STABILITY STUDIES

K.KRANTHI KUMAR M.Pharm.,M.B.A.,(Ph.D)Asst.Prof

Department of PharmaceuticsSKU college of Pharmaceutical Sciences

S.K. UniversityAnantapur

Andhra Pradesh

To gather information during Preformulation stage to produce a stable product. To determine maximum expiration date. To get an idea of storage condition. To determine the packaging components. To establish retest period of pharmaceuticals. To establish Transport conditions.

The main concept of stability testing of pharmaceuticals is to find out the product shelf life.

The Purpose of stability testing is to provide evidence how quality varies with time under influence of - temperature - humidity – light.

This stability studies are 2 types

1.Stability studies

2.Accelerated stability studies

There are different stages in stability studies

STAGE 1-Early stage stress-and accelerated testing with drug substances

STAGE 2-Stability on pre-formulation batches

STAGE 3-Stress testing on scale-up batches

STAGE4-Accelerated and long term testing for registration purposes.

STAGE5-On-going Stability Testing

STAGE 6-Follow-up Stabilities.

Q1A(R2)-Stability Testing of New Drug Substances and Products.

Q1B- Stability Testing : Photo stability Testing of New Drug Substances and Products.

Q1C- Stability Testing for New Dosage Forms.

Q1D- Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products.

Q1E- Evaluation of Stability Data.

Q1F- Stability Data Package for Registration Applications in Climatic Zones III and IV.

Q5 C-Stability testing of biotechnological /biological products

Degradation pathways

Physical degradation

1.Loss of volatile constituents

2.Loss of water

3.Absorption of water

4.Crystal growth

5.Polymorphisam

6.Colour changes

Loss of volatile constituents:-medicinal agents like iodine camphor menthol have tendency to evaporate from the product during storage. Similarly nitroglycerine tablets may loose its potency owing to volatilization of the medicament.

Loss of water:-loss of water from the product leads to decrease the weight, increase concentration of drug &increases potency.efferescent substances borax, caffeine losses water. Emulsions &semisolids exhibits cracking.

Absorption of water:- Absorption of water from atmosphere increases weight of the product,dilites the dose decreases potency.

Crystal growth:-fluctuation sin the ambient temperature causes crystal growth. When the solutions storage conditions are changes it becomes super saturation and crystal growth occurs.

Polymorphism:-it exhibits significance change in physicochemical properties like solubility,dissolution,melting point.

Colour change:-it indicates photochemical decomposition of the active ingredients

.

Chemical decomposition

1.1.hydrolisis

2.Oxidation

3.Environmental control measurements

4.Miscellaneous reactions

a.Isomerisation

b.epimerisation

c.Absorption of Co2

Statistical Considerations and EvaluationA stability protocol should describe not only how the stability study is to be designed and carried out, but also the statistical method to be used in analyzing the data. An acceptable statistical approach to the analysis of stability data and the specific features of the stability study that are pertinent to the analysis. Generally, an expiration dating or retest period should be determined based on statistical analysis of observed long-term data.

Expiration Dating Period for an Individual Batch

The time during which a batch may be expected to remain within specifications depends not only on the rate of physical, chemical or microbiological changes, but also on the initial average value for the batch.

The expiration dating period for an individual batch is based on the observed pattern of change in the quantitative attributes (e.g. content uniformity,assay,degradation products) under study and the precision by which it is estimated.

Bracketing:-

It is design of a stability schedule such that only samples on the extremes of certain design factors(strength ,container size,/fill) are tested at all time points as in a full design. the designs assumes that the stability of any intermediate levels is represented by the stability of extremes tested. The use of reduced stability testing, such as a bracketing design, may be a suitable alternative to a full testing program where the drug is available in multiple sizes or strengths.

Bracketing design is applicable to most types of drug products, including immediate- and modified-release oral solids, liquids, semi-solids, injectables. Certain types of drug products, such as metered-dosed inhalers (MDIs), dry powder inhalers (DPIs) and transdermal delivery systems (TDSs).Where a range of container/fill sizes for a drug product of the same strength is to be evaluated, bracketing design may be applicable if the material and composition of the container and the type of closure are the same throughout the range.

An example of bracketing design where both strengths and container/fill sizes are bracketed in one protocol and “X” denotes the combination of strength and container/fill size to be placed on stability study. In this hypothetical situation, the capsule dosage form is available in three different strengths made from a common granulation and packaged in three different sizes of HDPE bottles with different fills: 30 counts, C1; 100 counts, C2; and 200 counts, C3. 300 counts.The surface area/volume ratio, dead space/volume ratio, container wall thickness, and closure performance characteristics are assumed to be proportional among the three container/fill sizes for each strength of the capsules.

Batch 1 2 3

Strength 100mg 200mg 300mg 100mg 200mg 300mg 100mg 200mg 300mg

Containe/closer

C1

C2

C3

C1

C2

C3

C1

C2

C3

C1

C2

C3

C1

C2

C3

C1

C2

C3

C1

C2

C3

C1

C2

C3

C1

C2

C3

Sample stability

X X X X X X X X X X X X

Matrixing:- Matrixing is a statistical design for stability testing that requires experimental stability data to be obtained from all forms of the drug product but permits only a fraction of the total number of samples to be tested at any specified sampling point according to a specific sampling design The use of reduced stability testing, such as a Matrixing design, may be a suitable alternative to a full testing program where multiple factors involved in the

product are being evaluated..

Batch 1 2 3

Strength 100mg 200mg 300mg 100mg 200mg 300mg 100mg 200mg 300mg

Containe/closer

C1

C2

C3

C1

C2

C3

C1

C2

C3

C1

C2

C3

C1

C2

C3

C1

C2

C3

C1

C2

C3

C1

C2

C3

C1

C2

C3

Schdules

T1

T2

T3

T2

T3

T1

T3

T1

T2

T2

T3

T1

T3

T1

T2

T1

T2

T3

T3

T1

T2

T1

T2

T3

T2

T3

T1

TIME POIN

TS(min)

0 X X X X X X X X X X X X X X X X X X X

3 X X X X X X X X

6 X X X X X X X X X

9 X X X X X X X X X X X X X X X X X X

12

X X X X X X X X X X x x X X X X X X X

18

X X X X X X X X X X X X X X X X X X X X X X X X X X X

24

X X X X X X X X X X X X X X X X X X X X X X X X X X X

Matrixing design is applicable to most types of drug products, including immediate- and modified release oral solids, liquids, semisolids, injectables.

Matrixing designs can be applied to strengths with identical or closely related formulations.

1.Capsules with different strengths made different fill plug sizes.

2.Tablets with different strengths manufactured by compression varying amount of same granulation.

3.Oral solutions with different minor changes in excipients.

TIME POINTS(MONTHS) 0 3 6 9 12 18 24 36

STRENGTH

S1 BATCH-1 T T T T T T

BATCH-2 T T T T T T

BATCH-3 T T T T T

S2 BATCH-1 T T T T T

BATCH-2 T T T T T T

BATCH-3 T T T T T

“ONE-HALF REDUCTION”

TIME POINTS(MONTHS) 0 3 6 9 12 18 24 36

STRENGTH

S1 BATCH-1 T T T T T T

BATCH-2 T T T T T T T

BATCH-3 T T T T T T T

S2 BATCH-1 T T T T T T T

BATCH-2 T T T T T T

BATCH-3 T T T T T T

“ONE-THIRD REDUCTION”

Examples of Matrixing designs on time point for a product in two strengths(S1,S2).the term one-half reduction, one third reduction refer to the reduction strategy initially applied to fully study design.

Ex:-on half reduction initially eliminates one in every two points from the fully study design and a one third reduction initially removes in in every three. In the examples show in reduction are less than one-half & one-third due to the inclusion of full testing of all factors combination at some time points. These ex include full testing at the initial final and 12months time point. the ultimate reduction is therefore less than one-half(24/48) or one third (16/48)and is actually15/48 or 10/48.

Application:-Knowledge of data variability.Expected stability of the product.Availability of supporting data.Stability differences in the product within a factor or among factors.Number of factor combinations in the study.

ICH Guidelines• Quality Guidelines “Q” (chemical and pharmaceutical QA) • Safety Guidelines “S” (in vitro and in vivo pre-clinical studies) – covering Carcinogenicity Testing, Genotoxicity Testing, Toxicokinetics and Pharmacokinetics ….. etc.

• Efficacy Guidelines “E” (clinical studies in human subject) – Covering clinical safety, Dose Response Studies, Good Clinical Practices, Clinical evaluation …. etc.

• Multidisciplinary Guidelines “M” – Covering Medical Terminology, Electronic Standards for Transmission of Regulatory Information …… etc. – Important for Stability ! » Guideline M4: The Common Technical Document (CTD)

Stability Testing Q1

Stability Testing in Climatic Zone I and II (Q1A)

Photo stability Testing (Q1B)

Stability Testing for New Dosage Forms (Q1C)

Bracketing and Matrixing Designs (Q1D)

Evaluation of Stability Data (Q1E)

Stability Testing in Climatic Zones III and IV (Q1F)

Validation of Analytical Procedures (Q2)

Impurities (Q3)

Impurities in New Drug Substances (Q3A)

Impurities in New Drug Products (Q3B)

Pharmacopoeial Harmonization (Q4)

Biotechnological Products (Q5)

Specifications (Q6)

ICH – Q – Guidelines

DEFINITIONS

Shelf life (expiration dating period, conformance period)

Self life is the time period during which a drug product is expected to remain within the approved specification for use, provided that it is stored under the conditions defined on the container label.

Re-test period

The period of time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions.

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.

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 (see ICH Q1B) and compatibility testing on APIs with each other in FDCs and API(s) with excipients during formulation development.

Primary batch (called also exhibit batch)

A batch of an API or FPP used in a formal stability study, from which stability data are submitted in a registration application for the purpose of establishing a re-test period or shelf life, respectively. A primary batch of an API should be at least a pilot scale batch. For a FPP, two of the three batches should be at least pilot scale batch, and the third batch a production batch.

Commitment batches

Production batches of a drug substance or drug product for which the stability studies are initiated or completed post approval through a commitment made in the registration application.

Pilot (scale) batch

A batch of an API or FPP manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. (For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger.)

Production (scale) batch

A batch of an API or FPP manufactured at production scale by using production equipment in a production facility as specified in the application.

Specification - Release

The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug product at the time of its release.

Specification - Shelf life

The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of an API throughout its re-test period, or that anFPP should meet throughout its shelf life.

Mass balance

The process of adding together the assay value and levels of degradation products to see how closely these add up to 100% of the initial value, with due consideration of the margin of analytical error.

WORLDWIDE ZONES / TEMPERATURE AND HUMIDITY CONDITIONS

Zone Mean kinetic temperature

Yearly average humidity (%RH)

Zone I ( Moderate) 21 �C 45

Zone II (Mediterranean) 25 �C 60

Zone III (Hot, dry) 30 �C 35

Zone IV (Very hot, moist)

30� C 70

COUNTRIES AND ZONES

Regions Zone I &II Zone III&IV

EUROPE All countries

AMERICA Argentina, Bolivia, Canada, Mexico, US

Brazil, Columbia, Cuba, Jamaica

ASIA Afghanistan, China, Iran, Nepal, Turkey, Japan

Bahrain , Hong Kong, India, Oman , Pakistan,

Srilanka, UAE

AFRICA Egypt, Algeria, South Africa, Libya

Angola, Benin, Congo, Uganda, Sudan, Somalia,

Senegal

Study

Storage condition

Minimum time period covered by data at submission

Long term 25°C ± 2°C / 60% ± 5% r.h or30°C ± 2°C / 65% ± 5% r.h.

12 months

Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months

Accelerated 40°C ± 2°C / 75% ± 5% r.h. 6 months

STORAGE IN A REFRIGERATOR

Study Storage condition Minimum time period covered by data at submission

Long term 5°C ± 3°C 12 months

Accelerated 25°C ± 2°C / 60% ± 5% r.h. 6 months

STORAGE CONDITIONS FOR STABILITY STUDY

API/DRUG SUBSTANCES TO BE STOTRED AT AMBIENT TEMPERATURES

Study Storage condition Minimum time period covered by data at

submission

Long term -20°C ± 5°C 12 months

STORAGE IN FREEZER

DRUG PRODUCTS - PACKAGED IN SEMI-PERMEABLE CONTAINERS

Study Storage condition Minimum time period covered by data at submission

Long term 25°C ± 2°C / 40% ± 5% r.h. or

30°C ± 2°C / 35% ± 5% r.h.

12 months

Intermediate 30°C ± 2°C / 65% ± 5% r.h. 6 months

Accelerated 30°C ± 2°C / 65% ± 5% r.h. 6 months

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.

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).

Visible variability and trendThe simple linear regression analysis yields the equation:

Y = slope X + interceptwhere Y is the assay, X is the time factor expressed in months, the slope is the degradation rate and the intercept is the assay at time = 0. Regression analysis provides two additional factors: the p-value of the slope and the standard deviation about the regression line SX/Y

Evaluation – Change with Time

The hypothetical figure in the former 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 100% down to 95%.

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 Stability Chambers are designed for an operating range of 4°C to 70°C Temperature only, 5°C to 60°C Temperature with Humidity. These units employ a programmable controller to control the temperature, defrost and humidity settings. The cabinets use an evaporator coil, located on top of the cabinet as the heat-removing source. Through the refrigeration process, heat is captured in the evaporator, transferred to the condensing unit on top of the cabinet, and expelled to the surrounding outside air. It is extremely important to allow a four-inch clearance on the top, rear, and sides of the unit for the refrigeration process to function properly.

Decision Tree for Data Evaluation for Retest Period or Shelf Life Estimation for Drug Substances or Products