interpretation of laboratory findings. what qc can not say pr a. nicolas, phd head of the french...

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

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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


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


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.


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


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,…

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)


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


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)




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




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


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


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


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


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



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



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)



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)



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


EXCIPIENTSEXCIPIENTS

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


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)


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)?


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


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

– 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)


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




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


IMPURITIES/QUALITY OF THE DRUG PRODUCTS

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


IMPURITIES IN DRUG PRODUCTS ICHQ3B(R2)

IMPURITIES IN DRUG PRODUCTS ICHQ3B(R2)

DoseThreshold for

identification (%)Threshold for

qualification (%)

< 1 mg1.01.0

1 – 10 mg0.51.0

> 10 – 100 mg0.20.5

> 100 mg – 2 g0.20.2

> 2 g0.100.15


PRIMARY PACKAGINGPRIMARY 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


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




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


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 »


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


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

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


WHO STABILITY CONDITIONS BY REGION (partial)

WHO STABILITY CONDITIONS BY REGION (partial)


CONTENT vs DISSOLUTION CONTENT vs DISSOLUTION

ManufacturerBrand nameDrugcontentDrugreleased(%)

0 month6 months0 month3 months6 months

Intas

IndiaDicloflame 5097.8 ± 0.395.0 ± 7.194.7 ± 7.151.2 ± 6.542.9 ± 5.5

Camden

MalaysiaDiclo 5099.7 ± 0.297.8 ± 0.487.3 ± 4.812.1 ± 5.310.4 ± 4.3

P.G. RISHA et coll, Eur. J. Pharmacol., 2003, 59, 135-141


ANALYTICAL DATAANALYTICAL 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)


RULES OF WRITINGRULES 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


CONCLUSIONCONCLUSION

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


AKNOWLEDGEMENTSAKNOWLEDGEMENTS

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

interpretation of laboratory findings. what qc can not say pr a. nicolas, phd head of the french...

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