Stabil Testing

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
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Dr. Jnos Pogny | April 2008
Pharmaceutical Development with Focus on Paediatric formulations

Presented by: Name: Dr. Jnos Pogny Contact details:
pogany.janos@chello.hu
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Outline 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
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Pharmaceutical Development with Focus on Paediatric formulations

WHO working document QAS/06.179/Rev. DRAFT STABILITY TESTING OF ACTIVE PHARMACEUTICAL INGREDIENTS AND PHARMACEUTICAL PRODUCTS
INTRODUCTION
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Scientific approach to stability
Vapor pressure (Pa) at different %RH Temperature, 25 30 40

oC
75 2375 3182 5531
65 2058 2757 4794
60 1900 2545 4425
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Scientific approach to stability
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WHO 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
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Selected definitions
Re-test period
After 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.
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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.
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STABILITY PROTOCOLS AND REPORTS

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Protocol 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.
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Stability protocol - API

Protocol Parameter 25C/60% RH Storage conditions (including tolerances) and testing frequency 30oC/75% RH Batch number and size Container closure system(s) Tests and acceptance criteria Other(s) Description
0, 3, 6, 9, 12, (18, 24, 36) months 0, 3, 6, 9,12, (18, 24, 36) months 40C/75% RH 0,3,6 months L40438 (Jan. 2005), 80.50 kg L50041 (Feb.2005), 69.00 kg L50054 (March 2005), 73.00 kg Simulated: double PE bags in black PE bag kept in one-kg fiberboard drums well-closed Assay by(98.0-102.0%), ImpA (NMT 0.15%), ImpB (NMT0.3%), and so on 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.
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Stability protocol oral suspension

Protocol Parameter Description Storage conditions (including 25C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months tolerances) and testing frequency 30oC/75% RH 0, 3, 6, 9,12, (18, 24, 36) months 40C/75% RH 0,3,6 months Batch numbers and size NEV40438 (Jan. 2007), 4000 bottles (960 liters) NEV50439 (Jan.2007), 4000 bottles (960 liters) NEV50440 (Jan. 2007), 4000 bottles (960 liters) White HDPE bottle with two piece child-resistant Container closure system(s) proposed for marketing closure Tests and acceptance criteria Assay (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
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Bracketing
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.
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Bracketing design
Label strength and batch numbers (X,Y,Z) Pack type X Alu/Alu blister cards of 10 tablets HDPE pack of 30 tablets HDPE pack of 100 tablets HDPE pack of 1000 tablets + + + 10 mg Y + + + Z + + + X 20mg Y Z X + + + 30mg Y + + + Z + + +
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Matrixing
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
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Matrixing design
One-half matrix design long-term stability studies
Testing station Batch 1 S1 Batch 2 Batch 3 Batch 1 S2 Batch 2 Batch 3 0 + + + + + + 3 + + + 6 + + + 9 + + + 12 + + + + + + 18 + + + 24 + + + 36 + + + + + +
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A risk-based global stability protocol

Months Storage conditions 25oC 30oC 30oC 40oC 2oC and 60% 2oC and 65% 2oC and 75% 2oC and 75% 5% RH 5% RH 5% RH 5% RH + 0 3 + + + + 6 + + + 9 + + 12 + + 18 24 36 + + + + + +
50oC and ~70% RH
Source: Designing a globally acceptable registration stability protocol, Pharmaceutical Technology Europe, March 2007
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STRESS TESTING
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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 FPP Studies 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).
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ICH guidelines on stress testing

Standard
ICH Q1A(R2) ICH Q1B ICH Q2B ICH Q3A(R) ICH Q3B(R)
Title and reference

Stability Testing of New Drug Substances and Products (the parent guideline) Photostability Testing of New Drug Substances and Products Validation of Analytical Procedures: Methodology Impurities in New Drug Substances Impurities in New Drug Products
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Stress 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
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Stress testing
Temperature Assay: A thin layer of the API is wetted with water S1: and is kept at 80C for 4 weeks in a Petri D1: dish (open system) with sampling once a Total unspecified: week Total impurities: Assay: A thin layer of the API is wetted with water S1: and kept at 40C / 100% RH for 4 weeks in D1: a Petri dish (open system) with sampling Total unspecified: once a fortnight Total impurities: Assay: Oxygen is bubbled slowly through the S1: oxygen-saturated aqueous solution/suspension (under constant mixing) D1: of the API for 24 hours with sampling every Total unspecified: eight (8) hours Total impurities:
Humidity
Oxidation
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Increase 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.
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Stress testing (forced degradation)

Degradation factor Thermal Humidity Acid Base Oxidative Photolytic Metal ions (optional) 60 oC 75% RH 0.1N HCl 0.1N NaOH Oxygen gas, or 3% H2O2 Metal halide, Hg, Xe lamp, or UV-B fluorescent 0.05M Fe2+ or Cu2+ Conditions
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Stress 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.
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Stress stability testing - Nevirapine

Stress type Control 36% HCl 5N NaOH 30% w/w H2O2 Heat Light Water
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Conditions 25o C 80o C, 40 min. 80o C, 2h 20 80o C, 2h 20 130o C, 49h 500W/m2, 68h 25o C, 92% RH, 91h
Assay (%) 99.8 72.0 98.6 98.6 101.5 101.7 101.2

PRESENTATION AND EVALUATION OF RESULTS

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Types 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
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Stability 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
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Evaluation 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.
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Evaluation 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 longterm stability data
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Is there a visible variability?

Time Initial, % 3M, % 6M, % 9M, % 12M, % 18M, % 24M, % Mean, % Minimum, % Maximum, % Range, % STD RSD
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Nevirapine stability assay results in FDC tablets (25 2C/60 5%RH) (30 2C/75 5%RH) (30 2C/75 5%RH) (Batch 08040001) (Batch 08040002) (Batch 08040003) 96.90 98.65 97.55 99.25 99.90 100.40 99.20 99.05 99.55 104.00 98.10 96.70 99.30 101.30 101.30 97.60 94.55 94.20 100.20 101.40 98.95 99.49 98.99 98.38 96.90 94.55 94.20 104.00 101.40 101.30 7.10 6.85 7.10 2.28 2.33 2.43 2.30% 2.35% 2.46%
Analytical, sampling, process (control), compliance alert?
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Out-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?
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Out-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
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Significant 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.
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Reporting results
Test Description Assay Observations of Accelerated Studies E.g., conforms to specifications (white to off- white crystalline powder) E.g., results range between 99.0-101.1 % (spec: 97.5ranged 102.0%); no visible trends or variability were observed
ImpA: 0.15% ImpB: 0.1% Related substances 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 persons signature / QA approval
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SOP 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
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Evaluation 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%.
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ICH-Q1E Evaluation for Stability Data
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Carstensen, J.T. Drug stability
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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,
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ICH-Q1E Evaluation for Stability Data
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Evaluation 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.
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Stability 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.
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Post-approval protocol
Protocol Parameter Storage conditions Description 302oC, 755% RH Batches . for 18,24,36 months Testing frequency / Batches One additional production scale batch: 0, 3, 6, 9, 12, 18,24,36 months Container closure system(s) Description Assay Tests and acceptance criteria Related Substances white to off white crystalline powder 98.0-102.0% Impurity 1 NMT 0.15% Any unspecified NMT 0.10% Total: NMT 0.3%
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Additional 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
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Main 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.
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THANK YOU!
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Pharmaceutical Development with Focus on Paediatric Formulations

WHO/FIP Training Workshop

Dr. Jnos Pogny | April 2008

Pharmaceutical Development with Focus on Paediatric formulations

Dr. Jnos Pogny | April 2008

Dr. Jnos Pogny | April 2008

Pharmaceutical Development with Focus on Paediatric formulations

Dr. Jnos Pogny | April 2008

Scientific approach to stability

Vapor pressure (Pa) at different %RH Temperature, 25 30 40

75 2375 3182 5531

65 2058 2757 4794

60 1900 2545 4425

Dr. Jnos Pogny | April 2008

Scientific approach to stability

Dr. Jnos Pogny | April 2008

Dr. Jnos Pogny | April 2008

Dr. Jnos Pogny | April 2008

Pharmaceutical Development with Focus on Paediatric Formulations

STABILITY PROTOCOLS AND REPORTS

Protocol regulatory requirement

Dr. Jnos Pogny | April 2008

Stability protocol - API

Dr. Jnos Pogny | April 2008

Stability protocol oral suspension

Dr. Jnos Pogny | April 2008

Dr. Jnos Pogny | April 2008

Dr. Jnos Pogny | April 2008

A risk-based global stability protocol

50oC and ~70% RH

Dr. Jnos Pogny | April 2008

Pharmaceutical Development with Focus on Paediatric Formulations

Dr. Jnos Pogny | April 2008

ICH guidelines on stress testing

Title and reference

Dr. Jnos Pogny | April 2008

Dr. Jnos Pogny | April 2008

Dr. Jnos Pogny | April 2008

Increase in concentration of API

Dr. Jnos Pogny | April 2008

Stress testing (forced degradation)

Dr. Jnos Pogny | April 2008

Stress stability testing

Dr. Jnos Pogny | April 2008

Stress stability testing - Nevirapine

Assay (%) 99.8 72.0 98.6 98.6 101.5 101.7 101.2

Dr. Jnos Pogny | April 2008

Pharmaceutical Development with Focus on Paediatric Formulations

PRESENTATION AND EVALUATION OF RESULTS

Types of stability data

Dr. Jnos Pogny | April 2008

Evaluation Best Case

Dr. Jnos Pogny | April 2008

Evaluation Best Case

Dr. Jnos Pogny | April 2008

Is there a visible variability?

Dr. Jnos Pogny | April 2008

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

Dr. Jnos Pogny | April 2008

Out-of-trend (OoT) results

Out-of-trend (OoT) results

Dr. Jnos Pogny | April 2008

Significant change of FPPs

Dr. Jnos Pogny | April 2008