Stability programs, requirements

Current Good Manufacturing Practices [135] establish the requirements for maintaining a stability program and require that most pharmaceutical dosage forms have an established expiration date supported by test data [134]. There are few allowable exceptions. 

QA requires the efficient analysis of many samples to support routine production release and stability programs. Methods are typically established in the analytical development group. Efficiency and convenience issues, including the speed of media preparation and the relative convenience of data handling and documentation, are important here. While compliance is important in all aspects of the pharmaceutical industry, QA functions must approach compliance perfection. Depending upon the facility, the automated apparatus may be tailored to specific methods with fixed configurations. Dissolution methods may be routine enough that a custom system, optimized for productivity, may be justified. Compliance of USP and use of industry standard apparatus is important to maintain compatibility with other company laboratories or in the case contract laboratory services are required. 

Different companies define zero-time in different ways. It may be the date corresponding to the completion of the manufacture of the bulk product, the start or end of packaging, the release by quality assurance (QA), the placement of samples in the stability chambers, or other measures. These dates can differ significantly for a variety of reasons, such as scheduling conflicts in the manufacturing and packaging departments and the time required to initiate a stability program. 

A well-designed stability program meets all regulatory requirements and attains its objectives with minimal expenditure of resources. It provides all necessary data in a form that can be easily interpreted and evaluated, and distinguishes between analytical variability and instability. It specifies a testing frequency, which will provide early detection of instability and support the desired expiration-dating period. 

A product-specific stability protocol supplements the information provided in the stability program SOP. In some instances, the requirements in a product-specific stability protocol may differ from those specified in the stability program SOP for scientific, regulatory, or business reasons. In all cases, aproduct-specific stability protocol takes precedence over the general stability program SOP. The product-specific stability protocol should clearly define and justify both the conditions to be used and any deviations from the stability program SOP, including reason and justification. 

Preventative Action. This observation could have been avoided by establishing a stability testing program SOP that specifies batches that are to be entered into the annual stability program, including all container-closure systems, and that requires that all commercial container-closure systems be tested. The stability program must include an evaluation of degradants and impurities if it is intended to assess stability. Additionally, a product-specific stability protocol should have been developed that specified the methods to be used. 

There are three types of stability testing (technical, clinical, and registration) performed during formulation development. Requirements of a stability program increases going from technical to clinical to registration. The major requirements for each of these are summarized in Table 15-7. In addition, the... 

Stability testing will be guided mainly by the conditions approved in the IND. However, the manner in which the stability program is managed should be similar to that required for commercial products. For example (not an all inclusive list) ... 

The Corrective Action program requires corrective action (e.g., removal, stabilization, engineering controls) for all releases of hazardous waste or chemical constituents from any solid waste management unit at a facility seeking a permit under Subtitle C,... 

Chapter 8 in Reference 2 reviews the many facets of stability studies and describes what a modern stability program includes. Efforts have been made to relate scientific considerations with regulatory requirements. Degradation kinetics is discussed later in this section to highlight their importance in monitoring and evaluating impurities.2... 

Generally, a considerable waiting period is required to obtain data to establish the expiration date of a drug at shelf temperature (as most of the marketed products are relatively stable). The accelerated stability study, based on the study of rate of degradation in several storage conditions, is frequently used to circumvent this time limitation. Stability programs proposed by the FDA as part of the NDA submission are described below. 

Phase IV occurs after product approval and launch and the typical stability studies are focused on the marketed product stability program. These studies are conducted to assure that the product continues to meet the stability requirement for the approved expiration date. Therefore, these studies are conducted at the label storage conditions only. However, if new strengths, packages, or formulations are being developed, these studies would be conducted at accelerated storage conditions also. 

Not only is it important to consult these guidelines for structuring your stability program, but it is also important to be aware of other additional specific requirements of the various governing agencies. For example, the FDA published a draft stability guidance document, which included the ICH requirements and also defined and interpreted the ICH guidelines to include information they specifically require (e.g., site-specific stability). 

Because the stability chambers are an integral part of the stability program and require continuous performance to specifications for long-term studies, all aspects of the chambers must be described in detail in an SOP. The SOP should include the procedures and the schedule for calibration of the chambers, the description and operating parameters, a routine maintenance schedule, inventory system, IQ/OQ procedures and a monitoring system (PQ), and emergency procedures for malfunctions or unusual occurrences. 

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