ich impact on registration and post medication ...ª... · • critical steps may impact the...

Cornelia Nopitsch-Mai | Critical points in assessment and qualification of mutagenic impurities in DS and DP | 14 December 2015 |

ICH impact on registration and post

medication registration

18th June 2019

Dr. Cornelia Nopitsch-Mai


Contents

1. ICH Q11

2. ICH M7

3. ICH Q12

4. ICH Q3D


ICH Q11

Impact on RegistrationStarting Material


Starting Material (1)

Requirements

• The specification of a starting material should contain suitable limits for known, unknown and total impurities and where appropriate, limits for solvents, reagents and catalysts used during its synthesis.



Not acceptable:

• Statements from applicants/manufacturers such as “we commit to carrying out manufacture of starting materials to GMP and are willing to be inspected”

• “Compound X is a well-characterised isolated material of defined chemical properties and structure, and constitutes a significant structural fragment of the active substance. Therefore it is selected as a starting material as per ICH Q11.”

Ratio: Justification of a late intermediate as starting material by claiming it is a significant structural fragment is not considered a valid argument for short way synthesis as this could apply to any intermediate in the manufacturing process.



Not acceptable:

• A statement that a material is commercially available may not be considered sufficient to justify it as a starting material without additional supporting information. It is the responsibility of the applicant to show that a commercially available starting material is not custom synthesised, but a commodity material used in a non-pharmaceutical market

Ratio: Demonstration that the quality of a commercially available starting material is adequate for use in the manufacture of an active substance

:



Materials of plant origin as starting material:

• Source, processing, characterisation and control should be provided

• Information on the scientific name (genus, species, variety and author) of the plant and plant part used should be provided

• Specification should follow the principles set out in the European Pharmacopoeia monographs

• Pesticides, microbiological contamination,

• Total ash, heavy metals, mycotoxins

• Radioactive contamination, residual solvents


Starting MaterialCritical Steps (1)

Critical steps could be for instance:

• Steps involving formation and/or purge of key impurities which would otherwise be present in the active substance

• Steps which introduce key structural features of the active substance, for example key functional groups or stereochemistry

• Steps where careful control of stoichiometry, temperature, pH or other process variables is crucial for active substance quality



Critical steps could be for instance:

• Steps which employ or generate genotoxic compounds;

• Steps which employ class I solvents and/or toxic metals;

• Complex chemical transformations where multiple variables could impact reaction outcome (multiple reagents, catalysts, solvents, etc.)

• The final purification step.



• Critical steps may impact the impurity profile of the drug substance, therefore they should be included in the manufacturing process

Different approaches:

• Specification of the starting material includes e.g.

• enantiomeric purity,

• genotoxic impurities



Opportunity of short synthetic sequences exists, however should be clearly justified:

• Demonstration, that steps are not considered critical

• Steps to avoid contamination from non-GMP steps should be integral part of control strategy

• When the proposed starting material is itself an active substance covered by a monograph of the European Pharmacopoeia (Ph. Eur)

• Starting material may already be the active substance in a marketing authorisation in the EU.


Consequences (1)

• Re-defined starting material will become an intermediate

• Intermediate is under consideration of GMP

• QP Declaration

• Discussion on possible carry over of impurities coming from the newly defined intermediate

• Whole update of Module 3.2.S.2.2-2.4

• Update of flow chart

• Information on all materials used during the synthesis of the intermediate (own specification)

:


Consequences (2)

• Details on supplier of the newly defined starting material

• Flow chart of synthesis of the newly defined starting material

• Specification of the newly defined starting material with details on

• Specified impurities

•,Unspecified impurities

• Total impurities

• Residual solvents (if relevant)

• Catalysts (if relevant)

:


Case Study IStarting Material


Case Study I (2)Starting Material

The following information has been provided for the synthesis of a

new chemical substance “Axitinib”

Step 1 and step 2:

The 6-Iodoindazole is combined with 1-methyl-2-pyrrolidine (NMP)

to obtain the isolated intermediate Product D.

Step 3 to step 5

Intermediate D is combined with N,N-diisopropylethylamine, acetic

anhydride and NMP and the reaction mixture is heated. Palladium,

and the starting material 2-vinylpyridine are added to obtain crude

axitinib.

Step 6:

Recrystallisation step of axitinib



Proposal of the company:

The company proposes to start with the intermediate D which is

obtained after step 1 and 2. The company argues that due to the

purification step 6, all possible impurities are adequately removed.

In addition, this intermediate is commercial available.



Even if several steps are included in the synthesis of Axitinib, the

proposed starting material intermediate D should be re-defined,

step 1 and step 2 should be included to the synthesis.

Rational:

• Several reagents and substances are used during the synthesis

of intermediate D which are considered critical (Palladium, 2-

mercapto-N-methylbenzamide, 6-idodindazole)

• Complexity of the starting material D

• New chemical entity

• Commercial availability is questionable


Case Study IIStarting Material (1)


Case Study II (2)Starting Material

Synthesis of Caffeine

• Dimethyl urea and ethyl cyanoacetate are the starting materials

- condensation to obtain 4-aminouracil – several reaction steps

to obtain 1,3-Dimethylxanthine (Theobromine).

• Methylisation step to obtain Caffeine

Proposal : Starting with Theobromine

• This is not considered acceptable as this is a one step synthesis


Case Study III (1)

Starting Material


Case Study III (2)Starting Material

The following has been considered by the RMS:

• The route of synthesis as it is included in the submitted DMF is

adequately described.

• However, referring to the Guideline on the chemistry of new

active substance (CPMP/QWP/130/96) and ICH Q11: “generally

the full description of the process should cover all the synthetic

steps critical for the safety (impurities) and the efficacy

(structural part responsible for the activity) of the active

substance.”


Case Study IV (1)Starting Material



• The applicant was requested for re-definition of the starting

material in the first round:

• As the starting material has a complex structure and the

manufacturing process consists of two synthesis steps followed

by a salification step, the redefinition of the starting material is

requested. The manufacturing process of morphine base should

be included to the manufacturing process.

• In the second round the Applicant came up with the response

that the morphine base is extracted from poppy straw using

class 3 solvents. Details on the extraction process had been

provided. The response has been partially accepted. The

following information was requested:



• The suppliers of the starting material should be detailed. If

material of more than one supplier is used, the impurity profiles

should be compared taking into account possible different

extraction ways.

• It has been stated that solvents used for the extraction of

morphine base are class 3 solvents or closely resembling

alcohols.


Case Study V(1)Starting Material


Case Study V (2)Starting Material

The synthesis of Diclofenac diethylamine is a two step process.

The first step involves the reaction of the Sodium 2-[(2,6-

dichlorophenyl)-amino]-phenyl acetate (Diclofenac sodium,

Compound 1) with Acetic acid to produce 2-[(2,6-dichlorophenyl)-

amino]-phenyl acetic acid

(Diclofenac free acid, Compound 2). The obtained Diclofenac free

acid is treated with diethylamine to produce Diethylammonium 2-

[(2,6-dichlorophenyl)-amino]-phenyl acetate (Diclofenac

diethylamine, Compound 3), which is then purified, dried, milled

and packed.

Three suppliers are named; one supplier is the holder of a CEP for

the proposed starting material.

.


Case Study V (3)Starting Material

Re-definition of the staring material is requested as the synthesis

consists of salt formation and one purification step.

The source of Diclofenac sodium which is covered by a CEP is

acceptable (key intermediate).

.


ICH M7

History/Problem Statement


ICH M7 (1)

Guideline is applicable

•to post-approval submissions of marketed products

•to new marketing applications for products with a drug substance

that is present in a previously approved product

However, in both cases only where:

•Changes to the drug substance synthesis result in new impurities

or increased acceptance criteria for existing impurities


ICH M7 (2)

Guideline is applicable

However, in both cases only where:

•Changes in the formulation, composition or manufacturing process

result in new degradation products or increased acceptance criteria

for existing degradation products

•Changes in indication or dosing regimen are made which

significantly affect the acceptable cancer risk level. Assessment of

the mutagenic potential of impurities as described in this

guideline


ICH M7 (3)

Guideline is not applicable for the following types of drug

substances and drug products:

•Biological/biotechnological, peptide, oligonucleotide,

radiopharmaceutical, fermentation products, herbal products, and

crude products of animal or plant origin.

•Drug substances and drug products intended for advanced cancer

indications

•Additionally, there may be some cases where a drug substance

intended for other indications is itself genotoxic at therapeutic

concentrations and may be expected to be associated with an

increased cancer risk.


ICH M7 (4)

In some cases it may be possible, that a potential impurity is

not mentioned in the specification

– If a potential genotoxic impurity is just a theoretical impurity i.e.

based on theoretical considerations but not found in practice as

demonstrated by studies during development of the

manufacture, the impurity does not need to be included in the

drug substance specification.


ICH M7 (5)



– If a potentially genotoxic impurity is formed or introduced in a

step before the final synthesis step and it is controlled by an

intermediate, the impurity does not need to be included in the

drug substance specification. Additionally it should be

demonstrated that this impurity is found less than 30 % of the

acceptable limit in the final substance.


ICH M7 (6)



– Good control strategy that relies on process controls in lieu of

analytical testing can be appropriate.

– In many cases justification of this control approach based on

scientific principles alone is sufficient

– Risk assessment can be based on physicochemical properties

and process factors that influence the fate and purge of an

impurity including chemical reactivity, solubility, volatility,

ionizability and any physical process steps designed to remove

impurities.


Purge Factor (1)

Most synthesis will involve use of mutagenic reagents or

possess potential risk arising from an impurity formed in

the process.

Very reactive agents possess the same property that will

generally ensure its effective removal in the downstream

process.


Purge Factor (2)

Calculation of purging factor

The following key factors were defined in order to assess

the potential carry-over of a mutagenic impurity:

• reactivity, solubility, volatility, and any additional

physical process designed to eliminate impurities e.g.

chromatography.

The overall purge factor is a multiple of the factors for

individual stages.


Purge factor (3)


Example I (1)


Reactivity Solubility Volatility PredictedPurgefactor

AZD9056 Aldehyde

100 1 1 100

AZD9056 Chloride

Not present Not present Not present N/A

IsopropylChloride

Not present Not present Not present N/A

Example I (2)Step 1 (Predicted)



AZD9056 Aldehyde

1 10 1 10

AZD9056 Chloride

1 1 1 1

IsopropylChloride

1 10 10 100

Example I (3)

Step 2 (Predicted)



AZD9056 Aldehyde

1 10 1 10

AZD9056 Chloride

1 3 1 3

IsopropylChloride

1 10 10 100

Example I (4)

Step 3 (Predicted)


PredictedPurgeFactor

MeasuredPurgeFactor

AZD9056 Aldehyde

10,000 112,000

AZD9056 Chloride

3 10

IsopropylChloride

10,000 38,500

Example I (5)

Stage


ICH Q12

Possible Impacts


ICH Q12Categorisation of Post-Approval Changes

Categorisation of Post-Approval CMC Changes

•Categorisation of Post-Approval CMC Changes is a framework

that encompasses a risk-based categorisation for the type of

communication expecteked of the Marketing Authorisation Holder

(MAH) with the regulatory authority regarding CMC changes.


ICH Q12Established Conditions (1)

Established Conditions (EC)

•The concept of ECs provides a clear understanding between the

MAH and regulatory authorities regarding the necessary elements

to assure product quality and identify the elements that require a

regulatory submission, if changed.


ICH Q12Established Conditions (2)


•This guideline describes how ECs are identified as well as what

information can be designated as supportive information that would

not require a regulatory submission, if changed.

•In addition, guidance is included for managing revisions of the ECs

over a product’s lifecycle.


ICH Q12Established Conditions/Impact


•Established conditions are in close connection with ICH Q8

(enhanced approach for manufacturing process, development of

Quality by Design , Design Space)

•ICH Q9 should also be taken under considerations

•Impact on less workload for industry regarding variations

•Facilitate decisions concerning acceptability of enhanced

approach


ICH Q12Post-Approval Change Management Protocol

Post-Approval Change Management Protocol (PACMP)

•The PACMP is a regulatory tool that provides predictability

regarding the information required to support a change and the

type of regulatory submission based on prior agreement between

the MAH and regulatory authority.

•Such a mechanism enables planning and implementation of future

changes to ECs in an efficient and predictable manner.


ICH Q12Post-Approval Change Management

Protocol/Impact

Post-Approval Change Management Protocol (PACMP)

•A protocol describes the CMC change which a MAH intends to

implement during the commercial phase of a product,

•Implementation of these changes is done under a lower reporting

category and/or shortened review period as compared to similar

change procedure without an approved PACMP.


ICH Q12Product Lifecycle Management

Product Lifecycle Management (PLCM)

•The PLCM document serves as a central repository for the ECs

and the associated reporting category for changes made to ECs.

•The document also captures how a product will be managed

during the commercial phase of the lifecycle including relevant

post-approval CMC commitments and PACMPs.


ICH Q12Product Lifecycle Management/Impact

Product Lifecycle Management (PLCM)

•The PLCM document outlines the specific plan for product lifecycle

management that is proposed by the MAH, includes key elements

of the control strategy, the ECs, proposed reporting categories for

changes to ECs,

•PACMPs (if used) will encourage prospective lifecycle

management planning by the MAH and facilitate regulatory

assessment and inspection.

•The PLCM document should be updated throughout the product

lifecycle as needed.


ICH Q12Pharmaceutical Quality System/Change

Management

Pharmaceutical Quality System (PQS) and Change

Management

•An effective PQS as described in ICH Q10 and compliance with

regional GMPs are necessary for implementation of this guideline.

•In particular, management of manufacturing changes across the

supply chain is an essential part of an effective change

management system.

•This guideline provides recommendations for robust change

management across multiple entities involved in the manufacture of

a pharmaceutical product.


ICH Q12Regulatory Assessment/Inspection

Relationship between Regulatory Assessment and Inspection

•This guideline outlines the complementary roles of regulatory

assessment and inspection, and how communication between

assessors and inspectors facilitates the use of the tools included

herein.


ICH Q12Post-Approval Changes

Post-Approval Changes for Marketed Products

•Approaches to facilitate changes to marketed products are

outlined.

•This guideline provides detailed guidance to enable changes to

analytical methods to be made with immediate or other post-

implementation notification.

•Science- and risk-based approaches for stability studies in support

of the evaluation of CMC changes are also described.


ICH Q3D


ICH Q3D (1)

Guideline is applicable e.g. for:

•New finished drug products

•New drug products containing existing drug substances

•Drug products containing purified proteins and polypeptides

Guideline is not applicable e.g. for:

•Herbal products

•Radiopharmaceuticals

•Vaccines, cell metabolites, DNA products

•Drug products used during clinical research stages


ICH Q3D (2)

Class 1 elemental impurities:

•Significantly toxic across all rotes of administration

AS, Cd, Hg, and Pb


•Toxic to a greater or lesser extent based on route of administration

Class 2A (require assessment across all potential sources and

routes of administration): V, Mo, Se, and Co


ICH Q3D (3)


•Class 2B (require assessment across potential elemental impurity

sources only if they are intentionally added to the process): Au, TI,

Pd, Pt, IR, OS, Rh, Ag, and Ru.


•Relatively low toxicity

Sb, Ba, Li, Cr, Cu, Sn, and Ni


•Have been evaluated but a PDE (Permitted Daily Exposure) has

not been established

AL, B, Fe, Zn, K, Ca, Na, Mn, Mg, and W


ICH Q3D (4)

• In developing the control strategy for elemental impurities in

drug products, the principles of quality risk management,

described in ICH Q9, should be considered.

• Control Strategy is based on the risk assessment (section

3.2.P.5.6)

• The applicant’s risk assessment can be facilitated with

information about the potential elemental impurities provided by

suppliers of drug substances, excipients, starting materials,

reagents, container closure systems, and manufacturing

equipment


ICH Q3D (5)

• Control of elemental impurities includes decision making steps

designed to reduce or accept the presence of elemental

impurities and their respective concentrations that were

identified and evaluated through the assessment process.

• When the assessment determines that the levels of elemental

impurities are below the control threshold, no further control is

required but periodic verification testing may be used to confirm

that the expected levels are consistent and predictive of future.


Thank you very much foryour attention!

Contact

Federal Institute for Drugs and Medical DevicesDivision Licensing 3 Kurt-Georg-Kiesinger-Allee 3D-53175 Bonn

Contact personDr. Cornelia [email protected]. +49 (0)228 99 307-4258Fax +49 (0)228 99 307-3991

ich impact on registration and post medication ...ª... · • critical steps may impact the...

Documents