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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
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
QUALITY OF DRUG SUBSTANCES AND
DRUG PRODUCTS
 Quality is determined by :
–
–
–
–
–
–
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Design,
Development,
In-process controls
GMP controls,
Process validation
Specifications and Analytical Procedures
Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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.
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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)
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
specifications
:
normally
IPC,
not
included
– Uniformity of dosage units (Ph. Eur. 2.9.40)
– Water content : when appropriate
– Microbial limits : seen as an attribute of GMP (skip testing)
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
in
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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)
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
DRUG SUBSTANCES
 Related substances
– Specifications should be clearly indicated
– Difficult to differentiate origin of the impurities : synthesis
and/or degradation
– Possibility
of
existence
of
(EMEA/CHMP/QWP/251344/2006)
genotoxic
impurities
– Existence of a total for impurities
– Disregard limit not known if non compendial method
– Often, rounding rules not followed (decimal place)
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
DRUG SUBSTANCES
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
DRUG SUBSTANCES
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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)
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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)?
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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 active substances and excipients
– between active substances and impurities coming from
excipients and/or active substances
– with the packaging
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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)
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
EXCIPIENTS/QUALITY OF THE DRUG
PRODUCTS
 Chemical reaction with contaminants of 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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
IMPURITIES IN DRUG PRODUCTS
ICHQ3B(R2)
Threshold for
identification (%)
1.0
Threshold for
qualification (%)
1.0
1 – 10 mg
0.5
1.0
> 10 – 100 mg
0.2
0.5
> 100 mg – 2 g
0.2
0.2
>2g
0.10
0.15
Dose
< 1 mg
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
DRUG PRODUCTS
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
DRUG PRODUCTS
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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/leachables in 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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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 »
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
WHO long term stability conditions
(WHO Technical report series, N°953, 2009)
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
WHO STABILITY CONDITIONS BY REGION
(partial)
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
CONTENT vs DISSOLUTION
Manufacturer
Brand name
Drug
content
Drug
released
(%)
0 month
6 months
0 month
3 months 6 months
Dicloflame 50
97.8 ± 0.3
95.0 ± 7.1
94.7 ± 7.1
51.2 ± 6.5
42.9 ± 5.5
Diclo 50
99.7 ± 0.2
97.8 ± 0.4
87.3 ± 4.8
12.1 ± 5.3
10.4 ± 4.3
Intas
India
Camden
Malaysia
P.G. RISHA et coll, Eur. J. Pharmacol., 2003, 59, 135-141
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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)
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009
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
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Sampling and testing for Quality Control Laboratories, Nairobi, September 2009