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  1. 3-1 INTERPRETATION OF LABORATORY FINDINGS. WHAT QC CAN NOT SAY Pr A. NICOLAS, PhD Head of the French Laboratories and Controls Directorate AFSSAPS Interregional Seminar for Quality Control Laboratories involved in WHO Prequalification Programme and/or participating in respective sampling and testing projects, Nairobi, Kenya, 23-25 September 2009

  2. INTERPRETATION OF LABORATORY FINDINGS. WHAT QC CAN NOT SAY. • SPECIFICATIONS FOR DRUG SUBSTANCES AND DRUG PRODUCTS ACCORDING ICH Q6A • WHAT QC CANNOT SAY • For drug substances • For drug products • Excipients and primary packaging • Stability data • Analytical data and rules of writing • CONCLUSION

  3. QUALITY OF DRUG SUBSTANCES AND DRUG PRODUCTS • Quality is determined by : • Design, • Development, • In-process controls • GMP controls, • Process validation • Specifications and Analytical Procedures

  4. SPECIFICATIONS • Specifications • Are critical quality standards justified by the manufacturer and approved by the regulatory authorities • Assure the quality at release and during shelf life • Are only one part of a total control strategy to ensure product quality and consistency ; other parts include adherence to GMP Tests and corresponding specifications are listed on the CoA. Analytical procedures are known only if the method are compendial.

  5. ICHQ6A - UNIVERSAL TESTS FOR DRUG SUBSTANCES • Description Qualitative statement about the state (solid, liquid,..) and color • Identification Tests should be specific for structure (IR, HPLC/DAD) and chirality • Impurities Organic, inorganic, residual solvents • Water content or LOD : for determination of content • Assay • Specific and stability indicating (HPLC) • If non-specific (titration), combination with test for impurities

  6. ICHQ6A - SPECIFIC TESTS FOR DRUG SUBSTANCES • Phycochemical properties according the physical nature of the substance (pH aqueous solution, refractive index, melting point,… • Particle size (Ph. Eur. 2.9.31, laser) • Polymorphic forms (Ph. Eur. 5.9, Thermal analysis Ph. Eur. 2.2.34 : TG, DSC) • Chirality if required. Test for enantiomeric purity, in general by HPLC, only very few EC methods : levocabastine, HCl. • Catalysts : EMEA/CHMP/SWP/4446/2000 (01 Sept 2008) • Microbial limits (Ph. Eur. 5.1.4)

  7. ICHQ6A - UNIVERSAL TESTS FOR DRUG PRODUCTS • Description of the dosage form : qualitative • Identification of active substances/preservatives • Organic impurities • Arising during the manufacturing process and the storage • Degradation of the active substances, interaction with the excipients • Residual solvents (Ph. Eur. 5.4) Synthesis impurities which are not also degradation products are not controlled and not included in the total

  8. ICHQ6A - SPECIFIC TESTS FOR DRUG PRODUCTS • Solid oral dosage forms • Disintegration : for rapid dissolving products containing highly soluble drugs (dissolution > 80 % in 15 min) • Dissolution : when bioavailability is affected, for modified release dosage forms • Hardness/friability : normally IPC, not included in specifications • Uniformity of dosage units (Ph. Eur. 2.9.40) • Water content : when appropriate • Microbial limits : seen as an attribute of GMP (skip testing)

  9. ICHQ6A - SPECIFIC TESTS FOR DRUG PRODUCTS • Oral liquids • Uniformity of dosage units : may be performed in process but the acceptance criteria should be included in the specification • Antioxidants and antimicrobial preservatives contents • pH • Alcohol content

  10. ICHQ6A - SPECIFIC TESTS FOR DRUG PRODUCTS • Parenteral drug products • Uniformity of dosage units : may be performed in process but the acceptance criteria should be included in the specification • pH • Sterility • Endotoxins/pyrogens • Particulate matter • Antimicrobial/antioxidant preservative • Osmolarity

  11. ICHQ6A - GENERAL CONCEPTS • In-process controls (IPC) When only used for adjusting process parameters, they are not included in the specifications • Periodic testing, may be applicable to some tests after justification and approval by regulatory authorities • Release vs shelf-life acceptance criteria • This concept applies to drug products only • Include assay of active substances, preservatives and degradation products

  12. ICHQ6A - GENERAL CONCEPTS • Development considerations Data accumulated during development can justify exclusion of certain tests • Microbial testing for drug substances and solid dosage forms • Extractables from product containers • Particle size testing

  13. WHAT QC CAN NOT SAY • Considering drug substances/drug products • Representativity of the sampling (pre-analytical step) • Compliance to GMP • Quality system • Validation of the methods when non-compendial methods • Stability studies

  14. DRUG SUBSTANCES • Existence of a monograph (Ph. Eur, USP, JP, Chinese, Ph. Int.) • Existence of a CEP (monograph in Ph. Eur.) List of certificates in force, suspended or cancelled on edqm website www.edqm.eu • Data usually available • Name of manufacturer • Sometimes : site of manufacturing, batch number, batch size, date of manufacturing, re-test period

  15. DRUG SUBSTANCES • Data non usually available • Route of synthesis • Starting materials and key intermediates : quality, specifications • Solvents and /or toxic reagents used, at which step of the synthesis • Catalysts • Use of reagents from animal origin • Reprocessing procedure (if any) • Packaging, storage and transport conditions

  16. DRUG SUBSTANCES • Solid state • Data relative to polymorphism or pseudopolymorphism • Can influence biodisponibility of solid dosage forms • Hydration state • Can influence stability • Useful to prevent confusion in preparation of drug products (correction of mass)

  17. DRUG SUBSTANCES • Related substances • Specifications should be clearly indicated • Difficult to differentiate origin of the impurities : synthesis and/or degradation • Possibility of existence of genotoxic impurities(EMEA/CHMP/QWP/251344/2006) • Existence of a total for impurities • Disregard limit not known if non compendial method • Often, rounding rules not followed (decimal place)

  18. DRUG SUBSTANCES Contamination during the process : tests not described or limits too large • Heparines • Monographs in force in 2007/2008 did not allow the finding of contaminants such as oversulphated chondroitine sulphate (OSCS) or dermatane sulphate • Revision of the monographs by introduction of CE, NMR and perhaps strong anion exchange chromatography in the next future • Gentamicin : limits for endotoxins were tightened after several deaths by shock in US Contamination by illicit compounds difficult to find by application of monographs. In general analytical methods are irrelevant to detect the falsification

  19. DRUG SUBSTANCES

  20. DRUG SUBSTANCES

  21. EXCIPIENTS • Defined by their origin, their quality (tests), not by their content (generally assay is missing) • Functionality-related characteristics (FRC, Ph.Eur. 5.15) Recently introduced, not mandatory and published for information and guidance. • Gelatin • Purified protein obtained by partial hydrolysis of collagen from animals (including fish and poultry) • Sulphur dioxide (Ph. Eur. 2.5.29): max 50 ppm • Peroxides: max 10 ppm • Iron: max 30.0 ppm, Chromium: max 10.0 ppm, Zinc: 30.0 ppm

  22. EXCIPIENTS • Magnesium stearate • Compound of magnesium with a mixture of solid organic acids and consisting mainly of variable proportions of magnesium stearate and magnesium palmitate obtained from sources of vegetable or animal origin. • Loss on drying (Ph. Eur. 2.2.32): maximum 6.0 per cent • Cadmium: max 3.0 ppm, Nickel: max 5.0 ppm, Lead : max 10.0 ppm • FRC • Specific surface area (Ph. Eur. 2.9.26, Method I)

  23. DRUG PRODUCTS • Defined by its composition and its primary packaging • Active substances and preservatives (antioxidants, antimicrobial preservatives) are listed and must be identified and quantified • Excipients listed but quantitative composition of the drug product only described in the file • Manufacturing process usually not known • Are solvents used in the process (granulation)?

  24. DRUG PRODUCTS/IMPURITIES Origin of impurities • Impurities from the components (other than synthetic impurities which are not also degradation compounds) • Degradation of the active substances and/or the preservatives • Interaction • between activesubstances and excipients • between active substances and impurities coming from excipients and/or active substances • with the packaging

  25. RESIDUAL SOLVENTS AND INORGANIC IMPURITIES • Profile of residual solvents and/or of inorganic impurities can give a good idea of the quality of the drug and of its origin • Residual solvents : Ph. Eur. 5.4 and method 2.4.24 • Inorganic impurities : ICP-AES (Ph. Eur. 2.2.57) and ICP-MS (Ph. Eur. 2.2.58) Rao R.N. and KUMAR TALLURI MVN. J. Pharm. Biomed. Analysis, 2007,43,1-13 (Review)

  26. EXCIPIENTS/QUALITY OF THE DRUG PRODUCTS • Chemical reactivity of excipients : Maillard reaction • Reaction between primary or secondary amines and reducing sugars (lactose, fructose, dextrose, glucose, maltose) • Example : fluoxetine and lactose WIRTH D.D. et coll, J. Pharm. Sci., 1998, 87,31-39 Existence of a new impurity in generic drugs due to the replacement of starch (princeps) by lactose Can not be anticipated if exicipients are not known

  27. EXCIPIENTS/QUALITY OF THE DRUG PRODUCTS • Chemical reaction with contaminantsof excipients • Hydrolysis • Excipients with high water content : maize starch (15.0 %); potato starch (20.0%) • Oxidation Excipents containing trace of peroxides • Gelatin : 10 ppm • Crospovidone B type : 1 000 ppm • Povidone : 400 ppm

  28. IMPURITIES/QUALITY OF THE DRUG PRODUCTS • Possible interactions between impurities of an active substance and active ingredients in multi-substances drugs • Reaction between 3-formyl rifamycin SV (impurity from rifampicin) and isoniazid in tablets • Impurity limited to 5.0 % in the substance • Adduct product limited to 5.0 % in the tablets

  29. IMPURITIES IN DRUG PRODUCTS ICHQ3B(R2)

  30. DRUG PRODUCTS

  31. DRUG PRODUCTS

  32. PRIMARY PACKAGING Is part of the definition of the finished product • Data available in the file, but in case of use of an other quality or an other type • Possible reaction between active ingredient and primary packaging • Possible existence of extractibles/leachablesin the drug (liquid) • Influence on the stability of the drug • Permeation to gas from the atmosphere (H2O, O2, CO2) : increase of friability of orodispersible tablets • Transparency to light : photooxidation

  33. GUIDELINE « Plastic immediate packaging materials » CPMP/QWP/4359/03 • Scope of the guideline • Covers the specific requirements for plastic immediate packaging materials in direct contact with the active substance or medicinal product • The materials may be part of the container, the closure or seal. • Refer to if the packaging material from the marketed products is modified

  34. GUIDELINE « Plastic immediate packaging materials » CPMP/QWP/4359/03 • Interaction studies • For solid active substances and solid dosage forms : the risk of interaction is low. No content/container interaction study needed • For non-solid active substance and liquid dosage forms : risk of interaction requires suitable studies specific for each active substance/formulation

  35. SECONDARY PACKAGING • Data available in the file • At present time, first step for identification of counterfaiting drugs by : • Global visual examination • Characteristics of the printing : name, batch number, shelf-life, logos • Comparaison with original available in data bank (imaging) • Constitution of « photothèque »

  36. STABILITY DATA • Quality of drugs imported into emergent countries having a tropical climate may be adversely affected if their formulations have not been optimized under these conditions • Adverse effects • Chemical decomposition (compromise safety) • Reduced in vitro dissolution (compromise efficacy) • Not only drug content, but also drug release tests should be done to test stability in tropical climates WHO recommands testing the stability under tropical climate conditions

  37. WHO long term stability conditions (WHO Technical report series, N°953, 2009)

  38. WHO STABILITY CONDITIONS BY REGION (partial)

  39. CONTENT vs DISSOLUTION P.G. RISHA et coll, Eur. J. Pharmacol., 2003, 59, 135-141

  40. ANALYTICAL DATA • Analytical data related to the performance of the method and the results of the suitability tests are missing on the CoA • Results from the suitability tests (HPLC) : resolution, symetry factor, N • Method of quantitation, correction factors • Nature of the reference substances : CRS or working standards • Number of determinations • Sequence of injections • Disregard limit for detection of impurities • Mode of preparation of the samples, storage before analysis, stability (temperature, light, oxidation)

  41. RULES OF WRITING • Replace the mention « complies » by the exact value obtained for the test • Disintegration time • Sulphated ash • Loss on drying • ….. • Writing of the quantitative results : figures, rounding rules, same decimal places for the specifications and the results

  42. CONCLUSION • Quality is difficult to garantee when all the parameters are not known • For multi-sources active substances, route of synthesis and impurity profile are closely related • Use of active substances with a CEP in force is recommended • Composition and quality of excipients is not always known • Falsification or counterfaiting is difficult to put in evidence • Strategy of screening of the defaults by risk analysis could facilitate the work of the analyst

  43. AKNOWLEDGEMENTS • Thanks to Sylvie ARMEL, Pharmacopoeia Unit (AFSSAPS) for helpful scientific discussions during elaboration of this lecture • Thanks to Laurence MOUILLOT, Scientific Director of Saint-Denis site (AFSSAPS) for her daily smiling support