Anilkumar S. Chinchole1*, B.N.Poul2, C.V. Panchal1, D.V. Chavan1
1Department of Quality Assurance, Maharashtra College of Pharmacy, Nilanga, Latur, Maharashtra, India
2Principal of Maharashtra College of Pharmacy, Nilanga
Maharashtra College of Pharmacy, Nilanga, Latur, Maharashtra, India

Stability guidelines for new drug substance and new pharmaceutical formulations as per ICH and USP for the evaluation and consistency for new drug and pharmaceutical dosage form. The brief understanding of these guidelines can be easily recognized by this article. Stability testing Provide a evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light. To establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions. Because physical, chemical or microbiological changes might impact the efficiency and security of the final product. To minimize the Adverse Effects Of Instability In Drug Products Loss of potency of drug such as 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.


PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 8

Received On: 03/05/2014; Accepted On: 01/06/2014; Published On: 01/08/2014

How to cite this article: AS Chinchole, B Poul, CV Panchal, DV Chavan; A Review on Stability Guidelines by ICH and USFDA Guidelines for New Formulation and Dosage form; PharmaTutor; 2014; 2(8); 32-53

Stability studies means?

Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy1.

Protocol of Stability
Prior to the submission of an original or supplemental NADA, an applicant may wish to submit a stability protocol for comment before committing to studies that will become a permanent part of the NADA. The protocol should contain an outline of the proposed plan to be used in generating stability data. The protocol should describe the type of product being tested, sampling process, duration and frequency of testing, number of samples and replicates per time interval, storage conditions (length of storage, type of storage, temperatures and packaging), methods of analysis (description or reference of published methods) with accompanying support data, if available, and other tests. The information listed in these guidelines should be incorporated as appropriate in the development of a plan.

Definition of Active Ingredient

The active ingredient of an animal drug preparation is defined as that chemical whose biological, physiological, pharmacological, or chemical activities are claimed on the label to be beneficial for animals in normal or pathological conditions (diagnosis, prognosis, treatment, prophylaxis, therapy) or for animal production.

Strength (Potency)
The strength of a drug substance may be its concentration (quantity of the drug per unit measure), its potency, or both. The potency of a drug is a measurable (quantitative) extent of the biological, physiological, pharmacological, or chemical activities of the drug per unit weight or volume of the drug preparation.

Drug preparations are considered stable if the active ingredient can maintain its strength at the level specified on the label for the maximum anticipated shelf-life (the time period from the date of manufacture until administration to the animal) under environmental conditions likely to be encountered in actual use. However, few, if any, drug preparations maintain their full label-claimed strength under specified conditions. Therefore, allowances are made for some unavoidable deviations from drug levels declared on the label by designating specific limits for tolerable deviations.

A drug product is considered unstable when the drug substance (active ingredient) loses sufficient potency to adversely affect the safety or efficacy of the drug or falls outside labeled specifications as shown by stability-indicating methods. To properly evaluate the stability of a drug product, it is essential to determine the storage conditions under which the drug strength can be maintained in order to provide a safe and efficacious drug product. As a guide in determining drug strength in pharmaceutical dosage forms, the following is recognized by the scientific community:"Although there are exceptions, 90% of the labeled potency is generally recognized as the minimum acceptable potency level.”

Drug Preparation
The active ingredient should be formulated in any drug preparation at 100% of label claim. An overage of the active ingredient may be permitted in a product should the need exist. All overages should be justified. The assay limits must account for the overage. The overage should not exceed the limits of 5% for antibiotics and 3% for non-antibiotic chemicals as established by the Center for Veterinary Medicine.

Chemical and Physical Properties
Strength is not the only criterion of drug product stability. Maintenance of various chemical and physical properties to preserve the effectiveness and safety of the drug is also important. Properties, such as physical appearance, crystalline form, particle size, solubility, disintegration rate, pH, sterility, viscosity, palatability (taste and odor), may be stability related and thus require testing and the setting of specific storage conditions and limits. In addition, tests may also be needed to determine the absence or presence of harmful degradation products.

Added Substances
Stability data on substances that are added to a drug preparation to enhance its stability, usefulness, physical or chemical properties or as an aid in manufacturing may be required. The type of substance(s) used, its purpose and its relationship to the active drug ingredient(s) and total drug preparation will determine if testing for the substance is required. Examples of added substances that may commonly be used are antioxidants, antibacterials, absorbants (bentonite), etc.

Product Changes
Changes made in the composition (formulation) or dosage form of the original or succeeding product(s) present a new drug product and will require generation of new stability data. Data requirements will depend on the nature and degree of change.
Any change requires an evaluation as to the effect on the stability of the products.

Correlation with Efficacy and Toxicity Studies
Stability studies supporting an application should be performed on the drug preparation in its final formulation whose efficacy and safety has been demonstrated. Any change made in an approved preparation requires consideration of the effects on the efficacy and safety of the "changed" drug product. Degradation Products Degradation products that occur during storage (under shelf-life testing) should be identified. These products should be thoroughly investigated and evaluated for safety and toxicology purposes. The presence of degradation products may require additional safety and efficacy studies.

Product Stability Parameters
The established regulatory registration (NADA or NDA) specifications or Compendial standards are to be used for determining the stability of the products. There can be only one set of standards. Samples of products (from production lots) on stability should be representative of those in the market place. Expiration dating is based on the ability of the product to be measured over a certain period of time against the established specifications or standards1, 2.

In stability is defined as “the extent to which a preparation retains, within specified limits, and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of compounding.” This chapter defines beyond-use date as “the date after which a compounded preparation is not to be used and is determined from the date the preparation is compounded. Stability testing is used to determine a beyond-use date, which is required by USP guidelines to be on the label or package of a compounded preparation. The terms stability, shelf life, and beyond-use date can be used interchangeably when referring to compounded preparations. The term expiration date is used when referring to manufactured products. Pharmaceutical Compounding Sterile Preparations states, “It should be recognized that the truly valid evidence of stability for predicting beyond use dating can be obtained only through product-specific experimental studies.” It is important to remember that the analytical method employed is key to determining stability versus potency. Once again, a stability-indicating method must be used to establish stability. Furthermore, a potency test that used stability-indicating methods can be used to determine stability as well as Stability testing usually includes method development, method validation, and a stability study. The method must separate the active ingredient from its degradants and impurities, as well as any other excipients potencyin the preparation. This is done by force degrading the active ingredient and inactive ingredients to ensure that no degradants interfere with the analysis. In the process of force degradation, the compound is exposed to high heat and humidity, UV radiation, an acid, a base, and peroxide. It is this step that differentiates a stability indicating test from a simple potency test.

Stability can be determined from this type of study, simply because stability-indicating methods were used in the analysis. Method validation ensures that the method meets certain criteria. The typical analytical characteristics used in method validation include accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and ruggedness, as outlinedin.  The stability study includes storing the preparation in stability chambers, testing it at predetermined time points, and then determining stability. These time points may be specified by the compounder or dictated by the particular compound. Once again, it is crucial to understand that the methods used to determine stability must be stability indicating. Quality assurance programs are essential to establishing appropriate standards for compounded preparations. The specificprogram implemented is up to the compounding pharmacy but should include a standard operating procedure, documentation, verification, and testing as outlined in USP Chapter.The standards of the Pharmacy Compounding Accreditation Board state that “a pharmacy must provide documentation of the basis for its determination of the beyond-use date assigned to its compounded preparation.”

ICH guidelines 2
1. Stability Testing of New Drug Substances and ProductsQ1A(R2)
2. Stability Testing: Photostability Testing of New Drug Substances and Products Q1B
3. Stability Testing for New Dosage Forms(Q1C)
4. Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products(Q1D)
5. Evaluation for Stability Data(Q1E)
6. Stability Data Package for Registration Applications in Climatic Zones III and IV (Q1F)2.

1. Stability Testing of New Drug Substances and Products2,3
Objectives of the Guideline

The following guideline is a revised version of the ICH Q1A guideline and defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the three regions of the EC, Japan, and the United States. It does not seek necessarily to cover the testing for registration in or export to other areas of the world.

The guideline seeks to exemplify the core stability data package for new drug substances and products, but leaves sufficient flexibility to encompass the variety of different practical situations that may be encountered due to specific scientific considerations and characteristics of the materials being evaluated. Alternative approaches can be used when there are scientifically justifiable reasons.

Scope of the Guideline
The guideline addresses the information to be submitted in registration applications for new molecular entities and associated drug products. This guideline does not currently seek to cover the information to be submitted for abbreviated or abridged applications, variations, clinical trial applications, etc.

Specific details of the sampling and testing for particular dosage forms in their proposed container closures are not covered in this guideline.

Further guidance on new dosage forms and on biotechnological/biological products can be found in ICH guidelines Q1C and Q5C, respectively.

General Principles
The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.

The choice of test conditions defined in this guideline is based on an analysis of the effects of climatic conditions in the three regions of the EC, Japan and the United States. The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV. This guideline addresses climatic zones I and II. The principle has been established that stability information generated in any one of the three regions of the EC, Japan and the United States would be mutually acceptable to the other two regions, provided the information is consistent with this guideline and the labeling is in accord with national/regional requirements.


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