Stability Study Acceptance

For APIs, the registration stability study acceptance criteria should be derived from the quality profile of the material used in preclinical and clinical studies. The acceptance criteria should be numerical limits, ranges, and other criteria for specific tests, and should include limits for individual and total impurities and degradation products. 

The purpose of in-use stability studies is to establish the period for which a product intended to be used on more than one occasion may be used after reconstitution or dilution or the withdrawal of the first dose from the container without adversely affecting the integrity of the product and with the product retaining acceptable quality characteristics. This type of test can be applied to any multiple use product (e.g., sterile products in multiple-use containers, powders or granules including those used to produce oral solutions or suspensions) but is likely to be of particular importance in the case of products that are manufactured with an inert headspace gas, for products containing antioxidants to protect an active ingredient that is liable to oxidative decomposition, and for products that contain a volatile antimicrobial preservative. 

Any decision to establish automated or robotic systems must carefully consider prerequisites such as the annual numbers of samples to be processed to achieve an acceptable cost-to-benefit ratio. Late phase development stability studies may benefit from fully automated systems based on the enormous numbers of samples to be analyzed for each stability time point. The use of automated systems in manufacturing quality control is now required due to the sheer number of samples to be... 

Data for which statistical analysis does not apply The proposed shelf life can be up to 3 months beyond the period covered in the stability study for the long-term data. This will require relevant supporting data to show that the drug product will meet all the attribute acceptance criteria by the end of the proposed shelf life period. 

Drug Product Specifications The specification for each attribute of the drug product is required to define the acceptance criteria of the stability study. 

The application (or Type II DMF) should include a detailed description of the complete container closure system for the bulk drug substance as well as a description of the specific container, closure, all liners, inner seal, and desiccant (if any), and a description of the composition of each component. A reference to the appropriate indirect food additive regulation is typically considered sufficient to establish the safety of the materials of construction. The tests, methods, and criteria for the acceptance and release of each packaging component should be provided. Stability studies to establish a retest period for bulk drug substance in the proposed container closure system should be conducted with fillers or desiccant packs in place (if used). Smaller versions that simulate the actual container closure system may be used. 

Excipient compatibility and stability studies rely on two underlying assumptions. One is that there is no change in reaction mechanism as temperature increases the second is that the excipient is also chemically stable under the conditions of test. However, if the reaction mechanism does change with temperature, it is likely the result will show a disproportionately greater breakdown than would be anticipated from lower temperature studies. Thus the risk is that an excipient is rejected that might in reality be perfectly suitable for the formulation. In many cases this is probably an acceptable risk. 

Stability studies are developed to assure a desirable shelf-life period. These also establish limits of acceptability for impurities and degradation compounds, when present, and determine acceptable storage conditions for raw materials and the manufactured products. Stability studies are thus important to the determination of expiration dates for drug products. 

For drug products, the following considerations should be taken into account in setting acceptance criteria for registration stability studies ... 

Regulatory guidances specify appropriate testing frequency for stability studies but do not discuss how to define zero-time, analysis date, analysis time, or how much deviation from scheduled test dates is acceptable. 

Failure to establish yields or acceptable levels of rejects for both in-process and finished product Failure to conduct stability studies Manufacturing equipment not identified and/or qualified Inadequate training of employees working in aseptic operations Inadequate process change procedures Validation protocols that lack acceptance criteria Incomplete investigations of laboratory failures Failure to follow United States Pharmacopeia (USP) procedures for the bacterial endotoxin test... 

The goal of solution stability for different tests can vary. For assay and degradation product test, no new degradation products (over time and above LOQ) should be formed in solution. Certain acceptance criteria (max % increase) may be set for impurities at particular levels during the solution stability study. For assay determination (assay, CU, and dissolution), the content of assay over time should not change more than 2.0%. Also, refer to Chapter 9, which discusses method validation. 

ICH guidelines ° describe and discuss stability issues and testing requirement for NCEs and macromolecules. These guidelines provide manufacturers and CSOs with acceptance specifications for accelerated and long-term stability studies. In addition to the drug substance and drug product, stability assessment is frequently conducted on raw materials, key intermediates, formulation excipients, and packaging materials. 

With the exception of BA studies that are not conducted for the stability studies, all the above-mentioned tests are performed after storing the product in the package material to declare that products of acceptable quality after the manufacturing. In vitro... 

The formulator of liquid multivitamin pharmaceutical products such as baby drops, syrups, elixirs, and injectables encounters numerous problems in attempting to develop products having adequate physical and chemical stability as well as suitable taste, odor, color, and freedom from bacterial contamination. Many of these problems arise from the diflFering solubility and stability characteristics of the individual vitamins, particularly as these relate to the pH of the solutions and potential interactions. Despite these numerous problems, various ways have been devised for producing multivitamin combinations in liquid form containing L-ascorbic acid that have acceptable stability characteristics. Successful development of such products requires a knowledge of (i) the fundamental aspects of the physical and chemical properties of the vitamin forms available (ii) the use of adequate techniques of manufacture and (iii) the employment of suitable overages based on critical stability studies. 

Formal stability studies must be performed to determine key parameters to support an acceptable and successful marketed product. The following are some of the parameters required ... 

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