stability study by chirag

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it contains ICH guideline, solid state & liquid state stability & shelf life determination.

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Stability study :

Stability study Presented by: Mr. Chirag patel Guided by: Mr. Avinash K. Gupta MAHARISHI ARVIND INSTITUTE OF PHARMACY MANSAROVAR, JAIPUR

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What is Stability? capability of a sample material to retain the initial property of a measured constituent for a period of time within specified limits when the sample is stored under defined conditions. OBJECTIVES: To provide evidence on how the quality of an active substance or pharmaceutical product varies with time under the influence of a variety of environmental factors & product related factors. To establish shelf life & re-test period for the drug substance . To determine recommended storage conditions. To determine container-closure system suitability. Why stability study? 1. Patient safety 2. Drug activity

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3. To prevent bad image for manufacturer 4. Patient economy Basic Concepts For Stability Testing : There are two parts : 1) For Active Substances. 2) For pharmaceutical Products . For Active Substance : Stress Testing Selection of Batches Container -Closure System Specification Testing Frequency Storage Conditions Evaluation Statements/ Labeling

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2) For Pharmaceutical Product : Selection of Batches Container Closure System Specification Testing Frequency Storage Conditions Evaluation Statements/ Labeling In-use stability Variations On-going Stability Studies

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For Active Substance : Not described in an official pharmacopoeial monograph: stability studies are required. Described in an official pharmacopoeial monograph: which covers the degradation products and for which suitable limits have been set but a re-test period is not defined, two options are acceptable: a) The manufacturer of the pharmaceutical product confirms that the active substance complies with the pharmacopoeial monograph prior to the manufacture of the pharmaceutical product. In this case no stability studies on the active substance are required. b) The manufacturer establishes a re-test period based on the results of long term stability studies conducted on the active substance.

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1.1) stress testing: Helps to identify the likely degradation products, which can in turn helps to establish the degradation pathways and the stability of the molecule. For an active substance the following approaches may be used: a) Described in an official pharmacopoeial monograph: No data required. b) Not d escribed : two options, 1. Use the data published in literature to support degradation pathway. 2. No data are available in scientific literature, including official monograph , stress testing should be performed. “ It should include the effect of temperature , humidity , photolysis .”

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1.2) Selection of Batches: At least three primary batches Minimum of pilot scale level. 1.3) Container closer system: Same as or simulates the packaging proposed for storage and distribution. 1.4) Specification: Include testing of those attributes of the active substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. 1.5) Testing Frequency: For active substances with a proposed re-test period of at least 12 months , the frequency of testing at the long term storage condition should normally be every three months over the first year, every six months over the second year, and annually thereafter through the proposed re-test period.

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1.6) Storage Conditions: Test active substance thermal stability and if applicable, its sensitivity to moisture. The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use with due regard to the climatic zone(s) in which the active substance is intended to be stored. 1.6.1) General case : Long term 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65%RH ± 5% RH 12 months Intermediate 30°C± 2°C/65% RH ± 5% RH 6 months Accelerated 40°C± 2°C/75% RH ± 5% RH 6 months

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1.6.2) Active substances intended for storage in a refrigerator: Long term 5°C ± 3°C 12 months Accelerated 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 6 months 1.6.3) Active substances intended for storage in a freezer: Long term - 20°C ± 5°C 12 months

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1.7) Evaluation: The purpose of the stability study is to establish, based on testing a minimum of two or three batches of the active substance and evaluating the stability information & a re-test period applicable to all future batches of the active substance manufactured under similar circumstances. 1.8) Statements / Labeling: A storage statement should be established for the labeling , based on the stability evaluation of the active substance. Where applicable, specific instructions should be provided, particularly for active substances that cannot tolerate freezing. Terms such as “ambient conditions” or “room temperature” must be avoided.

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2) Pharmaceutical product : The design of the formal stability studies for the pharmaceutical product should be based on knowledge of the behavior and properties of the active substance, and from stability studies on the active substance and on experience gained from pre-formulation studies and investigational pharmaceutical products. 2.1) Selection of Batches: 2.2) Container Closure System: 2.3) Specification: The testing should covers the physical, chemical, biological, and microbiological attributes and preservative content . Analytical procedures should be fully validated .

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2.4) Testing Frequency: 2.5) Storage Conditions: Photostability testing should be conducted on at least one primary batch of the pharmaceutical product if appropriate. In Japan : Xenon lamp (simulate sunlight ) In European countries :white fluorescent lamp (room light ) 2.5.1) General case: 2.5.2) Pharmaceutical products packaged in impermeable containers: Sensitivity to moisture or potential for solvent loss is not a concern for pharmaceutical products packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent loss. Thus, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition .

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2.6.3) Pharmaceutical products packaged in semi-permeable containers: Aqueous-based products should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability. This evaluation can be carried out under conditions of low relative humidity. Long term 25°C ± 2°C/40% RH ± 5% RH or 30°C ± 2°C/35% RH ± 5% RH 12 months Intermediate 30°C ± 2°C/35% RH ± 5% RH 6 months Accelerated 40°C ± 2°C/not more than 25% RH 6 months

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2.5.4) Pharmaceutical products intended for storage in a refrigerator: Long term 5°C ± 3°C 12 months Accelerated 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 6 months 2.5.5 ) Pharmaceutical products intended for storage in a freezer: Long term - 20°C ± 5°C 12 months

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2.7) Evaluation: If analysis shows that the batch-to-batch variability is small, it is advantageous to combine the data into one overall estimate. This can be done by first applying appropriate statistical tests. If it is inappropriate to combine data from several batches, the overall shelf life should be based on the minimum time a batch can be expected to remain within acceptance criteria . 2.8) In-use stability: The purpose of in-use stability testing is to establish – where applicable – the period of time during which a multi-dose product can retaining acceptable quality once the container is opened and the first dose is removed. A minimum of two batches, at least pilot scale batches, should be subjected to the test.

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2.9 ) Variations: Once the pharmaceutical product has been registered, additional stability studies are required whenever major variations are made like the following: 1. Change in the manufacturing process. 2. Change in the composition of the pharmaceutical product. 3. Change of the packaging. 2.10 ) On-going Stability Studies: After approval , the stability of the pharmaceutical product should be monitored according to a continuous appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of impurities or dissolution profile) associated with the formulation in its marketed container closure system. The purpose of the on-going stability programme is to monitor the product over its shelf life and to determine that the product remains, and can be expected to remain, within specifications under the labeled storage conditions.

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TESTING PARAMETERS 1. Tablets Dissolution (or disintegration, if justified), water content and hardness / friability. 2. Capsules Hard gelatin capsules: brittleness, dissolution (or disintegration, if justified), water content, and level of microbial contamination. Soft gelatin capsules: Dissolution (or disintegration, if justified), level of microbial contamination , pH and leakage 3. Emulsions Phase separation, pH, viscosity, level of microbial contamination, and mean size and distribution of dispersed globules. 4. Suppositories Softening range, dissolution (at 37°C).

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5.Oral Solutions and Suspensions Formation of precipitate, clarity for solutions, pH, viscosity, level of microbial contamination. Also, polymorphic conversion may be examined, if applicable. Additionally for suspensions, redispersibility, rheological properties and mean size and distribution of particles should be considered. 6. Powders for oral solution or suspension Water content, and reconstitution time. Reconstituted products (solutions and suspensions) should be evaluated as described in “Oral Solutions and Suspensions” above, after preparation according to the recommended labeling, through the maximum intended use period. 7. Metered-dose Inhalers and Nasal Aerosols Dose content uniformity, particle size distribution, microscopic evaluation, water content, leak rate, level of microbial contamination, valve delivery and extractable / leachables from plastic and elastomeric components.

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8. Nasal Sprays: Solutions and Suspensions Cla rity (for solution), level of microbial contamination, pH, particulate matter, droplet and / or particle size distribution, weight loss, pump delivery, microscopic evaluation (for suspensions), foreign particulate matter and extractable / bleachable from plastic and elastomeric components of the container, closure and pump. 9. Topical, Ophthalmic and Otic Preparations Included in this broad category are ointments, creams, lotions, paste, gel, solutions, eye drops, and cutaneous sprays. Topical preparations should be evaluated for clarity, pH, resuspendability , consistency, viscosity, particle size distribution (for suspensions), level of microbial contamination/sterility and weight loss .

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10. Small Volume Parenterals (SVPs) Color, clarity (for solutions), particulate matter, pH, sterility, endotoxins . Stability studies for powders for injection solution should include monitoring for color , reconstitution time and water content. stability studies for Suspension for Injection should include in addition particle size distribution, redispersibility and rheological properties. 11. Large Volume Parenterals (LVPs) Color, clarity, particulate matter, pH, sterility, pyrogen / endotoxin, and volume. 12. Transdermal Patches In-vitro release rates, leakage, level of microbial contamination/sterility, peel and adhesive forces.

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Solution stability STABILITY PROTOCOL Remain clear at wide range of temperature 4 °c to 47°c. TEST FOR CLARITY OF SOLUTION Change in odour , appearance , color , viscosity Visual inspection Microscopic inspection By coulter counter instruments By light scattering instruments

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Solid stability FOR TABLET PROTOCOL FOR STABILITY Original size, shape, color, odor during shelf life. In vitro avability . FOR CAPSULE PROTOCOL FOR STABILITY Capsule shell should not soften. Should not stick together. Should not harden or crack under slight pressure. No microbial growth develop.

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Accelerated stability testing : All medicinal products decompose with time. To assess the stability of a formulated product it is usual to expose it to “high stress”, i.e. condition of temperature, humidity and light intensity that cause break down High stress conditions enhance the deterioration of the product and so reduce the time required for testing . Enables more data to be gathered in shorter time, which in turn will allow unsatisfactory formulation to be eliminated early in a study and will also reduce the time for a successful product to reach a market. Objective: Used for selecting the best formulation from a series of possible choice. Prediction of shelf life, which the time a product will remain satisfactory when stored under expected or directed storage condition.

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Prediction of shelf-life

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Simplify technique for stability predication. Log of days to 90% potency

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Q 10 Method : Where, Example: An antibiotic solution has shelf life of 48 hours in refrigerator (5 ˚c) hat is estimated shelf life at room temperature(25 ˚c )? Answer : 48/3 = 5.32 hours Kennon method : Used for purpose of comparison of shelf life during formulation development work. Used activation energies of 10 & 20 kcal/mole. t 90 (T2) = t 90 (T 1 ) Q 10 (∆T/10) t 90 (T2) = Estimated shelf life t 90 (T 1 ) = Given shelf life 2

Reference :

Reference 1. Lachman leon , liberman a. herbert ,kanig l. joseph . “The Theory and Practice of Industrial Pharmacy” Third edition , varghese publication house , Bombay , page no: 760-800 2. Allen v. loyd , popovich g. nicholas , ansel c. howard , “Ansel’s Pharmaceutical dosage form & Drug delivery System” Eight edition , published by B.Z. PVT. LTD., page no :118 3. Yoshioka sumie , stella j. valentino , “stability of drugs & dosage forms” springer International edition , page no :1-268 4. www.ich.org/products/guidelines/quality.html 5. www.ipapharma.org/events/ Stability /Saranjit%20singe.pdf 6. www.unicef.org/supply/files/9_Trends_in_ Stability _B_Schmauser.pdf

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THANK YOU … …

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