Impurities-

Regulatory Requirements

ICH guidelines – the basic fundaments

• ICH: International Conference on Harmonisation

– Members from regulation authorities and industrial pharmaceutical

associations

– From Japan, USA and Europe

– ICH guidelines also considered by authorities in other regions (e.g. PIC/S 48

members and 4 partners)

– Also for generics, see next topic (Europe and USA)

– Plus considered by further countries

– For example Brazil adopted impurity thresholds

from ICH Q3A, in December 2013 for generics as well

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ICH guidelines – the basic fundaments

• Four ICH Guidelines important (www.ich.org)

– Q3A(R2): Impurities in new drug substances

– Q3B(R2): Impurities in new drug products

– Q3C(R5): Impurities – Guideline for residual solvents

– Q3D(R1): Impurities – Guideline for elemental impurities

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Thresholds for impurities in API

Thresholds for degradation products in FPP

Thresholds for degradation products in FPP

Specification Parameters - Related substances

Any impurity

• > reporting threshold should be reported

• > Identification Thresholds (IT) should be Specified

• Unspecified (individual unknowns) ≤ Identification Thresholds (IT)

• > Qualification Thresholds (QT) should be qualified

Specification Parameters - Related substances

Qualification of limits: adopt limit ≤ QT, or qualify:

• Level present in a product used in safety and/or clinical studies (ICH

Q3)

• If a limit refers to a significant metabolite, it is considered qualified

(confirm it is a metabolite, e.g. WHOPAR, EPAR, SmPC).

• Literature i.e. Pharmacopoeial (ORC) limits for specified related

compounds are considered qualified; an unspecified/unknown limit

in a monograph is not qualified.

• Limit is similar to levels found in unstressed innovator product

Influence ICH impurity guidelines

on generics

• Europe

• European Pharmacopoeia (Ph.Eur.)

• Two documents of importance:General monograph Substances for pharmaceutical use (2034) General chapter Control of impurities in substances forpharmaceutical use (5.10.)

• Above documents link applicablePh.Eur. monographs (new monographs) to ICH Q3A and itsthresholds

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Influence ICH impurity guidelines

on generics

• Europe

• European Medical Agency (EMA):Guideline on Control of Impurities in Pharmacopoeial Substances(CPMP/QWP/1529/04) from 2004

• Guideline requests that marketing approval be granted only whenreferred-to monographs for pharmacopoeial ingredients are compliantwith 2034 and 5.10.

• Also guideline requests EDQM not to grant CEPs (certificates ofsuitability) based on old monographsnot compliant with 2034 and 5.10.

• Consequences: Broad changes of Ph. Eur. monographssince 2003/2004

• From TLC to HPLC related substances methods, but also to different limits, see examples

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Ph. Eur. monograph changes,

amlodipine besilate

Monograph 1/2008

TLC + HPLC methods

• TLC, any impurity:NMT 0.3%, only 2 imps MT 0.1%

• HPLC, imp. D:NMT 0.3%

• HPLC, total imps.:NMT 0.3%

• HPLC, disregard limit:NMT 0.03%

Monograph 4/2009

only HPLC, noTLC anymore

• Imps. A-F:NMT 0.15%

• Unspecified imps.:NMT 0.10%

• Total imps.:NMT 0.6%

• Disregard limit:0.05%

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Influence ICH impurity guidelines

on generics

• USA

• USP in May/June 2014 issued two draft chapters on impurities to update USP‘s opinion on impurities

• New chapter <476>:Organic impurities in drug substances and drug products

• Amendment to <1086>: Impurities in drug substances and drug products

• Chapter also features the ICH thresholds

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Influence ICH impurity guidelines

on generics

• USA

• FDA issued two guidances for industry ANDAs: Impurities in drugsubstances / products

• June 2009 (drug substances), November 2010 (drug products)

• Statement there

• ICH Q3A and Q3B were developed for new drug applications (NDAs)

• However, FDA takes position that ICH principles are applicable to ANDAs (abbreviated NDAs, i.e. generic products) as well:

“FDA believes that much of the content of the Q3A(R) guidanceapplies to ANDAs. See especially sections I through Vand the Attachment, Thresholds.”

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FDA impurity guidance:

Relevant points

• Setting acceptance criteria

• First point of reference:

Pharmacopoeias (namely USP)

• If impurity specified in USP, then specification there should be kept

• If pharmacopoeia specification cannot be kept then impurity enters into qualification process

• If impurity is not specified in compendia

• Use decision tree provided (based on ICH design)

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General Chapter on Impurities in IP in 2007• 5.5 Impurities

• This chapter provides guidance on the control of impurities in drug substances and formulated preparations. It applies mainly to totally synthetic organic medicinal substances and those substances obtained by synthetic modification of a naturally-produced precursor; it is not necessarily relevant to other organic substances e.g. those of plant or animal origin, biological and biotechnological products, inorganic substances and pharmaceutical excipients. It provides an approach to the setting of limits for impurities in articles for which the individual monographs do not provide either a test or specific limits.

• An impurity is defined as any component of a drug substance for pharmaceutical use or of a drug product that is not the chemical entity that defines the substance, or in the case of a drug product, not an excipient in the product. It includes among other things, degradation products of the drug substance that may develop on storage and in the case of dosage forms, those that may also be formed during manufacture and storage.

Acceptance criteria for impurities in drug substances:

Each identified specified impurity

Not more than 0.5 per cent

Each unidentified impurity Not more than 0.3 per cent

Total impurities Not more than 1.0 per cent

Provided it has been determined that the impurities are not toxic. Higher limits may be set if scientifically justified.

Acceptance criteria for degradation products in drug

products:

Each identified degradation product

Not more than 1.0 per cent

Each unidentified degradation products

Not more than 0.5 per cent

Total degradation products Not more than 2.0 per cent

Provided it has been determined that the impurities are not toxic. Higher limits may be set if scientifically justified.

FDA

impurity guidance:

Decision tree #

##Check impurity level

with a dedicated

reference standards before

taking further actions!

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Requirements for a candidate CRS

Pharmaceutical Substance subject of a monograph:

The CRS must comply with the requirements of the monograph,

no special purity required.

Impurity CRS (i.e. not subject of a monograph)

Minimum content :

qualitative use: 90%;

quantitative use: 95% , otherwise value assigned

CRS used in the test for related substances

Qualitative use

- System suitability

- Peak identification

Quantitative use

- Limit test

- Quantitative test

CRS used in the test for related

substances

In general an impurity is to be identified, i.e. located in the chromatogram or electropherogram:

- when it has an individual limit and/or

- when a correction factor must be applied

Impurity CRS : qualitative use

Individual impurity : preferred option but sometimes difficult to

obtain

�Mixtures of impurities

�Batches containing one or more impurities

�Spiked samples

Impurity CRS : qualitative use

A representative chromatogram is

supplied together with the CRS when

indicated in the monograph

Rs

CF CF

Elution order

Example : Torasemide for system suitability CRS

foeniculin

Example Monograph Anise oil, GC-test for foeniculin

Info provided with a CRS

Non-official information, intended to facilitate

the use of the CRS can be found in the

knowledge database (web site).

Impurity CRS : quantitative use

� Individual impurities, with an assigned

value if necessary

� Batch containing the impurity, with an

assigned value

Impurity Reference Standards

New opportunities / Development Areas

The Challenge:

The new Ph. Eur. policy on Impurities requires that most if not all the specified impurities be identified.

Strategy:

- Develop new compounding/dispensing techniques

- Hyphenated techniques for establishment

- New rapid techniques for monitoring

- Keep no. of CRS/monograph as low as possible

- Keep price reasonable

CONTROL OF IMPURITIES is more stronger regulatory and GMP issue, than compendial

So only reasonable control, except for those related substances that are known or even doubted to adversely influence safety of the product

Information on impurities associated with side effects or toxic reactions, including genotoxicity, so that specific named tests can be added in existing or new monographs of Pharmacopoeia

Simple tests for these impurities

Take home messages

• They are official, primary standards

• They constitute an essential part of the monograph

• They are guaranteed only for the intended purpose

• The assay value is assigned “as is”

• Their continuous fitness for purpose is assured by a regular

monitoring programme

• User interface => website

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Any questions?

Thank You