Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies.
The design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, package size) 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. Where a range of strengths is to be tested, bracketing is applicable if the strengths are identical or very closely related in composition (e.g., for a tablet range made with
different compression weights of a similar basic granulation, or a capsule range made by filling different plug fill weights of the same basic composition into different size capsule shells).
Bracketing can be applied to different container sizes or different fills in the same container closure system.
The four zones in the world that are distinguished by their characteristic,prevalent annual climatic conditions.
Production batches of a drug substance or drug product for which the stability studies are initiated or completed post-approval through a commitment made in the registration application.
Container closure system:
The sum of packaging components that together contain and protect the dosage form. 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.
A pharmaceutical product type (e.g., tablet, capsule, solution, cream) that contains a drug substance generally, but not necessarily, in association with excipients.
The dosage form in the final immediate packaging intended for marketing.
The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form.
Excipient: Anything other than the drug substance in the dosage form.
The date placed on the container label of a drug product designating the time prior to which a batch of the product is expected to remain within the approved shelf life specification, if stored under defined conditions, and after which it must not be used.
Formal stability studies:
Long-term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the retest period of a drug substance or the shelf life of a drug product.
Containers that provide a permanent barrier to the passage of gases or solvents (e.g., sealed aluminum tubes for semi-solids, sealed glass ampoules for solutions).
Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long-term at 25°C.
Stability studies under the recommended storage condition for the retest period or shelf life proposed (or approved) for labeling.
The process of adding together the assay value and levels of degradation products to see how closely these add up to 100 percent of the initial value, with due consideration of the margin of analytical error.
The design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and, possibly in some cases, different container closure systems.
Mean kinetic temperature:
A single derived temperature that, if maintained over a defined period of time, affords the same thermal challenge to a drug substance or drug product as would be experienced over a range of both higher and lower temperatures for an equivalent defined period. The mean kinetic temperature is higher than the arithmetic mean temperature and takes
into account the Arrhenius equation.
New molecular entity:
An active pharmaceutical substance not previously contained in any drug product registered with the national or regional authority concerned. A new salt, ester, or non-covalent bond derivative of an approved drug substance is considered a new molecular entity for the purpose of stability testing under this guidance.
Pilot scale batch:
A batch of a drug substance or drug product manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is larger.
A batch of a drug substance or drug product used in a formal stability study,from which stability data are submitted in a registration application for the purpose of establishing a retest period or shelf life, respectively.
A primary batch of a drug substance should be at least a pilot scale batch. For a drug product, two of the three batches should be at least pilot scale batch, and the third batch can be smaller if it is representative with regard to the critical manufacturing steps. However, a primary batch may be a production batch.
A batch of a drug substance or drug product manufactured at production scale by using production equipment in a production facility as specified in the application.
The date after which samples of the drug substance should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given drug product.
The period of time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions. After this period, a batch of drug substance destined for use in the manufacture of a drug product should be retested for compliance with the specification and then used immediately.
A batch of drug substance can be retested multiple times and a different portion of the batch used after each retest, as long as it continues to comply with the specification. For most biotechnological/biological substances known to be labile, it is more appropriate to establish a shelf life than a retest period. The same may be true for certain antibiotics.
Containers that allow the passage of solvent, usually water, while preventing solute loss. The mechanism for solvent transport occurs by absorption into one container surface, diffusion through the bulk of the container material, and desorption from the other surface. Transport is driven by a partial pressure gradient.
Examples of semipermeable containers include plastic bags and semirigid, low-density polyethylene (LDPE) pouches for large volume parenterals (LVPs), and LDPE ampoules, bottles, and vials.
Shelf life (also referred to as expiration dating period):
The time period during which a drug product is expected to remain within the approved shelf life specification, provided that it is stored under the conditions defined on the container label.
The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug substance throughout its retest period, or that a drug product should meet throughout its shelf life.
Storage condition tolerances:
The acceptable variations in temperature and relative humidity of storage facilities for formal stability studies. The equipment should be capable of controlling the storage condition within the ranges defined in this guidance. The actual temperature and humidity (when controlled) should be monitored during stability storage. Short-term spikes due to opening of doors of the storage facility are accepted as unavoidable.
The effect of excursions due to equipment failure should be addressed and reported if judged to affect stability results.
Excursions that exceed the defined tolerances for more than 24 hours should be described in the study report and their effect assessed.
Stress testing (drug substance):
Studies undertaken to elucidate the intrinsic stability of the drug substance. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing.
Stress testing (drug product):
Studies undertaken to assess the effect of severe conditions on the drug product. Such studies include photostability testing and specific testing of certain products (e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products).
Data, other than those from formal stability studies, that support the analytical procedures, the proposed retest period or shelf life, and the label storage statements.
Such data include
(1) stability data on early synthetic route batches of drug substance, small scale batches of materials, investigational formulations not proposed for marketing, related formulations, and product presented in containers and closures other than those proposed for marketing;
(2) information regarding test results on containers; and
(3) other scientific rationales.
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Referance:Q1A(R2) Stability Testing of New Drug Substances and Products