Presented by

P.KRANTHI KUMAR
Pharmaceutics M.Pharmacy-I Semester St.john college of pharmacy Yellapur -warangal

Introduction
Essential ICH definitions

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Planning of stability study

Guidelines on Stability Testing Stability testing of API Stability testing of FPP
Evaluation of stability results

References

STABILITY
Stability of a pharmaceutical product may be defined as the capability of a particular formulation in a specific container/closure system to remain within its Physical Chemical Microbiological Therapeutic

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Toxicological Specifications.

Type of stability studies conducted

Long term stability studies Intermediate stability studies Accelerated stability studies

ADVERSE EFFECTS OF INSTABILITY IN DRUG PRODUCTS

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Loss of potency of drug Change in concentration of active drug Alteration of bioavailability Loss of content uniformity Loss of pharmaceutical elegance and patient acceptability Formation of toxic degradation products

 The International Conference on Harmonization of Technical Requirements

for Registration of Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry

ICH's mission is to achieve greater harmonization to ensure that safe,

effective, and high quality medicines are developed and registered in the most resource-efficient manner.

ICH Products:
Quality guidelines Efficacy guidelines
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Safety guidelines

Multi disciplinary guidelines

uality guidelines
Stability Q1A - Q1F
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Analytical Validation Q2 Impurities Q3A - Q3D Pharmacopoeias Q4 - Q4B Quality of Biotechnological Products Q5A - Q5E Specifications Q6A- Q6B Good Manufacturing Practice Q7

Pharmaceutical Development Q8
Quality Risk Management Q9 Pharmaceutical Quality System Q10
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Development and Manufacture of Drug Substances Q11

The ICH Q1 topic on stability testing is covered by 5 separate

guidelines The ICH Q1 series of guidelines are designed for stability programs ICH Q1A(R2) ICH Q1B ICH Q1C
Stability Testing of New Drug Substances and Products (the parent guideline) Photostability Testing of New Drug Substances and Products Stability Testing of dosage forms Bracketing and matrixing Design for stability testing of new drug substance and products Evaluation of stability Data Stability data package for registration applications in climatic zones III and IV
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ICH Q1D
ICH Q1E ICHQ1F

Classification of climatic zones

Climatic Zone I Definition Temperate climate Storage conditions
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21C / 45% r.h.

II

Subtropical and Mediterranean climate

25C / 60% r.h.

III

Hot, dry climate

30C / 35% r.h 30C / 70% r.h.

IV

Hot, humid climate

Criteria used to classify a site according to climatic zone Mean annual temperature measured in the open air Calculated mean annual Temperature (< 19C) Mean annual Water vapour partial pressure

Countries which come under different climate zones

I II III IV
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Europe: EU, Belarus, Bulgaria, Estonia, Hungary, Latvia, Lithuania, Norway, Rumania, Russia, Switzerland, Ukraine America: USA, Argentina, Bolivia, Chile, Canada, Mexico, Peru, Uruguay Africa: Egypt, Algeria, Canary Islands, Libya, Morocco, Namibia, Rwanda, South Africa, Tunisia, Zambia, Zimbabwe Asia: Japan, Afghanistan, Armenia, Azerbaijan, China, Georgia, Iran, Israel, Kazakhstan, Kirghizia, Korea, Lebanon, Nepal, Syria, Tadzhikistan, Turkey, Turkmen, Uzbekistan, Australia, New Zealand.

America: Barbados,Brazil, Costarica, Dominican Republic, Equador, Salvador, Guatmela, Haiti, Handures, Jamaica, Columbia, Cuba, Dutch, Antiles, Panama, Paragua. Africa: Angola, Ethiopia, Benin, Cameron, Kenya, Liberia, Congo, Madagascar, Mahwi, Mali, Mayrtiania, Mozambique, Niger, Somalia, Sudan, Tanzania, Uganda, Zaire, Central African Republic. Asia: Behrain, Bangladesh, Hongkong, India, Indonesia, Iraq, Jordan, Kambechev, Quatar, Kuwait, Malaysia, Maldives, Myanmar, UAE, Oman, Yemen. Australian oceanic: Fisi, Society Island, Marshal Island, Piping New Guinea.
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SELECTED DEFINITIONS
Re-test date
The date after which samples of an API should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given FPP.
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Shelf life (expiration dating period, conformance period)

The time period during which an API or a FPP is expected to remain within the approved shelf-life specification, provided that it is stored under the conditions defined on the container label.
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Formal stability studies

Long term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the re-test period of an API or the shelf life of a FPP.
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Stress testing forced degradation (API)

Studies undertaken to elucidate the intrinsic stability of the API. 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 forced degradation (FPP)

Studies undertaken to assess the effect of severe conditions on the FPP. Such studies include photostability testing and compatibility testing on APIs with each other in FDCs and API(s) with excipients during formulation development.
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STABILITY PROTOCOL AND REPORT

Batches tested General information Container/closure system Literature and supporting data Stability-indicating analytical methods Testing plan Test parameters Test results Other requirements (post-approval commitments) Conclusions

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

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ILLUSTRATIVE DATA OF API STABILITY BATCHES

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Batch number
Date of manufacture Site of manufacture Batch size (kg) Primary packing materials Date of initial analysis
The batches should be representative of the manufacturing process and should be manufactured from different batches of key intermediates.

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ILLUSTRATIVE DATA OF CAPSULE/TABLET STABILITY

BATCHES
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Batch number Date of manufacture Site of manufacture Batch size (kg)

Batch size (number of units) Primary packing materials Date of initial analysis Batch number of the API
The batches should be representative of the manufacturing process and should be manufactured from different batches of APIs.
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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:

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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 15 discussion of the relative permeation rates of the closure systems.

EXAMPLE OF BRACKETING DESIGN

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MATRIXING
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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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EXAMPLE OF MATRIX DESIGN

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Guidelines are laid for both API(drug substance) and FPP( drug product)
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API
(Active pharmaceutical ingredient)

FPP

(Finished pharmaceutical product)

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STABILITY PROTOCOL - API

Protocol Parameter Storage conditions (including tolerances) and testing frequency
Batch number and size Container closure system(s) Tests and acceptance criteria Other(s)

Description
25C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months 30oC/75% RH 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

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STABILITY PROTOCOL FOR ORAL SUSPENSION(FPP)

Protocol Parameter Storage conditions (including tolerances) and testing frequency
Batch number and size

Description
25C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months 30oC/75% RH 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

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Container closure system(s)

Tests and acceptance criteria Other(s)

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Guidelines for drug substance (API) and drug product(FPP)

Drug Substance Stress testing Selection of batches Container Closure system Drug Product Photo stability testing Selection of batches Container Closure system
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Testing frequency
Storage conditions Stability commitment

Testing frequency
Storage conditions Stability commitment

Evaluation
Statements/Labeling

Evaluation
Statements/Labeling In use stability

Variations
Ongoing stability studies Ongoing stability studies
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GUIDELNES ON STRESS TESTING

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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 IN API

Stress testing of the API can help identify the likely degradation products, which, in turn, can help establish the degradation pathways tress testing may be carried out on a single batch of the API. It should include the effect of temperature, humidity.
Storage conditions pH 2, room temperature pH 7, room temperature pH 10-12, room temperature Testing period* 2 weeks 2 weeks 2 weeks
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H2O2, 0.1-2% at neutral pH, room temperature

2 weeks
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FORMAL STABILITY STUDIES

In general an API should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its 91 sensitivity to moisture. The storage conditions and the lengths of studies chosen should be sufcient to cover storage and shipment.
Minimum time period covered by data at submission 12 Months
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Type of study

Storage condition

Long term

25C 2C/60% RH 5% RH or 30C 2C/65% RH 5% RH 30C 2C/65% RH 5% RH

Intermediate

6 Months

Accelerated

40C 2C/75% RH 5% RH

6 Months

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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 re-test 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 302oC and 655% RH for 2 years and at 402oC and 755%RH for 6 months.

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POTENTIAL INSTABILITY ISSUES OF FPPS

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Loss/increase in concentration of API

Formation of (toxic) degradation products

Modification of any attribute of functional relevance Alteration of dissolution time/profile or bioavailability

Decline of microbiological status

Loss of package integrity Reduction of label quality

Loss of pharmaceutical elegance and patient acceptability

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STABILITY-INDICATING QUALITY 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 friability dissolution time assay hardness moisture content degradants microbial purity

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STRESS TESTING OF FPPS

Storage conditions Testing
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40C, 75 % RH; open storage** 50-60 C, ambient RH; open storage

3 months

3 months

Photostability

according to ICH

* 3 months or 5-15% degradation, whatever comes first ** For API1-API2, or API-excipient, or FPP without packing material, typically a thin layer of material is spread in a Petri dish. Open storage is recommended, if possible.

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SELECTION OF BATCHES

At the time of submission data from stability studies should be provided for batches of the same formulation and dosage form in the container closure system proposed for marketing. Stability data on three primary batches are to be provided. The composition, batch size, batch number and manufacturing date of each of the stability batches should be documented and the certificate of analysis at batch release should be attached. Where possible, batches of the FPP should be manufactured by using different batches of the API.
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TESTS AT ELEVATED TEMPERATURE AND/OR EXTREMES OF HUMIDITY (ICH-Q1F)

Special transportation and climatic conditions outside the storage conditions recommended in this guideline should be supported by additional data. For example, these data can be obtained from studies on one batch of drug product conducted for up to 3 months at 50C/ambient humidity to cover extremely hot and dry conditions and at 25C/80% RH to cover extremely high humidity conditions.
Stability testing at a high humidity condition, e.g., 25C/80% RH, is recommended for solid dosage forms in water-vapour permeable packaging, e.g., tablets in PVC/aluminum blisters, intended to be marketed in territories with extremely high humidity conditions in Zone IV. However, for solid dosage forms in primary containers designed to provide a barrier to water vapour, e.g. aluminum/aluminum blisters, stability testing at a storage condition of extremely high humidity is not considered necessary.

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EVALUATION

A systematic approach should be adopted in the presentation and evaluation of the stability information. Where the data show so little degradation and so little variability that it is apparent from looking at the data that the requested shelf life will be granted, it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be sufficient.

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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).
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EVALUATION BEST CASE

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1. 2. 3. 4. 5. 6.

No significant change at accelerated conditions within six (6) months. Long-term data show little or no variability and little or no change over time. Accelerated data show little or no variability and little or no change over time. Statistical analysis is normally unnecessary. Proposed retest period or shelf life = double of period covered by long-tem data 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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VARIATIONS
Once the FPP has been registered, additional stability studies are required
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whenever variations that may affect the stability of the API or FPP are made, such as major variations

The following are examples of such changes:

change in the manufacturing process; change in the composition of the FPP;

change of the immediate packaging;

change in the manufacturing process of an API.

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ONGOING STABILITY STUDIES

The purpose of the ongoing stability programme is to monitor the API and to determine that the API /FPP remains, and can be expected to remain, within specications under the storage conditions indicated on the label, within the re-test period in all future batches. This mainly applies to the FPP in the container closure system in which it is supplied, but consideration should also be given to inclusion in the programme of bulk products. The number of batches and frequency of testing should provide suf cient data to allow for trend analysis. Unless otherwise justi ed, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability programme (unless none is produced during that year).
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CONCLUSION
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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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REFERENCES
ICH official web site. www.ich .org World Health Organization
WHO Technical Report Series, No. 953, 2009 Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C. T. Rhodes Statistical Evaluation of Stability Data: Criteria for Change-over-time and Data Variability (PDA Journal of Pharmaceutical Science and Technology, Vol. 57. No.5, Sept./Oct. 2003, pp. 369-377)
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Thank you
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