entitled 'Expiration dating of solid oral dosage form containing. Iron. WHO, in stability testing of drug substances and products existing in India has also Note for Guidance for In-Use Stability Testing of Human. Medicinal. Expiration Dating and Stability Testing for Human Drug Products the expiration date on a drug product and stability testing to assure the. Drug substances and stability testing of solid oral the expiration dating and stability testing cpg human drug methods are performed, 88% of drug products.
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.
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.
Expiration dating and stability testing for human drug products 1 | Steve’s PaleoNotes
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. Representative Nature of Batches 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.
Guideline for the Stability Testing of Nonprescription (OTC) Drug
Certainly from a manufacturing validation point of view when making process changes other representative properties such as process related impurity levels may need to be determined; however these would not affect the representative nature of earlier batches as far as stability performance is concerned.
Scale As discussed, scale is not a stability related material attribute. Increasingly, some agencies appear willing to accept data of a shorter duration when combined with a scientific rationale or other relevant justification.
The WHO stability guideline states that a minimum of 6 or 12 months data may be provided; 6 months if API is known to be stable and no significant changes occur at long term or accelerated conditions. Analysis we have performed on data from stability studies demonstrated that 6 months acceptable accelerated data can accurately predict whether a minimum 18 or 24 month shelf life for a drug product can be applied .
The use of accelerated predictive models should challenge the traditional duration of data expectations still further. There is no explicit requirement for annual lot stability studies.
Although the Inspection Guide is dated Octoberthe webpage was last updated April A similar statement is made for API. As discussed in previous sections, confirmation that batches continually conform to the stability related material attributes should be an acceptable scientific justification to negate the need to do further routine including annual stability studies.
As an example, Table 2 contains a summary of the stability studies outlined in the FDA guideline for scale-up and post-approval changes for immediate release solid oral dosage forms . The FDA guidelines on post-approval changes are essentially pragmatic risk management matrices classifying the risks associated with changes in a way to give a simple common position for all products in the absence of any specific data.
For example, a change in mixing times may have no effect at all on any of the stability related material attributes but a batch would be placed on long-term stability regardless. Site, manufacturing and process, in addition to scale as previously discussedare not stability related material attributes.
The European guideline on variations states for API batches that if the quality characteristics e. Summary Although the introduction of a number of quality guidelines has helped industry move to a more harmonized approach and allowed constructive dialogue between industry and regulators, there is a danger that both can become over-reliant on following the letter of these guidelines at the expense of applying science and risk-based approaches.
The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes. Analytical test procedures should be fully validated and stability indicating. There are some test methodologies where it may not be necessary or appropriate, using good scientific judgment, to validate a test procedure e.
Acceptance criteria for shelf-life specifications should be based on all of the available stability information and compendial requirements.
Specifications for product release may be more restrictive than shelf-life specifications in order to account for changes observed during storage of stability samples. For multi-dose liquid and semi-solid drug products, antimicrobial preservative effectiveness testing AET should be demonstrated in the multi-dose container s. If differences between the release and shelf-life acceptance criteria for AET are necessary, the difference should be scientifically justified based on a correlation between preservative content and preservative effectiveness.
This testing frequency will typically be 0, 3, 6, 9, 12, 18, 24 months and annually thereafter through the proposed shelf-life. Justification for doing less than these time points should be provided.
At the accelerated storage condition, a minimum of three time points are recommended to be tested over a three month period including the initial and final time; e. The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use. The general case applies if the drug product is not specifically covered by a subsequent section.
Alternative storage conditions can be used, if justified. Container orientation should be considered when designing stability study protocols for liquid and semi-solid products. Thus, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition. This evaluation can be carried out under conditions of low relative humidity, as discussed below. Ultimately, it should be demonstrated that aqueous-based drug products stored in semi-permeable containers can withstand low relative humidity environments.
Other comparable approaches can be developed and reported for non-aqueous, solvent-based products. However, for small containers 1 mL or less or unit-dose products, a www. An alternative approach to studying at the reference relative humidity as recommended in the table above for either long term or accelerated testing is performing the stability studies under higher relative humidity and deriving the water loss at the reference relative humidity through calculation.
This can be achieved by experimentally determining the permeation coefficient for the container closure system or, as shown in the example below, using the calculated ratio of water loss rates between the two humidity conditions at the same temperature.
The permeation coefficient for a container closure system can be experimentally determined by using the worst case scenario e. Example of an approach for determining water loss: For a product in a given container closure system, container size, and fill, an appropriate approach for deriving the water loss rate at the reference relative humidity is to multiply the water loss rate measured at an alternative relative humidity at the same temperature by a water loss rate ratio shown in the table below.
A linear water loss rate at the alternative relative humidity over the storage period should be demonstrated. For example, at a given temperature, e.
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Results from research and development batches on similar or closely related formulations, on similar or closely related marketed products, and data published in the literature, as well as results from the specific stability study may be considered a body of knowledge that can be used in the scientific assessment.
Results from physical, chemical and microbiological tests as appropriate for the dosage form should be included in this evaluation.
The purpose of the accelerated stability study is to establish, based on testing a minimum of one batch of the drug product, a tentative expiry period and label storage instructions applicable to all future batches of the drug product manufactured and packaged under similar circumstances. When the data from an accelerated stability study remains within established limits, while maintaining potency, a tentative expiry period can be assigned prior to marketing the product.
A twenty-four month expiry period may be assigned upon successful completion of three months accelerated testing. For those products that cannot tolerate 40C accelerated testing, stability data at the intermediate condition may be used to support a tentative expiry period of twenty-four months. Using sound scientific judgment, shorter expiry periods may be assigned based on less than three months of accelerated testing and longer tentative expiry periods may be justified using extended periods of accelerated testing or a combination of long term and accelerated testing.
When the data clearly exhibits no change or stability trend over time, a formal statistical analysis is not necessary.
If analysis shows that the batch-to-batch or among package configuration variability is small, it is advantageous to combine the data into one overall estimate.
This can be done by first applying appropriate statistical tests e. 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. If it is inappropriate to combine data from several package configurations, then each configuration should be evaluated separately with an expiry period being assigned to the individual package configuration rather than to the product as a whole.
The statement should be based on the stability evaluation of the drug product. Where applicable, specific instructions should be provided, particularly for drug products which require special storage conditions. Accelerated testing Studies designed to increase the rate of chemical or physical change of a drug product by using exaggerated storage conditions as part of the formal stability studies.
Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical effects at non-accelerated conditions and to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping.
However, results from accelerated studies are not always representative of similar results from the long-term label storage studies. Bracketing The design of a stability schedule such that only samples on the extremes of certain design factors, e.
The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. Where a range of strengths is to be tested, bracketing is applicable if the strengths are identical or very closely related in composition e.
Bracketing can be applied to different container sizes or different fills in the same container closure system.
Expiration dating and stability testing for human drug products
This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection to the drug product. A packaging system is equivalent to a container closure system. Development studies Stability studies initiated during the development of a drug product.
Dosage form A pharmaceutical product type e. Drug product The dosage form in the final immediate packaging intended for marketing. Drug Substance The unformulated active pharmaceutical ingredient that may subsequently be formulated with excipients to produce the dosage form.