stability protocol

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STABILITY PROTOCOL:

STABILITY PROTOCOL BY R RAMESH REDDY M.pharmacy 1 st year-pharmaceutical analysis

STABILITY PROTOCOL:

STABILITY PROTOCOL The ongoing stability programme should be described in a written protocol and results formalized as a report . 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 The design of the stability studies for the product should be based on knowledge of the behavior and properties of the drug substance and dosage form.

Photostability Testing:

Photostability Testing Photostability testing should be conducted on at least one primary batch of the drug product if appropriate. The standard conditions for photo stability testing are described in ICH Q1B.

Selection of Batches:

Selection of Batches Stability data should be provided on at least three primary batches of the drug products For conventional dosage forms and when the drug substances are known to be stable, stability data on at least two pilot scale batches are acceptable. For critical dosage forms or when the drug substances are known to be unstable, stability data on three primary batches are to be provided. Two of the three batches should be at least of a pilot scale; the third batch may be smaller.

Specification (Testing Parameter):

Specification (Testing Parameter ) list of tests, reference to analytical procedures, and proposed acceptance criteria, including the concept of different acceptance criteria for release and shelf-life specifications. The testing should cover, as appropriate, the physical, chemical, biological and microbiological attributes, preservative content and functionality tests

Testing Parameters:

Testing Parameters 1. Tablets Tablets should be evaluated for appearance, odour, colour, assay, degradation products, dissolution, moisture and hardness/friability. 2. Emulsions An evaluation should include appearance , odour, assay, degradation products, pH, viscosity, microbial limits, preservative content, and mean size and distribution of dispersed globules.

Testing Parameters:

Testing Parameters 3. Capsules Hard gelatin capsules should be evaluated for appearance, odour of content, assay, degradation products, dissolution, moisture and microbial content. Testing of soft gelatin capsules should include appearance, colour, and odour of content, assay, degradation products, dissolution, microbial content, pH, leakage, and pellicle formation. In addition, the fill medium should be examined for precipitation and cloudiness.

Testing Parameters:

Testing Parameters 4. Metered-dose Inhalations and Nasal Aerosols Dose content uniformity, labeled number of medication actuations per container, aerodynamic particle size distribution, microscopic evaluation, water content, leak rate, microbial limits, valve delivery (shot weight) and extractables /leachables from plastic and elastomeric components. Samples should be stored in upright and inverted/on-the-side orientations

Testing Parameters:

Testing Parameters 5. Suppositories Suppositories should be evaluated for appearance, colour, assay, degradation products, particle size, softening range, dissolution (at 37oC) and microbial limits. 6. Freeze-dried Products Appearance of both freeze-dried and its reconstituted product, assay, degradation products, pH, water content and rate of solution.

Testing Frequency:

Testing Frequency The frequency of testing at the long term storage condition should normally be every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed shelf life Reduced designs, i.e., matrixing or bracketing

Bracketing:

Bracketing Bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested

Bracketing design:

Bracketing design Pack type Label strength and batch numbers (X,Y,Z) 10 mg 20mg 30mg X Y Z X Y Z X Y Z Alu/Alu blister cards of 10 tablets + + + - - - + + + HDPE pack of 30 tablets + + + - - - + + + HDPE pack of 100 tablets - - - - - - - - - HDPE pack of 1000 tablets + + + - - - + + +

Matrixing:

Matrixing Matrixing is t he statistical design of a stability schedule . Each storage condition should be treated separately under its own matrixing design A t 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 design:

Matrixing design One-half matrix design – long-term stability studies Testing station 0 3 6 9 12 18 24 36 S1 Batch 1 + + - - + - + + Batch 2 + - + + + - + + Batch 3 + - + - + + - + S2 Batch 1 + - + + + + - + Batch 2 + + - - + + - + Batch 3 + + - + + - + +

Storage Condition:

Storage Condition

Container Closure System:

Container Closure System Generally considered moisture-impermeable containers include glass ampoules, aluminum/aluminum blisters, High Density Polyethylene (HDPE) or glass bottles fitted with metal or HDPE closures

Evaluation:

Evaluation 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 and microbiological tests, including particular attributes of the dosage form (for example, dissolution rate for solid oral dosage forms).

Stability protocol - API :

Stability protocol - API Protocol Parameter Description Storage conditions (including tolerances) and testing frequency 25°C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months 30 o C/75% RH 0, 3, 6, 9,12, (18, 24, 36) months 40°C/75% RH 0,3,6 months Batch number and size L40438 ( Jan. 2005 ), 80.50 k g L50041 ( Feb.2005 ), 69.00 k g L50054 (March 2005 ), 73.00 kg Container closure system(s) Simulated: double PE bags in black PE bag kept in one-kg fib er board drums well-closed Tests and acceptance criteria Assay 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 T he batches should be representative of the manufacturing process and should be manufactured from different batches of key intermediates .

Stability protocol – oral suspension:

Stability protocol – oral suspension Protocol Parameter Description Storage conditions ( including tolerances ) and testing frequency 25°C/60% RH 0, 3, 6, 9, 12, (18, 24, 36) months 30 o C/75% RH 0, 3, 6, 9,12, (18, 24, 36) months 40°C/75% RH 0,3,6 months Batch numbers and size NEV 40438 ( Jan. 200 7), 4000 bottles (960 liters) NEV 50 439 (Jan .200 7), 4000 bottles (960 liters) NEV 50 440 (Jan. 200 7), 4000 bottles (960 liters) Container closure system(s) proposed for marketing White HDPE bottle with two piece child-resistant 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) T he 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

A risk-based global stability protocol:

A risk-based global stability protocol Storage conditions Months 0 3 6 9 12 18 24 3 6 25 o C ± 2 o C and 60% ± 5% RH + + + + + + + + 30 o C ± 2 o C and 65% ± 5% RH - - - - - - - 30 o C ± 2 o C and 75% ± 5% RH + + + + + + + 40 o C ± 2 o C and 75% ± 5% RH + + 50 o C and ~ 70% RH +

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R Ramesh Reddy