ICH - The Quality Guidelines

The Q-Family Q 1 Stability Testing Q 2 Analytical Validation Q 3 Impurities Q 4 Pharmacopoeias Q 5 Biotechnological Products Q 6 Specifications Q 7 Good Manufacturing Practices Q 8 Pharmaceutical Development Q 9 Quality Risk Management Q 10 Pharmaceutical Quality System

 ICH Q 1 Stability Testing

A set of originally five guidelines (Q1A to Q1F)

defining General aspects of stability testing (storage conditions, batch size and number, length of time...) - Photo stability - Application to new dosage forms - Possibilities for reduced test designs (bracketing and matrixing)

STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS Q1A(R2)

 ICH Q 1 A (R2) Scope For new API and related medicinal products

To provide evidence on how the quality of an API/finished product changes with time under the influence of environmental factors such as

temperature, humidity and light and to establish a re-test period/shelf-life for the API/finished product.

 ICH Q 1 A (R2) In a Nutshell... Stress testing required for API Long-term and accelerated testing required for API and product, where necessary intermediate testing - Minimum of three representative batches - Testing over a minimum of 12 months at LT and 6 months at accelerated conditions (with defined testing frequency) - Storage conditions for the general case, aqueous products in semi-permeable containers, products to be stored in a refrigerator and a freezer Stability commitment

 The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time

under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions.

 The choice of test conditions defined in this guideline is based on an analysis of the effects of climatic conditions in the three

regions of the EC, Japan and the United States. The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV.

Stress Testing
Stress testing of the drug substance can help identify the likely degradation products, which can in turn help establish the

degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used.

 Stress testing is likely to be carried out on a single batch of the drug substance. It should include the effect of temperatures (in 10C increments (e.g., 50C, 60C, etc.) above that for accelerated testing), humidity (e.g., 75% RH or greater) where appropriate, oxidation, and photolysis on the drug substance. The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension

 Examining degradation products under stress conditions is useful in establishing degradation pathways and developing and

validating suitable analytical procedures.

 Selection of Batches Data from formal stability studies should be

provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route Container Closure System The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution.

 Testing Frequency For long term studies, frequency of testing

should be sufficient to establish the stability profile of the drug substance. For drug substances with a proposed re-test period 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

 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.

 Long term, accelerated, and, where appropriate, intermediate storage conditions for drug substances are detailed in the sections below.

 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 re-test period. a commitment should be made to continue these studies through the proposed re-test period.

 Evaluation
An approach for analyzing the data on 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.

Drug Product
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. Two of the three batches should be at least pilot scale batches and the third one can be smaller, if justified.

 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).

 Specification
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.

 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.

 Testing Frequency
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 6month study is recommended.

 Storage Conditions
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 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.

 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 products 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)

 Aqueous-based products packaged in semipermeable 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.

 Stability Commitment 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. 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

 Statements/Labeling
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.

 ICH Q 1 B In a Nutshell - Describes requirements on photo stability

testing and defines light exposure to be applied - To be tested on API if not photosensitive, no further testing required - If photosensitive, to be continued on exposed finished product and product in primary package, product in marketing package, where relevant - Where necessary, impact of light during manufacturing process to be evaluated - Confirmatory testing required, where applicable

 A systematic approach to photo stability testing is recommended covering, as appropriate, studies such as: i) Tests on the drug substance;
ii) Tests on the exposed drug product outside of the

immediate pack; iii) Tests on the drug product in the immediate pack; iv) Tests on the drug product in the marketing pack.

 Light Sources Any light source that is designed to produce an

output similar to the D65/ID65 emission standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp. OR the same sample should be exposed to both the cool white fluorescent and near ultraviolet lamp.

 samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet

energy of not less than 200 watt hours/square meter Samples may be exposed side-by-side with a validated chemical actinometric system to ensure the specified light exposure is obtained

 DRUG PRODUCT Normally, the studies on drug products should be

carried out in a sequential manner starting with testing the fully exposed product then progressing as necessary to the product in the immediate pack and then in the marketing pack. Normally, only one batch of drug product is tested during the development phase,

 ICH Q 1 C In a Nutshell Additional guidance to ICH Q1 A(R2) on new

dosage forms (line extensions) for new substances Stability protocols for new dosage forms 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 .

 ICH Q 1 D In a Nutshell...

- Describes possibilities to apply reduced test designs, i.e. bracketing and matrixing
- Defines situations where reduced testing can be

applied without additional justification, with justification or where it is not applicable Bracketing: testing of extremes only Matrixing: testing of a different samples of factor combinations at different time points during the study Provides example designs

 ICH Q 2 Analytical Validation A guideline defining the validation parameters

needed for a variety of analytical methods and describing characteristics to be considered for the validation of analytical procedures included in a marketing authorization dossier

 ICH Q 2 ... In a Nutshell Defines criteria for the validation of the four

most common types of analytical procedures: - identification tests - quantitative tests for impurities - limit tests for the control of impurities - quantitative tests for the active moiety in API or finished product or other selected components in the product

 ICH Q 2 ... In a Nutshell Defines typical analytical validation characteristics, to which tests to apply them and

examples on the how to - Accuracy - Precision - Repeatability - Intermediate Precision - Specificity - Detection Limit - Quantitation Limit - Range

 ICH Q 3 Impurities A set of three guidelines addressing the

chemistry and safety aspects of impurities, including the listing of impurities in specifications. Defines the thresholds for reporting, identification and qualification of impurities in API and finished product. Specific guideline on residual solvents

 ICH Q 3 A(R) in a Nutshell

Defines rationale for the reporting and control of

impurities as well as requirements for listing impurities in specifications: Organic Impurities - Each specified identified impurity - Each specified unidentified impurity - Any unspecified impurity with acceptance criterion of NMT the identification threshold Residual solvents Inorganic impurities

 ICH Q 3 A(R) in a Nutshell

Definitions Identified impurity: impurity for which a

structural characterisation has been achieved Qualification: is the process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified.

 ICH Q 3 A(R) in a Nutshell Definitions Specified impurity that is individually listed and

limited with a specific acceptance criterion in the specification. Can be either identified or unidentified. Unidentified impurity: impurity for which a structural characterisation has not been achieved and that is solely defined by qualitative analytical properties, e.g. chromatographic retention time Unspecified impurity: impurity that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion in the specification

 ICH Q 3 C in a Nutshell Recommends acceptable amounts for residual

solvents in pharmaceuticals for the safety of patients, recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some solvents. Nonexhaustive list of solvents included in the guideline as annex.

Options for Describing Limits of Class 2 Solvents

Option 1: Concentration (ppm) =1000 x PDE/dose Here, PDE is given in terms of mg/day and dose is given in g/day. If all excipients and drug substances in a formulation meet the limits given in Option 1, then these components may be used in any proportion. No further calculation is necessary provided the daily dose does not exceed 10 g .

 Option 2:

It is not considered necessary for each component of the drug product to comply with the limits given in Option 1. The PDE in terms of mg/day as stated in Table 2 can be used with the known maximum daily dose and equation (1) above to determine the concentration of residual solvent allowed in drug product.

THANKS