© AL IPA/EDQM/IDMA Symposium 2007, All rights reserved The Ph. Eur. policy on impurities Dr Andrea Lodi Deputy Head, Laboratory Department, EDQM, Council

© AL IPA/EDQM/IDMA Symposium 2007, All rights reserved

The Ph. Eur. policy on The Ph. Eur. policy on impuritiesimpurities

The Ph. Eur. policy on The Ph. Eur. policy on impuritiesimpurities

Dr Andrea LodiDeputy Head, Laboratory Department, EDQM, Council of Europe

Dr Andrea LodiDeputy Head, Laboratory Department, EDQM, Council of Europe


Impurities controlImpurities control

• Adapt to global trade

• Define practice for future monographs

• Reflect regulatory practice in monographs

• Harmonise the approach for different authors of monographs

• Define the needs for revision

• Adapt to global trade

• Define practice for future monographs

• Reflect regulatory practice in monographs

• Harmonise the approach for different authors of monographs

• Define the needs for revision


Impurities controlImpurities control

• Impurities are either controlled or not by the test of the current Ph. Eur. monograph

• Older monographs may not have a test for related substances or use TLC

• Impurities are either controlled or not by the test of the current Ph. Eur. monograph

• Older monographs may not have a test for related substances or use TLC


Impurities: key datesImpurities: key dates

General monograph Substances for Pharmaceutical Use January 2002

General chapter 5.10 Control of impurities in substances for pharmaceutical use January 2005

General monograph Substances for Pharmaceutical Use January 2002

General chapter 5.10 Control of impurities in substances for pharmaceutical use January 2005


Directive 2003/63/ECDirective 2003/63/EC

“However, where a starting material in the European Pharmacopoeia … has been prepared by a method liable to leave impurities not controlled in the pharmacopoeia monograph, these impurities and their maximum tolerance limits must be declared and a suitable test procedure must be described.”

“However, where a starting material in the European Pharmacopoeia … has been prepared by a method liable to leave impurities not controlled in the pharmacopoeia monograph, these impurities and their maximum tolerance limits must be declared and a suitable test procedure must be described.”


Basis for monographsBasis for monographs• SAFETY FIRST!

• Products of proven safety

• Products evaluated and approved by competent authorities of Member States

• Impurity profiles for existing, approved synthetic routes

• Robust, validated analytical methods based on collaborative laboratory testing

• SAFETY FIRST!

• Products of proven safety

• Products evaluated and approved by competent authorities of Member States

• Impurity profiles for existing, approved synthetic routes

• Robust, validated analytical methods based on collaborative laboratory testing


Basis for impurities control

Basis for impurities control

• Specifications for approved products and batch analysis data for approved products

• Specified impurities are those normally found above identification threshold or those in the specifications for approved products

• Specified impurities are qualified at or above the level indicated in the monograph

• Specifications for approved products and batch analysis data for approved products

• Specified impurities are those normally found above identification threshold or those in the specifications for approved products

• Specified impurities are qualified at or above the level indicated in the monograph


RequirementsRequirementsLimits for:

• Specified impurities

• Unspecified impurities

• Total impurities

Impurities section


• Other detectable impurities

If the Impurities section is not divided, all the impurities cited are specified

Limits for:


• Unspecified impurities

• Total impurities

Impurities section


• Other detectable impurities

If the Impurities section is not divided, all the impurities cited are specified


Impurities unusually potent or unusually

toxic

Impurities unusually potent or unusually

toxic

producing toxic or pharmacological effects at a level < the identification threshold

must be qualified and properly controlled

producing toxic or pharmacological effects at a level < the identification threshold

must be qualified and properly controlled


PRODUCTION SECTIONPRODUCTION SECTIONNormally gives limits but not methods

case 1 Paroxetine anhydrousImpurity G: maximum 1 ppm, determined by LC, coupled with tandem mass spectrometry using a suitable, validated method.

not necessarily verifiable by an independent analyst

Examination of data, inspection

Normally gives limits but not methods

case 1 Paroxetine anhydrousImpurity G: maximum 1 ppm, determined by LC, coupled with tandem mass spectrometry using a suitable, validated method.

not necessarily verifiable by an independent analyst

Examination of data, inspection


PRODUCTION SECTIONPRODUCTION SECTION

case 2 Pethidine hydrochloride Impurity B

(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

for non-parenteral usemaximum 10 ppm (method given)

for parenteral usemaximum 0.1 ppm (method not given)

case 2 Pethidine hydrochloride Impurity B

(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

for non-parenteral usemaximum 10 ppm (method given)

for parenteral usemaximum 0.1 ppm (method not given)


Other detectable impurities (ODI)Other detectable impurities (ODI)

• Specific Ph. Eur. category

• Impurities sections in monographs may have a list of ODIs

• Analytical information only: the impurity is detected (not necessarily controlled) by the monograph method

• ODIs are limited in the monograph by the limit for “unspecified impurities” (or Substances for Pharmaceutical Use)

• Specific Ph. Eur. category

• Impurities sections in monographs may have a list of ODIs

• Analytical information only: the impurity is detected (not necessarily controlled) by the monograph method

• ODIs are limited in the monograph by the limit for “unspecified impurities” (or Substances for Pharmaceutical Use)


Ph.Eur. texts to consultPh.Eur. texts to consult• Specific monograph

• General monograph on Substances for Pharmaceutical Use

• General chapter 5.10 Control of impurities

• Any other relevant general monograph (for example Products with TSE Risk)

• General chapter 5.4 Residual Solvents

• Specific monograph

• General monograph on Substances for Pharmaceutical Use

• General chapter 5.10 Control of impurities

• Any other relevant general monograph (for example Products with TSE Risk)

• General chapter 5.4 Residual Solvents


Substances for Substances for Pharmaceutical UsePharmaceutical UseSubstances for Substances for

Pharmaceutical UsePharmaceutical Use

This monograph does not apply to herbal drugs, herbal drug preparations or extracts, which are the subject of separate general monographs [Herbal drugs (1433), Herbal drug preparations (1434), Extracts (0765)].

This monograph does not apply to herbal drugs, herbal drug preparations or extracts, which are the subject of separate general monographs [Herbal drugs (1433), Herbal drug preparations (1434), Extracts (0765)].


Substances for Substances for Pharmaceutical UsePharmaceutical UseSubstances for Substances for

Pharmaceutical UsePharmaceutical Use

Related substances Organic impurities in active substances

are to be reported, identified wherever

possible, and qualified as indicated in

Table 2034.-1.

Related substances Organic impurities in active substances

are to be reported, identified wherever

possible, and qualified as indicated in

Table 2034.-1.


Requirements do not apply toRequirements do not apply to

• biological and biotechnological products• oligonucleotides• radiopharmaceuticals• products of fermentation and semi-synthetic products derived therefrom

• crude products of animal or plant origin or herbal products

• peptides (*)

(*) draft thresholds applicable to synthetic peptides published in Pharmeuropa 19.3 (July 2007)

• biological and biotechnological products• oligonucleotides• radiopharmaceuticals• products of fermentation and semi-synthetic products derived therefrom

• crude products of animal or plant origin or herbal products

• peptides (*)

(*) draft thresholds applicable to synthetic peptides published in Pharmeuropa 19.3 (July 2007)


Monograph revisionMonograph revision

Impurities control has to be updated for newly authorised products/sources:

“[Where] a monograph … [may] be insufficient … the competent authorities shall inform the European Pharmacopoeia. The marketing authorisation holder shall provide the European Pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied.”

Impurities control has to be updated for newly authorised products/sources:

“[Where] a monograph … [may] be insufficient … the competent authorities shall inform the European Pharmacopoeia. The marketing authorisation holder shall provide the European Pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied.”


Impurities Summary: Strategy for compliance

Impurities Summary: Strategy for compliance• Use state-of the-art methods for impurity control

• Know your product and its impurity profile

• Know your suppliers

• Request certificate of suitability to ensure smooth approval procedure

• Maintain liaison with Ph.Eur.

• Use state-of the-art methods for impurity control

• Know your product and its impurity profile

• Know your suppliers

• Request certificate of suitability to ensure smooth approval procedure

• Maintain liaison with Ph.Eur.


Impurity SectionImpurity Section

• Gives impurities known to be detected by monograph tests

• Usually controlled by related substances test, but may be other tests

• Not necessarily exhaustive

• Based on information obtained and verified during elaboration

• Gives impurities known to be detected by monograph tests

• Usually controlled by related substances test, but may be other tests

• Not necessarily exhaustive

• Based on information obtained and verified during elaboration


How to use the general How to use the general monograph monograph

“Substances for “Substances for Pharmaceutical Use” Pharmaceutical Use” to control impuritiesto control impurities

How to use the general How to use the general monograph monograph

“Substances for “Substances for Pharmaceutical Use” Pharmaceutical Use” to control impuritiesto control impurities


Substances for Pharmaceutical Substances for Pharmaceutical Use Use

UseMaximum daily dose

Reporting threshold

Identification

threshold

Qualification

threshold

Human or human and veterinar

y

≤ 2 g / day

> 0.05 per cent

> 0.10 per cent or daily intake > 1.0 mg

(whichever lower)

> 0.15 per cent or daily intake > 1.0 mg

(whichever lower)

Human or human and veterinar

y

> 2 g / day

> 0.03 per cent

> 0.05 per cent

> 0.05 percent

Veterinary only

Not applicabl

e

> 0.10 per cent

0.20 per cent

> 0.50 per cent


General chapter 5.10General chapter 5.10

• Defines:

• Basis for monographs and impurities control

• Terminology

• Interpretation of related substances tests

• Other aspects of impurities control

• ESSENTIAL READING!

• Defines:

• Basis for monographs and impurities control

• Terminology

• Interpretation of related substances tests

• Other aspects of impurities control

• ESSENTIAL READING!



Example no.1Example no.1

• Monograph has:

• Impurity A ≤ … (2 per cent)

• Impurity D ≤ … (1 per cent)

• Any other impurity ≤ … (0.5 per cent)

• Impurities section: •Specified impurities A, B, C, D, E;

•Other detectable impurities F, G

• Monograph has:




• Impurities section: •Specified impurities A, B, C, D, E;



EXAMPLE 1


Example no. 1 (continued)Example no. 1 (continued)• Impurities A and D are specified impurities with their own acceptance criteria (2%, 1%)

• “Any other impurity” refers to B, C and E as specified impurities (limit is above identification threshold) (0.5%)

• Apply Substances for Pharmaceutical Use for all other impurities (including F, G) (0.1%)Substance is an active ingredient for human use with maximum daily dose ≤ 2 g: identification threshold > 0.10%; qualification threshold >0.15%

• Impurities A and D are specified impurities with their own acceptance criteria (2%, 1%)

• “Any other impurity” refers to B, C and E as specified impurities (limit is above identification threshold) (0.5%)

• Apply Substances for Pharmaceutical Use for all other impurities (including F, G) (0.1%)Substance is an active ingredient for human use with maximum daily dose ≤ 2 g: identification threshold > 0.10%; qualification threshold >0.15%


Example no. 2Example no. 2• Monograph has:

•Impurity A ≤ … (1 per cent)

•Any other impurity ≤ … (0.1 per cent)

•Impurities section: •Specified impurities A, B, C, D, E;


• Monograph has:

•Impurity A ≤ … (1 per cent)

•Any other impurity ≤ … (0.1 per cent)

•Impurities section: •Specified impurities A, B, C, D, E;



EXAMPLE 2


Example no. 2 (continued)Example no. 2 (continued)

Any other impurity refers to B, C, D, E, F, G and any others (0.1%)

=> Specific thresholds to be applied to unusually potent or toxic impurities

=> 0.2 % of impurity G or of any other impurity not in the list must be qualified

Any other impurity refers to B, C, D, E, F, G and any others (0.1%)

=> Specific thresholds to be applied to unusually potent or toxic impurities

=> 0.2 % of impurity G or of any other impurity not in the list must be qualified


Example no. 3Example no. 3

The monograph has a TLC test:

•No spot more intense … (0.5 per cent)

•No impurities section

The monograph has a TLC test:

•No spot more intense … (0.5 per cent)

•No impurities section

© AL IPA/EDQM/IDMA Symposium 2007, All rights reserved EXAMPLE 3


Example no. 3 (continued)Example no. 3 (continued)

Apply Substances for Pharmaceutical Use

• Monograph ( => 0.5%) but General monograph 2034 (=> 0.1%) are

monograph needs to be revised

Apply Substances for Pharmaceutical Use

• Monograph ( => 0.5%) but General monograph 2034 (=> 0.1%) are

monograph needs to be revised


Example no. 4Example no. 4Monograph:




Impurities section: •Specified impurities A, B, C, D, E;


Substance is a semi-synthetic product derived from a fermentation product:

Monograph:




Impurities section: •Specified impurities A, B, C, D, E;


Substance is a semi-synthetic product derived from a fermentation product:


EXAMPLE 4


Example no. 4 (continued)

Example no. 4 (continued)

Impurities A and D are specified impurities

“Any other impurity” refers to B, C and E as specified impurities and to all other impurities (including F, G) (0.5%)

Impurities A and D are specified impurities

“Any other impurity” refers to B, C and E as specified impurities and to all other impurities (including F, G) (0.5%)


Residual solventsResidual solvents• Referred to in Substances for Pharmaceutical Use and General Chapter 5.4 Residual solvents

• Specific monographs do not include a test for residual solvents, except:

– Where a product has been approved with a limit higher than the one indicated in 5.4, option 1.

– Class 1 solvents

• Referred to in Substances for Pharmaceutical Use and General Chapter 5.4 Residual solvents

• Specific monographs do not include a test for residual solvents, except:

– Where a product has been approved with a limit higher than the one indicated in 5.4, option 1.

– Class 1 solvents


Residual solventsResidual solvents

• Class 1 solvents are always named and limited in monographs

• Class 3 solvents are only named and limited in monographs when they exceed 0.5% (impact on assay results)

• Class 2 solvents are NOT named and limited in monographs: chapter 5.4 applies

• Class 1 solvents are always named and limited in monographs

• Class 3 solvents are only named and limited in monographs when they exceed 0.5% (impact on assay results)

• Class 2 solvents are NOT named and limited in monographs: chapter 5.4 applies

Documents

© AL IPA/EDQM/IDMA Symposium 2007, All rights reserved The Ph. Eur. policy on impurities Dr Andrea Lodi Deputy Head, Laboratory Department, EDQM, Council