ICH Q1C new formulation stability testing

ICH Q1C stability testing guidance describe new formulation stability testing information required for submission to the regulatory bodies of the European Union, Japan and USA.

what is new formulation means?

A new dosage form or new formulation is defined as a drug product which is a different pharmaceutical product type, but contains the same active substance. For example :

• Pharmaceutical product types include products of different administration route e.g., oral to parenteral.
• New specific functionality/delivery systems e.g., immediate release tablet to modified release tablet
• Different dosage forms of the same administration route e.g., capsule to tablet, solution to suspension.

ICH Q1C new formulation stability testing

Stability protocols for Formulation should follow the guidance in the parent stability guideline in principle. However, a reduced stability database at submission time (e.g., 6 months accelerated and 6 months long term data from ongoing studies) may be acceptable in certain justified cases.

Selection of Batches for new formulation stability testing

Stability studies should be provided on at least three primary batches using different AR Number of the API of the drug product. The primary batches should be of the same formulation and packaged in the same container closure system as proposed for marketing. Two of the three batches should be at least pilot scale batches and the third one can be smaller, if justified.

Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied.

Photostability testing (ICH Q1B) should be conducted on at least one primary batch of the drug product if appropriate.

Container Closure System selection for new formulation

Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing (including, as appropriate, any secondary packaging and container label).

Specification

The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), functionality tests (e.g., for a dose delivery system) and shelf life acceptance criteria. Analytical procedures should be fully validated and stability indicating.

Testing Frequency

Storage conditions for stability testing of Drug products

Study	Storage condition	Minimum time period covered by data at submission
Long term	25 ± 2°C and 60 ± 5% RH or 30 ± 2°C and 65 ± 5% RH	12 months
Intermediate	30 ± 2°C and 65 ± 5% RH	6 months
Accelerated	40 ± 2°C and 75 ± 5% RH	6 months

Storage conditions for Drug products packaged in impermeable containers

Stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.

Storage conditions for Drug products packaged in semi-permeable containers

Study	Storage condition	Minimum time period covered by data at submission
Long term	25 ± 2°C and 40 ± 5% RH or 30 ± 2°C and 35 ± 5% RH	12 months
Intermediate	30 ± 2°C and 65 ± 5% RH	6 months
Accelerated	40 ± 2°C and NMT 25% RH	6 months

Storage conditions for Drug products intended for storage in a refrigerator

Study	Storage condition	Minimum time period covered by data at submission
Long term	5 ± 3°C	12 months
Accelerated	25 ± 2°C and 60 ± 5% RH	6 months

Storage conditions for Drug products intended for storage in a freezer

Study	Storage condition	Minimum time period covered by data at submission
Long term	– 20 ± 5°C	12 months

Storage conditions for Drug products intended for storage below -20°C

Drug products intended for storage below -20°C should be treated on a case-by-case basis.

How to Evaluate stability testing of new formulation

A systematic approach should be adopted in the presentation and evaluation of the stability information, which should include, as appropriate, results from the physical, chemical, biological, and microbiological tests, including particular attributes of the dosage form (for example, dissolution rate for solid oral dosage forms).

The purpose of the stability study is to establish, based on testing a minimum of three batches of the drug product, a shelf life and label storage instructions applicable to all future batches of the drug product manufactured and packaged under similar circumstances.

Labeling requirement as per ICH Q1C new formulation stability testing

A storage statement should be established for the labeling in accordance with relevant national/regional requirements and based on the stability evaluation. An expiration date should be displayed on the container label.

what is Significant change ?

In general, “significant change” for a drug product is defined as:

1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures;
2. Any degradation product’s exceeding its acceptance criterion; Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, re-suspendibility, caking, hardness, dose delivery per actuation);
3. Failure to meet the acceptance criterion for pH.
4. Failure to meet the acceptance criteria for dissolution for 12 dosage units.

what is 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.

what is 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.

what is 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.

what is 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.

what is Shelf life?

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.