STABILITY TESTING OF NEW DRUG PRODUCTS Q1A(R2)
Selection of Batches
Container Closure System
The design of the formal stability studies for the drug product should be based on knowledge of the behavior and properties of the drug substance and from stability studies on the drug substance and on experience gained from clinical formulation studies.
The likely changes on storage and the rationale for the selection of attributes to be tested in the formal stability studies should be stated.
Photostability testing should be conducted on at least one primary batch of the drug product if appropriate. The standard conditions for photostability testing are described in ICH Q1B.
Selection of Batches
Data from stability studies should be provided on at least three primary batches 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.
The manufacturing process used for primary batches should simulate that to be applied to production batches and should provide product of the same quality and meeting the same specification as that intended for marketing.
Two of the three batches should be at least pilot scale batches and the third one can be smaller, if justified. Where possible, batches of the drug product should be manufactured by using different batches of the drug substance.
Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied.
Other supporting data can be provided.
Container Closure System
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).
Any available studies carried out on the drug product outside its immediate container or in other packaging materials can form a useful part of the stress testing of the dosage form or can be considered as supporting information, respectively.
Specification, which is a list of tests, reference to analytical procedures, and proposed acceptance criteria, including the concept of different acceptance criteria for release and shelf life specifications, is addressed in ICH Q6A and Q6B. In addition, specification for degradation products in a drug product is addressed in Q3B.
Stability studies should include testing of those attributes of the drug product that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy.
The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system).
Analytical procedures should be fully validated and stability indicating. Whether and to what extent replication should be performed will depend on the results of validation studies.
Shelf life acceptance criteria should be derived from consideration of all available stability information. It may be appropriate to have justifiable differences between the shelf life and release acceptance criteria based on the stability evaluation and the changes observed on storage.
Any differences between the release and shelf life acceptance criteria for antimicrobial preservative content should be supported by a validated correlation of chemical content and preservative effectiveness demonstrated during drug development on the product in its final formulation (except for preservative concentration) intended for marketing.
A single primary stability batch of the drug product should be tested for antimicrobial preservative effectiveness (in addition to preservative content) at the proposed shelf life for verification purposes, regardless of whether there is a difference between the release and shelf life acceptance criteria for preservative content.
For long term studies,
Frequency of testing should be sufficient to establish the stability profile of the drug product.
For products with a proposed shelf life of at least 12 months,
The frequency of testing at the long term storage condition should normally be
Every 3 months over the first year.
Every 6 months over the second year, and
Annually thereafter through the proposed shelf life.
At the accelerated storage condition
A minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended.
Where an expectation (based on development experience) exists that results from accelerated testing are likely to approach significant change criteria, increased testing should be conducted either by adding samples at the final time point or by including a fourth time point in the study design.
When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended.
Reduced designs, i.e., matrixing or bracketing, where the testing frequency is reduced or certain factor combinations are not tested at all, can be applied, if justified.
In general, a drug product should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture or potential for solvent loss.
The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use.
Stability testing of the drug product after constitution or dilution, if applicable, should be conducted to provide information for the labeling on the preparation, storage condition, and in-use period of the constituted or diluted product.
This testing should be performed on the constituted or diluted product through the proposed in-use period on primary batches as part of the formal stability studies at initial and final time points and, if full shelf life long term data will not be available before submission, at 12 months or the last time point for which data will be available.
In general, this testing need not be repeated on commitment batches.
The long term testing should cover a minimum of 12 months’ duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed shelf life.
Additional data accumulated during the assessment period of the registration application should be submitted to the authorities if requested.
Data from the accelerated storage condition and, if appropriate, from the intermediate storage condition can be used to evaluate the effect of short term excursions outside the label storage conditions (such as might occur during shipping).
Long term, accelerated, and, where appropriate, intermediate storage conditions for drug products are detailed in the sections below. The general case applies if the drug product is not specifically covered by a subsequent section. Alternative storage conditions can be used, if justified.
If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria.
The initial application should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition.
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;
3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation); however, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions;
and, as appropriate for the dosage form:
4. Failure to meet the acceptance criterion for pH; or
5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.
Drug products packaged in impermeable containers
Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent. Thus, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.
Drug products packaged in semi-permeable containers
Aqueous-based products packaged in semi-permeable containers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability. 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.
For long-term studies conducted at 25°C ± 2°C/40% RH ± 5% RH, additional testing at the intermediate storage condition should be performed as described under the general case to evaluate the temperature effect at 30°C if significant change other than water loss occurs during the 6 months’ testing at the accelerated storage condition.
A significant change in water loss alone at the accelerated storage condition does not necessitate testing at the intermediate storage condition.
However, data should be provided to demonstrate that the drug product will not have significant water loss throughout the proposed shelf life if stored at 25°C and the reference relative humidity of 40% RH.
A 5% loss in water from its initial value is considered a significant change for a product packaged in a semi-permeable container after an equivalent of 3 months’ storage at 40°C/NMT 25% RH. However, for small containers (1 mL or less) or unit-dose products, a water loss of 5% or more after an equivalent of 3 months’ storage at 40°C/NMT 25% RH may be appropriate, if justified.
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.g., the most diluted of a series of concentrations) for the proposed drug product.
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.g., 40°C, the calculated water loss rate during storage at NMT 25% RH is the water loss rate measured at 75% RH multiplied by 3.0, the corresponding water loss rate ratio.
If the drug product is packaged in a semi-permeable container, appropriate information should be provided to assess the extent of water loss.
Data from refrigerated storage should be assessed according to the evaluation section of this guideline, except where explicitly noted below.
If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, the proposed shelf life should be based on the real time data available from the long term storage condition.
If significant change occurs within the first 3 months’ testing at the accelerated storage condition, a discussion should be provided to address the effect of short term excursions outside the label storage condition, e.g., during shipment and handling.
This discussion can be supported, if appropriate, by further testing on a single batch of the drug product for a period shorter than 3 months but with more frequent testing than usual. It is considered unnecessary to continue to test a product through 6 months when a significant change has occurred within the first 3 months.
For drug products intended for storage in a freezer, the shelf life should be based on the real time data obtained at the long term storage condition.
In the absence of an accelerated storage condition for drug products intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period should be conducted to address the effect of short term excursions outside the proposed label storage condition.
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.
When available long term stability data on primary batches do not cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the shelf life.
Where the submission includes long term stability data from three production batches covering the proposed shelf life, a post approval commitment is considered unnecessary. Otherwise, one of the following commitments should be made:
1. If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue the long term studies through the proposed shelf life and the accelerated studies for 6 months.
2. If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue the long term studies through the proposed shelf life and the accelerated studies for 6 months, and to place additional production batches, to a total of at least three, on long term stability studies through the proposed shelf life and on accelerated studies for 6 months.
3. If the submission does not include stability data on production batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed shelf life and on accelerated studies for 6 months.
The stability protocol used for studies on commitment batches should be the same as that for the primary batches, unless otherwise scientifically justified.
Where intermediate testing is called for by a significant change at the accelerated storage condition for the primary batches, testing on the commitment batches can be conducted at either the intermediate or the accelerated storage condition.
However, if significant change occurs at the accelerated storage condition on the commitment batches, testing at the intermediate storage condition should also be conducted.
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.
The degree of variability of individual batches affects the confidence that a future production batch will remain within specification throughout its shelf life.
Where the data show so little degradation and so little variability that it is apparent from looking at the data that the requested shelf life will be granted, it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be sufficient.
An approach for analyzing data of a quantitative attribute that is expected to change with time is to determine the time at which the 95 one-sided confidence limit for the mean curve intersects the acceptance criterion.
If analysis shows that the batch-to-batch 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.g., p values for level of significance of rejection of more than 0.25) to the slopes of the regression lines and zero time intercepts for the individual batches.
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 criteria.
The nature of the degradation relationship will determine whether the data should be transformed for linear regression analysis. Usually the relationship can be represented by a linear, quadratic, or cubic function on an arithmetic or logarithmic scale.
Statistical methods should be employed to test the goodness of fit on all batches and combined batches (where appropriate) to the assumed degradation line or curve.
Limited extrapolation of the real time data from the long term storage condition beyond the observed range to extend the shelf life can be undertaken at approval time, if justified. This justification should be based on what is known about the mechanisms of degradation, the results of testing under accelerated conditions, the goodness of fit of any mathematical model, batch size, existence of supporting stability data, etc.
However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the observed data.
Any evaluation should consider not only the assay but also the degradation products and other appropriate attributes. Where appropriate, attention should be paid to reviewing the adequacy of the mass balance and different stability and degradation performance.
A storage statement should be established for the labeling in accordance with relevant national/regional requirements.
The statement should be based on the stability evaluation of the drug product. Where applicable, specific instruction should be provided, particularly for drug products that cannot tolerate freezing.
Terms such as “ambient conditions” or “room temperature” should be avoided.
There should be a direct link between the label storage statement and the demonstrated stability of the drug product. An expiration date should be displayed on the container label.
Referances :ICH HARMONISED TRIPARTITE GUIDELINE -STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS Q1A(R2) .
Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field.
During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube