Phase 1 Stability; Agency Expectations

Phase 1 Stability; Agency Expectations


My Company Plans to Manufacture a Phase 1 Product for which Stability may be an Issue. What kind of Focus on Stability do we Need to Satisfy Health Authorities’ Expectations?


Before you decide how much stability data you require, it is vital to understand the nature of your Dosage Form and Delivery System Requirements (the route of administration and delivery system). Even if there is a diversity of testing in place, these choices have a significant impact on the scientific and regulatory aspects of a stability protocol, which can still fail to meet the most stringent regulatory reviews. From a regulator’s point of view, and in general, all dosage forms are evaluated for appearance, assay, and degradation products. Additional tests (i.e., potency) are needed for specific dosage forms. For example, sterility is needed for sterile products but not for tablets or capsules. In addition, not every test will be performed at each time point.

Studies of drugs for injection (i.e., parenteral) include monitoring for appearance, clarity, color, reconstitution time, and residual moisture content. The stability of the drug for injection products must also be evaluated after reconstitution, according to the recommended labeling. Small volume parenteral (SVPs) are a wide range of injection products (e.g., drugs for injection, drugs for injectable suspension, and drugs for injectable emulsion). Large volume parenteral (LVPs) studies include evaluation of product stability following exposure to at least the maximum specified process lethality. Interaction of administration sets and dispensing devices are considered to ensure that absorption and adsorption during dwell time do not occur. Some LVPs are designed for multiple uses. These products are evaluated for stability after opening with part of the content removed. The “in-use” studies last from seven days to four weeks.

The functionality and integrity of parenterals in prelled syringe delivery systems needs to be evaluated throughout the expiration dating period with regard to factors, such as the applied extrusion force, syringeability, pressure rating and leakage. Continued assurance of sterility for products is by a variety of means, including evaluation of the container and closure integrity.

Specific parameters to be examined for reconstituted drug products include appearance, clarity, color, pH, assay (i.e., potency), preservative, degradation products/aggregates, sterility, pyrogenicity and particulate matter. Studies for drug injectable suspension and drug for injectable suspension also include particle size distribution, dispersibility and rheological properties. The studies for drug injectable emulsion products also include phase separation, viscosity and mean size and distribution of dispersed phase globules.

When a drug product or diluents is intended for use as an additive to another product, the potential for incompatibility exists. In these cases, the drug product labeled to be added to another (e.g., parenteral, inhalation solutions) should be evaluated for stability and compatibility in the mixture both in upright and inverted/on-the-side orientations. The tests should provide for tests to be conducted at appropriate time points over the intended use period at the recommended storage and use conditions.

The evaluation of inhalation powders includes aerodynamic particle size distribution of the emitted dose, microscopic evaluation, microbial limit, moisture content, foreign particulates, content uniformity of the emitted dose and number of medication doses per device that meets content uniformity of the emitted dose (metered-dose products). The unique characteristics of metered-dose and dry-powder inhalers can affect the product’s efficacy as well as the ability of the product to deliver reproducible doses. These factors must be considered during development with respect to formulation, stability, manufacturing, container and closure system and quality control.

Stability data for products supplied in closed-end tubes should support the maximum anticipated use period after the tube seal is punctured, allowing product contact with the cap. Ointments, pastes, gels and creams in large containers, including tubes, should be assayed by sampling at the surface, top, middle and bottom of the container. In addition, tubes should be sampled near the crimp.

Evaluation of ophthalmic or optic products (e.g., creams, ointments, solutions and suspensions) includes sterility, particulate matter and extractable. Evaluation of nonmetered topical aerosols includes appearance, assay, degradation products, pressure, weight loss, net weight dispensed, delivery rate, microbial limits, spray pattern, water content and particle size distribution (for suspensions).

In summary, stability is an integral component of a CMC program and a comprehensive testing regimen includes a broad scope of analytical evaluations. The importance of assuring the physical and chemical properties early on and throughout the development and commercialization of a compound is key to effectively managing resources and costs. The inclusion of a well-designed stability program in the development pathway can help alleviate devastating regulatory pitfalls and facilitate a cost-effective process.

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