dar es salaam, august, 21-25, 2006dr. birgit schmauser, bfarm, bonn pharmaceutical quality...

Dar es Salaam, August, 21-25, 2006Dar es Salaam, August, 21-25, 2006 Dr. Birgit Schmauser, BfArM, BonnDr. Birgit Schmauser, BfArM, Bonn

Pharmaceutical Quality Pharmaceutical Quality Information FormInformation Form

(PQIF)(PQIF)

APIAPI


PQIFPQIF

• Summary of quality characteristicsSummary of quality characteristics– Focus on Focus on critical quality attributescritical quality attributes

• Designed to facilitate prequalificationDesigned to facilitate prequalification– For For assessorsassessors – For For applicantsapplicants


AbbreviationsAbbreviations

• APIAPI AActive ctive PPharmaceutical harmaceutical Ingredientngredient• APIMFAPIMF APIAPI MMaster aster FFileile

– DMFDMF DDrug rug MMaster aster FFileile– ASMFASMF AActive ctive SSubstance ubstance MMaster aster FFile ile

• CHMPCHMPCCommitteeommittee forfor MMedicinaledicinal PProductsroducts forfor HHumanuman UseUse

• CPMPCPMP CCommitteeommittee forfor PProprietaryroprietary MMedicinaledicinal PProductsroducts • FPPFPP FFinishedinished PPharmaceuticalharmaceutical PProductroduct• ICHICH IInternationalnternational CConferenceonference onon HHarmonisationarmonisation• OOSOOS OOutut ooff SSpecificationpecification• QWPQWP QQualityuality WWorkingorking PPartyarty


GuidelinesGuidelines• Guideline on Submission of Documentation for Prequalification of Multi-Guideline on Submission of Documentation for Prequalification of Multi-

Source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis [Treatment of HIV/AIDS, Malaria and Tuberculosis [GuideGenericGuideGeneric]]

• Guidance on Variations to a prequalified Dossier [Guidance on Variations to a prequalified Dossier [Variation GuideVariation Guide]]• Guideline on Active Substance Master File Procedure [Guideline on Active Substance Master File Procedure [CPMP/QWP/227/02 CPMP/QWP/227/02

Rev1Rev1]]– Guideline on Active Pharmaceutical Ingredient Master File (APIMF) ProcedureGuideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure

[[DraftDraft]]• Guideline on Summary of Requirements for Active Substances in the Guideline on Summary of Requirements for Active Substances in the

Quality Part of the Dossier [Quality Part of the Dossier [CPMP/QWP/297/97 Rev 1 corrCPMP/QWP/297/97 Rev 1 corr]]• ICH Q3A [R] Impurities Testing Guideline: Impurities in New Drug ICH Q3A [R] Impurities Testing Guideline: Impurities in New Drug

Substances [Substances [CPMP/ICH/2737/99CPMP/ICH/2737/99]]• ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New

Drug Substances and New Drug Products: Chemical Substances Drug Substances and New Drug Products: Chemical Substances [[CPMP/ICH/367/96 corrCPMP/ICH/367/96 corr]]

• ICH Q2A Validation of Analytical Procedures: Definitions and Terminology ICH Q2A Validation of Analytical Procedures: Definitions and Terminology [[CPMP/ICH/381/95CPMP/ICH/381/95]]

• ICH Q2B Validation of Analytical Procedures: Methodology ICH Q2B Validation of Analytical Procedures: Methodology [[CPMP/ICH/281/95]CPMP/ICH/281/95]


2. Active Pharmaceutical 2. Active Pharmaceutical Ingredient(s) [API(s)]Ingredient(s) [API(s)]

• Options for presentation of API-dataOptions for presentation of API-data– As As integralintegral part of the dossier according to Section 2 part of the dossier according to Section 2

of:of:• Guideline on Submission of Documentation for Guideline on Submission of Documentation for

Prequalification of Multi-Source (Generic) Finished Prequalification of Multi-Source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of Pharmaceutical Products (FPPs) Used in the Treatment of HIV / AIDS, Malaria and TuberculosisHIV / AIDS, Malaria and Tuberculosis

– As As independentindependent part according to an API Master File part according to an API Master File ProcedureProcedure

• Guideline on Active Substance Master File Procedure Guideline on Active Substance Master File Procedure [CPMP/QWP/227/02 Rev 1][CPMP/QWP/227/02 Rev 1]

• Guideline on Active Pharmaceutical Ingredient Master File Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure - (APIMF) Procedure - DraftDraft


2. Active Pharmaceutical 2. Active Pharmaceutical Ingredient(s) [API(s)] IIIngredient(s) [API(s)] II

• Essentials of an APIMFEssentials of an APIMF– Scientifically equivalent to Section 2 of:Scientifically equivalent to Section 2 of:

• Guideline on Submission of Documentation for Guideline on Submission of Documentation for Prequalification of Multi-Source (Generic) Finished Prequalification of Multi-Source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of Pharmaceutical Products (FPPs) Used in the Treatment of HIV / AIDS, Malaria and TuberculosisHIV / AIDS, Malaria and Tuberculosis

– Presented in two different partsPresented in two different parts• OP (open part)OP (open part)• RP (restricted part)RP (restricted part)

– Accompanied by Accompanied by essentialessential references references• Letter of accessLetter of access• Covering letter Covering letter


2. Active Pharmaceutical 2. Active Pharmaceutical Ingredient(s) [API(s)] IIIIngredient(s) [API(s)] III

• Advantages of an APIMF (DMF, ASMF)Advantages of an APIMF (DMF, ASMF)– Independent (Stand alone) evaluation procedure of Independent (Stand alone) evaluation procedure of

the APIthe API– Reference to prequalified APIsReference to prequalified APIs

• Saving timeSaving time

• „„Good APIMF PracticeGood APIMF Practice““– Clear identificationClear identification

• Letter of accessLetter of access• Covering letterCovering letter

– Automatic information on Changes and UpdatesAutomatic information on Changes and Updates• Covering letter Covering letter


Deficiencies from PQDeficiencies from PQ

• No No transparencytransparency with APIMFs with APIMFs– No letter of accessNo letter of access

• Version no.?Version no.?• Version date?Version date?

– No adequate presentation of No adequate presentation of updatesupdates and and changeschanges• No covering letterNo covering letter

– No tabulated summary, no „history“-overview, No tabulated summary, no „history“-overview,

• No proper justification of update/changeNo proper justification of update/change– Change of critical parametersChange of critical parameters


2.2 Properties of API(s)2.2 Properties of API(s)

• Categories of APIsCategories of APIs– 2.2.1 API 2.2.1 API not describednot described in BP, PhInt, PhEur or USP in BP, PhInt, PhEur or USP

• Considered newConsidered new– (?) information on (adverse) drug reaction(?) information on (adverse) drug reaction

• Risk estimation highRisk estimation high• Profound information necessaryProfound information necessary

– 2.2.2 API 2.2.2 API describeddescribed in BP, PhInt, PhEur or USP in BP, PhInt, PhEur or USP• Considered in useConsidered in use

– Information on (adverse) drug reaction (monitored)Information on (adverse) drug reaction (monitored)

• Risk estimation based on available dataRisk estimation based on available data• Information necessary limited to data Information necessary limited to data beyond the monographbeyond the monograph

– Essential control by the monographEssential control by the monograph


2.2 Properties of API(s) II2.2 Properties of API(s) II

• Categories of AntimalarialsCategories of Antimalarials– APIs described in monographs of major international APIs described in monographs of major international

pharmacopoeias (pharmacopoeias ( 1 decade 1 decade))• AmodiaquineAmodiaquine, Chloroquine, Dapsone, Quinine, , Chloroquine, Dapsone, Quinine, MefloquineMefloquine, ,

Sulfadoxine/PyrimethamineSulfadoxine/Pyrimethamine, Trimethoprim, Trimethoprim

– APIs described in monographs of major international APIs described in monographs of major international pharmacopoeias (pharmacopoeias (recentlyrecently))

• ArthemetherArthemether, , ArtemisininArtemisinin, Artemotil, Artenimol, , Artemotil, Artenimol, ArtesunateArtesunate

– APIs APIs not describednot described in monographs of major in monographs of major international pharmacopoeiasinternational pharmacopoeias

• Chlorproguanil, Chlorproguanil, LumefantrineLumefantrine, Naphthoquine, Piperaquine, , Naphthoquine, Piperaquine, PyronaridinePyronaridine


Properties of AntiinfectivesProperties of Antiinfectives

• Well established use (+)Well established use (+)– Widely used in a sufficiently large number of patients Widely used in a sufficiently large number of patients

to permit assumption that efficacy and safety are well-to permit assumption that efficacy and safety are well-knownknown

• Well established use (-)Well established use (-)– Widely used in a large number of patients - Widely used in a large number of patients -

mechanisms of mechanisms of resistance resistance developeddeveloped

• CombinationsCombinations– Artemisinines and well established APIs/new APIsArtemisinines and well established APIs/new APIs

• Prevent/prolong new resistancePrevent/prolong new resistance• Overcome established resistanceOvercome established resistance


2.2 Properties of API(s) III2.2 Properties of API(s) III

• 2.2.1 APIs 2.2.1 APIs notnot described in BP, PhInt, described in BP, PhInt, PhEur or USPPhEur or USP

• a) evidence of a) evidence of chemical structurechemical structure– spectral dataspectral data– interpretation of data (narrative)interpretation of data (narrative)

• b)b) evidence of evidence of chemical structurechemical structure– IsomerismIsomerism– StereochemistryStereochemistry– Discussion of potential isomeric formsDiscussion of potential isomeric forms


2.2 Properties of API(s) III cont.2.2 Properties of API(s) III cont.

• Properties relevant/critical for the Properties relevant/critical for the performanceperformance of the API of the API

• c) potential polymorphic formsc) potential polymorphic forms– Influence on physicochemical and physical Influence on physicochemical and physical

characteristics (solubility, hardness, compressibility, characteristics (solubility, hardness, compressibility, density, melting point, etc.)density, melting point, etc.)

» Must be controlledMust be controlled

• d) particle size distributiond) particle size distribution– requirement for low solubility drugs (dissolution, requirement for low solubility drugs (dissolution,

bioequivalence)bioequivalence)

• e) additional characteristicse) additional characteristics– critical characteristics to be controlled to ensure critical characteristics to be controlled to ensure

consistent performance of the API (e.g. hygroscopicity)consistent performance of the API (e.g. hygroscopicity)


2.2 Properties of API(s) IV2.2 Properties of API(s) IV

• 2.2.1 APIs 2.2.1 APIs describeddescribed in BP, PhInt, PhEur or USP in BP, PhInt, PhEur or USP– Evidence of chemical structureEvidence of chemical structure

• control of structure by control of structure by suitablesuitable compendial compendial identificationidentification tests tests– Properties relevant/critical for the Properties relevant/critical for the performanceperformance of the of the

API (not necessarily covered by the monograph)API (not necessarily covered by the monograph)• a) potential polymorphic formsa) potential polymorphic forms

– Influence on physicochemical and physical characteristics Influence on physicochemical and physical characteristics (solubility, hardness, compressibility, density, melting point, (solubility, hardness, compressibility, density, melting point, etc.)etc.)

» Must be controlledMust be controlled• b) particle size distributionb) particle size distribution

– requirement for low solubility drugs (dissolution, requirement for low solubility drugs (dissolution, bioequivalence)bioequivalence)

• c) additional characteristicsc) additional characteristics– critical characteristics to be controlled to ensure consistent critical characteristics to be controlled to ensure consistent

performance of the API (e.g. hygroscopicity)performance of the API (e.g. hygroscopicity)


Properties of ArtemisininsProperties of Artemisinins

• Artemisinin Artemisinin (C(C1515HH2222OO55))– 7 centers7 centers of asymmetry of asymmetry– 2277 potential isomerspotential isomers– OneOne isomer in biosynthesis isomer in biosynthesis– Chemical synthesisChemical synthesis

• FeasableFeasable• Economically unacceptableEconomically unacceptable

• Chemical Chemical derivatizationderivatization at at C-10 (carbonyl-moiety)C-10 (carbonyl-moiety) converts converts C-10 into an C-10 into an additional stereoisomeric additional stereoisomeric centercenter::

• - and - and -isomers are formed-isomers are formed

1

2

34

5

65a

8a7

8

910

1112

12a


Properties of Artemisinins IIProperties of Artemisinins II• 3D-image Artemisinin3D-image Artemisinin

•

• www.chemexper.comwww.chemexper.com

Endo-peroxide-

bondCarbonyl-

moiety

1010 1111

12a12a

11

2 233

44

555a

5a

66

7 7

88

8a8a

991212

1313


Properties of ArtemisininsProperties of Artemisinins• Proposed by ManufacturersProposed by Manufacturers

• DiastereomersDiastereomers may differ in their melting may differ in their melting point/specific optical rotationpoint/specific optical rotation

Melting rangeMelting range Specific optical rotationSpecific optical rotation

-Artemether-Artemether 100°C100°C

-Artemether-Artemether 84 - 86°C, 84 - 86°C, 86 – 90°C86 – 90°C +166°-+173°+166°-+173°,, +168°-+173°+168°-+173°20mg/ml 20mg/ml CC22HH55OHOH

-Artesunate-Artesunate 144°C, 143°C, 142-144°C, 143°C, 142-146°C146°C

132-135°C132-135°C, 131-134°C, 131-134°C

+2.5°-+3.5°, +2.5°-+3.5°, +4.5°-+6.5°+4.5°-+6.5°, +11°-+14°, +11°-+14°10mg/ml CH10mg/ml CH22ClCl22

+11°-+14°, +11°-+14°, 40mg/ml CH40mg/ml CH33ClCl, +10°-+14° , +10°-+14° (CH(CH33Cl)Cl)

-Artesunate-Artesunate 132-135°C132-135°C +2.5°-+3.5°+2.5°-+3.5°

~~~~ArtenimolArtenimol(in solution)(in solution)

+146° (15°C)+146° (15°C)(?mg/ml MeOH)(?mg/ml MeOH)



• Pharmacopoeial Pharmacopoeial specifications are not metspecifications are not met without justificationwithout justification

• StereospecificityStereospecificity not adequately addressed not adequately addressed • Pharmacopoeial methods are not being followedPharmacopoeial methods are not being followed

to generate respective data on propertiesto generate respective data on properties• Data on properties are simply Data on properties are simply not provided at allnot provided at all

(without justification)(without justification)• IR-spectraIR-spectra are not compared to a are not compared to a primaryprimary

referencereference spectrum spectrum


2.3 Site(s) of manufacture2.3 Site(s) of manufacture

• Identification of each API-manufacturerIdentification of each API-manufacturer– NameName– Street addressStreet address– Phone, Fax, EmailPhone, Fax, Email– If applicableIf applicable

• Referenced DMFs (APIMFs)Referenced DMFs (APIMFs)• Letters of accessLetters of access

– Why is identification of API-manufacturers Why is identification of API-manufacturers essential?essential?


2.3 Site(s) of manufacture II2.3 Site(s) of manufacture II

• The quality of APIs is dependent onThe quality of APIs is dependent on– Manufacturing siteManufacturing site

• Equipment, personal, technology…Equipment, personal, technology…

– Route of synthesis, operational conditions, IPCs…Route of synthesis, operational conditions, IPCs…• Impurity profile, stability (API & FPP)Impurity profile, stability (API & FPP)

• The quality of an API may consequently impact The quality of an API may consequently impact the quality of a FPPthe quality of a FPP– Change in manufacturing siteChange in manufacturing site

• Alternate API-manufacturersAlternate API-manufacturers

– Change in route of synthesisChange in route of synthesis• Alternate API-manufacturersAlternate API-manufacturers



• Quality of Quality of alternate API-sourcesalternate API-sources– Site of manufactureSite of manufacture– Description of the API-qualityDescription of the API-quality

• BeforeBefore prequalification prequalification– Submission as part of the applicationSubmission as part of the application

• AfterAfter prequalification prequalification– Submission as variation applicationSubmission as variation application

• Guidance on variations to a prequalified dossierGuidance on variations to a prequalified dossier


2.4 Route(s) of synthesis2.4 Route(s) of synthesis

• 2.4.1 API 2.4.1 API not not described in BP, PhInt, PhEur or described in BP, PhInt, PhEur or USPUSP– Controls of critical steps and intermediatesControls of critical steps and intermediates

• Potential impact on the quality of the API and intermediatesPotential impact on the quality of the API and intermediates– Process conditions, test requirements and other relevant Process conditions, test requirements and other relevant

parameters to be controlled within predetermined limitsparameters to be controlled within predetermined limits• Examples of potentially critical stepsExamples of potentially critical steps

– MixingMixing of multiple components of multiple components– PhasePhase change and phase separation steps change and phase separation steps– Steps where control of Steps where control of pHpH and and temperaturetemperature are critical are critical– Introduction of an Introduction of an essential structural elementessential structural element or major or major

chemical transformationchemical transformation– Introduction/removal of Introduction/removal of significant impuritiessignificant impurities to the API to the API– FinalFinal purification step purification step– Steps with an impact on Steps with an impact on solid state properties/homogeneitysolid state properties/homogeneity of of

the APIthe API


2.4 Route(s) of synthesis II2.4 Route(s) of synthesis II

• 2.4.1 API 2.4.1 API notnot described in BP, PhInt, described in BP, PhInt, PhEur or USPPhEur or USP– Process Validation and/or EvaluationProcess Validation and/or Evaluation

• All steps that are identified as All steps that are identified as criticalcritical for the API for the API• All steps covering All steps covering aseptic processingaseptic processing or or

sterilizationsterilization


2.4 Route(s) of synthesis III2.4 Route(s) of synthesis III

• 2.4.1 API 2.4.1 API notnot described in BP, PhInt, described in BP, PhInt, PhEur or USPPhEur or USP– Manufacturing process developmentManufacturing process development

• Description and discussion of Description and discussion of any changeany change to the to the manufacturing process and/or manufacturing site manufacturing process and/or manufacturing site in developmental order:in developmental order:

– ClinicalClinical– ComparativeComparative– StabilityStability– ScaleupScaleup– PilotPilot– ProductionProduction


2.4 Route(s) of synthesis IV2.4 Route(s) of synthesis IV

• 2.4.1 API 2.4.1 API notnot described in BP, PhInt, PhEur or described in BP, PhInt, PhEur or USPUSP– ImpuritiesImpurities

• Identification of Identification of potentialpotential and and actualactual impurities arising from impurities arising from synthesis, manufacture and/or degradationsynthesis, manufacture and/or degradation

– Potential sources of origin in sequential orderPotential sources of origin in sequential order» impurities contained in the starting materialimpurities contained in the starting material» starting material unreactedstarting material unreacted» intermediates unreactedintermediates unreacted» by-products (unwanted reaction products)by-products (unwanted reaction products)» reagentsreagents» catalystscatalysts» residual solventsresidual solvents» degradantsdegradants

– Elucidation of origin may help to minimize impuritiesElucidation of origin may help to minimize impurities


2.4 Route(s) of synthesis V2.4 Route(s) of synthesis V

• 2.4.1 API 2.4.1 API notnot described in BP, PhInt, PhEur or described in BP, PhInt, PhEur or USPUSP– Setting the acceptance criteria for impuritiesSetting the acceptance criteria for impurities

• Maximum daily dose (total daily intake)Maximum daily dose (total daily intake)• ICH thresholds for drug-related impuritiesICH thresholds for drug-related impurities• Concentration limits for process related impuritiesConcentration limits for process related impurities

– Residual solventsResidual solvents– Heavy metalsHeavy metals

• Available safety and toxicity dataAvailable safety and toxicity data– Documented impurity levels according to the scheme providedDocumented impurity levels according to the scheme provided

– Reference to the analytical procedures usedReference to the analytical procedures used• Specificity, sensitivitySpecificity, sensitivity

– Justification of proposed acceptance criteriaJustification of proposed acceptance criteria


2.4 Route(s) of synthesis VI2.4 Route(s) of synthesis VI

• 2.4.1 API 2.4.1 API notnot described in BP, PhInt, PhEur or described in BP, PhInt, PhEur or USPUSP– Setting the acceptance criteria for impuritiesSetting the acceptance criteria for impurities

• ICH thresholds for drug related impurities [ICH Q3A (R)]ICH thresholds for drug related impurities [ICH Q3A (R)]

Maximum Maximum Daily DoseDaily Dose

Reporting Reporting ThresholdThreshold

Identification Identification ThresholdThreshold

Qualification Qualification ThresholdThreshold

≤ ≤ 2g/day2g/day 0.05%0.05% 0.10%0.10% or or 1mg1mg per day intake per day intake ((whichever is lower)whichever is lower)

0.15%0.15% or or 1mg1mg per day intake per day intake ((whichever is lower)whichever is lower)

≥ ≥ 2g/day2g/day 0.03%0.03% 0.05%0.05% 0.05%0.05%


2.4 Route(s) of synthesis VII2.4 Route(s) of synthesis VII

• 2.4.2 Specifications of raw materials and 2.4.2 Specifications of raw materials and intermediates used in the synthesisintermediates used in the synthesis– Quality and controlsQuality and controls of materials coming into the of materials coming into the

processprocess• Starting materialsStarting materials• Raw materialsRaw materials• IntermediatesIntermediates• ReagentsReagents• CatalystsCatalysts• SolventsSolvents

– SpecificationsSpecifications


2.4 Route(s) of synthesis VIII2.4 Route(s) of synthesis VIII

• 2.4.2 Specifications of raw materials and 2.4.2 Specifications of raw materials and intermediates used in the synthesisintermediates used in the synthesis– TSE-safetyTSE-safety of all materials coming into the of all materials coming into the

processprocess• CEPCEP• Letter of attestationLetter of attestation


2.4 Route(s) of synthesis IX2.4 Route(s) of synthesis IX

• 2.4.3 API 2.4.3 API describeddescribed in BP, PhInt, PhEur or in BP, PhInt, PhEur or USPUSP– Impurities that are not included in the Impurities that are not included in the

monographmonograph• Process related impuritiesProcess related impurities

– Key intermediatesKey intermediates– Residual solventsResidual solvents– Potential organic impurities not covered by the Potential organic impurities not covered by the

monographmonograph


Potential impurities of ArtemisininsPotential impurities of Artemisinins

• Starting material (extracted from herbal Starting material (extracted from herbal sources)sources)– GuideGeneric:GuideGeneric:

• Starting materials from vegetable origin should be Starting materials from vegetable origin should be fully characterized and a contaminant profile fully characterized and a contaminant profile should be established and submitted.should be established and submitted.

– CPMP/QWP/297/97 Rev 1 corr:CPMP/QWP/297/97 Rev 1 corr:• In the case of substances isolated form herbal In the case of substances isolated form herbal

sources, the potential for impurities arising from sources, the potential for impurities arising from cultivation and/or preparation (e.g. pesticide cultivation and/or preparation (e.g. pesticide residues, fumigants, mycotoxins) should be residues, fumigants, mycotoxins) should be addressed.addressed.


Potential impurities of Artemisinins Potential impurities of Artemisinins IIII

• Impurities contained in the „Impurities contained in the „starting materialstarting material“ “ ArtemisininArtemisinin– Biosynthetic by-productsBiosynthetic by-products

• Arteannuin BArteannuin B , , ArtemisiteneArtemisitene, Artemisinic acid,, Artemisinic acid,– Extraction from fresh leaves with CHClExtraction from fresh leaves with CHCl33 within 1 min > 97% within 1 min > 97%

» Localisation in subcuticular space of the glands on the Localisation in subcuticular space of the glands on the surface of the leavessurface of the leaves

• Thujone (?)Thujone (?)

– Cultivation reagentsCultivation reagents• Pesticide residues, fumigants, mycotoxinsPesticide residues, fumigants, mycotoxins

– Solvents from the extraction processSolvents from the extraction process• Hexane, benzene, acetonitril, ether, pentane, chloroforme…..Hexane, benzene, acetonitril, ether, pentane, chloroforme…..

(?) diesel, fuel (?) [ICH Q3A (R)](?) diesel, fuel (?) [ICH Q3A (R)]


Localisation of ArtemisininLocalisation of Artemisinin(isolation from fresh leaves)(isolation from fresh leaves)

• Picture of a glandular trichome on a leaf of Artemisia annua L. before (A Picture of a glandular trichome on a leaf of Artemisia annua L. before (A and B) and after (C and D) chloroforme extraction (black bar = 10 µm)and B) and after (C and D) chloroforme extraction (black bar = 10 µm)

• The cuticule is crumpled after chloroforme extractionThe cuticule is crumpled after chloroforme extraction• The epidermal cells are unaffected by this treatmentThe epidermal cells are unaffected by this treatment

• From: F.C.W. Van Nieuverburgh et al., J Chromatogr. A 1118 (2006) 180-187From: F.C.W. Van Nieuverburgh et al., J Chromatogr. A 1118 (2006) 180-187


Potential impurities of Artemisinins Potential impurities of Artemisinins IIIIII

• Unreacted starting materialUnreacted starting material– Artemisinin (starting material for derivatives)Artemisinin (starting material for derivatives)– Artemisinic acid (starting matrial for Artemisinic acid (starting matrial for

dihydroartemisinin)dihydroartemisinin)– Dihydroartemisinin (starting material for derivatives)Dihydroartemisinin (starting material for derivatives)– ……..

• Unreacted intermediates, by-productsUnreacted intermediates, by-products– -Arthemether, -Arthemether, -Artheether-Artheether– //-Dihydroartemisinin -Dihydroartemisinin – -Artesunate-Artesunate– ……..


Potential impurities of Artemisinins Potential impurities of Artemisinins III cont.III cont.

• Reagents, catalysts, residual solventsReagents, catalysts, residual solvents– Methanol, acetonitril, chloroforme, acetone …Methanol, acetonitril, chloroforme, acetone …– NaBHNaBH44, succinic acid/anhydride, triethylamine, , succinic acid/anhydride, triethylamine,

dimethylaminopyridinedimethylaminopyridine• DegradantsDegradants

– Stability ofStability of• ester-derivative (Artesunate)ester-derivative (Artesunate)• ether-derivative (Artemether, Arteether)ether-derivative (Artemether, Arteether)• lactone (Artemisinin)lactone (Artemisinin)

– Stability of artenimol (oxidation)Stability of artenimol (oxidation)– Susceptibility of endoperoxide bond to reductionSusceptibility of endoperoxide bond to reduction

• Deoxyartemisinine Deoxyartemisinine (loss of active principle (loss of active principle ))– Zn / AcOH or FeBrZn / AcOH or FeBr2 2 / THF/ THF



• Description of synthesis only covers Description of synthesis only covers part of the part of the synthesis routesynthesis route– Evaluation regarding impurities and degradants (?)Evaluation regarding impurities and degradants (?)

• Details on Details on stereospecificitystereospecificity of reaction steps are of reaction steps are not addressednot addressed

• Flow chart of the synthetic route is Flow chart of the synthetic route is too cryptictoo cryptic– quantity of materials, IPCs, operational conditions, quantity of materials, IPCs, operational conditions,

intermediates, purification stepsintermediates, purification steps• Narrative of the synthetic process is not providedNarrative of the synthetic process is not provided

– Final batch sizeFinal batch size• Environmental impact statement missingEnvironmental impact statement missing


Deficiencies from PQ cont.Deficiencies from PQ cont.

• Impurities, intermediates, by-products, Impurities, intermediates, by-products, degradantsdegradants– Potential to be expected from synthesis is Potential to be expected from synthesis is not not

discusseddiscussed• Side reactions at critical process stepsSide reactions at critical process steps

– are are not analysednot analysed– MethodsMethods to assess impurities are to assess impurities are not sensitive not sensitive

enoughenough• Quantitation limit (Quantitation limit (1%1%) far above the identification and ) far above the identification and

qualification thresholdqualification threshold((0.05 – 0.15%0.05 – 0.15%))


2.5 Specifications2.5 Specifications

• 2.5.1 API 2.5.1 API notnot described in BP, PhInt, PhEur or USP described in BP, PhInt, PhEur or USP– Presentation of the API-specificationPresentation of the API-specification

• Any test that is not performed on a batch to batch-basis must be Any test that is not performed on a batch to batch-basis must be indicated (periodic testing or indicated (periodic testing or skip testingskip testing))

Standard claimedStandard claimed (e.g. in-house, BP, (e.g. in-house, BP, PhInt, PhEur, USPPhInt, PhEur, USP

Reference or versionReference or version numbernumber

Specific test parameterSpecific test parameter Analytical procedure Analytical procedure usedused

Acceptance criteriaAcceptance criteria


2.5 Specifications II2.5 Specifications II

• 2.5.1 API 2.5.1 API notnot described in BP, PhInt, PhEur or described in BP, PhInt, PhEur or USPUSP– Skip testingSkip testing

• ICH Q6AICH Q6A– performance of specified tests at release on pre-selected performance of specified tests at release on pre-selected

batches and/or predetermined intervals, rather than on a batch-batches and/or predetermined intervals, rather than on a batch-to-batch basis to-batch basis with the understanding that those batches not with the understanding that those batches not being tested must still meet all acceptance criteria established being tested must still meet all acceptance criteria established for that productfor that product..

– As this represents less than full testing it should be As this represents less than full testing it should be justifiedjustified..– Any failure to meet acceptance criteria established for the Any failure to meet acceptance criteria established for the

periodic test should be handled by proper notification (inform periodic test should be handled by proper notification (inform WHO immediately). WHO immediately). If the data demonstrate a need to restore If the data demonstrate a need to restore routine testing, batch-by-batch release testing should be routine testing, batch-by-batch release testing should be reinstated.reinstated.


2.5 Specifications III2.5 Specifications III

• 2.5.1 API 2.5.1 API notnot described in BP, PhInt, PhEur or described in BP, PhInt, PhEur or USPUSP– Skip testingSkip testing

• ICH Q6AICH Q6A– The concept may be applicable to, f.ex., The concept may be applicable to, f.ex., residual solventsresidual solvents and and

microbiological testingmicrobiological testing, for , for solid oral dosage formssolid oral dosage forms..– Since only limited data may be available at the time of Since only limited data may be available at the time of

submission, the concept should generally be implemented post-submission, the concept should generally be implemented post-approvalapproval ( ( post prequalificationpost prequalification))

• GuideGenericGuideGeneric– Where testing forWhere testing for possible impurities possible impurities is omittedis omitted, particular , particular

attention must be given to itsattention must be given to its justification justification» f. ex. particular method of productionf. ex. particular method of production» f.ex. impuritiy has never been detectedf.ex. impuritiy has never been detected


2.5 Specifications IV2.5 Specifications IV

• 2.5.1 API 2.5.1 API notnot described in BP, PhInt, PhEur or USP described in BP, PhInt, PhEur or USP– Batch analysesBatch analyses

• Description of the batchesDescription of the batches

• Results of the batchesResults of the batches– Certificates of AnalysisCertificates of Analysis

• Discussion of the results with respect to the use of the batchDiscussion of the results with respect to the use of the batch– Clinical, Comparative etc.Clinical, Comparative etc.

Batch numberBatch number Batch sizeBatch size Date and site Date and site of productionof production

Use (e.g. Use (e.g. clinical, clinical,

comparativecomparative


2.5 Specifications V2.5 Specifications V

• 2.5.1 API 2.5.1 API notnot described in BP, PhInt, described in BP, PhInt, PhEur or USPPhEur or USP– Justification of SpecificationsJustification of Specifications

• Evolution of testsEvolution of tests• Evolution of analytical proceduresEvolution of analytical procedures• Evolution of acceptance criteriaEvolution of acceptance criteria• Differences from compendial standardsDifferences from compendial standards

– f.ex. assay and impurities, heavy metals, residue on f.ex. assay and impurities, heavy metals, residue on ignitionignition


2.5. Specifications VI2.5. Specifications VI

• 2.5.1 API 2.5.1 API notnot described in BP, PhInt, PhEur or described in BP, PhInt, PhEur or USPUSP– Justification of SpecificationsJustification of Specifications

• ICH Q6AICH Q6A– Justification for each procedure and each acceptance criterion Justification for each procedure and each acceptance criterion

with reference towith reference to» relevant development datarelevant development data» pharmacopoeial standardspharmacopoeial standards» Test data for batches used in toxicology and clinical Test data for batches used in toxicology and clinical

studiesstudies» Results from accelerated and long term studiesResults from accelerated and long term studies» Reasonable range of analytical and manufacturing Reasonable range of analytical and manufacturing

variabilityvariability» Alternate justified approachesAlternate justified approaches

– Actual resultsActual results obtained should form the obtained should form the primary basisprimary basis for any justificationfor any justification



• Different versionsDifferent versions of specifications at different places of specifications at different places (DMF, batch analyses, specification, FPP)(DMF, batch analyses, specification, FPP)

• Essential Essential parameters missing parameters missing in specificationsin specifications• Test Test methods missingmethods missing• Impurities Impurities insufficientlyinsufficiently specified specified• Limits to be Limits to be tightenedtightened (impurities) according to real (impurities) according to real

values)values)• Residual solvents not specified (w/o justification)Residual solvents not specified (w/o justification)• Microbial purity not part of specificationMicrobial purity not part of specification• Less than 3 batch certificates submittedLess than 3 batch certificates submitted• Batch sizes, manufacturing site and date missing on Batch sizes, manufacturing site and date missing on

certificates of analysis (CoAs)certificates of analysis (CoAs)


2.5 Specifications VII2.5 Specifications VII

• 2.5.1 API 2.5.1 API notnot described in BP, PhInt, PhEur or described in BP, PhInt, PhEur or USPUSP– Reference standards or materialsReference standards or materials

• ICH Q2BICH Q2B– Reference standards/materials should be well characterized Reference standards/materials should be well characterized

with documented puritywith documented purity• SourceSource

– Official pharmacopoeial standardsOfficial pharmacopoeial standards– In-house standardsIn-house standards

• Characterization and evaluation of non-official standardsCharacterization and evaluation of non-official standards– Method of manufactureMethod of manufacture– Elucidation of structureElucidation of structure– Certificate of analysis Certificate of analysis – Calibration against an official standard (if available)Calibration against an official standard (if available)


2.5 Specifications VIII2.5 Specifications VIII

• 2.5.1 API 2.5.1 API notnot described in BP, PhInt, PhEur or USP described in BP, PhInt, PhEur or USP– Reference standards or materials (in-house)Reference standards or materials (in-house)

• Primary (absolute) standardPrimary (absolute) standard– Documented Documented puritypurity (with purification procedure) (with purification procedure)– AssayAssay by two independent procedures, by two independent procedures, one of which must be specificone of which must be specific– Mass balance must be achievedMass balance must be achieved

» Assay value and all impurities found must amount to 100% Assay value and all impurities found must amount to 100% (relative to the analytical procedure)(relative to the analytical procedure)

– All further impuritiesAll further impurities (residue on ignition/inorganic substances, loss on (residue on ignition/inorganic substances, loss on drying etc.) must be considered to drying etc.) must be considered to determine the absolute assay valuedetermine the absolute assay value

• Secondary (working) standardSecondary (working) standard– Documented purity with reference to the primary (absolute) standardDocumented purity with reference to the primary (absolute) standard– Intervals of control of content and duration of useIntervals of control of content and duration of use



• The role of the primary standard is not adequately The role of the primary standard is not adequately reflectedreflected– Working standardsWorking standards are calibrated against other working are calibrated against other working

standardsstandards– Working standards are calibrated against Working standards are calibrated against unofficial reference unofficial reference

standardsstandards

• The The sourcesource of the primary standard is unclear of the primary standard is unclear• IdentityIdentity of primary reference standard is established by of primary reference standard is established by

comparison with IR-spectra of secondary standardcomparison with IR-spectra of secondary standard• Information on Information on preparationpreparation and and quality specificationquality specification of of

primary (absolute) and secondary (working) standards is primary (absolute) and secondary (working) standards is not providednot provided


2.5 Specifications IX2.5 Specifications IX

• 2.5.1 API 2.5.1 API notnot described in BP, PhInt, described in BP, PhInt, PhEur or USPPhEur or USP– Validation of analytical proceduresValidation of analytical procedures

• Any in-house analytical procedure needs to be Any in-house analytical procedure needs to be validatedvalidated

– ICH Q2A, ICH Q2BICH Q2A, ICH Q2B

– Assay and impuritiesAssay and impurities• Capability to detect impurities and degradants from Capability to detect impurities and degradants from

synthesissynthesis• Stability indicating potentialStability indicating potential


2.5 Specifications X2.5 Specifications X

• 2.5.1 API 2.5.1 API notnot described in BP, PhInt, PhEur or described in BP, PhInt, PhEur or USPUSP– Stress testing provides degradants that may occur Stress testing provides degradants that may occur

during storageduring storage• Isolation of impurities and (stable) degradants in the Isolation of impurities and (stable) degradants in the

development phasedevelopment phase• In situ generation of potential degradantsIn situ generation of potential degradants

– Validation of analytical procedures for assay and Validation of analytical procedures for assay and impurities/degradantsimpurities/degradants

• Spiking experimentsSpiking experiments with isolated degradants/impurities with isolated degradants/impurities• In situ useIn situ use of stressed samples of stressed samples• Peak purityPeak purity analysis of API-peaks analysis of API-peaks



• Methods are Methods are in use beforein use before they are they are validatedvalidated

• Validation is Validation is not considered not considered at allat all– Serious deficiencySerious deficiency

• Results of batch analysis are Results of batch analysis are not reliablenot reliable• Stability studies are Stability studies are not evaluablenot evaluable


2.5 Specifications XI2.5 Specifications XI

• 2.5.2 API 2.5.2 API describeddescribed in BP, PhInt, PhEur or USP in BP, PhInt, PhEur or USP– Name the monographName the monograph

• Name any test methods referenced in the monograph but not Name any test methods referenced in the monograph but not appearing in itappearing in it

– List of tests List of tests beyond the scope of the monographbeyond the scope of the monograph• Residuals, particle size, polymorphs, loss on dryingResiduals, particle size, polymorphs, loss on drying

– Generic guideGeneric guide::• Whenever an API has been prepared by a method Whenever an API has been prepared by a method liable to liable to

leave leave impurities not controlled in the impurities not controlled in the pharmacopoeial monographpharmacopoeial monograph, these impurities (based on 3 to , these impurities (based on 3 to 10 batch analysis results) 10 batch analysis results) including residual organic solvents, including residual organic solvents, as well as their maximum tolerance limits should be declared as well as their maximum tolerance limits should be declared and controlled by a suitable test procedure.and controlled by a suitable test procedure.


Specifications XIISpecifications XII

• 2.5.2 API 2.5.2 API describeddescribed in BP, PhInt, PhEur or in BP, PhInt, PhEur or USPUSP– Additional requirementsAdditional requirements

• Generic guideGeneric guide::– The quality of the API should meet not only the The quality of the API should meet not only the

requirements of specific monographs but also those requirements of specific monographs but also those described in the described in the general monographs of a general monographs of a pharmacopoeia on APIspharmacopoeia on APIs, excipients and other substance , excipients and other substance for pharmaceutical use.for pharmaceutical use.

» f. ex. Substances for pharmaceutical use (PhEur)f. ex. Substances for pharmaceutical use (PhEur)» f. ex. Control of impurities for substances for f. ex. Control of impurities for substances for

pharmaceutical use (PhEur)pharmaceutical use (PhEur)


2.5 Specifications XIII2.5 Specifications XIII

• 2.5.2 API 2.5.2 API describeddescribed in BP, PhInt, PhEur or USP in BP, PhInt, PhEur or USP– Validation of analytical methodsValidation of analytical methods

• Pharmacopoeial methods are considered validated, Pharmacopoeial methods are considered validated, however, there is common understanding that certain however, there is common understanding that certain parameters need to be adapted: parameters need to be adapted:

– New chapter USP <1226> Verification of analytical proceduresNew chapter USP <1226> Verification of analytical procedures» Pharmacopoeial Forum 31, No. 2, March/April 2005Pharmacopoeial Forum 31, No. 2, March/April 2005

– System suitability testSystem suitability test– PhEur 2.2.46PhEur 2.2.46– Insufficient Precision (RSD=Insufficient Precision (RSD=) leads to OOS results) leads to OOS results

» 3 x 3 x ≤ 2% (assay specification)≤ 2% (assay specification)

– Validation with respect to the stability indicating Validation with respect to the stability indicating nature of the methodsnature of the methods

• For impurities/degradants not covered by the monographFor impurities/degradants not covered by the monograph• If the pharmacopoeial method is modifiedIf the pharmacopoeial method is modified


Deficiencies from PQDeficiencies from PQ• Pharmacopoeial acceptance criteria are not considered Pharmacopoeial acceptance criteria are not considered

for APIs described in the pharmacopoeiafor APIs described in the pharmacopoeia– API cannot be adequately controlled by wider rangesAPI cannot be adequately controlled by wider ranges

• Acceptance ranges of test parameters are much wider Acceptance ranges of test parameters are much wider than actual test results.than actual test results.– Acceptance ranges do not control the quality of the APIAcceptance ranges do not control the quality of the API

• The Reference standard in use simply represents The Reference standard in use simply represents API API from a normal batchfrom a normal batch..– The reference is missingThe reference is missing

• In-house absolute reference standards are not validated In-house absolute reference standards are not validated against against available official standardsavailable official standards..

• Pharmacopoeial methods are modified but impurity Pharmacopoeial methods are modified but impurity profile is not adapted.profile is not adapted.– f.ex. Impurity A (in-house method) is different from Impurity A f.ex. Impurity A (in-house method) is different from Impurity A

(pharmacopoeial method)(pharmacopoeial method)


2.6 Container closure system2.6 Container closure system

• DescriptionDescription of the container closure system of the container closure system(for storage and shipment of the API)(for storage and shipment of the API)

– PrimaryPrimary packaging material packaging material• Identity of materialsIdentity of materials of construction ofof construction of each primary each primary

packaging componentpackaging component• Reference to specification for each packaging componentReference to specification for each packaging component

– DescriptionDescription

– Identification, ADEQUATELY TESTEDIdentification, ADEQUATELY TESTED

– Drawings of critical dimensionsDrawings of critical dimensions

– SecondarySecondary packaging material packaging material• Non-functional (briefly)Non-functional (briefly)• FunctionalFunctional


2.6 Container closure system II2.6 Container closure system II

• Discussion of the Discussion of the suitabilitysuitability of the of the container closure systemcontainer closure system– ChoiceChoice of material of material– FunctionFunction of material of material

• f.ex. protectionf.ex. protection– Moisture, light, oxygenMoisture, light, oxygen

– SafetySafety of material of material• Compatibility with APICompatibility with API• SorptionSorption• LeachingLeaching


2.6 Container closure system III2.6 Container closure system III

• ArtemisininesArtemisinines– Storage conditions PhInt:Storage conditions PhInt:

• Should be kept in a Should be kept in a well closed containerwell closed container, , protected from lightprotected from light and kept in a cool place and kept in a cool place

– Discussion of the suitability of the container Discussion of the suitability of the container closure system with respect to:closure system with respect to:• Protection from lightProtection from light

– f.ex. types/colour of inner and outer bags/drumsf.ex. types/colour of inner and outer bags/drums

• Protection from oxygen and moisture (well-closed)Protection from oxygen and moisture (well-closed)– f.ex. type of inner/outer container (f.ex. type of inner/outer container (permeabilitypermeability))– f.ex. use of seals, joints, gasketsf.ex. use of seals, joints, gaskets


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dar es salaam, august, 21-25, 2006dr. birgit schmauser, bfarm, bonn pharmaceutical quality...

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