The following definitions are provided to facilitate interpretation of the ICH Guidelines:
Accelerated testing
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. 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. Results from accelerated testing studies are not always predictive of physical changes.
Bracketing
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.
Climatic zones
The four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions. This is based on the concept described by W. Grimm (Drugs Made in Germany, 28:196-202, 1985 and 29:39-47, 1986).
Commitment batches
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.
Dosage form
A pharmaceutical product type (e.g., tablet, capsule, solution, cream) that contains a drug substance generally, but not necessarily, in association with excipients.
Drug product
The dosage form in the final immediate packaging intended for marketing.
Drug substance
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.
Expiration date
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 re-test period of a drug substance or the shelf life of a drug product.
Impermeable containers
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.
Intermediate testing
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.
Long term testing
Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labeling.
Mass balance
The process of adding together the assay value and levels of degradation products to see how closely these add up to 100% of the initial value, with due consideration of the margin of analytical error.
Matrixing
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.
When establishing the mean kinetic temperature for a defined period, the formula of J. D. Haynes (J. Pharm. Sci., 60:927-929, 1971) can be used.
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 the larger.
Primary batch
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 re-test 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.
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.
Re-test date
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.
Re-test period
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 re-tested for compliance with the specification and then used immediately. A batch of drug substance can be re-tested multiple times and a different portion of the batch used after each re-test, 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 re-test period. The same may be true for certain antibiotics.
Semi-permeable containers
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 semi-permeable containers include plastic bags and semi-rigid, 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.
Specification
See Q6A and Q6B.
Specification – Release
The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug product at the time of its release.
Specification – Shelf life
The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug substance throughout its re-test 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 guideline. 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 (see ICH Q1B) and specific testing on certain products, (e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products).
Supporting data
Data, other than those from formal stability studies, that support the analytical procedures, the proposed re-test 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.
REFERENCES:
Q1A (R2): STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS.
ICH Q1B: “Photostability Testing of New Drug Substances and Products”
ICH Q1C: “Stability Testing of New Dosage Forms”
ICH Q3A: “Impurities in New Drug Substances”
ICH Q3B: “Impurities in New Drug Products”
ICH Q5C: “Stability Testing of Biotechnological/Biological Products”
ICH Q6A: “Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances”
ICH Q6B: “Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Biotechnological/Biological Products”