Deficiencies Presentations

Istanbul October 2005

CERTIFICATIONOF SUITABILITY OF MONOGRAPHS

OF THE EUROPEANPHARMACOPOEIA 5TH EDITION

WORKSHOP SESSION:An outline of the main

deficiencies in dossiers andhow to avoid them


The main deficiencies found indossiers for chemical purity

Dr P.Poukens-Renwart and Dr D. ByrneScientific officers

Certification Unit, EDQM


Summary:

• Figures• Deficiencies at receipt• Top ten deficiencies• Other deficiencies (new development)• Presentation of data• Conclusions


Average time to get a CEP:21 months (min 6 months, max 6 years)


Number of assessments for CEP


Requests for add info after 1st assessment:Average number of questions: 11 (9 in 2004)

(min 0, max 25)


Content of the dossier• PA/PH/CEP (04) 1, 3R:

Content of dossier for chemical purity:Revision of annex 1 of the Resolution AP-CSP (99) 4: CTD format

• Application form (declarations)


Dossiers blocked at receipt 9% of applications received in 2004 (24% in 2002)

• ADMINISTRATIVE REASONS:Missing application form/declarations/samples/ QOS

• TECHNICAL REASONS:2 processes / incomplete documentation / Class Isolvents / Referred monograph ≠ current Ph. Eurmonograph / related substances controlled by TLC


Application form– Details on holder, manuf. site: on the CEP– Details on contact person/company for correspondence– History of the substance– Retest period– Declarations (templates): GMP, willingness to be

inspected, absence / presence of material ofanimal/human origin

NB: 2 different forms: new requests and revisions


CTD format

• (3.2.S.1) General information• (3.2.S.2.2) Manufacturing process• (3.2.S.2.3) QC of Starting materials• (3.2.S.3.2) Impurities / solvents / catalysts• (3.2.S.4.1) Specifications and routine tests


CTD format (cont)

• (3.2.S.4.3) Analytical validation / suitabilityof the monograph

• (3.2.S.4.4) Batch results• (3.2.S.5) Packaging material• (3.2.S.7) Stability


Repartition of questions after thefirst evaluation


TOP TEN of deficiencies1. (3.2.S.2.3) Description of the route of synthesis

of the declared starting material(s), descriptionof impurity profile (related subst, reagents,solvents, catalysts), and carry-over of impuritiesto the final substance : 83.5% of dossiers (58%in 2004)

2. (3.2.S.2.3) Specification for all reagents,solvents and water. Include purity tests: 64.6%(38% in 2004)


TOP TEN deficiencies (cont)

3. (3.2.S.2.3) Specification of the starting materialsshould include suitable limits for impurities andsolvents: 48.1% (29% in 2004).

4. (3.2.S.2.2) Detailed description of each step ofthe manufacturing process: quantities of startingmaterials, reagents, solvents,…operatingconditions: 35.4%



4. Limits for impurities should be in accordancewith the specific monograph + generalmonograph 2034 (unspecified imp: 0.10%):35.4% (38% in 2004).

5. Demonstration that all solvents used areremoved or suitably limited (validated method):34.2% (42% in 2004)



6. (3.2.S.2.2) Maximum/typical batch size: 29.1%(38% in 2004)

6. (3.2.S.5) Characterisation of referencestandards: 29.1%

7. (3.2.S.2.3) Proof of absence of particularreagents in the final substance (catalysts,alkylating agents, …): 27.8 % (42% in 2004)


TOP TEN deficiencies (cont)8. (3.2.S.3.2) Illustration of the impurity profile

based on typical chromatograms : 26.6%

9.(3.2.S.3.2) Detailed discussion on impurities: - origin, correspondence with transparency list : 22.8%- levels found, setting of limits: 22.8%



9. (3.2.S.4.4) Results on 3 batches (size +manufacturing date) : 22.8%

10.(3.2.S.1) History of the substance : 21.5% (29%in 2004)


Deficiencies linked to the newdevelopments of the procedure

• General monograph for substances forpharmaceutical use (2034)

=>Quantitative methods should be used for thecontrol of related substances:TLC IS NO LONGER ACCEPTABLE !!!


Deficiencies linked to newdevelopments of the procedure(cont)• Implementation PA/PH/CEP (04) 1, 3R:

Content of dossier for chemical purity:Revision of annex 1 of the Resolution AP-CSP(99) 4:

- CTD format- Declaration of the absence of any material of human / animal origin


Data presentation

• Data given in the dossier should be :– Clear– Concise– Readable– Obtained from recent analysis


Conclusions: how to avoiddeficiencies ?• Revised annex 1 to resolution « content of

the dossier » (including CTD format)

• Top ten deficiencies

• Implementation of recent developments


THANK YOU!

• EDQM Internet sitewww.pheur.org

• for questions on the [email protected]


CERTIFICATIONOF SUITABILITY OF MONOGRAPHS

OF THE EUROPEANPHARMACOPOEIA 5TH EDITION

WORKSHOP SESSION:An outline of the main

deficiencies in dossiers and howto avoid them

Deficienciesrelated to manufacturing process, control

of drug substance and stability

Dr. Samuel SteinerCantonal Pharmacist of the Canton of Berne

Switzerland

Certification Conference,Istanbul, 27-28 October 2005

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3.2.S.2.2. Manufacturing Method

• Brief outline and flow chart• Detailed description, including

- typical / maximum batch size- narrative description, including explanation of chemical reactions- all materials and reagents introduced and typical quantities, yields- operating conditions (ranges of T°C, time, pH..)- structure of isolated intermediates


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- re-processing, re-working, recovery (where, how) typical quantities, yields

operating conditions (ranges of T°C, time, pH..)

- IPC (in process controls) :where, how, methods, specifications

- options (alternatives)

- Blending, mixing sub batches (QC where?)


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• Semi-synthetic products: Fermentation steps involved in synthesis of starting

material ?

- Characterisation of fermented starting material, incl. detailed impurity profile- Compliance with general monograph Products of Fermentation 1468- Carry over of fermentation impurities- TSE risk substances!


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3.2.S.2.3. Quality Control of Materials

• Definition of starting material(s)- manufactured in-house or purchased?- few steps synthesis: details of the synthesis of the starting materials (flow chart) detailed specifications for impurities

• Suitable specification for all materials used- incl. purity tests for solvents, quality of water..

Compliance with EP requirements for startingmaterial/key intermediates/solvents

=> cannot be imposed

3.2.S.2.4. Control of Critical Steps and intermediates


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3.2.S.4. Control of the Drug Substance

• Reference to the right (EP) monograph and its tests

• Include additional/alternative tests (if necessary)

• Appropriate limits for impurities, solvents,... inaccordance with the process and relevantguidelines => General monograph 2034

• Adequate methods description=> format to be appended to the CEP

• Biological substances – information oninactivation/removal infectious material when required?


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3.2.S.4.3 Validation of analyticalprocedures

• All in-house methods should be validated (incl.non-routine methods)- ICH Q2B for methodology- Typical chromatograms (selection, illustration of the chromatograms)

• Cross-validation against Ph.Eur.- comparative results from the same samples


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Other requirements

• 3.2.S.4.4 Batch data (3 batches)- in line with specification (methods used?)- Details on batches tested (batch nr., size, date of manufacture, date of analyses)- Numerical figures (adequate digits, “complies” not appropriate)


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Other requirements

• 3.2.S.5 Reference substances:Characterisation of reference standardsPh.Eur. Standards (CRS)

• 3.2.S.6 Packaging Material:- Description + specifications of materials- compliance with foodstuff legislation should be declared.


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3.2.S.7 Stability

When a retest period is to be stated on the certificate:Guideline on Stability testing: Stability testing of existing

active substances and related finished productsCPMP/QWP/122/02 rev 1)

• ICH conditions (long-term + accelerated) + Fit themonograph statements

• Study description – relevant parameters (incl. referenceto methods used)

• Detailed results (figures) - Impurities• Validation of in-house methods (stability indicating)• Proposed retest period, packaging material and storage

conditions


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3.2.S.7 Stability (cont.)

• Quality specifications in accordance with the GeneralMonograph „Substances for Pharmaceutical use“

• Proposed retest period and storage conditions:- in accordance with stability results- Extrapolation: see Guideline Note for guidance on declaration of storage conditions (CPMP/QWP/96/Rev 1)


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Thank you

Questions?

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Safeguarding public health

Deficiencies: ImpuritiesRelated Substances,Residual Solvents and Catalysts

Sean JonesPharmaceutical AssessorMedicines and Healthcare products Regulatory Agency, UK

Slide 2October 2005Sean Jones

Deficiencies: Impurities

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Introduction

• The Regulatory Framework• Top 10 Deficiencies: Impurities• Control of Starting Materials (3.2.S.2.3

and 2.4)• Impurities (3.2.S.3.2)

- Impurity Profiling• Control of Active Substance (3.2.S.4)• Summary• NfGs, Bibliography, Websites

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Regulatory Framework

• EU Directives- Medicines, Plastics, TSE.

• Notes for Guidance- EU and ICH

• European Pharmacopoeia- General Monograph “Substances for

Pharmaceutical Use”- Specific Monographs



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General Monograph: ImpuritiesSUBSTANCES FOR PHARMACEUTICAL USEOrganic Impurity Threshold Limits• All Impurities to be reported, identified wherever possible, and

qualified, (in line with Q3A).• New impurities to be investigated and controlled.• Limits for single unknown and total impurities should also be

controlled.

Quantitative Techniques Required• HPLC to replace semi-quantitative TLC• System Suitability Testing

Unusually Toxic Impurities• Specific limits may be applied for impurities known to be

unusually potent or to produce toxic or unexpectedpharmacological effects.

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Impurity Threshold Limits

> 0.05%> 0.05%> 0.03%> 2 g/day

> 0.15% or >1.0mg/day

(whichever the lower)

> 0.10% or > 1.0 mg/day

(whichever the lower) > 0.05%≤ 2 g/day

Qualificationthreshold

Identificationthreshold

Reportingthreshold

Maximumdaily dose

EXEMPT: Less stringent limits possible, if justifiedBiologicals, biotechnological products, peptides,oligonucleotides, radiopharmaceuticals, products offermentation and semi-synthetic products derived therefrom,herbal products and crude products of animal or plant origin.



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Ph Eur 5.10 Control of Impurities (1)• Drug Monograph covers organic and inorganic

impurities• The ‘Related substances’ test is a general test, which

covers relevant organic impurities- May be supplemented by specific tests to control a specific

impurity- If only specific tests, control of organic impurities is still

required• Different impurity profiles: one test or several tests to

control all known profiles• Only the tests necessary for a known profile for the

source need be performed to establish compliance.• Residual solvents to be controlled (Ph Eur 5.4 and

2.4.24).

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Ph Eur 5.10 Control of Impurities (2)

• The active substance monograph is based oninformation at time of preparation

• May not be exhaustive• Specified impurities and Other detectable impurities• New Impurities / Specified impurities above set limit• New impurities may require new analytical techniques

- To be controlled according to the Generalmonograph

- To be qualified according to the General monograph- Revision of the monograph initiated



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Drug Substance SpecificationDrug Substance Specification =

• Drug Substance Monograph plus• General Monograph (2034) “Substances for

Pharmaceutical Use” plus• General Text (5.10) “Impurities in Substances

for Pharmaceutical Use” plus• General Text (5.4) “Residual Solvents”

The joint application of these monographs providean assurance of quality and safety

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Top 10 Deficiencies: ImpuritiesCONTROL OF STARTING MATERIALS (3.2.S.2.3 and 2.4)1 Absent, insufficient or unjustified impurity profile for starting

materials. No discussion of carry-over to the final substance2 Specification for all reagents, solvents and water. Include purity

tests3 Specification for the starting materials should include suitable

limits for impurities and solventsIMPURITIES (3.2.S.3.2)8 Detailed discussion on impurities: origin, correspondence with

transparency statement.CONTROL OF ACTIVE SUBSTANCE (3.2.S.4)4 Limits for impurities should be in accordance with the specific

and general monographs



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Simple Synthesis Scheme

A+B(B’)

C(C’)

~D(~D’)

D(D’)

DegradantsBy productsBy products

OrganicImpurities

Reagents

Solvents

Starting Materials

Intermediate Crude Active Pure Active

-------------

------------------------------

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Control Of Starting Materials(Sections 3.2.S.2.3 and 2.4 of the Dossier)

• Information demonstrating that the materials meetstandards appropriate for their intended use should beprovided.

• Specifications should be justified, supported by appropriatedetails of the materials’ synthesis and batch data.

• Potentially reactive and isomeric impurities, which may carrythrough, unchanged or as derivatives, should be fullydiscussed and controlled.

• For critical attributes, tested by non-pharmacopoeialmethods, then validation data may be required.

• The specifications for intermediates should be similarlyaddressed.



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Control Of Solvents and Reagents(Section 3.2.S.2.3 of the Dossier)

• Water should comply with NfG on Quality of Water forPharmaceutical Use

• Solvents used at the final stages of the synthesis requiremore stringent control than those used in earlier stages.- Class I solvents to be avoided.

• Specifications for all reagents should be provided.- Novel reagents should be fully discussed

• Identification tests and an assay should be specified• Reactive and toxic impurities should be specified• Important performance attributes should be specified

e.g. Adsorption Power for Activated Charcoal

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Impurities(Section 3.2.S.3.2 of the Dossier)

Information on impurities should be provided:• Potential impurities should be discussed arising

from synthesis and degradation• Data for impurities found should be provided• Data to support the absence of toxic impurities

(and absence of control in the Drug SubstanceSpecification) should be provided

• Analytical systems should be fully described andappropriate validation data provided.

• Easier said than done!



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Impurity Profiling

Id of all significant impuritiesAbsence of possible impurities

DetermineOrigin

Minimise and / or EliminateRevise Synthesis and / or Storage

Qualify, if necessary.Control: Revise DSS

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Impurity Profiling: Getting Started

• Literature Review• New vs. Well Established Synthesis• New vs. Known Impurities• Development, Optimisation and Scale up,

Validation Data



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Impurity Profiling: General Cues• General Properties and Characterisation Cues

- Appearance / Crystalinity / Colour and Clarity ofSolution / Odour

- Additional spectral peaks,- Specific Absorbance- Optical Rotation- Acidity / Alkalinity and pH- Thermal Analysis, including Melting Point

•Assay- Sensitivity and Specificity

• Compare with Certificated Reference Standard

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Impurity Profiling:Potential Organic Impurities

• The Starting Materials and Intermediates• By-Products

- Under and over reactants- Side reactions with reagents and solvents

• Impurities from Starting Materials andIntermediates

• Chiral Products



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Impurity Profiling: Known Impurities

• Ph Eur quantitative method is available (not TLC)• System Suitability Testing to assure resolution

and sensitivity• Specified Impurity Reference standards• Defined chromatographic characterisation of

known impurities• Peak purity measurements in case of new

impurities

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Impurity Profiling: New Impurities

• Validation data required to show suitability ofPh Eur method

• New method may be required - developmentand optimisation to be discussed

• Potential of coupled techniques• Reference standards• Degradation of new impurities



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Impurity Profiling: New Impurity

Int.J.Tox, (2004), 23, 41-45

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Impurity Profiling: By-Products

Scheme for the formation of some impurities in ethynodiol diacetateAnal.Bioanal.Chem.(2003), 317, 852-862



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Impurity Profiling:Reagents and Catalysts• The description of the synthesis should be explicit.

- How each reagent and solvent is removed, especially toxicmaterials, should be clearly described.

• Toxic reagents should be controlled, using specific tests,in the specifications for intermediates and / or the drugsubstance.- unless justified by provision of development and validation

data that show successful removal, using a validated andsensitive analytical method.

- Catalysts should be similarly addressed.- See NfG Specification Limits for Residues of Metal Catalysts

• Role of General tests methods e.g. Heavy Metals Test,Sulphated Ash, should be discussed

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Impurity Profiling: Toxic impuritiesSpecific toxic impurities• Impurity G in Paroxetine,• Chloroacetanilide in Paracetamol• Impurity B in Pethidine (tighter limit for parenteral use)• Dimethylaniline in Semi-synthetic antibiotics

Production Section of Monograph• Use of tandem techniques LC –MS (Impurity G)

Specific Test Methods in monographs• Dimethylaniline• Impurity F in Ibuprofen

General Test Methods• Dimethylaniline Ph Eur 2.4.26• Ethylene oxide and dioxan Ph Eur 2.4.25



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Impurity Profiling: Residual Solvents

• Comprehensive guidance available• Toxicity of Solvents

- Class I to be avoided- Class II to be limited- Class III GMP limited (nmt 0.5%)

• Fate of solvents and their removal used shouldbe fully discussed

• Limits for solvents used in the purification andlast steps should be specified.

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Control of Active Substance(Section 3.2.S.4 of the Dossier: Organic Impurities)

• Organic Impurities in the Transparency Statement- Specified impurities are limited by the Drug Substance

Monograph- Other Detectable impurities, if present, to be limited by

the General Monograph

• Organic Impurities NOT in the Transparency Statement- New Impurities: To be limited by the General Monograph

• Single Unknown Impurities:- To be limited by the General Monograph

• Total Impurities:- Limit to be justified by reference to batch data.



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Control Of Active Substancee.g. KetoprofenMONOGRAPH IMPURITIESMaximum Daily Dose < 2g/day

• Specified impurities: A, B, C, D, E, F.• Other detectable impurities: G, H, I, J, K, L .

• Organic Impurity Acceptance criteria:• Related Substances (HPLC):

Impurities A and C: 0.2%, Any other impurity: 0.2%• Total impurities (excluding Impurities A and C) 0.4%• Disregard limit: 0.02%

• Method includes system suitability test and relativeretention times for all Impurities A to L.

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Control Of Active Substancee.g. KetoprofenIMPURITIES FOUNDSpecified impurities : A, C, E. (use specific monograph)Other detectable impurities: G, H. (use general monograph)Unidentified impurities: > 0.05% - < 0.10% (use general monograph)

DRUG SUBSTANCE SPECIFICATION:Related substances (HPLC Ph Eur method)Impurities A, C and E: ≤ 0.2%Impurities G and H: ≤ 0.15% (added to EDQM certificate)Any other impurity (notspecified in the monograph): ≤ 0.10% (added to EDQM certificate)Total impurities(excluding Impurities A and C): ≤ 0.4%



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Control Of Active Substancee.g. SulfadiazineMONOGRAPH IMPURITIESMaximum Daily Dose > 2g/day

• No transparency statement

• Organic Impurity Acceptance criteria:• Related Substances (TLC):

Any impurity: 0.5%

•The impurity investigation to be undertaken usinga quantitative and validated method e.g. HPLC

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Control Of Active Substancee.g. SulfadiazineIMPURITIES FOUNDSulfanilamide: up to 0.3% (use general monograph)2-hydroxypyrimidine up to 0.1% (use general monograph)Unidentified impurities > 0.03% - < 0.05% (use general monograph)Both known impurities qualified, by reference to published data.

MONOGRAPH Test for Related substancesTLC test superseded by HPLC method (use Chapter 5.10).DRUG SUBSTANCE SPECIFICATION:Related substances(HPLC method to be annexed to certificate replacing TLC in monograph)Sulfanilamide: ≤ 0.3% (added to EDQM certificate)2-hydroxypyrimidine ≤ 0.1% (added to EDQM certificate)Single unknown impurity: ≤ 0.05% (added to EDQMcertificate)Total Impurities: ≤ 0.5%



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SummaryThe Regulatory Framework• DSS = General Monograph + Specific monograph• Quantitative methods required

Top 10 Deficiencies: Impurities• Control of Starting Materials (3.2.S.2.3 and 2.4)• Impurities (3.2.S.3.2)

- Impurity Profiling• Control of Active Substance (3.2.S.4)

Further Information• Directives, NfG, Bibliography and Websites

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EU DirectivesMedicinesDIRECTIVE 2001/83/EC relating to medicinal productsfor human use.Amended by Directives 2002/98/EC, 2003/63/EC,2004/24/EC and 2004/27/EC.

TSEEMEA/410/01 Rev. 2 NfG on minimising the risk oftransmitting animal spongiform encephalopathy agentsvia human and veterinary medicinal products(has force of law by reference to Annex 1 of Medicines Directive)

PlasticsDIRECTIVE 2002/72/EC relating to plastic materials andarticles intended to come into contact with foodstuffs



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Notes for GuidanceCHEMISTRY OF ACTIVE SUBSTANCE• CHMP/QWP/297/93 Rev. 1 corr Guideline on Summary of

Requirements for Active Substances in the Quality Part of theDossier

• CPMP/QWP/130/96 Rev. 1 Note for guidance on Chemistry ofthe New Active Substance

• 3CC29A Investigation of Chiral Active Substances

IMPURITIES OF ACTIVE SUBSTANCE• CPMP/QWP/1529/04 Guideline on Control of Impurities of

Pharmaceutical Substances: Compliance with the EuropeanPharmacopoeia General monograph “Substances forPharmaceutical Use” and General Chapter “Control of Impuritiesin Substances for Pharmaceutical Use”

• CPMP/QWP/1529/04 Guideline on Control of Impurities ofPharmacopoeial Substances

• Topic Q3A, NfG on Impurities Testing: Impurities in New DrugSubstances

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Notes for GuidanceSPECIFICATIONS, METHODOLOGY AND VALIDATION• Topic Q6A, NfG Specifications: Test procedures and

Acceptance Criteria for New Drug Substances and New DrugProducts: Chemical Substances

• Topic Q2B NfG on Validation of Analytical Procedures:Methodology

• Topic Q2A NfG on Validation of Analytical Methods:Definitions and Terminology

STABILITY TESTIG OF THE ACTIVE SUBSTANCE• CPMP/QWP/122/02 Rev. 1 Note for guidance on Stability

Testing of Existing Active Substances and Related Finishedproducts

WATER• CPMP/QWP/158/01Note For Guidance on Quality of Water

for Pharmaceutical Use



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Notes for GuidanceRESIDUAL SOLVENTS• Topic Q3C NfG on Impurities: Residual Solvents• CPMP/QWP/450/03: Annexes to Specifications for class 1

and class 2 residual solvents in active substances• Topic Q3C(M) NfG on Impurities: Residual Solvents -

Permissible Daily Exposure (TDE) for Tetrahydrofuran and N.Methylpyyrolidone

• Topic Q3C(M) Maintenance for NfG on Impurities:ResidualSolvents - Type of Maintenance: Updating based on newinformation

CATAYLSTS AND GENOTOXIC IMPURITIES• CPMP/SWP/QWP/44446/00 Draft Note for Guidance on

Specification Limits for Residues of Metal Catalysts• CPMP/SWP/5199/02 Draft Guideline on the Limits of

Genotoxic Impurities

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Bibliography• Handbook of Isolation and Characterisation of Impurities

in Pharmaceuticals. Eds: A Aahuja and K Mills Alsante.Academic Press, 2003, ISBN 012044982X

• Identification and Determination of Impurities in DrugsEditor: S. Görög. Elsevier, 2000, ISBN 0444828990

• Impurities Evaluation of Pharmaceuticals.Author: S Ahuja. Marcel Dekker, 1998, ISBN 0-8247-9884-8



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Internet Sites

• Ph Eur / EDQM: http://www.pheur.org• EMEA: http://www.emea.eu.int• EU Commission (Pharmaceuticals):

http://pharmacos.eudra.org/F2/home.html• Heads of Agencies:

http://heads.medagencies.org• ICH: http://www.ich.org• FDA: http://www.fda.cder.index.html• WHO: http://www.who.int/en/

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