pqif-api

Guilin, January, 9 -13, 2006Guilin, January, 9 -13, 2006 Dr. Birgit Schmauser, BfArM, BonnDr. Birgit Schmauser, BfArM, Bonn

Pharmaceutical Quality Pharmaceutical Quality Information FormInformation Form

(PQIF) - API(PQIF) - API

Guilin, January, 9 – 13, Guilin, January, 9 – 13, 20062006 Dr. Birgit Schmauser, BfArM, BonnDr. Birgit Schmauser, BfArM, Bonn

AbbreviationsAbbreviations

API API AActive ctive PPharmaceutical harmaceutical IIngredientngredientASMF ASMF AActive ctive SSubstance ubstance MMaster aster FFileileCHMPCHMP CCommittee for ommittee for MMedicinal edicinal PProducts for roducts for HHuman Use uman Use CPMPCPMP CCommittee for ommittee for PProprietary roprietary MMedicinal edicinal PProductsroductsDMF DMF DDrug rug MMaster aster FFileileEDQM EDQM EEuropean uropean DDirectorate for the irectorate for the QQuality of uality of MMedicinesedicinesFPP FPP FFinished inished PPharmaceutical harmaceutical PProductroductICHICH IInternational nternational CConference on onference on HHarmonizationarmonizationOOSOOS OOut ut OOf f SSpecificationpecificationPQIFPQIF PPharmaceutical harmaceutical QQuality uality IInformation nformation FFormormQWPQWP QQuality uality WWorking orking PPartyarty


GuidelinesGuidelinesGuideline 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]]

Guideline on Active Substance Master File Procedure [Guideline on Active Substance Master File Procedure [CPMP/QWP/CPMP/QWP/227/02227/02 Rev 1]Rev 1]

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/CPMP/QWP/297/97 Rev 1 corr]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/CPMP/ICH/2737/99]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/CPMP/ICH/367/96 corr]367/96 corr]

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

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


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

Presentation of information on the APIPresentation of information on the API Full details as required according to Full details as required according to Section 2Section 2 of the: of the:

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 Tuberculosis [GuideGeneric]HIV / AIDS, Malaria and Tuberculosis [GuideGeneric]

Full details according to the Full details according to the Drug Master FileDrug Master File (Active (Active Substance Master File) ProcedureSubstance Master File) Procedure

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]

With or without certification (EDQM)With or without certification (EDQM)

(applicable only to Ph. Eur. - APIs) (applicable only to Ph. Eur. - APIs)


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

Advantages of the use of a DMF (ASMF)Advantages of the use of a DMF (ASMF) Full details of chemistry, manufacturing Full details of chemistry, manufacturing

process, quality controls during manufacture process, quality controls during manufacture process validation, quality controls at batch process validation, quality controls at batch release and stabilityrelease and stability

Once the DMF (ASMF) is prequalified, Once the DMF (ASMF) is prequalified, reference may be made to it in subsequent reference may be made to it in subsequent applicationsapplications

Conditions for the referenceConditions for the reference Information on regular updates must be providedInformation on regular updates must be provided Version number and date must be assignedVersion number and date must be assigned


Deficiencies from prequalificationDeficiencies from prequalification

DMF (ASMF)DMF (ASMF) No No version numberversion number and and no dateno date assigned assigned Deficiency lettersDeficiency letters from WHO/prequalification are from WHO/prequalification are not not

addressedaddressedInstead an update without reference to the deficiency list is Instead an update without reference to the deficiency list is submittedsubmitted

No tabular overviewNo tabular overview is provided to WHO outlining the is provided to WHO outlining the nature and the nature and the extent of the changesextent of the changes (updates) (updates) compared to the previous versioncompared to the previous version

Updates are not properly Updates are not properly justifiedjustified/explained/explainedChange in the route of synthesisChange in the route of synthesisChange in the last step of purificaton/crystallizationChange in the last step of purificaton/crystallization

No transparencyNo transparency with the use of DMFs with the use of DMFs


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 new, used for the first time in a FPPConsidered new, used for the first time in a FPP

Risk estimation highRisk estimation high

Full information necessary Full information necessary 2.2.2 API 2.2.2 API describeddescribed in BP, PhInt, PhEur or USP in BP, PhInt, PhEur or USP

In use for a certain period of timeIn use for a certain period of time

Information on safety and efficacy availableInformation on safety and efficacy available

Risk estimation low(er)Risk estimation low(er)

Control by the monograph, additional information beyond the Control by the monograph, additional information beyond the scope of the monograph necessaryscope of the monograph necessary


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

Categories of AntimalarialsCategories of Antimalarials APIs with existing monographs in major international APIs with existing monographs in major international

pharmacopoeiaspharmacopoeiasAmodiaquine, Chloroquine (-phospate, -sulfate), Dapsone, Amodiaquine, Chloroquine (-phospate, -sulfate), Dapsone, Quinine (-sulfate, -phosphate), Quinine (-sulfate, -phosphate), MefloquineMefloquine, , Sulfadoxine/Pyrimethamine, TrimethoprimSulfadoxine/Pyrimethamine, Trimethoprim

APIs with existing monographs in major international APIs with existing monographs in major international pharmacopoeias (pharmacopoeias (recentlyrecently))

Arthemether, Artemisinine, Artemotil, Artenimol Arthemether, Artemisinine, Artemotil, Artenimol (Dihydroartemisinine), Artesunate,(Dihydroartemisinine), Artesunate,

APIs APIs withoutwithout existing monographs in major existing monographs in major international pharmacopoeiasinternational pharmacopoeias

Chlorproguanil, Lumefantrine, Naphthoquine, Piperaquine, Chlorproguanil, Lumefantrine, Naphthoquine, Piperaquine, Pyronaridine Pyronaridine


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 chemical structurea) evidence of chemical structure spectral dataspectral data interpretation of data (narrative)interpretation of data (narrative)

b) evidence of chemical structureb) evidence of chemical 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.

2.2.1 APIs not described in BP, PhInt, PhEur or 2.2.1 APIs not described in BP, PhInt, PhEur or USPUSP Properties relevant/critical for the Properties relevant/critical for the performanceperformance of the of the

APIAPIc) potential polymorphic formsc) potential polymorphic forms

physicochemical and physical characteristics (solubility, physicochemical and physical characteristics (solubility, hardness, compressibility, density, melting point, etc.) may hardness, compressibility, density, melting point, etc.) may differdiffer

polymorphism must be controlledpolymorphism must be controlledd) 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 consistent critical characteristics to be controlled to ensure consistent

performance of the API (e.g. hygroscopicity)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 USPchemical structure elucidatedchemical structure elucidated [a) – b)], control of structure by [a) – b)], control of structure by suitablesuitable identification tests identification 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 physicochemical and physical characteristics (solubility, physicochemical and physical characteristics (solubility,

hardness, compressibility, density, melting point, etc.) may hardness, compressibility, density, melting point, etc.) may differdiffer

polymorphism must be controlledpolymorphism must be controlledb) 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)


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

Each API-manufacturer to be listedEach API-manufacturer to be listed Information on the quality of the API must be Information on the quality of the API must be

clearly linked to the respective clearly linked to the respective manufacturing manufacturing site (synthesis, production)site (synthesis, production)

NameNameStreet addressStreet addressPhone, Fax, EmailPhone, Fax, Email

If applicableIf applicablereferenced DMFsreferenced DMFsletters of accessletters of access



Quality of API missingQuality of API missing Detailed quality description on the API provided by Detailed quality description on the API provided by one manufacturer, alternative manufacturers are one manufacturer, alternative manufacturers are named without presentation of information on the named without presentation of information on the APIAPI

API-manufacturer and quality of API missingAPI-manufacturer and quality of API missingAlternative API-manufacturers are not listed, but Alternative API-manufacturers are not listed, but are revealed from the FPP-part of the dossierare revealed from the FPP-part of the 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 USPdescribed in BP, PhInt, PhEur or USP 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 parameters to Process conditions, test requirements and other relevant parameters to

be controlled within predetermined limitsbe 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 chemical or major chemical

transformationtransformation 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 the API of the 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 to for the API to be validatedbe validated

All steps covering All steps covering aseptic processingaseptic processing or or sterilizationsterilization to be validated to be validated


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 orderimpurities contained in the starting materialimpurities contained in the starting materialstarting material unreactedstarting material unreactedintermediates unreactedintermediates unreactedby-products (unwanted reaction products)by-products (unwanted reaction products)reagentsreagentscatalystscatalystsresidual solventsresidual solventsdegradantsdegradants

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

Potential impurities of ArtemisininesPotential impurities of Artemisinines Starting material (extracted from herbal Starting material (extracted from herbal

sources)sources)GuideGeneric:GuideGeneric:

Starting materials from vegetable origin should be fully Starting materials from vegetable origin should be fully charcterized and a contaminant profile should be charcterized and a contaminant profile should be established and submitted.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 sources, In the case of substances isolated form herbal sources,

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


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

Potential impurities of ArtemisininesPotential impurities of Artemisinines Subsequent chemical reactionsSubsequent chemical reactions

Application of the scheme provided in Application of the scheme provided in PQIF 2.4.1, a) PQIF 2.4.1, a) ImpuritiesImpurities

Critical process stepsCritical process steps to be controlled to be controlled Stereochemistry of the hydration stepStereochemistry of the hydration step

- stereoselective control method?- stereoselective control method? Derivatisation/Ether-/Esterification (stereoselectivity?)Derivatisation/Ether-/Esterification (stereoselectivity?)

Artemether, Artesunate, ArtemotilArtemether, Artesunate, Artemotil- stereoselective purification procedure?- stereoselective purification procedure?- stability of the - ether versus -ester- stability of the - ether versus -ester

Transformation Artenimol>>>Artemisinine?Transformation Artenimol>>>Artemisinine?


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

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 impuritiesConcentration 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 usedSpecificity, sensitivitySpecificity, sensitivity

Justification of proposed acceptance criteria Justification of proposed acceptance criteria


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

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%



Methods to assess impurities are not sensitive Methods to assess impurities are not sensitive enough to assess impuritiesenough to assess impurities 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%))

Listing of impurities limited to those actually Listing of impurities limited to those actually detecteddetected Potential impurities are not discussedPotential impurities are not discussed

Impurity levels are far above the qualification Impurity levels are far above the qualification limit without justificationlimit without justification


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

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

processprocessStarting materialsStarting materials

Raw materialsRaw materials

IntermediatesIntermediates

ReagentsReagents

CatalystsCatalysts

SolventsSolvents SpecificationsSpecifications


2.4 Route(s) of synthesis X2.4 Route(s) of synthesis X

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 Particularly addressing the Particularly addressing the TSE-safetyTSE-safety of all of all

materials coming into the processmaterials coming into the processProof of safety by relevant dataProof of safety by relevant data

CEPCEP Letter of attestationLetter of attestation


2.4 Route(s) of synthesis XI2.4 Route(s) of synthesis XI

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

monographmonographProcess 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


2.5 Specifications2.5 Specifications

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

Any test that is not performed on a batch to batch-basis must Any test that is not performed on a batch to batch-basis must be indicated (periodic testing or be 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 justificationf. ex. particular method of productionf. ex. particular method of productionf.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 Batch numbernumber

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

ignition ignition


2.5. Specifications VI2.5. Specifications VI

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

ICH Q6AICH Q6A Justification for each procedure and each acceptance criterion with Justification for each procedure and each acceptance criterion with

reference toreference torelevant development datarelevant development datapharmacopoeial standardspharmacopoeial standardsTest data for batches used in toxicology and clinical studiesTest data for batches used in toxicology and clinical studiesResults from accelerated and long term studiesResults from accelerated and long term studiesReasonable range of analytical and manufacturing variabilityReasonable range of analytical and manufacturing variabilityAlternate justified approachesAlternate justified approaches

Actual resultsActual results obtained should form the obtained should form the primary basisprimary basis for any for any justificationjustification


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 puritySourceSource

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


2.5 Specifications IX2.5 Specifications IX

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

Stability indicating potentialStability indicating potential Any in-house analytical procedure needs to be validatedAny in-house analytical procedure needs to be validated

ICH Q2A, ICH Q2BICH Q2A, ICH Q2B Assay and impuritiesAssay and impurities

Stress testing provides degradants that may occur during storageStress testing provides degradants that may occur during storage Isolation of impurities and (stable) degradants in the development Isolation of impurities and (stable) degradants in the development

phasephase 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


2.5 Specifications X2.5 Specifications X

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 monographResiduals, particle size, polymorphs, loss on dryingResiduals, particle size, polymorphs, loss on drying

Generic guideGeneric guide::Whenever an API has been prepared by a method liable to Whenever an API has been prepared by a method liable to leave leave impurities not controlled in the impurities not controlled in the pharmacopoeial monograph, these impurities (based on 3 to pharmacopoeial monograph, 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 XISpecifications XI

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 XII2.5 Specifications XII

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 proceduresPharmacopoeial 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 methodsFor impurities/degradants not covered by the monographFor impurities/degradants not covered by the monographIf the pharmacopoeial method is modifiedIf the pharmacopoeial method is modified



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

Only one type of Reference standard is provided and Only one type of Reference standard is provided and simply represents simply represents API from a normal batchAPI from a normal batch..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 materials of construction of each primary Identity of materials of construction of each primary packaging componentpackaging component

Reference to specification for each packaging componentReference to specification for each packaging component DescriptionDescription IdentificationIdentification Drawings of critical dimensionsDrawings of critical dimensions

SecondarySecondary packaging material packaging materialNon-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 materialCompatibility with APICompatibility with APISorptionSorptionLeachingLeaching


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 containerf.ex. type of inner/outer container f.ex. use of seals, joints, gasketsf.ex. use of seals, joints, gaskets

pqif-api

Documents