ICH GUIDELINES FOR STABILITY TESTING

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ICH GUIDELINES FOR STABILITY TESTING : 

ICH GUIDELINES FOR STABILITY TESTING Dept. of Pharmaceutical Analysis gvrr416@gmail.com

CONTENTS: 

CONTENTS Photostability Testing Of New Drug Substances and Products ( Q1B ) Stability Testing For New Dosage Forms (Q1C) Bracketing and Matrixing Designs For Stability Testing Of New Drug Substances And Products (Q1D)

Photostability Testing Of New Drug Substances and Products ( Q1B ) : 

Photostability Testing Of New Drug Substances and Products ( Q1B ) Introduction : This is to demonstrate that light exposure does not result in an unacceptable change. Normally it is carried out on a single batch of material.

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This testing is recommended for : Tests on the drug substance Tests on the exposed drug product outside of the immediate pack and if necessary Tests on the drug product in the immediate pack and if necessary Tests on the drug product in the marketing pack Light Sources : For option 1 any light source that is designed to produce emission standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet outputs, xenon, or metal halide lamp.

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For option 2 1. A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977 (1993); 2. A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm with a maximum energy emission between 350 nm and 370 nm; a significant proportion of UV should be in both bands of 320 to 360nm and 36 0 to 400 nm. gvrr416@gmail.com

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PROCEDURE : Samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter to allow direct comparisons to be made between the drug substance and drug product. If protected samples (e.g., wrapped in aluminum foil) are used as dark controls to evaluate the contribution of thermally induced change to the total observed change , these should placed alongside the authentic sample.

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Drug Substance : For drug substances, photostability testing should consist of two parts: Forced degradation testing and confirmatory testing. The purpose of forced degradation testing studies is to evaluate the overall photosensitivity of the material for method development purposes or degradation pathway elucidation. This testing may involve the drug substance alone or in simple solutions/suspensions to validate the analytical procedures. gvrr416@gmail.com

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Under forcing conditions, decomposition products may be observed that are unlikely to be formed under the conditions used for confirmatory studies. This information may be useful in developing and validating suitable analytical methods. Confirmatory studies should then be undertaken to provide the information necessary for handling, packaging, and labeling.

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Presentation of samples : Care should be taken to ensure that the physical characteristics of the samples under test are taken into account and efforts should be made, such as cooling or placing the samples in sealed containers, to ensure that the effects of the changes in physical states such as sublimation, evaporation, or melting are minimized. For samples of solid drug substances, an appropriate amount of sample should be taken and placed in a suitable glass or plastic dish and protected with a suitable transparent cover if considered necessary. gvrr416@gmail.com

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Drug substances that are liquids should be exposed in chemically inert and transparent containers. Analysis of samples : At the end of the exposure period, the samples should be examined for any changes in physical properties (e.g., appearance, clarity or color of solution). Judgment of results : The confirmatory studies should identify precautionary measures needed in manufacturing or in formulation of the drug product, and if light resistant packaging is needed. The results of confirmatory studies is to determine whether change due to exposure to light is acceptable.

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Annex : Quinine Chemical Actinometry : The following provides details of an actinometric procedure for monitoring exposure to a near UV fluorescent lamp. Prepare a sufficient quantity of a 2 percent w/v aqueous solution of quinine monohydrochloride dihydrate. Option 1 : 10ml of solution 20 ml colorless ampoule seal it sample

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Option 2 : 10ml of solution 20ml colorless ampoule seal it wrap in aluminum foil to protect completely from light control

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Expose the sample and control to the light source for an appropriate number of hours. After exposure determine the absorbance's of the sample (AT) and the control (AO) at 400 nm using a 1centimeter(cm) path length. Calculate the change in absorbance, ∆ A = AT – AO. The length of exposure should be sufficient to ensure a change in absorbance of atleast 0.9 gvrr416@gmail.com

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Option 2: Fill 1cm quartz cell sample Fill 1cm quartz cell wrap in aluminum foil to protect completely from light, control. Repeat the same as above. The length of exposure should be sufficient to ensure a change in absorbance of atleast 0.5

Stability Testing For New Dosage Forms (Q1C): 

Stability Testing For New Dosage Forms (Q1C) The ICH Guideline on Stability Testing of New Drug Substances and Products was issued on October 27, 1993. This document is an annex to the ICH parent stability guideline and addresses the recommendations on what should be submitted regarding stability of new dosage forms by the owner of the original application, after the original submission for new drug substances and products. gvrr416@gmail.com

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A new dosage form is defined as a drug product which is a different pharmaceutical product type, but contains the same active substance as included in the existing drug product approved by the pertinent regulatory authority. These may include products of different administration route ( e.g. oral to parenteral ) specific delivery systems (e.g. immediate release tablet to modified release tablet ) and different dosage forms of the same administration route (e.g., capsule to tablet, solution to suspension)

Bracketing and Matrixing Designs For Stability Testing Of New Drug Substances And Products (Q1D): 

Bracketing and Matrixing Designs For Stability Testing Of New Drug Substances And Products (Q1D) Introduction : The parent guidance notes that the use of matrixing and bracketing can be applied, if justified, to the testing of new drug substances and products. This document provides guidance on bracketing and matrixing study designs. Specific principles are defined in this guidance for situations in which bracketing or matrixing can be applied.

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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 use of a bracketing design would not be considered appropriate if it cannot be demonstrated that the strengths or container sizes and/or fills .

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Design Factors : Design factors are variables (e.g., strength, container size and/or fill) to be evaluated in a study design for their effect on product stability Strength : Bracketing can be applied to studies with multiple strengths of identical or closely related formulations. Example : (1) capsules of different strengths made with different fill plug sizes from the same powder blend. gvrr416@gmail.com

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(2) Tablets of different strengths manufactured by compressing varying amounts of the same granulation, (3) oral solutions of different strengths with formulations that differ only in minor excipients (e.g., colorants, flavorings). Where different excipients are used among strengths, bracketing generally should not be applied. Container Closure Sizes and/or Fills : Bracketing can be applied to studies of the same container closure system where either container size or fill varies while the other remains constant.

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Care should be taken to select the extremes by comparing the various characteristics of the container closure system that may affect product stability. These characteristics include container wall thickness, closure geometry, surface area to volume ratio, headspace to volume ratio, water vapor permeation rate or oxygen permeation rate per dosage unit or unit fill volume . Design Considerations and Potential Risks : If, one of the extremes is no longer expected to be marketed, the study design can be maintained to support the bracketed intermediates. gvrr416@gmail.com

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Before a Bracketing design is applied, its effect on the retest period or shelf life estimation should be assessed. Design Example : An example of a bracketing design is given ,This example is based on a product available in three strengths and three container sizes. In this example, it should be demonstrated that the 15(ml) and 500-ml high-density polyethylene container sizes truly represent the extremes.

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Strength 50 mg 75mg 100mg Batch 1 2 3 1 2 3 1 2 3 Conta-iner size 15ml T T T T T T 100 ml 500 ml T T T T T T Example of a Bracketing Design : gvrr416@gmail.com

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Matrixing : Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all Factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point.

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Design Factors : The factors considered for bracketing is similar here. It can be applied to Different strengths where the relative amounts of drug substance and excipients change or where different excipients are used or to different container closure systems. To matrix across two different closures or container closure systems, supporting data could be supplied showing relative moisture vapor transmission rates or similar protection against light. Supporting data could be supplied to show that the drug Product is not affected by oxygen, moisture, or light.

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Design Considerations : Where time points are matrixed, all selected factor combinations should be tested at the initial and final time points, while only certain fractions of the designated combinations should be tested at each intermediate time point. All selected combinations of batch, strength, container size, and fill, among other things, should also be tested at 12 months or at the last time point prior to submission. If one strength or container size and/or fill is no longer intended for marketing, stability testing of that strength or container size and/ or fill can be continued to support the other strengths or container sizes and/ or fills in the design.

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Design examples : Examples of Matrixing Design on Time Points for a Product with Two Strengths : “One-Half Reduction” Time point (months) 0 3 6 9 12 18 24 S T R E N G T H S1 Batch 1 T T T T T T Batch2 T T T T T T Batch3 T T T T T S2 Batch1 T T T T T Batch2 T T T T T T Batch 3 T T T T 36

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Applicability and Degree of Reduction : The following, should be considered when a matrixing design is considered: 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

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REFERENCES : www .ICH guidelines.com gvrr416@gmail.com

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THANK U gvrr416@gmail.com