1 Impurities: Positions of the regulatory authorities (like FDA and EMA) worldwide Dr. Christian Zeine, Warsaw, Nov 18, 2014 Science for a safer world.

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Impurities: Positions of the regulatory authorities (like FDA and EMA) worldwideDr. Christian Zeine, Warsaw, Nov 18, 2014

Science for a safer world

Topics of today‘s talk

• Fundamental guidelines from ICH

• Influence of ICH impurity guidelines on testing of generic drug substances/products

• Practical validation examples

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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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• Three 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

– A fourth one (Q3D) on heavy metal impurities to come– Draft published July 2013, plan to have step 4 status in September

2014

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• Threshold table ICH Q3A:

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Influence ICH impurity guidelineson generics

• Europe

– European Pharmacopoeia (Ph.Eur.)• Two documents of importance:

General monograph Substances for pharmaceutical use (2034) General chapter Control of impurities in substances for pharmaceutical use (5.10.)

• Above documents link applicable Ph.Eur. monographs (new monographs) to ICH Q3A and its thresholds

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• 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 when referred-to monographs for pharmacopoeial ingredients are compliant with 2034 and 5.10.

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

– Consequences: Broad changes of Ph. Eur. monographs since 2003/2004

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

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Ph. Eur. monograph changes,acetylsaliclylic acid

Monograph 1/2008 Monograph 1/2011

• Imps. A-F:NMT 0.15%

• Unspecified imps:NMT 0.05%

• Total imps.:NMT 0.25%

• Disregard limit:0.03%

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• Any impurity:NMT 0.1%


• Disregard limit:NMT 0.025%

Ph. Eur. monograph changes,amlodipine besilate

Monograph 1/2008

TLC + HPLC methods

Monograph 4/2009

only HPLC, noTLC anymore

• Imps. A-F:NMT 0.15%

• Unspecified imps.:NMT 0.10%


• Disregard limit:0.05%

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• 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%

Ph. Eur. monograph changes,ibuprofen

Monograph 1/2008

HPLC, imp. F by GC (NMT 0.1%)

Monograph 4/2008

HPLC, imp. F by GC (NMT 0.1%)

• Imps. A, J, N:NMT 0.15%

• Unspecified imps.:NMT 0.05%



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• Imp. B:NMT 0.3%

• Imps. A, C-E:NMT 0.3%

• Total imps. (w/o imp. B):NMT 0.7%



• USA

– USP issued in PF May/June 2014 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

– New chapter resp amendment was necessary to be in consistence with FDA approach

• Monograph changes already ongoing

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• USA

– FDA issued two guidances for industry ANDAs: Impurities in drug substances / 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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New 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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New FDAimpurity guidance:Decision tree (!)

(!)(!)

Check impurity levelwith a dedicatedreference standards beforetaking further actions!

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Validation guideline ICH Q2(R1), parameters

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Examples

• Specifity of HPLC assay method (1)

– Show absence of interference of • solvent, • matrix (in case of drug preparation), • mobile phase, • and of the individual (specified) impurities.

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Examples

• Specifity of HPLC assay method (2)– Chromatograms (Drug Product, 3 specified imps.)

Blank

Placebo

Imp. A

Imp. B

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Examples

• Specifity of HPLC assay method (3)– Chromatograms (Drug Product, 3 specified imps.)

Imp. B

Imp. C

API XYZ

Chromatogram of the API and all three impurities (imps. at limit conc.)

Need to define resolution criteria(SST) at this point at the latest

Imp. CAPI

Imp. A

Imp. B

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Examples

• Specifity of HPLC assay method (4)

– Alternatively, set up two analytical series of drug product

– One with original drug product• Another one with imps. spiked in,

preferably to maximum concentration– Do statistical analysis (t-Test, additionally F-Test)

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Examples

• Specifity of HPLC assay method (5)– Statistical approach

Series 1(mg API/dosage form)

Series 2 (imps. spiked)(mg API/dosage form)

19,62 19,74

20,12 19,52

19,76 19,64

19,98 19,34

19,86 19,72

19,66 19,8

Mean value 19,83 19,63

Standard deviation 0,19 0,17

t-Test and F-Test show a coincidental difference.The test value for the t-Test (significance in mean value!) is 1.92, being lower than the tabulated value (t(5%;10)=2.228) => statistically no difference.The test value for the F-Test (significance in standard deviation!) is 1.25, being lower than the tabulated value (F(5%;5,5)=5.05) => no systematic deviation. 22

Examples

• Accuracy (trueness) of impurity determination by HPLC (1), example acetylsalicylic acid– Recovery of impurity A (spiked into drug substance)– Range from reporting level - 120% of specification

(spec. 0,15%) (0.05-0.18%, resp. 0.15-0.54 mg for 300 mg samples)

– See ICH

Examples

• Accuracy (trueness) of impurity determination by HPLC (2), example acetylsalicylic acid– See ICH

Examples

• Accuracy (trueness) of impurity determination by HPLC (1)– Range from reporting level - 120% of specification

(spec. 0,15%) (0.05-0.18%, resp. 0.15-0.54 mg for 300 mg samples)

Level (%) Amount added (µg) Amount found (µg) Recovery rate (%) Recovery at level (%)

0,05

155 158 101,7

100,6161 162 100,9

164 162 99,1

0,1

303 301 99,3

99,1306 304 99,3

295 292 98,8

0,15

454 457 100,6

99,5459 456 99,3

444 437 98,5

0,18

545 542 99,5

99,6551 549 99,6

531 530 99,7


• Fundamental guidelines from ICH• More and more accpeted worldwide,

not just in core ICH regions

• Influence of ICH impurity guidelines on testing of generic drug substances/products• Will increase further, already the case in Europe/USA/Brazil• Reference standards important for correct measurements

• Practical validation examples• Neat impurity materials (reference standards) most effective

tool for validation tests

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QUESTIONS?Now, or to [email protected]

1 Impurities: Positions of the regulatory authorities (like FDA and EMA) worldwide Dr. Christian Zeine, Warsaw, Nov 18, 2014 Science for a safer world.

Documents

gc nmt

total imps

europe ich guidelines

unspecified imps

imps mt

disregard limit

impurities guideline

well3ich guidelines