edqm

Control of Impurities in

the European Pharmacopoeia –

Principles and update on new

developments

Dr. Michael Wierer

Deputy Head,

European Pharmacopoeia Department,

EDQM, Council of Europe

Contents

1. Principles of Ph.Eur. impurity control

2. Potentially genotoxic impurities in

monographs

3. New methods for mesilate salts etc.

4. New Expression of Acceptance

criteria for impurities

M. Wierer, 02/12/10 ©2009 EDQM, Council of Europe, All rights reserved

2

1) Principles of Impurity Control in

the European Pharmacopoeia

Reflect regulatory practice in monographs

Application of ICH guideline Q3A R to

pharmacopoeial substances focus on

quantitative aspects

Adaptation to globalisation constant need for

updating

Revision of old monographs , in particular progressive replacement of TLC by LC or GC

3


Control of Impurities in Substances for

Pharmaceutical Use

Residual solvents

Control is provided by the general monograph

“Substances for pharmaceutical use” and general

chapter 5.4 “Residual solvents”.

Inorganic impurities

Specific tests in individual monographs

Organic impurities

“Related substances test “ and/or further tests

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Impurities control - key features• Selective related substances tests

• Limits based on ICH Q3A R

• Transparency statements

• Information column brands

• Correct identification of impurities

• Meaningful system suitability criteria

Separation

Sensitivity

see chapter 5.10 Control of Impurities

5


Standard requirements in an

Ph.Eur. monograph

Limits for:

Specified impurities

Unspecified impurities

Total impurities

Disregard limit

Impurities section (transparency list)

Specified impurities

Other detectable impurities

6M. Wierer, 02/12/10 ©2009 EDQM, Council of Europe, All rights reserved

Transparency list

Bromazepam


Impurities Section

• Gives impurities that are known to be

detected by monograph tests

• Usually controlled by related substances test,

but may be other tests

• Based on information obtained and verified

during elaboration

• Not necessarily exhaustive

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Specified Impurities

are those in specifications for approved

products

limits based on specifications for

approved products and batch analysis

data

specified impurities are qualified at or

above the level indicated in the

monograph

9


Other Detectable Impurities

• Unique Ph.Eur. category

• Impurities sections in monographs may have

a list of ODIs

• Analytical information only: the impurity is

detected by the monograph method

• ODIs are limited in the monograph by the limit

for “unspecified impurities” (or Substances for

Pharmaceutical Use)

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General monograph

Substances for Pharmaceutical

Use (2034)

To be read in conjunction with the

individual monographs

Bridges general requirements to those

monographs, which are not yet updated

General monograph 2034:Related substances

• Unless otherwise prescribed, organic

impurities in active substances are to be

reported, identified wherever possible, and

qualified as indicated in Table 2034.-1.

(general) or in table 2034.-2 (for peptides

obtained by chemical synthesis)

• Specific thresholds may be applied for

impurities known to be unusually potent or to

produce toxic or unexpected pharmacological

effects

Requirements for active substances

except synthetic peptides

Use Maximum

daily dose

Reporting

threshold

Identification

threshold

Qualification

threshold

Human or

human and

veterinary

≤ 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

veterinary

> 2 g/day >0.03 per

cent

>0.05 per

cent

> 0.05

percent

Veterinary

only

Not

applicable

>0.10 per

cent

0.20 per cent >0.50 per

cent

M Wierer, 14/09/10 ©2010 EDQM, Council of Europe, All rights reserved

Requirements for peptides

obtained by chemical synthesis

Reporting

threshold

Identification

threshold

Qualification

threshold

> 0.1 % > 0.5 % > 1.0 %

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Thresholds do not apply for

Biological and biotechnological products

Peptides (not obtained by chem. synthesis)

Oligonucleotides

Radiopharmaceuticals

Products of fermentation and semi-synthetic products derived therefrom

Crude products of animal or plant origin or herbal products

Excipients

Identification of

impurities


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CEFEPIME FOR SST CRS 1

Alltima C18

250 mm x 4.6 mm, 5µm

Kromasil C18

250 mm x 4.6 mm, 5µm

Inertsil ODS 3

250 mm x 4.6 mm, 5µm

��Is retention time a system suitability requirement ?

LC methods in the Ph. Eur. originally developed and validated

by manufacturers, i.e. well-defined equipment and column(s).

Robustness challenged by the fact that only a general

description of the column can be given. The chromatographic

behaviour with the variety of commercially available “C 18”

columns is very often too variable, esp. with gradients.

Essentials for adequate test application

need to provide CRS and chromatogram

info on the columns used

need to set appropriate criteria (SST)


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Peak identification

The identification of a given impurity is needed

when the impurity has an individual limit, and/or

when a correction factor must be applied.

In all the other cases although desirable, the identification is not required.

The method of choice to identify an impurity in a chromatogram is by comparison with an authentic sample.


18

Rs

CF CF

Specified

impurities:

A, B, C, D.

Example : Torasemide for

system suitability CRS

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Ph. Eur. Reference Substances

Use of the isolated impurity as impurity CRS

CONSTRAINT: often impurities are available in

scarce quantities only

CRS: a sample containing the impurity of interest

(a “bad batch”, a spiked batch, a mixture of

substance and its impurities).


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Description of HPLC columns:

Example: Amiodarone HClreversed phase LC elution, UV detection

Column:

_ size: l =0.15 m, Ø = 4.6 mm

_ stationary phase: octadecylsilyl silica gel for chrom. (5µm)

_ temperature: 30 °C

What you will find in the monograph:

dimensions, type of stationary phase, particle size

Not given: brand names of columns

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EDQM Knowledge database

… contains information on

- Reference standards

- Column or reagent brand names

23


Column ranking/classification

systems available on the internet

www.rheodyne.com

www.pharm.kuleuven.ac.be/pharmchem/

columnclassification

www.acdlabs.com/columnselector

http://www.rheodyne.com/

http://www.rheodyne.com/

http://www.pharm.kuleuven.ac.be/pharmchem/columnclassification





http://www.acdlabs.com/columnselector

http://www.acdlabs.com/columnselector

System Suitability criteria:

Limits to ensure adequate test performance

Resolution of two closely eluting peaks (critical peak pair)

Peak-to-valley ratio (incomplete separation, peaks of very different size)

“Similarity” or “concordance” with a chromatogram supplied

Signal to noise ratio for sensitivity


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Sumatriptan impurity mixture CRS

(spiked samples)

- resolution imp C / sumatriptan

minimum 1.5

- 5 clearly separated peaks


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Peak-to-valley ratio


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Example: Anhydrous paroxetine

Signal-to-noise ratio

Min. 3 for the peak due impurity H in ref. solution (e). = 0.05%


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Why are revisions needed?


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Revision Needs

Replace TLC by LC, GC or CZE

Add a limit for total of impurities

Allow unambiguous peak identification

Bring general acceptance criterion in line with

“Substances for pharmaceutical use“

Introduce impurity section (transparency list)

Updates for new active substance sources

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Special revision programme: Example NorfloxacinTLC: max. 3 spots, each <= 0.2%, now replaced by LC:

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2) Potentially genotoxic

impurities in monographs

• CHMP Guideline on the limits of genotoxic

impurities in effect 1.1. 2007

• CPMP/SWP/5199/02,

EMEA/CHMP/QWP/251344/2006

• Applicable to

• New active substances

• New applications of existing active substances

unless there is assurance that no new or higher

levels are introduced as compared to products

currently authorised in EU 32


Problem statement

• What about existing substances covered by an

EP monographs ?

• Transparency lists may contain structures of

potentially genotoxic substances

• Structural alert does not automatically imply

genotoxicity

• Sometimes production section to flag up PGIs

33


PGIs in transparency statements (1)

• Classified as « other detectable impurities »

• This in analytical information only

• This does not necessarily confirm the

occurrence of the impurity at relevant levels

• Rarely adequate control of such substances

• EP monographs may relate to several routes

of synthesis

• The PGI may be irrelevant for certain routes

of synthesis

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PGIs in transparency statements (2)

• Introduction of regular testing would not be

helpful in many cases

• Analytical challenge: sensitivity, specificity

• Problem for authors of monograph revisions,

new monographs and users

• Policy paper for European Pharmacopoeia

Commission has been adopted after

consultation of EMA QWP and SWPwww.edqm.eu/medias/fichiers/NEW_Potentialy_genotoxic_impuriti

es_PhEur_monographs.pdf

35


Basic principle of the policy

• For substances uses in human or human and

veterinary products:

• Folllow the approach of the CHMP guideline

• For substances solely used in vet. products:

case-by case guidance by comp. authorities

36


Case 1

• Substance included in a medicinal product

authorised after application of the CHMP

guideline*

►Monograph should be based on marketing

authorization(s)


37

Case 2


authorised before application of the CHMP

guideline*:

• no PGI expected from synthetic route.

►No action needed, monograph based on

marketing authorization


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Case 3

• Substance included in a medicinal product authorised

before application of the CHMP guideline*:

• PGI expected from synthetic route of first authorised

product and

• subsequently authorised products (if any) have no

expected PGI or same PGI as the first authorised

product at same or lower level and

• no data showing genotoxicity.

►No action needed during elaboration of monograph

(based on marketing authorization), no revision of

existing monographs


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Case 4


authorised before application of the CHMP

guideline*:

• PGI expected from synthetic route of an

authorised product and

• data showing genotoxicity of an expected

PGI.

►Monograph should be elaborated or revised

based on evaluation by the Competent

Authority.M. Wierer, 02/12/10 ©2009 EDQM, Council of Europe, All rights reserved

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Case 5

• Substance included in a medicinal product authorised

before application of the CHMP guideline*:

• PGI expected from synthetic route of first authorised

product, and

• subsequently authorised products have a new

expected PGI or same PGI as innovator product at a

higher level and

• data showing genotoxicity of an expected PGI.

►Monograph should be elaborated or revised based on

evaluation of new PGI or high level of previously

known PGI by the Competent Authority


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Consquences

• Monographs (limit and tests) will be updated

if relevant information is submitted from

stakeholders

(in particular National Competent Authorities)

• The existence/use of a monograph does not

release the user from his responsibility to

review the synthetic route, the process control

and the impurity profile as regards PGIs

• Certification Unit will apply the Guideline and

Regulatory guidance

42


CH3

S

O

O

O H + R-OH

Methanesulfonic

acid

CH3

S

O

O

O H

Mesilates (Esters)

R= Methyl, Ethyl, Isopropyl

3) Update on methods concerning

Mesilates

Alkylated Agents

• by-product

• impuritiesSources:

R

Potentially genotoxic !

Overview of methods developed

• Determination of methansulfonyl chloride in

methanesulfonic acid (Pharmeuropa 22.3)

• Methyl, ethyl and isopropyl methanesulfonate

in methanesulfonic acid (Ph. Eur. 7.1);

• Determination of methyl, ethyl and isopropyl

methanesulfonate in active substances

(adopted, supplement 7.3)


44

2.5.38. Determination of Methyl-, Ethyl- and

Isopropyl- methanesulfonate in active substance

mesilates

• General method has been validated for the determination of methyl, ethyl and isopropyl esters of methanesulfonic acid ( in concentrations between 0.1 ppm and 5 ppm) for Betahistine mesilate

• Method has been examined for 10 further mesilate APIs described in Ph. Eur.

• Solutions need to be adapted to target concentrations and validated by the user


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1 Methyl- 2 EthyI- 3 Isopropyl- 4 Butyliodide

Method principle:

• Dissolution of the mesilate API in H2O/ Acetonitrile

• Derivatisation of MMS, EMS and IprMS with NaI and

Na2S2O3 to the respective iodide derivatives

• Headspace-GC with MS detection / SIM mode

• Internal standard Butylmethanesulphonate


46

Monograph titleLimit calculated based

on maximum daily dose and TTC (ppm)

Lower concentration tested during method

verification (ppm)

Betahistine mesilate 42 5

Bromocriptine mesilate 25 2

Codergocrine mesilate 188 20

Deferoxamine mesilate 0.3 0.1

Dihydroergocristine mesilate 313 30

Dihydroergotamine mesilate 150 15

Doxazosin mesilate 188 20

Pefloxacin mesilate dihydrate 1.9 0.5

Pergolide mesilate 300 30

Phentolamine mesilate 300 30

Saquinavir mesilate 0.7 0.1

4) New Expression of Acceptance

Criteria in the Test for Related

Substances

Acceptance Criteria in the Test for

Related Substances “limit test style”

So far usually expressed in terms of comparison

of peak areas:

“Not more than the area of the principal peak in

the chromatogram with the reference solution ...”

Pass/fail result (limit test)

– not a true quantitative (numerical) test result

Reasons for the proposed change to

new (“quantitative”) style

• Related substances tests were aligned with ICH

Q3R and VICH GL 10 requirements

• Users have requested a format more adapted to

quantitative purposes and to industrial practice

of calculating/reporting results


50

Proposed change

(“quantitative” style)

“Calculate the percentage content of impurity X from the concentration of reference solution ...”

Numerical result for each impurity

Total of impurities can directly be calculated

rather than summing up areas or corrected areas

Use of term “reporting threshold”

Current status

• Numerous (mostly positive) comments received

• Agreed by Chairs of Chemical Expert Groups

• Due to the large impact

o No retrospective application

o Use for new and revised texts via Pharmeuropa

o General Notices , Chapter 5.10 to be amended to

take account of “limit test” style and “quantitative”

style

o Adoption at Ph.Eur. Commission 3/2011 expectedM. Wierer, 02/12/10 ©2009 EDQM, Council of Europe, All rights reserved

52

Conclusion

• Impurity control is the key item in Ph.Eur. active substance monographs

• Related substances TLC tests are replaced by LC or GC test (spec. revision programme)

• Ph.Eur. is updating old monographs whereever possible but ongoing

• New challenge: control of genotoxic impurities

• New methods for control of mesilates elaborated

• Style for impurity acceptance criteria now aligned with ICH Q3AR2 and VICH GL 10

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Thank you!54


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