ICGM Basel September 25th Dr A Teasdale - AstraZeneca

Explaining and demonstrating successful use of purging and depletion strategies to control mutagenic impurities

Background

• The threat posed by mutagenic impurities (MIs) in drug substances generally arises from the use of electrophilic agents (alkylating agents) within the synthesis.

• Used in the build up of the molecular structure

• E.g. through carbon-carbon and carbon-nitrogen bond formation

- ubiquitous, given the current methodology

• Suggests that any

synthetic drug therefore possesses a latent MI-related risk.

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N

OHN

O N+

O-

NA

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

NON

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)

AAEpoxides

A A

O

PropiolactonesPropiosultonesAziridines

Halogen

S or NN or S Mustards(beta haloethyl)

N NR

A

A

AHydrazines andAzo Compounds

Group 3: Heteroatomic Groups

EWG

Michael-reactiveAcceptors

P

O

OR

S

O

ORAlkyl Esters of

Phosphonates or Sulfonates

Halogen

Halo-alkenes

Halogen

A

Primary Halides(Alkyl and aryl-CH2)

Legend: A = Alkyl, Aryl, or HHalogen = F, Cl, Br, IEWG = Electron withdrawing group (CN, C=O, ester, etc)

Structural Alerts for Mutagenicity

Background Continued

• Most synthesis will involve use of a mutagenic reagent or possess potential risk arising from an impurity formed in the process. - ORIGINAL APPROACH WAS TO TEST FOR ALL IMPURITIES

• Very simplistic - Fails to take into account the inherently reactive nature of the agent

of concern and its likely fate.

• It is a paradox that the very reactivity that renders the agent a concern from a safety perspective is the same property that will generally ensure its effective removal in the downstream process.

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Resource Impact

• Originally assessed by Delaney - (Reg. Tox. Pharmacology, 49 (2007) - Expressed concern that the regulatory burdens associated with the

guideline could lead to a significant, new, added cost.

• Also examined by Mueller (2008) - Estimated the cost as equating to an approximate 5-10% increase in

project costs for a Phase I ready candidate. • About $300, 000 in financial terms.

• A lot of this relates to analysis

• Analytical Strategy has improved significantly but still a major issue.

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Resource Impact

• Delaney (Ref – FDA-2008-D-0269-022.01) examined the financial cost in more detail, key areas included: - Method development cost. - The cost of process development efforts to ensure TTC levels are

reached for each impurity of interest. - Losses of API during manufacture made necessary by additional

purification efforts. - The allocation of added time and effort to negotiate TTC-based

specifications with RAs.

• Estimated additional cost to industry of in excess of $100 million

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ICH M7 Section 5 – Drug substance and Drug Product Impurity Assessment

•KEY – In practical terms this is essentially advocates the same approach as current guidelines.

• Emphasis remains focused on actual impurities and potential impurities likely to be present in the API / DP.

•Also looks to link the guideline to ICH Q3A/Q3B reporting and identification requirements • 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.

•DO NOT NEED TO ATTEMPT TO IDENTIFY EVERY POSSIBLE IMPURITY AT A TTC LIKE LEVEL

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ICH M7 Section 8 - CONTROL •Greater flexibility in terms of mechanism to prove absence. • Options other than to simply test for presence in final API.

• Ability to more widely use chemical / process based arguments to

assess purging. (will examine this further in case studies)

•Expressed in terms of a series of control options

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ICH M7 Section 8 - Control

Option 4 • So reactive – no testing

required Option 3

• Test at intermediate stage with a higher limit + understanding of process capacity.

Option 2 • Test for the impurity in the

specification for a raw material, starting material or intermediate at permitted level

Option 1 • Test for the impurity in the

drug substance

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Is this the right way around ?? YES (in my view) A Teasdale 8

ICH M7 Section 8 Control – examination of Option 4

•Where the control strategy that relies on process controls in lieu of analytical testing must understand how we the process chemistry and process parameters impact levels of mutagenic impurities.

•.The risk assessment can be based on physicochemical properties and process factors that influence the fate and purge of an impurity • This include chemical reactivity, solubility, volatility, ionizability and any

physical process steps designed to remove impurities. ***

•Option 4 is useful for those impurities that are inherently unstable (e.g., thionyl chloride that reacts rapidly and completely with water) and for those impurities that are effectively purged.

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Control Option 4 How do I apply this? in practice?

• The principle of relating the physico-chemical properties of the mutagenic impurity to the chemical process is defined in the concept of purge factor calculations.

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• The following key factors were defined in order to assess

• the potential carry-over of a MI: - reactivity, solubility, volatility, ionisability, and any additional physical

process designed to eliminate impurities e.g. chromatography.

• Score assigned on the basis of the physicochemical properties of the MI relative to the process conditions. - These are then simply multiplied together to determine a ‘purge factor’

(for each stage)

• The overall purge factor is a multiple of the factors for individual stages.

Control Option 4 Purge Factor Calculation – Basic principles

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Control Option 4 Purge Factor Calculation – Basic principles

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Physicochemical Parameters Purge Factor

Reactivity Highly Reactive = 100

Moderately reactive = 10

Low Reactivity / un-reactive = 1

Solubility 1 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.

Control Option 4 Practical Use of Purge Tool

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CO2Bu

F

B N

N

OH

OH

N

HCl.HNSO2Me

N

NCO2Bu

F

N

N

F

OH N

N

F

TsO

N

BocNSO2Me

N N

N

F

NSO2Me

Ester

Coupled Ester AlcoholTosylate

Boronic Acid

DIBAL

THF

TosCl

Toluene solution

Toluene

SulphonamideBocSulphonmide

HCl, IPA

stage 1

stage 2 stage 3

stage 4stage A Toluene

K2CO3

Mesylate salt

MSA / EtOHMolecular Weight =428.53Exact Mass =428.17

THF

Control Option 4 Practical Use of Purge Tool •Calculations are quick and simple

• Conduct an assessment for all MIs.

•This is a risk assessment tool, used to identify risk.

•Using this approach helps to focus effort on those MIs that pose an actual risk.

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Control Option 4 Practical Use of the Purge Tool

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Identity / Structure of GI of Concern Stage Details

Reactivity (H=100, M=10, L=1)

Solubility (F=10, M=3, L=1)

Volatility ( H=10, M=3, L=1) Ionisability

Physical Processes Rationale

Total multiple per stage

Boronic acid Stage 1 100 10 1 1 1

IPC <1% remaining, highly soluble in THF 1000

Stage 2 1 10 1 1 1 Soluble in THF 10

Stage 3 1 1 - non-isolated 1 1 1 1

Stage 4 1 3 1 1 1 3 Final API 1 10 1 1 1 10

tosyl chloride Stage 3 100 1 –non isolated 1 1 1 High reactivity 100

Stage 4 100 10 1 1 1 High reactivity 1000 Final API 10 10 1 1 1 100 tosylate Stage 4 100 10 1 1 1 1000 Final API 10 10 1 1 1 10 Isopropyl Chloride Stage A 1 10 10 1 1 B pt <Solvent 100 Stage 4 1 10 10 1 1 100 Final API 1 10 10 1 1 100

Overall calculated purge factor * water introduced into process through aqueous solution of MSA) Boronic acid 300000

Tosyl chloride 10000000 Tosylate 100000 IPC 1000000

Control Option 4 Practical Use of the Purge Tool •Next Step is to relate to the theoretical purge to the required purge.

•Examined case by case but would expect this to be at least 10X, preferably 100x greater than required

• Even though purge tool systematically under-predicts.

•What if predicted purge is lower than required? • Analytical Testing

• Proximity to point of introduction • Spike / Purge Studies

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Control Option 4 What relevance is this to toxicologists?

• If a suspected MI is clearly shown to be purged is Ames testing necessary?

•This is especially pertinent in early / mid phase, to demonstrate…

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Control Option 4 What relevance is this to toxicologists?

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CO2Bu

F

B N

N

OH

OH

N

HCl.HNSO2Me

N

NCO2Bu

F

N

N

F

OH N

N

F

TsO

N

BocNSO2Me

N N

N

F

NSO2Me

Ester

Coupled Ester AlcoholTosylate

Boronic Acid

DIBAL

THF

TosCl

Toluene solution

Toluene

SulphonamideBocSulphonmide

HCl, IPA

stage 1

stage 2 stage 3

stage 4stage A Toluene

K2CO3

Mesylate salt

MSA / EtOHMolecular Weight =428.53Exact Mass =428.17

THF

PF >1 million

If this route won’t be used long term would I test this ?

Control Option 4 Regulatory experience

• To date no direct challenge to use of purge tool. • NDA / MAA

•Request for more data on concept (papers)

•Request for clarification of how figures were derived

• Reactivity = 100 – What evidence to support?

• In some cases supported by data, but purge factor calculation presented as argument for control through the process.

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Purge Tool Next Steps

• Industry Consortia now established

•Lhasa press release

•On the 17th of March 2014 the first face to face meeting took place at Burlington House, home of the Royal Society of Chemistry, in London between Lhasa Limited and the initial partners (which include AbbVie, AstraZeneca, Hoffman-La Roche, Novartis and Pfizer). Building on the approach taken by Dr. Andrew Teasdale at AstraZeneca, Lhasa limited and its partners will steer the development of the software whilst providing their expertise and data. The project is expected to last for three years and will result in the delivery of fully functional software. A Teasdale 20

Current Status

• Multiple Consortium members including; Abbvie, AZ, Novartis, Pfizer, Roche.

• Letter of Intent • High Level Requirements collected • Steering group meetings began 21st November 2013 • F2F meeting – 17th March 2014, RSC, Burlington House, London

• Regular meetings now established – rapid progress is being made

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Sub-Groups

• Sub-Group A: Established to define the Project Glossary e.g. ionisation term, solubility (crystallisation rates etc). Now part of Sub-group C

• Sub-Group B: Discuss Experimental Protocols and methodology for initial experiments & deliver initial studies.

• Sub-Group C: Provide expert input to build the Reaction Knowledgebase

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Sub-Group C – Top 5 Impurities & Transformations

0

1

2

3

4

5

Impurity Types

0

1

2

3

4

5

6

7

Reaction Types

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Sub-Group C

- Reaction grid company feedback: • Alkylations/Reductions • Analysis • C-C & C-N Bond Formation

Critical in the development of the tool is a knowledge base used to predict reactivity

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Timeline

Pre-Project Phase Funding

Requirements Letter of Intent

Project Start Jan ’14

First Release Jan ’15

Second Release Jan ’16

Product Release Jan ’17

Quarterly Consortium Meetings

Quarterly Consortium Meetings

Quarterly Consortium Meetings

Prototype Testing/ Show & Tells

Product Phase

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Purge Tool Conclusions •ICH M7 provides the regulatory platform to allow for the scientific risk assessment of MIs.

• Option 4 .

•The guideline provides specific guidance as to the principles upon which such an assessment can be made.

•Critically these are the basis of the Purge Tool.

•Over the next 3 years plan to deliver an in silico tool to efficiently calculate purge values

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