4), 1404-1418 (2013).

41

42

How well do the (Q)SAR Methods

Work for Predicting Mutagens?

• For Process Impurities, approx. 55% of (Q)SAR

(DEREK and Ashby-Tennant predicted positive) were

Ames Positive when tested

• If you remove Boronic Acid Derivatives → ~52%

43

• There are certain functionalities that are

considered alerting structures for mutagenicity*

• Which alerting structures are the most common

to drug degradation, and what are the most

common degradation pathways leading to these

structures?

Alerting Structures*: Concerns for Common

Degradation Products

*(a) J. Ashby, R.W. Tennant, Mutat. Res. 204 (1988) 17–115;

(b) Benigni and Bossa, Mutation Research 659 (2008) 248–261, Table 2

(31 structure alerts contained within “Toxtree 1.50” software)

44

Frequency of Alerting Structures in

the Drug Degradation Database

• A drug degradation database (no longer active)

http://d3.arxspan.com, contained the structures of

more than 393 drugs and 1200 related deg.

products.

• The database was analyzed using ToxTreeTM

software* for the presence of alerting structures.

*Benigni and Bossa, Mutation Research 659 (2008)

248–261, Table 2 (structure alerts contained within

“Toxtree 1.50” software)

45

Frequency of Alerting Structures in

the Drug Degradation Database

Total # of

Degradants with

AlertsAlerts Shared with

parent

Total # of Degradants with

Unique Alerts

Total # of DegradantsProcessed

356 201 155 1021

35% 20% 15%

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Summary of Analysis: Risk of Producing an

Alerting Structure from Drug Degradation

• ~15% of degradation products have alerting structures

unique from the parent (as found in database)*

• A smaller percentage were flagged as toxicity alerting

from analysis using DEREKTM or MultiCASETM (~5-8%)**,

which take into account not only the presence of an

alerting structure but also apply more sophisticated rules

and machine learning.

• Roughly 50% of these alerting structures can be

expected to be Ames positive

*Raillard, S.P., Bercu, J., Baertschi, S.W., and Riley, C.M. “Prediction of Drug

Degradation Pathways Leading to Structural Alerts for Potential Genotoxic

Impurities”, Org. Proc. Res. and Dev., 14, 1015-1020 (2010).

**Nigel Green, J. Thom Deahl, J. Bercu, Bob Jolly, et al., manuscript in

preparation

47

Most Common Alerting Structures From

Drug DegradationStructural Alert and

Corresponding ToxTree™ Alert Number

Number of hits in Degradants

Number of unique hits in Degradants*

Aldehydes (SA 11) 40 34α, β-Unsaturated Carbonyls (SA 10)**

126 30

Primary Aromatic Amines, Hydroxyl amines and its Derived Esters (SA 28)

93 23

Heterocyclic,Polycyclic Aromatic Hydrocarbons (SA 19)

15 13

Epoxides and Aziridines (SA 7) 17 12

Nitro Aromatics (SA 27) 25 6Aromatic ring N-Oxides (SA 26)

6 6

Aliphatic Halogens (SA 8) 12 6

Total 334 130

% of Total Alerts 93.8 83.9

48

N

OH

N

O N+

O-

N

A

A

Aminoaryls and alkylated aminoarylsAza-aryl N-oxides

A

N-Hydroxyaryls

A

A

N-Acylated aminoaryls

Purines or Pyrimidines, Intercalators, PNAs or PNAHs

Group 1: Aromatic Groups

Group 2: Alkyl and Aryl Groups

O

N

OH

NO

N

O NH2

O

NO2

A H A A

A

AA

A

Aldehydes N-Methylols N-Nitrosamines Nitro Compounds Carbamates (Urethanes)

O NH O C (or S)

AA

Epoxides

A A

O

Propiolactones

PropiosultonesAziridines

Halogen

S or N

N or S Mustards

(beta haloethyl)

N N

R

A

A

A

Hydrazines and

Azo Compounds

Group 3: Heteroatomic Groups

EWG

Michael-reactive

Acceptors

P

O

OR

S

O

OR

Alkyl Esters of

Phosphonates or Sulfonates

Halogen

Halo-alkenes

Halogen

A

Primary Halides

(Alkyl and aryl-CH2)

Legend: A = Alkyl, Aryl, or H

Halogen = F, Cl, Br, I

EWG = Electron withdrawing group (CN, C=O, ester, etc)

Structural Alerts for Mutagenicity

49

Predicted Probability of Finding a

Potential Mutagenic Deg Product…

• If, on average, 8 major stress degradants are

identified per API through Stress Testing….

Between~33-66% of all APIs will require one of the degradants to have an Ames test conducted

i.e., 8% DEREK positive means 2 out of 24 degradants (3 APIs x 8 degs per API)

Between ~16-33% of all APIs will give rise to a positive Ames result for one of the degradants

1 out of 24 degradants is predicted to be Ames positive. (Significant analytical effort will be required – TTC detection, aged / stressed samples.)

Between ~4-12% of all APIs are predicted to have 1 confirmed Ames positive degradant that forms in the drug product

36% stress degradants observed on stability in historical DPs

Analytical

resources required

Synthetic and/ or

isolation resources

required

50

Determining “Relevancy” of Potential Degradants:

Using Semi-Empirical Modeling Outlined in M7

• ICH M7: 8.4 Control of Degradation Products

• “For a potential degradation product that has been characterized as mutagenic, it is important to understand if the degradation pathway is relevant to the drug substance and drug product manufacturing processes and/or their proposed packaging and storage conditions. A well-designed accelerated stability study(e.g., 40°C/75% relative humidity, 6 months) in the proposed packaging, with appropriate analytical procedures is recommended…”

• “Alternatively, well designed kinetically equivalent shorter term stability studies at higher temperatures in the proposed commercial package may be used…”

51

Determining “Relevancy” of Potential Degradants

(Translating from “Potential” to “Actual”)

• ICH M7: 8.4 Control of Degradation Products

• “Based on the result of these accelerated studies, if it is anticipated that the degradation product will form at levels approaching the acceptable limit under the proposed packaging and storage conditions, then efforts to control formation of the degradation product is expected.”

• …“In these cases, monitoring….in long term primary stability studies…is expected unless otherwise justified.”

52

“Well-designed kinetically-equivalent”

shorter study

• Kinetically-Equivalent Accelerated Study: • Use higher temperatures and leverage the Arrhenius

relationship to equate higher temperatures to long term storage conditions

k = A * exp(-Ea / RT)

53

Using the Arrhenius Relationship:

k = A * exp(-Ea / RT)• “Well-designed kinetically equivalent”: Use higher temperatures

and leverage the Arrhenius relationship to equate higher

temperatures to long term storage conditions

➢ Determining the Ea (energy of activation) is often not practical

• Leverage the 6 months at 40C/75%RH to 2 years at 25C/60%RH

assumption

➢ This assumes a conservative Energy of Activation assumption of 17 kcal/mol (71

kJ/mol).

➢ Use the actual Ea if it is known or can be obtained (average for Solid Oral Dosage

forms appears to be around 29 kcal/mol*)

• Target thermal / humidity equivalent (or greater) of 6 months at

40C/75%RH

*Data from more than 100 studies; Waterman KC. Accelerated Stability Assessment

Program (ASAP): Using science to set shelf-life. Presented at the AAPS workshop on

Stability Testing in Pharm. Dev., AAPS Annual Meeting Nov 14, 2010: New Orleans, LA

54

See USP <1079> for Mean Kinetic Temperature Calculation

55

Humidity considerations

• Relative humidity is a critical parameter

• Two options:

1. Build RH into the Arrhenius equation (e.g., by applying

the “Accelerated Stability Assessment Program”

principles*)

ln k = ln A - Ea / RT + B(RH)

• OR…

2. Maintain the same %RH at the elevated stress

temperatures• Consider a degradation reaction with an Ea of 19.87 kcal/mol (USP

<1150> MKT) as an example. A stress testing study at 70°C / 75% RH

for 11 days would yield the kinetic equivalence of 40C / 75% RH for 6

months.

*Waterman KC, Adami RC 2005. Accelerated aging: Prediction of chemical stability of pharmaceuticals. Int J Pharm

293:101-125; Waterman KC, Carella AJ, Gumkowski MJ, Lukulay P, Macdonald BC, Roy MC, Shamblin SL 2007.

Improved Protocol and Data Analysis for Accelerated Shelf-Life Estimation of Solid Dosage Forms. Pharm Res 24:780-

790

56

Photostability considerations

• ICH Q1B Photostability Guideline

• Confirmatory photo-exposure (1.2 million lux-h and

200 W-h/m2) is, in some fashion, analogous to 6

months at 40C/75% RH

• Proposal: photo-stressing of drug substance and

product for 2X ICH to define major

photodegradants (potential).

• 1 x ICH in packaging to define “relevance”.

• Mitigation strategy for photo-induced degradants

(protection from light via packaging) is more

straightforward than heat/humidity.

57

ICH M7 is COMPLEX…

…Especially when dealing with

Degradation Products

58

Overview of Deg Product

Mutagenic Risk Assessment

59

Summary / Conclusions

• The prediction and assessment of degradation-

derived GTIs is complex

➢Many companies are struggling with development of sound,

practical, relevant strategies

➢ The field of Degradation Chemistry is still too immature and

complex to allow RELIABLE predictions a priori (Hypothetical

/ Theoretical)

➢ Two main options for a company to define “Potential”: (1)

Well-Designed Stress Testing and/or (2) Accelerated Stability

Studies (including photostability)

➢ Using “well-designed” accelerated stability studies and

Arrhenius kinetics can help focus on “relevant” or “actual”

degradants (i.e., those that will form on accelerated / long-

term stability studies, properly packaged)

60

Summary / Conclusions

• Analysis of over 1100 known degradation

products suggest that degradation of drugs may

lead to unique mutagenic structure alerts in ~5-

8% of the degradation products.➢ Roughly 50% or less of these alerting structures expected to be

Ames positive (roughly 2-4% overall)

➢ Using a Stress Testing → Potential Deg Product approach,

➢~8 deg products per API will be identified

➢~4-12% of all APIs are predicted to have 1 confirmed Ames

positive degradant that forms in the drug product

61

Impact of M7: Some of the

Significant Questions to Consider

1. What strategies will your company embrace to meet the

expectations of M7?

--Strategy for structural identification of impurities?

2. Do you / should you elucidate structures of deg

products observed during stress testing?

--No clear regulatory mandate – up to individual company and

regulatory agency expectations

--On what basis? “Major” or “Significant” deg products?

--How do you define “Major” in stress testing studies?

-- When in relation to the timeline?

--Stress testing strategy results in Identification of about 3-4X

more than “actual” degs, but enables timely mitigation

--How significant is the risk to discovering a problem late in the

timeline?

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Impact of M7: Some of the

Significant Questions to Consider

3. How do you determine which stress testing-derived

deg. products are relevant to the drug product?

4. Do you have access to two complementary in silico

tools?

5. What about degradants formed in the GI tract? Who

owns the GUT?!

6. Does your company have a strategy and the

expertise to be able to discharge risks of potential

deg products known to be mutagenic?

63

Acknowledgements

• Altox – Carlos Eduardo Matos dos Santos

<carlos@altox.com.br>

64

Thank you!!!

See baertschiconsulting.com

65

Back-up Slides

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Option 1: Stress Testing –> Potential

• Specifics of stress conditions need to be defined

• Stress testing needs to include both DS and DP

• Photostability needs to be included, and exposure should be

more than 1 x ICH Q1B

• Strategy for identification of deg products needs to be defined

• Consideration should also be given to deg pathways leading

to identified deg products.

• If a pathway implies an intermediate with alerting structure,

consideration should be given

• For oral dosage forms, consider what happens in the“gut”(!)

• An important an often overlooked area

• Don’t overlook just because it isn’t spelled out in M7…!

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Option 2: Accelerated Stability and

ICH Q1B Photostability → Potential

• Minimal or no packaging protection for DS/DP

• If we limit to only properly packaged DS/DP, it can be

argued this only uncovers “actual” degradants

• DS/DP Photostability (Q1B confirmatory) should be included

with direct exposure

• Identification threshold? M7 indicates “potential” to be

aligned with Q3A/B ID threshold, but I would recommend

using “reporting threshold” as a conservative measure

• Consideration should also be given to deg pathways leading

to identified deg products.

• If a pathway implies an intermediate with alerting structure,

consideration should be given

• For oral dosage forms, consider what happens in the “gut”(!)

• An important an often overlooked area

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Daily Dose (mg)

ICH Identification

Thresholds (%)

Maximum Concentration of Genotoxic Degradants Calculated from the Proposed FDA Staged-TTC Values

(%)

DS DP <14 days (120 µg)14 days to 1 month

(60 µg)1-3 months (20

µg)3-6 months

(10 µg)6-12 months

(5 µg)>12 months

(1.5 µg)

3000 0.05 0.1 0.004 0.002 0.00067 0.00033 0.00017 0.00005

1000 0.1 0.2 0.012 0.006 0.002 0.0001 0.0005 0.00015300 0.1 0.2 0.04 0.02 0.0067 0.0033 0.0017 0.0005

100 0.1 0.2 0.12 0.06 0.02 0.01 0.005 0.0015

30 0.1 0.2 0.4 0.2 0.067 0.033 0.017 0.005

10 0.1 0.2 1.2 0.6 0.2 0.1 0.05 0.015

3 0.1 0.5 4 2 0.67 0.33 0.17 0.051 0.1 0.5 12 6 2 1 0.5 0.15

0.3 0.1 1 40 20 6.7 3.3 1.7 0.5

Green: Standard HPLC-UV method will likely be suitable for controlling GTI

Orange: Standard HPLC-UV method may be suitable, but a more sensitive (e.g., LC-MS) method may be

required

Red: A more sensitive (e.g., LC-MS) method may be required for controlling GTI

Analytical Sensitivity Required as a Function

of Dose

68