Alaa Khedr Ph.D. Professor

Faculty of PharmacyKing Abdulaziz University

E-mail: akhedr@kau.edu.sa R

الرحيم الرحمن الله بسممحمد سيدنا على وسلم صلي اللهم

STABILITY STUDY and EXPIRATION DATE

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AbbreviationsAPI Active Pharmaceutical Ingredient FDC Fixed-Dose CombinationFPP Finished Pharmaceutical Product GMP Good Manufacturing PracticesICH International Conference on HarmonizationMA Marketing AuthorizationDRA Drug Regulatory Authority MCA: Medicine Control AgencyFDA: Food and Drug Administration NDA: New Drug ApplicationsANDA: Abbreviated New Drug ApplicationsEU: European Union EMEA: European Medicinal Evaluation Agency CPMP: Committee for Proprietary Medicinal ProductsNTA: Notices To ApplicantCDER / CFR: Code of Federal Register

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Applicable guidelines• Guidance for Industry

Q1A(R2) Stability Testing of New Drug Substances and ProductsU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)November 2003, ICH

• Guidance for IndustryQ1E Evaluation of Stability DataU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)June 2004, ICH 

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1- The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and enables recommended (1) storage conditions, (2) re-test periods and (3) shelf lives to be established.

Objectives

Drug100%

Drug 95.5%

+Time(month)

Temp.HumidityLight

2- Safety and efficacy.

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Specification of ProductAll SOP’s

Drug product

Equipment & tools

Reference Standards

Stability Indicating Analytical Method

Design

Written/Approved

IQ/OQ/PQ, Data LoggerLog sheets

Compendia& Company SpcsApproved Docs

ICH Stress testingDevelopmentValidationRepresent. Chromatograms

Batch size3 batchesSampling protocol

Purchase USP / Europ. RSPurchase Potential ImpuritiesStorage cabinetVerified

Before starting program execution we should have;

Stability Protocol

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Design

Written/Approved

Before starting program execution we should have;

Stability Protocol

Who doing what? How to do the taskClear interpretation of proceduresStepwise manner

1

Stability protocol is a signed/dated and approved document that describe the exact and clear procedure to start the stability testing of drug. The procedure should be described in a sequential stepwise manner, who doing what, how to do the task.

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Specification of ProductAll SOP’s

Design Before starting program execution we should have;

Info. Source 1 = Compendia (USP/BP)Info. Source 2 = FDA / ICH guidelines (Limits / general Official Procedure)Info. Source 3 = Supplier of raw materialInfo. Source 4 = Company approved specs of API and PFP

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Equipment & tools

Design

IQ/OQ/PQ, Data LoggerLog sheets

Before starting program execution we should have;

Documentations are available = IQ/OQ/PQData Logger (calibrated) = Temp., HumidityDocuments = Log sheets of operation, time, dateHow to operate the machine = SOP for machine

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Stability Cabinets

+ Data loggers !!!!

HPLC

Dissolution

UV

Karl Fisher

BalancesCalibrated Glassware

Equipment & tools3

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1. A special cabinet for each condition

2. Should be qualified / calibrated3. Monitor Temp. / humidity vs time.

Time4. Three General conditions

required.

Stability Cabinets

Data loggers

Deep freeze

+ Data loggers !!!!Equipment & tools3

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Data Loggers (Types)

sensor probe / thermocouple

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Why we use Data Loggers ?How many sensor probe?How to position sensors?

1. To monitor Both, temperature and Relative Humidity along 24 hours.

2. To ensure consistency of the adjusted Temp. and RH.3. Should be calibrated by supplier4. Any deviation for NLT 6 hours, we should stop study

and repeat using new samples.5. Ex: Electricity shutdown, or instrument failer, no enough

water inside instrument.

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Why we defined some products to be photosensitive, to which degree ?

(use UV-A, 200 watts hours/m2 )Illumination   : 1.2 million Lux hoursHumidity range   : 40% to 95% ± 2% RHTemperature range    : 100c to 500C, ± 0.50C

-- Use calibrated machine (candles/inch = ?) 3. Exposure time limit = ?(according to the limit of potential degradation

products formed, and quinine HCl standard)

Photostability CabinetsAt least one primary batch Should be tested

Equipment & tools3

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Stability Indicating Analytical Method

Design

ICH Stress testingDevelopmentValidationRepresent. Chromatograms

Before starting program execution we should have;

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Stability indicating Analytical MethodThe method is able to discriminate between principle drugand the degradation products and/or impurities

Method: Compendial methods are claimed to be stability indicatingRules: ICH stress Guideline Plus: Photodegradation products & reconstitution testingMonitoring: Peaks of Potential impurities & Degradation products (previously define the cause)

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Rules of Stress testing:-- expose drug subs. To abnormal environmental variables.-- Forced degradation to NLT 90%.-- Do not degraded the drug completely ? To provide selectivity of the method.

Example of STRESS TESTING OF BETAHISTINE HCl

Representative chromatograms of betahistine hydrochloride; heated in solid state [a], boiled in 1M NaOH [b], boiled with 1M HCl [c], extracted from tablet powder exposed to UV light [d], extracted from Betaserc tablets [e], and left to stand in 0.1% H2O2 solution [f].

heated

NaOH

HCl

UV light

Betaserc tablets

H2O2

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Chromatographic parameters* of TIA degraded with 1M HCl, (detection; UV at 254 nm, claimed TIA concentration is 250 ng/μL). n = 3.

RT (min)(RSD)

Area(RSD)

Width(min)

% Amount

± SDK ‘ R

(RSD) α As N

12.31(0.14)

1397070(0.06)

0.83 48.60±0.01

5.15 1.11 20393

21.37(0.02)

694064(0.88)

0.70 7.32±1.02

9.68 11.82(0.02)

1.88 1.32 107053

28.05(0.27)

1759762(0.75)

1.07 18.55±0.68

13.03 7.57(0.26)

1.35 1.29 59909

29.17(0.15)

601828(0.58)

0.85 6.34±1.33

13.59 1.17(0.12)

1.04 1.19 152496

30.54(0.11)

1794384(0.55)

0.73 18.92±1.20

14.27 1.73(0.08)

1.05 1.20 157276

32.57(1.20)

18284(1.00)

0.47 0.19±0.66

15.28 3.37(0.95)

1.07 1.13 189448

33.49(0.02)

7442(0.65)

0.38 0.08±0.34

15.74 2.17(0.01)

1.03 1.03 191957

* k’ capacity factor; α, selectivity coefficient; R, resolution; and As, peak asymmetry; N, USP plate count.

Analytical Method Performance

How to present the analytical HPLC method PERFORMANCE PARAMETERS

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Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. For instance, in case of tablets:

♦ appearance ♦ hardness ♦ friability ♦ moisture content ♦ dissolution time ♦ degradants♦ assay ♦ microbial purity

STABILITY-INDICATING QUALITY PARAMETERS What are the

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Design

Batch size3 batchesSampling protocol

Before starting program execution we should have;

5 Drug Product

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How many batches should be tested ?

Batch size = ? Product unit

Which Batches should be tested ?

When should we repeat stability testing?

Selection of batches: Drug product

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Selection of batches:

How many batches should be tested ?three, using 3 different batches of starting drug substance

Batch size = ? Product unitTwo pilot scale batches, third smaller if justified)

Which Batches should be tested ?Stability studies should be performed on each individual strength and container size.

When we should repeat stability testing?

[1] In case of failed

stability ..!

[2] Modification?using raw material from different manufacturer, excepients type/ratio change manufacturing procedure modified.change of package, closure.

[3] ApplicationFor ANDA (Pharm. Bioeq) !!

Drug product

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The stability testing should be conducted on the dosage form stored in the proposed containers / closure system for marketing.

Container / closure systems:

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Reference Standards

Design

Purchase USP / Europ. Reference Standard)Purchase Potential ImpuritiesStored in Special Storage cabinet + log book (amount used, when, for what?)Verified (Melting point, IR, HPLC-RT as per USP/BP)

Before starting program execution we should have;

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Major Variables

TemperatureRelative HumidityLight (Photostability)

Stability after Reconstitution (dilution)

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[a] General Case (PERMEABLE)

[b] Drug Products packaged in IMPERMEABLE containers

[c] Drug Products packaged in SEMIPERMEABLE containers

[d] Drug Products intended for storage in refrigerator

[e] Drug Products intended for storage in freezer

[f] Drug Products intended for storage below -20 ºC

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teTypical storage condition and study duration

Study Storage condition Minimum time period

Frequency of sampling (months)

Long-term252C / 60 % RH 5% RH

or302C / 65 % RH 5% RH

12 months 0,3,6,9,12,18,24

Intermediate 302C / 65 % RH 5% RH 6 months 0,3,6,12

Accelerated 402C / 75 % RH 5% RH 6 months 0,1,2,3,6

[a] General Case (PERMEABLE containers to moisture)

• It is up to the applicant to decide the tem/RH for long term.• If 302C / 65 % RH 5% RH is the long term, then NO INTERMEDIATE cond.

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teTypical storage condition and study duration

Study Storage condition Minimum time period

Frequency of sampling (months)

Long-term252C

or302C

12 months 0,3,6,9,12,18,24

Intermediate 302C 6 months 0,3,6,12

Accelerated 402C 6 months 0,1,2,3,6

[b] Drug product packaged in IMPERMEABLE containers (to moisture or solvent loss)

Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent.

Thus, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.

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teTypical storage condition and study duration

Study Storage condition Minimum time period

Frequency of sampling (months)

Long-term252C / 40% RH 5% RH

or302C / 35% RH 5% RH

12 months 0,3,6,9,12,18,24

Intermediate 302C / 65 % RH 5% RH 6 months 0,3,6,12

Accelerated 402C / NMT 25 % RH 6 months 0,1,2,3,6

[c] Drug products stored in SEMIPERMEABLE containers

• It is up to the applicant to decide the tem/RH for long term.• If 302C / 35% RH 5% RH is the long term, then NO INTERMEDIATE cond.

Aqueous-based products packaged in semipermeable containers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability.

5% loss of water (after 3 months) is considered significant change.

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teTypical storage condition and study duration

Study Storage condition Minimum time period

Frequency of sampling (months)

Long-term 5 3C 12 months 0,3,6,9,12,18,24

Accelerated 252C / 60 % RH 5% RH 6 months 0,1,2,3,6

[d] Drug products intended for storage in a REFRIGERATOR

[e] Drug products intended for storage in FREEZER

Study Storage condition Minimum time period

Frequency of sampling (months)

Long-term -20 5C 12 months 0,3,6,9,12,18,24

[f] Drug products intended for storage BELOW -20 C

Drug products intended for storage below -20°C should be treated on a case-by-case basis.

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THE SIGNIFICANT CHANGES

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THE SIGNIFICANT CHANGE IS DEFINED AS

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• The assay value is still within the limits but the change during stability is more than 5.0%

• Example– Release assay limit: 95.0 – 105.0%– Release assay: 101.0% (within spec)– 6-Month assay: 95.5% (within spec)– Loss in potency: 5.5%.– This is a significant change.

EXAMPLE OF FAILED STABILITY

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Stability Data and Report

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attaché Real Chromatograms attaché RecordsEx: Karl fisher data, tablet weight. .

Attaché auto dissolution readings Attaché Cabinet temp./RH chart data.

Batches testedProduct name.Name and potency of active ingredient.Validated Stability indicating assay methodBatch size.Batch number.Manufacturing site.Manufacturing date.Date stability study was started.Date sample(s) was withdrawn from chamber.

Date of sample analysis.Storage conditions (e.g., 40C / 75% RH).Container / closure system.Supplier and manufacturer of active ingredient(s).Supplier and manufacturer of container / closure system.Supplier and manufacturer of packaging components, cartons, etc.Cumulative tabulation of all tests result.

Literature review Records, reports, and certificates

Conclusion, QA approval and Decision

Stability Data and Report

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Additional or New Stability Data is Required if;

• Change in the route of synthesis of an API • Change in composition of the FPP• Change in immediate packaging of the FPP

• In case of failed stability, (chemical, instrumental, regulatory)

• using raw material from different manufacturer, • excepients type/ratio change • manufacturing procedure modified.• change of package, closure.

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العالمين رب لله الحمد و

Thank you