Istanbul October 2005 CERTIFICATION OF SUITABILITY OF MONOGRAPHS OF THE EUROPEAN PHARMACOPOEIA 5TH EDITION WORKSHOP SESSION: An outline of the main deficiencies in dossiers and how to avoid them Istanbul October 2005 The main deficiencies found in dossiers for chemical purity Dr P.Poukens-Renwart and Dr D. Byrne Scientific officers Certification Unit, EDQM
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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
Istanbul October 2005
The main deficiencies found indossiers for chemical purity
Dr P.Poukens-Renwart and Dr D. ByrneScientific officers
Certification Unit, EDQM
Istanbul October 2005
Summary:
• Figures• Deficiencies at receipt• Top ten deficiencies• Other deficiencies (new development)• Presentation of data• Conclusions
Istanbul October 2005
Average time to get a CEP:21 months (min 6 months, max 6 years)
Istanbul October 2005
Number of assessments for CEP
Istanbul October 2005
Requests for add info after 1st assessment:Average number of questions: 11 (9 in 2004)
(min 0, max 25)
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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)
Istanbul October 2005
Dossiers blocked at receipt 9% of applications received in 2004 (24% in 2002)
• TECHNICAL REASONS:2 processes / incomplete documentation / Class Isolvents / Referred monograph ≠ current Ph. Eurmonograph / related substances controlled by TLC
Istanbul October 2005
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
Istanbul October 2005
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
Istanbul October 2005
CTD format (cont)
• (3.2.S.4.3) Analytical validation / suitabilityof the monograph
Repartition of questions after thefirst evaluation
Istanbul October 2005
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)
Istanbul October 2005
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%
Istanbul October 2005
TOP TEN deficiencies (cont)
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)
Istanbul October 2005
TOP TEN deficiencies (cont)
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)
Istanbul October 2005
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%
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
Certification Conference,Istanbul, 27-28 October 2005
- IPC (in process controls) :where, how, methods, specifications
- options (alternatives)
- Blending, mixing sub batches (QC where?)
Certification Conference,Istanbul, 27-28 October 2005
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3.2.S.2.2. Manufacturing Method
• 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!
Certification Conference,Istanbul, 27-28 October 2005
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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
Certification Conference,Istanbul, 27-28 October 2005
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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?
Certification Conference,Istanbul, 27-28 October 2005
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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
Certification Conference,Istanbul, 27-28 October 2005
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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)
Certification Conference,Istanbul, 27-28 October 2005
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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.
Certification Conference,Istanbul, 27-28 October 2005
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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
Certification Conference,Istanbul, 27-28 October 2005
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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)
Certification Conference,Istanbul, 27-28 October 2005
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.
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.
• 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
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
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
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
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%
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%
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
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