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Expiration Dating and Stability Testing for Human Drug Products . FDA

Accelerated Stability Testing of Biologics DVD

Each strength of a drug product, and each primary package and closure system in which it is distributed must be supported by stability testing. If you are contracting this work to a third party laboratory be sure that they can provide guidance to help navigate the regulatory and compendial guidelines, and you perform a quality system audit of their facility. A stability study is a program of testing that is designed 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 which enables recommended storage conditions, retest periods, and shelf lives to be established. Stability testing is required to be conducted for OTC drug products under the recommended conditions of storage appearing on the label, and at any other condition the drug product might be exposed to during manufacturing, storage and shipping activities. As a result, there are a number of stability conditions which are commonly utilized in determining the stability of a drug product in its marketed package s. Examples of the most common stability conditions are as follows:. A stability study conducted under controlled temperature and humidity approximating conditions of long-term storage.

There must be separate stability studies to support each expiration date. Initial stability testing by accelerated testing may be performed on a batch smaller than the normal production size as long as the batch is produced by similar equipment as would be used for regular production. Generally, the placing of three initial batches into the long term stability program is considered minimal to assure batch uniformity for establishing an expiration date.

Since a dosage form is a complex unit and there are continued variables in the production process, such as change in personnel, raw material lots and suppliers, and equipment, it is imperative that stability studies are not limited only to initial production batches but a portion of annual production batches be the subject of an ongoing stability program.

When accelerated stability studies are performed, one batch may be adequate in order to establish a tentative expiration date. This is acceptable since it is not the purpose of an accelerated test to determine batch uniformity but rather to test for kinetic degradation. The use of accelerated testing data to establish a tentative expiration dating period of greater than three years is discouraged when it is based solely on accelerated data. Combining data compiled at room temperature and at accelerated temperature is possible to justify an expiration dating period of over two years.

This can be done, as an example, by taking a sample product that has been at room temperature for one year and subjecting that sample to accelerated temperature conditions. The expiration dating period used would then be the sum of that justified individually at each storage condition. We do not believe it is reasonable to perform accelerated testing at very high temperatures for a very short time and expect to extrapolate results to a very long expiration dating period since the actual mechanism of degradation at high temperature may be different than at room temperature.

It is commonly recommended that stability testing be performed initially, than every three months for the first year, then every six months for the second year, and then annually thereafter. However, more frequent testing near the end of the anticipated expiration date is often likely to give better information about the actual stability of the finished product.

Nonetheless, testing at least annually is considered minimal for compliance with CGMPs. Some firms have chosen, for economical purposes, random dates to test all stability samples of a given product.

As long as there is at least one test performed annually, this approach can be quite satisfactory. If a product was stored under controlled conditions, those actual conditions temperature and humidity should be recorded. Merely stating that a product was stored at room temperature is not sufficient for purposes of determining stability.

A product stored for stability at or near 15 C may have quite a different quality profile at its expiration date than a product stored at or near 30 C.

Stability testing is required to be conducted for OTC drug products under the FDA requires that the expiration date of each OTC drug product be alone cannot be used to support the expiration dating of OTC drug products. This guidance is the second revision of Q1A Stability Testing of New Drug Substances and Products, which was first published in September. U.S. Department of Health and Human Services .. This guidance is the second revision of Q1A Stability Testing of New Drug Substances and Shelf life (also referred to as expiration dating period): The time period during which a drug.

Based on published information, it appears that C is a reasonable reference for thermal exposure at room temperature. Stability studies should be conducted on product stored under normal storage conditions or, preferably, under exaggerated conditions. Products liable to degradation by light or moisture should be stored either in a lighted area or under conditions of high humidity unless it can be demonstrated that the packaging will prevent deterioration by that condition of interest. For example, a product liable to degrade by light need not be stored in a lit area if it is normally packaged and stored for use in an opaque container.

The first stability studies performed are usually forced degradation studies [1].

These are carried out to understand the primary degradation products of the molecule and to aid analytical method development stability-indicating methods to be subsequently used during long-term stability studies.

Long-term stability studies will also be initiated on both the active pharmaceutical ingredient API and the drug product, generally following many of the principles contained in the ICH stability guidelines, with storage at accelerated and long-term conditions. Unless the expectations outlined in ICH guideline Q1A R2 have been met as part of the clinical stability program, registration stability studies are traditionally performed before filing a Common Technical Document CTD.

Q1A R2 also states that if the registration stability batches are not made at commercial scale, then the first three commercial batches need to be placed on stability. Furthermore, after this point batches are usually placed on stability annually, an expectation which has been included in the WHO stability guideline [3].

In addition, when changes are made e. Although real-time stability studies are an absolute necessity during development at the very least in order to confirm the validity of any alternative modelsby following a science and risk-based approach to stability a better understanding of stability performance can be achieved and a number of unnecessary studies may be avoided [6].

Accelerated Stability Testing of Biologics DVD

An appropriate science and risk-based approach can be achieved by applying the principles of Quality by Design QbD to stability. The application of these principles should be based around generating scientific understanding and controlling the attributes affecting the stability performance of the API and drug product.

The only remaining attributes that may affect stability are those that are essentially determined during manufacture: polymorph, surface area and water content being probably the three most important attributes.

If these are then mapped out in a dimensional space alongside storage temperature and shelf life i. It should be noted that it may not be necessary to test for the stability related material attributes during the stability study; only shelf life limiting attributes e.

Another area of increasing interest in the stability world is in the use of accelerated predictive models for stability determination.

Stability Requirements For OTC Drug Products in the USA

Waterman et al. They have combined an experimental design that decouples temperature and relative humidity effects with an isoconversion paradigm to predict shelf lives at long-term storage conditions using data gathered over a relatively short period of time.

This tool allows faster and more accurate prediction of shelf lives than current one-condition accelerated stability studies e. In addition, the combination of an accelerated predictive model with a science and risk-based approach allows the determination of a scientifically sound, robust stability space to be developed which could be used to underwrite future changes to factors such as manufacturing process, scale or site.

Once these are identified then any subsequent changes to other factors such as site, scale, process or synthetic route only need to be assessed in terms of their potential effects on the stability related material attributes identified for the API or drug product in question.

For example, if polymorph is determined as the only stability related material attribute for a particular API, then any effects that a change in scale may have on stability can be determined simply by determining the polymorph after manufacture of the scaled-up batches, negating the need to perform further stability studies.

Highlighted in Table 1 are some of the statements from available guidance and expectations for registration stability batches which could be challenged from a scientific point of view if a science and risk-based approach is followed for determining stability. In the following sections these traditional registration stability expectations, plus those expectations covering subsequent stability studies, are discussed in the context of their relevance if science and risk-based and accelerated predictive approaches are followed.

Stability Testing – Doing Everything or Doing the Right Thing?

The ICH guideline states that 3 batches at a certain scale need to be placed on stability and that they are representative. The science and risk-based approach outlined essentially renders the registration stability study an unnecessary activity.

The batches would not need to be made by a certain synthetic route or process or scale to be representative in terms of stability performance.

Intermediate Stability Study A stability study that is conducted under conditions that are intermediate between long-term and accelerated storage conditions. Photostability Study A study that is conducted to determine the effect that either whole or ultraviolet light has upon the stability of a product.

Expiration Dating and Stability Testing for Human Drug Products the expiration date on a drug product and stability testing to assure the. Copies also may be U.S. Department of Health and Human Services. Food and Drug . Expiration Dating Period/ Retest Period. Stability Testing of Biotechnology Drug Products. Expiration Dating and Stability Testing of Solid Oral Dosage Form Drugs statements and unit-dose packaging for solid oral drug products that.

Bulk Hold Stability Study A stability study that is conducted under long-term conditions to assess the stability of a product batch in its bulk container. Interpretation of Accelerated Stability Studies As stated in the previous section, the results of accelerated stability studies may be used to approximate the shelf life of a new OTC drug product for launch.

Fda expiration dating and stability testing for human drug products

The first three 3 commercial batches of the drug product must be placed on RT Stability. Each year that a drug product continues to be manufactured, one 1 batch must be placed on RT Stability. Any substantial change that is made to the drug product such as but not limited to a change in formula, its container system, the site of manufacturing, or the process itself must be supported by stability testing so as to demonstrate the continuing stability of the product.

Critical changes require the re-establishment of shelf life. Test methods used for drug Assay and Impurity testing must be validated and stability indicating for the specific product formulation under test.

A stability indicating assay is one which is demonstrated to be free from interferences from impurities, degradants, or other constituents which may be present in the product. Stability studies must be conducted in marketed containers with primary labeling in place. Products packaged in containers equipped with dispensing devices e. By taking samples which have been stored under RT stability conditions for two 2 years, and subjecting them to an additional three 3 months storage under accelerated conditions and then obtaining acceptable test results from the samples.

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FDA regulations require drug applicants to provide stability testing data an approved drug product may extend the expiration date for the drug. From a pharmaceutical development point of view, stability studies are frequently . Guide on “Expiration Dating and Stability Testing for Human Drug Products” The FDA guidelines on post-approval changes are essentially. U.S. Department of Health and Human Services. Food and Drug Administration ANDAs: Stability Testing of Drug Substances and Products. Questions and Answers . ICH Q1E principles will help in the calculation of shelf life. Data from the.
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