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 3-1
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INTERPRETATION OF LABORATORY FINDINGS. WHAT QC CAN NOT SAY Pr A. NICOLAS, PhD Head of the French Laboratories and Controls Directorate AFSSAPS Interregional.
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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
3-1
Sampling and testing for Quality Control Laboratories, Nairobi, September 20092 |
INTERPRETATION OF LABORATORY FINDINGS. WHAT QC CAN NOT SAY.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
Sampling and testing for Quality Control Laboratories, Nairobi, September 20093 |
QUALITY OF DRUG SUBSTANCES AND DRUG PRODUCTS
QUALITY OF DRUG SUBSTANCES AND DRUG PRODUCTS
Quality is determined by :
– Design,– Development,– In-process controls– GMP controls,– Process validation– Specifications and Analytical Procedures
Sampling and testing for Quality Control Laboratories, Nairobi, September 20094 |
SPECIFICATIONSSPECIFICATIONS
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.
Sampling and testing for Quality Control Laboratories, Nairobi, September 20095 |
ICHQ6A - UNIVERSAL TESTS FOR DRUG SUBSTANCES
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
Sampling and testing for Quality Control Laboratories, Nairobi, September 20096 |
ICHQ6A - SPECIFIC TESTS FOR DRUG SUBSTANCES
ICHQ6A - SPECIFIC TESTS FOR DRUG SUBSTANCES
Phycochemical properties according the physical nature of the substance (pH aqueous solution, refractive index, melting point,…
Sampling and testing for Quality Control Laboratories, Nairobi, September 20097 |
ICHQ6A - UNIVERSAL TESTS FOR DRUG PRODUCTS
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
Sampling and testing for Quality Control Laboratories, Nairobi, September 20098 |
ICHQ6A - SPECIFIC TESTS FOR DRUG PRODUCTS
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)
Sampling and testing for Quality Control Laboratories, Nairobi, September 20099 |
ICHQ6A - SPECIFIC TESTS FOR DRUG PRODUCTS
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
Sampling and testing for Quality Control Laboratories, Nairobi, September 200910 |
ICHQ6A - SPECIFIC TESTS FOR DRUG PRODUCTS
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
Sampling and testing for Quality Control Laboratories, Nairobi, September 200911 |
ICHQ6A - GENERAL CONCEPTSICHQ6A - 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
Sampling and testing for Quality Control Laboratories, Nairobi, September 200912 |
ICHQ6A - GENERAL CONCEPTSICHQ6A - 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
Sampling and testing for Quality Control Laboratories, Nairobi, September 200913 |
WHAT QC CAN NOT SAYWHAT 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
Sampling and testing for Quality Control Laboratories, Nairobi, September 200914 |
DRUG SUBSTANCESDRUG 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
Sampling and testing for Quality Control Laboratories, Nairobi, September 200915 |
DRUG SUBSTANCESDRUG 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
Sampling and testing for Quality Control Laboratories, Nairobi, September 200916 |
DRUG SUBSTANCESDRUG 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)
Sampling and testing for Quality Control Laboratories, Nairobi, September 200917 |
DRUG SUBSTANCESDRUG 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)
Sampling and testing for Quality Control Laboratories, Nairobi, September 200918 |
DRUG SUBSTANCESDRUG 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
Sampling and testing for Quality Control Laboratories, Nairobi, September 200919 |
DRUG SUBSTANCESDRUG SUBSTANCES
Sampling and testing for Quality Control Laboratories, Nairobi, September 200920 |
DRUG SUBSTANCESDRUG SUBSTANCES
Sampling and testing for Quality Control Laboratories, Nairobi, September 200921 |
EXCIPIENTSEXCIPIENTS
Defined by their origin, their quality (tests), not by their content (generally assay is missing)
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
Sampling and testing for Quality Control Laboratories, Nairobi, September 200922 |
EXCIPIENTSEXCIPIENTS
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)
Sampling and testing for Quality Control Laboratories, Nairobi, September 200923 |
DRUG PRODUCTSDRUG 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)?
Sampling and testing for Quality Control Laboratories, Nairobi, September 200924 |
DRUG PRODUCTS/IMPURITIESDRUG 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 active substances and excipients– between active substances and impurities coming from
excipients and/or active substances– with the packaging
Sampling and testing for Quality Control Laboratories, Nairobi, September 200925 |
RESIDUAL SOLVENTS AND INORGANIC IMPURITIES
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
– 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
Sampling and testing for Quality Control Laboratories, Nairobi, September 200935 |
SECONDARY PACKAGINGSECONDARY 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 »
Sampling and testing for Quality Control Laboratories, Nairobi, September 200936 |
STABILITY DATASTABILITY 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
Sampling and testing for Quality Control Laboratories, Nairobi, September 200937 |
WHO long term stability conditions (WHO Technical report series, N°953, 2009)
WHO long term stability conditions (WHO Technical report series, N°953, 2009)
Sampling and testing for Quality Control Laboratories, Nairobi, September 200938 |
WHO STABILITY CONDITIONS BY REGION (partial)
WHO STABILITY CONDITIONS BY REGION (partial)
Sampling and testing for Quality Control Laboratories, Nairobi, September 200939 |