the global regulatory context for impurity testing · 2018-08-10 · impurities (i.e. no discussion...

The Global regulatory context for impurity testing

Agenda

Introduction

• Definition of the term impurity

• Reasons and times for testing

Different types of impurities

Approach to impurity limits from different sides

• Pharmacopeial approach

• Approach from industry

• for compounds described in the pharmacopeia(s)

• for non-pharmacopeial compounds (ICH guidelines)

• FDA‘s new guidance on impurities for ANDAs (generics)

• ICH vs. Pharmacopeias

• Summary

Introduction

Introduction

Definition of the term „impurity“ (according to ICH)

• Any compound in a drug substance or a drug preparation which

• is not the active ingredient itself

• is not an excipient used to produce the drug preparation

• derives from the manufacturing and/or degradation processes

• Could be

• an organic impurity (from manufacturing and/or degradation processes)

• an inorganic impurity (from reagents, catalysts used during manufacturing)

• a solvent

Introduction

Reasons for testing and controlling on impurities

• Overall reason: Testing on impurities mandatory for registration purposes and marketing authorisation

• Because of several risk potentials of impurities:

• Pharmacological effects

• Toxicity

• Adverse side effects

• Influence on the performance of the drug substance

Introduction

Time points for testing

• Already during development of drug substances/products

• To change to a synthesis route with other, more advantageous impurity profile

• For analytical method development parallel to drug product/drug substance development

• Release testing/quality control ...

• ... of the drug substance and as quality control of incoming goods

• ... of the drug preparation (e.g. tablets)

• For and during the anticipated shelf life of the preparation (stability testing)

Different

types

of

impurities


Organic impurities

HOOC OOC-CH3 HOOC OH

HOOC-CH3 + + H2O Salicylic Acid MM0133.07

• Organic impurities

• Starting materials (or intermediates) of the drug substance Example Aspirin (Acetylsalicylic acid):


Organic impurities

• Organic impurities

• By-products during synthesis Example Aspirin:

HOOC OH

+ Salicylic Acid MM0133.07

HOOC OH

+ H2O

OH HOOC O OC

MM0133.03: Salicylsalicylic Acid


Organic impurities

• Degradation products of the drug substance Example Aspirin (presence of moisture):

HOOC OOC-CH3

+ H2O

HOOC OH

HOOC-CH3 +


Organic impurities

• Degradation products also from interaction of API with

• Temperature

• Light (e.g. rearrangement products)

Pantoprazole N-oxide Pantoprazole Sodium

• Oxygen (e.g. N-oxides, S-oxides like sulphines and sulphones)

• pH changes


Organic impurities

• Degradation products can also be substances deriving from interaction between API and excipient present in dosage forms (or with immediate container closure system like infusion bags)

• For example esters of Ibuprofen (iso-propanol and ethanol often present in Ibuprofen gels)

Ibuprofen Ibuprofen Isopropyl Ester

Ibuprofen Ethyl Ester


Inorganic impurities

• Residues from substances used during production, e.g.

• Phosphat salts from buffer solutions (used to maintain a certain pH level during production)

• Chlorides due to the use of hydrochloric acid (common chemical used for several techniques during production)

• Heavy metals from catalysts (used to ease a chemical reaction)

• Filter aids, charcoal etc.


Residual solvents

• Production of drug substances normally in solution

• Sometimes critical parameter

• Enhance yield

• Determine product characteristics: Crystal form, purity, solubility

• After Production: Evaporation of solvents necessary

• In case of organic solvents: Evaluation/Controlling of successful evaporation mandatory because of health risks

Approach to impurity limits from different sides

Pharmacopoeial approach to impurity limits

Organic impurities

• General monograph and text on organic impurities in EP

• Discussed later

• General chapter <466> and <1086> in USP

• Draft impurity chapters (5/2014, new <476>, revision <1086>)

• Limits are set in the individual monographs in special paragraphs

• „Related Substances“ (EP, BP)

• In paragraphs just stating the

impurity´s name (EP, BP)

• „Related Compounds“ (USP)

• „Limit of ...“ (USP)

• „Chromatographic purity“ (USP)

• Limits differ from monograph to monograph

• sometimes from impurity to impurity

• due to different toxicological/pharmacological potencial


• Ibuprofen monograph EP


Inorganic impurities

• Limits are set in the monographs in special paragraphs

• „Heavy metals“ (EP, BP, USP)

• New legislation out for metal impurities (in order to accomodate ICH Q3D guideline (not discussed here)), heavy metals chapters might be revised/deleted and replaced by others

• In paragraphs just stating the impurity´s name e.g. „Iron.“ or „Phosphates.“ (EP, BP, USP)


Residual Solvents

• Limits are set in the monographs in special paragraphs

• „Loss on drying“ (EP, BP, USP)

• Special chapters describe the methods of LOD

• „Identification and control of residual solvents“; „residual solvent“ (EP, BP)

• Special chapters describe the method of solvent controlling

• „Organic volatile impurities“ (USP)


• Ibuprofen monograph EP

Approach from industry

• for compounds described in the pharmacopeia(s)

• for non-pharmacopeial compounds (ICH guidelines)

• FDA‘s new guidance on impurities for ANDAs (generics)

Industrial approach to impurity limits

For drug substances described in the pharmacopeia(s)

• Industry normally following the monographs or comparable measures

• In case of insufficient description by a monograph (due to a manufacturing process with impurities not mentioned in a monograph)

• Industry is referring to other guidelines (ICH Guidelines, see later)

• US FDA and European EMA see them mandatory for generic substances as well, see later

For new (original) drug substances / products

• Industry refers to ICH Guidelines directly


• ICH: International Council on Harmonisation • Members from regulation

authorities and industrial pharmaceutical associations • From Japan, USA and Europe originally

• Meanwhile, also regulatory members from Canada, Switzerland, Brazil, China and Korea

• ICH guidelines also considered by authorities in other regions (e.g. PIC/S 48 members and 4 partners)

• Plus considered by further countries – Long list of observers (e.g. India,

South Africa, Mexico, Australia etc.)


• 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

– Additionally Q3D: Guideline for elemental impurities – Official since December 2014 (not

discussed here)

– New USP chapters <232> and <233> to reflect ICH Q3D

– Revised EP chapters 2.4.20. and 5.20.

Industrial approach to impurity limits – ICH Guidelines

Q3C: Impurities – Guideline for residual solvents

• Includes four lists with

• Solvents to be avoided (due to unacceptable health risks)

• Solvents to be limited (with detailed limits for each solvent)

• Solvents with low toxic potential (with an overall limit for all solvents)

• Solvents with no toxicological data found

• Limits based on PDE (permitted daily exposure, mg/day)

• For „Solvents to be avoided“ no PDE

• Indication as „concentration limit“ (ppm)


Q3A: Impurities in new drug substances

• Dealing with organic and inorganic impurities

• Inorganic impurity usually known, no identification problem

• For inorganics only a short reference to pharmacopeial or other scientifically sound limits (now also Q3D in addition)

• For organic impurities: Different thresholds for different actions

• Reporting

• Identification

• Qualification


Q3A: Impurities in new drug substances

• Originally intended for new drug substances and products

• FDA statement on applying ICH approach also to generic products Guidance for Industry – ANDAs: Impurities in Drug Substances (June 2009):

• A similar guidance existent for impurities in drug products

• Official status since November 2010


Q3A: Impurities in new drug substances - tresholds


Q3A: Impurities in new drug substances – treshold examples


Q3A: Impurities in new drug substances –

decision tree

(Discussion see slides FDA guidance)


Q3B: Impurities in new drug products

• Fulfillment of limit specifications during the entire shelf life of product

• Q3B only looking on degradation impurities (i.e. no discussion on inorganic impurities or „stable“ organic impurities in the drug substance)

• Besides that, the same mechanisms as in Q3A

• Different thresholds for different actions again

• Reporting

• Identification

• Qualification

• Also decision tree with same mechanisms available as in Q3A

• Also to be applied to generic products


Q3B: Impurities in new drug products - tresholds


Q3B: Impurities in new drug products – treshold examples


Q3B: Impurities in new drug products –

decision tree

(analogue to Q3A, discussion at FDA guidance)

New FDA Impurity Guidance

Published in June 2009

Background

• First published 1999

• January 2005: New draft

• Based on ICH Q3A (R)

• A comparable draft for drug products based on Q3B was published in August 2005 as well, official also since November 2010

Most important statement:

• 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) guidance applies to ANDAs. See especially sections I through V and the Attachment, Thresholds.”

Industrial approach to impurity limits – 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

• Probably other pharmacopoeia specifications would be acknowledged as well

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

In case of no pharmacopoeial specification

• Decision tree provided (based on ICH design)


New FDA impurity guidance –

decision tree

Industrial approach to impurity limits - New FDA impurity guidance – decision tree

A

Impurity structure identified?

Yes

No

Yes Impurity specified in USP monograph?

No

Yes

No

Greater than USP limit?

Qualification process (next slide)

Additions in red are not part of original FDA decision tree!

New FDA impurity guidance: Decision tree

A

B

Greater than USP limit?

Yes

Additions in red are not part of original FDA decision tree!

Industrial approach to impurity limits - New FDA impurity guidance – decision tree

B

Overall conclusions

Overall conclusions

Pharmacopeias provide impurity limits

ICH/FDA guidelines provide thresholds, not limits

Limit specifications have to be considered individually, there are no rigid rules

Expensive and time intensive qualification studies should be avoided

• According to FDA‘s thinking, it is the last resort in qualification process

• „Toxicity tests are the least preferred method to qualify impurities. We recommend the tests be used only when impurities cannot be qualified by either of the above procedures.“

• Extremely important to avoid qualification at all:

• Identification of impurities

• Exact quantification of impurities

• Impurity reference standards helpful

Certificate of Analysis (CoA)

Impurity Reference Standards

ICH vs. Pharmacopoeias


For generic drug substances, mandatory to consider ICH additionally

• US: e.g. FDA (already discussed)

• USP is updating their texts at the moment as regards impurities

• 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


For generic drug substances, mandatory to consider ICH additionally

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

• Guideline requests that marketing approval for medicinal products should only be granted when referred-to monographs for pharmacopoeial ingredients are compliant with 2034 and 5.10.

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

Ph. Eur. monograph changes, acetylsaliclylic acid

Monograph 01/2008

• Any impurity: NMT 0.1%

• Total imps.: NMT 0.25%

• Disregard limit: NMT 0.025%

New Monograph 01/2011

• Imps. A-F: NMT 0.15%

• Unspecified imps: NMT 0.05%


• Disregard limit: 0.03%

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%

New Monograph 4/2009 only HPLC, no TLC anymore

• Imp. D: NMT 0.3%

• Imps. A, E, F: NMT 0.15%

• Unspecified imps.: NMT 0.10%



Monograph 1/2008, HPLC methods only

• Imps. A-F: NMT 0.15%




Ph. Eur. monograph changes, ibuprofen

Monograph 1/2008

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

• Imp. B: NMT 0.3%

• Imps. A, C-E: NMT 0.3%

• Total imps. (w/o imp. B): NMT 0.7%


New Monograph 4/2008

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

• Imps. A, J, N: NMT 0.15%




ICH vs. Pharmacopeias

Further aspects

• Not much specific EP drug product monographs, mainly just the general ones

• Testing on drug product impurities (stability testing) completely to be developed by manufacturer

• ICH stability testing guideline available

• Limited guidance in USP, JP and BP on impurities in drug products

• Mainly very general tests on “stability testing” only

• Often only very “general” analytical methods available

• Retention times only given on rare occasions, often assumption of same analytical response of API and impurity

• Very limited supply with suitable impurity reference standards from pharmacopoeias

• Commercial suppliers fill the gap

Summary

Definition of the term „impurity“

Rationales and times for testing

Close look to certain types of impurities

• Organic, inorganic, residual solvents

Setting specification limits on impurities

• From pharmacopeial side

• From industrial side

Overall conclusions

• Accurate identification and quantification can prevent expensive and time intensive qualification studies

• Limited guidance by pharmacopoeias

• Accurate identification and quantification with help of special impurity reference standards

Thanks for your attention!

Dr. Jens Boertz

Senior Product Manager Pharmaceutical

Mercatorstr. 51

46485 Wesel

Germany

[email protected]

mailto:[email protected]

the global regulatory context for impurity testing · 2018-08-10 · impurities (i.e. no discussion...

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