Stability Testing WHO2008

Dr. János Pogány | April 20081 |

Pharmaceutical Development with Focus on Paediatric Formulations


WHO/FIP Training Workshop Hyatt Regency Hotel

Sahar Airport Road

Andheri East, Mumbai, India

28 April 2008 – 2 May 2008


Pharmaceutical Development with Focus on Paediatric formulations


Presented by:

Name: Dr. János Pogány

Contact details:

[email protected]


Outline of presentationOutline of presentation

Regulatory issues on stability of APIs and FPPs

Introduction

• Scientific approach to pharmaceutical stability

• Introduction to the new WHO Stability guideline

Planning stability studies and reporting results

Evaluation of stability results

Risk-based inspection of stability studies

Main points again




WHO working document QAS/06.179/Rev.

DRAFT STABILITY TESTING OF ACTIVE PHARMACEUTICAL INGREDIENTS AND

PHARMACEUTICAL PRODUCTS

INTRODUCTIONINTRODUCTION


Scientific approach to stabilityScientific approach to stability

Temperature, oCVapor pressure (Pa) at different %RH

756560

25237520581900

30318227572545

40553147944425


Scientific approach to stabilityScientific approach to stability


WHO guidelinesWHO guidelines

„Stability of drug dosage forms” in 1990 initiated the global harmonization of regulatory stability requirements

„Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms” (1996)

WHO amendment of the above guideline in TRS 937 (2006)

Working document QAS/06.179/Rev.2 – „Stability Testing of Active Pharmaceutical Ingredients and Pharmaceutical Products” divides countries with tropical and subtropical moist climates into:

– Zone IVA with long-term conditions: 30oC ± 2oC and 65% ± 5% RH

– Zone IVB with long-term conditions: 30oC ± 2oC and 75% ± 5% RH, which is the worst case and the recommended long-term condition for the Prequalification Project

Each individual Member State within the former Zone IV would need to indicate whether its territory should be classified as Zone IVa or IVb


Selected definitionsSelected definitions

Re-test periodAfter this period a batch of API destined for use in the manufacture of a pharmaceutical product should be re-tested for compliance with the specification and then used immediately. A batch of active pharmaceutical ingredient can be re-tested multiple times and a different portion of the batch used after each re-test, as long as it continues to comply with the specification. A retest period should be proposed on the basis of stability results and may be extended to five years (e.g., Ethambutol 2HCl, or Isoniazid)

For most biotechnological/biological substances known to be labile, it is more appropriate to establish a shelf-life than a re-test period. The same may be true for certain antibiotics.



Shelf-life (also referred to as "expiration dating period“)The period of time during which a pharmaceutical product, if stored correctly, is expected to comply with the specification as determined by stability studies on a number of batches of the product. The shelf-life is used to establish the expiry date of each batch.







STABILITY PROTOCOLS AND REPORTS

STABILITY PROTOCOLS AND REPORTS


Protocol – regulatory requirementProtocol – regulatory requirement

The ongoing stability programme should be described in a written protocol and results formalized as a report. The protocol should extend to the end of the re-test period and should include parameters illustrated in slide 12

The stability protocol used for long-term studies for the stability commitment should be the same as that for the primary batches, unless otherwise scientifically justified.


Stability protocol - API Stability protocol - API

Protocol ParameterDescription

Storage conditions (including tolerances) and testing frequency

25°C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months30oC/75% RH 0, 3, 6, 9,12, (18, 24, 36) months40°C/75% RH 0,3,6 months

Batch number and sizeL40438 (Jan. 2005), 80.50 kgL50041 (Feb.2005), 69.00 kgL50054 (March 2005), 73.00 kg

Container closure system(s)Simulated: double PE bags in black PE bag kept in one-kg fiberboard drums well-closed

Tests and acceptance criteriaAssay by(98.0-102.0%), ImpA (NMT 0.15%), ImpB (NMT0.3%), and so on

Other(s)Stress testing, including photostability testing according to ICH Q1B

The batches should be representative of the manufacturing process and should be manufactured from different batches of key intermediates.


Stability protocol – oral suspensionStability protocol – oral suspension

Protocol ParameterDescription

Storage conditions (including tolerances) and testing frequency

25°C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months30oC/75% RH 0, 3, 6, 9,12, (18, 24, 36) months40°C/75% RH 0,3,6 months

Batch numbers and sizeNEV40438 (Jan. 2007), 4000 bottles (960 liters)NEV50439 (Jan.2007), 4000 bottles (960 liters)NEV50440 (Jan. 2007), 4000 bottles (960 liters)

Container closure system(s) proposed for marketing

White HDPE bottle with two piece child-resistant closure

Tests and acceptance criteriaAssay (95.0-105.0%), there are no degradants, dissolution testing (and profile), in-use stability test, preservative contents, antimicrobial preservative effectiveness, re-suspendibility (sedimentation rate)

The batches should be representative of the manufacturing process and should be manufactured from different batches of APIs. Executed manufacturing records and certificates of analysis on the above batches should be submitted


BracketingBracketing

Stability studies should be performed on each individual strength, dosage form and container size of the pharmaceutical product. If dosage form is the same, then bracketing can be applied to:

Different strengths (including FDC products)– have identical formulations (including FDC products)

– are made with closely related formulations

Container-closure system is the same and either the container size or the fill size varies

Even when the container-closure system varies bracketing is possible with some justification. Such justification might be the demonstration that the product is not water sensitive, or the discussion of the relative permeation rates of the closure systems.


Bracketing designBracketing design

Pack type

Label strength and batch numbers (X,Y,Z)

10 mg20mg30mg

XYZXYZXYZ

Alu/Alu blister cards of 10 tablets+++---+++

HDPE pack of 30 tablets+++---+++

HDPE pack of 100 tablets---------

HDPE pack of 1000 tablets+++---+++


MatrixingMatrixing

Matrixing is the statistical design of a stability schedule .

Each storage condition should be treated separately under its own matrixing design

At a given time point (other than the initial or final ones) not every batch on stability needs to be tested

Full testing must be performed at the maximum storage period at the time of submission


Matrixing designMatrixing design

One-half matrix design – long-term stability studiesTesting station036912182436

S1

Batch 1++--+-++

Batch 2+-+++-++

Batch 3+-+-++-+

S2

Batch 1+-++++-+

Batch 2++--++-+

Batch 3++-++-++


A risk-based global stability protocolA risk-based global stability protocol

Storage conditionsMonths

036912182436

25oC ± 2oC and 60% ± 5% RH

+

+++++++

30oC ± 2oC and 65% ± 5% RH-------

3030ooC ± 2C ± 2ooC and 75% ± 5% RHC and 75% ± 5% RH+++++++

40oC ± 2oC and 75% ± 5% RH++

50oC and ~70% RH+

Source: Designing a globally acceptable registration stability protocol, Pharmaceutical Technology Europe, March 2007







STRESS TESTINGSTRESS TESTING



Stress testing – API Studies undertaken to elucidate the intrinsic stability of the active pharmaceutical ingredient. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing.

Stress testing – FPPStudies undertaken to assess the effect of severe conditions on the pharmaceutical product. Such studies include photostability testing and specific testing on certain products, (e.g. metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products).


ICH guidelines on stress testingICH guidelines on stress testing

Standard Title and reference

ICH Q1A(R2)Stability Testing of New Drug Substances and Products (the parent guideline)

ICH Q1BPhotostability Testing of New Drug Substances and Products

ICH Q2BValidation of Analytical Procedures: Methodology

ICH Q3A(R)Impurities in New Drug Substances

ICH Q3B(R)Impurities in New Drug Products


Stress testingStress testing

To validate the stability indicating power of the analytical procedures.

To identify stability-affecting factors such as ambient temperature, humidity and light and to select packing materials, which protect the FPP against such effects.

To identify potential degradants of the API and assess if they can be formed during manufacture or storage of the FPP.

To select manufacturing process of the FPP


Stress testingStress testing

Temperature

A thin layer of the API is wetted with water and is kept at 80°C for 4 weeks in a Petri dish (open system) with sampling once a week

Assay: S1: D1:Total unspecified:

Total impurities:

Humidity

A thin layer of the API is wetted with water and kept at 40°C / 100% RH for 4 weeks in a Petri dish (open system) with sampling once a fortnight

Assay: S1: D1: Total unspecified: Total impurities:

Oxidation

Oxygen is bubbled slowly through the oxygen-saturated aqueous solution/suspension (under constant mixing) of the API for 24 hours with sampling every eight (8) hours

Assay: S1: D1: Total unspecified: Total impurities:


Increase in concentration of APIIncrease in concentration of API

During stability studies of Artesunate, the assay results were increasing. The hydrolysis yields artenimol and succinic acid. The formation of succinic acid justifies the increase in assay. The assay method is „stability indicating” but not specific.

+


Stress testing (forced degradation)Stress testing (forced degradation)

Degradation factorConditions

Thermal≥ 60 oC

Humidity≥ 75% RH

Acid0.1N HCl

Base0.1N NaOH

OxidativeOxygen gas, or 3% H2O2

PhotolyticMetal halide, Hg, Xe lamp, or UV-B fluorescent

Metal ions (optional)0.05M Fe2+ or Cu2+


Stress stability testingStress stability testing

An optimal degradation pattern generated during stress testing would show only those degradation products observed at the end of shelf life in regulatory stability studies and those that might appear if the API or FPP if not manufactured, handled or packed properly.

Chromatograms thus obtained will be representative and not too complicated to evaluate, which may be the case if drastic conditions are applied and many second- and third-generation degradation products are formed.


Stress stability testing - NevirapineStress stability testing - Nevirapine

Stress typeConditionsAssay (%)

Control25o C 99.8

36% HCl80o C, 40 min. 72.0

5N NaOH 80o C, 2h 20’ 98.6

30% w/w H2O280o C, 2h 20’ 98.6

Heat130o C, 49h 101.5

Light 500W/m2, 68h 101.7

Water 25o C, 92% RH, 91h 101.2







PRESENTATION AND EVALUATION OF RESULTS

PRESENTATION AND EVALUATION OF RESULTS


Types of stability dataTypes of stability data

Three types of data can be collected during stability studies– reported as a single result such as assay, loss on drying, etc.

– data with multiple results such as dissolution testing

– third type is degradation product

Most analytical laboratories will not quantify the result if it falls below the LOQ. The value usually is reported as “˂ LOQ.”

A special situation arises when a new peak forms during the analysis. When a new peak forms during a stability study, one may expect that it should not exist and hence it would constitute a type of OoT.

If some of the results are below the LOQ value, if the assumption of normality is not reasonable, or if linearity cannot be assumed, then an attempt to identify OoT results using data from the same batch is not recommended


Stability reportsStability reports

A systematic approach should be adopted in the presentation and evaluation of the stability information, which should include, as appropriate, results from the physical, chemical, biological and microbiological tests, including particular attributes of the dosage form

The results should be presented both as a table and as a graph and not as data sheets

The Applicant should evaluate the stability data


Evaluation – Best CaseEvaluation – Best Case

1. Tabulate and plot stability data on all attributes at all storage conditions and evaluate each attribute separately.

2. No significant change at accelerated conditions within six (6) months.

3. Long-term data show little or no variability and little or no change over time.


Evaluation – Best CaseEvaluation – Best Case

4. Accelerated data show little or no variability and little or no change over time.

5. Statistical analysis is normally unnecessary and providing a justification for the omission should be sufficient

6. Proposed retest period or shelf life = double of period covered by long-tem data (X) but NMT X + 12 months

7. A retest period or shelf life granted on the basis of extrapolation should always be verified by additional long-term stability data


Is there a visible variability?Is there a visible variability?

TimeNevirapine stability assay results in FDC tablets

(25±2°C/60±5%RH)(Batch 08040001)

(30±2°C/75±5%RH)(Batch 08040002)

(30±2°C/75±5%RH)(Batch 08040003)

Initial, %96.9098.6597.553M, %99.2599.90100.406M, %99.2099.0599.559M, %104.0098.1096.70

12M, %99.30101.30101.3018M, %97.6094.5594.2024M, %100.20101.4098.95

Mean, %99.4998.9998.38Minimum, %96.9094.5594.20Maximum, %104.00101.40101.30

Range, %7.106.857.10STD2.282.332.43RSD2.30%2.35%2.46%


Analytical, sampling, process (control), compliance alert?

Analytical, sampling, process (control), compliance alert?


Out-of-trend (OoT) resultsOut-of-trend (OoT) results

An OoT result is a stability result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study.

The identification of an OoT data point only notes that the observation is atypical:• within a batch

• across historical stability batches

When an “odd-looking” stability pattern occurs, it is common to ask whether the pattern reflects an underlying mechanism (i.e., a “cause”) or is merely a normal process or analytical variation.

Any out of trend/out of specification (OoT/OoS) observations “Do the data obtained so far indicate that the batch will go outside

specification during its shelf life?”


Out-of-trend (OoT) resultsOut-of-trend (OoT) results

Are all values above LOQ?

Are all values below LOQ?

Is a part of the data below LOQ?

What is the analytical and sampling variation and a measured characteristic's normal change over time?

Timeliness is especially important when an analytical error is suspected of causing OoT results


Significant change of FPPsSignificant change of FPPs

A 5% change in assay from its initial value.

Any degradation product exceeding its acceptance criterion.

Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., colour, phase separation, hardness).

As appropriate for the dosage form, e.g., failure to meet the acceptance criteria for dissolution for 12 dosage units.


Reporting resultsReporting results

Test Observations of Accelerated Studies Accelerated Studies

Description E.g., conforms to specifications (white to off- white crystalline powder)

Assay E.g., results rangeranged between 99.0-101.1 % (spec: 97.5-102.0%); no visible trends visible trends or variabilityvariability were observed

Related substances

ImpA: ≤ 0.15%ImpB: ≤ 0.1%Any other unspecified Imp : ≤ 0.1%Disregard any Imp ˂ 0.05%Total impurities: ≤ 0.4%Insert as many rows as necessary

Result sheets must bear date and responsible person’s signature / QA approval


SOP requirementsSOP requirements

A written stability-testing program to assess the stability characteristics of drug products

Review and investigation of OoT stability results

Written procedures for conducting a thorough investigation of any unexplained discrepancy

A review of the OoT alert procedures' performance might coincide with the annual product review

The depth of an investigation and the corrective measures taken may depend on the potential or implied risk to product quality


Evaluation – Change with TimeEvaluation – Change with Time

An approach for analysing data on a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided confidence limit for the mean curve intersects the (lower) acceptance criterion (95% assay).

The majority of degradation processes results in an essentially linear line in this range of the label claim thus the method is generally applicable for the estimation of the expiry date at the studied storage conditions.

The hypothetical figure in the next slide illustrates that the extrapolated shelf life is 29 months (25oC/60%RH) and there is only a 5% chance that this estimate will be high. Such a plot covers assay values from 105% down to 95%.


ICH-Q1E Evaluation for Stability DataICH-Q1E Evaluation for Stability Data


Carstensen, J.T. – Drug stabilityCarstensen, J.T. – Drug stability


Evaluation – Change with Time*Evaluation – Change with Time*

The hypothetical figure in the former slide illustrates that the shelf life is 24 months (at a given temperature). There is a 5% chance that this estimate will be high. Such a plot covers potency values from 100% down to 90%.

* DRUG STABILITY — Principles and Practices

Edited by Jens T. Carstensen and C. T. Rhodes

Third edition, revised and expanded (2000)

Marcel Dekker, Inc., 270 Madison Avenue, New York,


ICH-Q1E Evaluation for Stability DataICH-Q1E Evaluation for Stability Data


Evaluation – Change with TimeEvaluation – Change with Time

The hypothetical figures in the former slides illustrate that the shelf life is 31-32 months

(25oC/60%RH) and there is only a 5% chance that this estimate will be high. Such a plot covers degradant values from 0.6% up to 1.4%.

For FPPs in semipermeable containers, loss of vehicle can result in an increase in the API concentration. In such cases, the point where the upper 95% confidence bound intersects the 105% assay value will define the conformance period.


Stability resultsStability results

A storage statement should be proposed for the labeling (if applicable), which should be based on the stability evaluation of the API.

A retest period should be derived from the stability information, and the approved retest date should be displayed on the container label.

An API is considered as stable if it is within the defined/regulatory specifications when stored at 30±2oC and 65±5% RH for 2 years and at 40±2oC and 75±5%RH for 6 months.


Post-approval protocolPost-approval protocol

Protocol Parameter Description Storage conditions 30±2oC, 75±5% RH

Testing frequency / Batches Batches …. for 18,24,36 months One additional production scale batch: 0, 3, 6, 9, 12, 18,24,36 months

Container closure system(s)

Tests and acceptance criteria

Description white to off white crystalline powder

Assay 98.0-102.0%

Related Substances

Impurity 1 NMT 0.15%Any unspecified NMT 0.10% Total: NMT 0.3%


Additional or New Stability DataAdditional or New Stability Data

Modifications affecting one or more steps of the same route of

synthesis of an API

Change in the route of synthesis of an API

Change in composition of the FPP

Change in immediate packaging of the FPP


Main points againMain points again

Stability studies should be planned on the basis of pharmaceutical R+D and regulatory requirements.

Forced degradation studies reveal the intrinsic chemical properties of the API, while formal stability studies establish the retest date.

The shelf life (expiry date) of FPPs is derived from formal stability studies.

Variability and time trends of stability data must be evaluated by the manufacturer in order to propose a retest date or expiry date.


THANK YOU!THANK YOU!

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Stability Testing WHO2008