Hold-Time Studies

As the name implies, a study must exist for every time lapse (that is, hold time) anticipated or intended to occur between any two API and drug manufacturing process steps. Tests used to judge the quality of the material in question after any hold time must be scientifically reliable and, ideally (but not necessarily), validated. Product and process design risk identification is expected to identify all hold times in API and drug manufacturing processes, and those risks assessed through hold-time studies. Cleaning processes have hold times that must be characterized and the maximum duration established. Bulk hold time represents the time lapse between completion of most of an API or drug manufacturing process and the primary packaging. For materials consisting of an emulsion, a suspension, or other multiple-phase combination, hold-time studies are most critical. Hold times are critical for cold-chain products (for example, proteins, vaccines, sensitive antibiotics) that undergo a primary or secondary packaging operation at ambient temperature.

Physico-Mechanical Simulations and Shipping Studies

In addition to ICH and any competent authority–mandated stability (and photostability) studies minimally required to be approved to ship and market a new drug product through and into various climatic zones, several studies are usually expected or mandated: physicomechanical simulations of vibration, shaking, package impact, and pressure changes, and shipping studies. The best reference for these physicomechanical and shipping studies is USP General Chapter <1079> “Good Storage and Shipping Practices.” According to <1079>, a drug can take any number of routes to the ultimate consumer or patient, which may include a complex series of transfers outside the marketing owner’s control.

It is usually expected in shipping studies for APIs and finished drugs that within the secondary or tertiary packaging will be judiciously placed (and calibrated) temperature and other indicators that may be inspected or downloaded at the receiving site. The API or drug product must undergo complete release testing at its destination. APIs and drug products with temperature sensitivities reflected in the labeling must use temperature cycling and shipping studies that greatly stress the insulating or refrigerating properties of the tertiary package. PDA Technical Report 39 provides strategies for cold-chain dominated shipping studies. Stability, physicomechanical, shipping, and cold-chain studies enable the product development team to conclude what excursions in labeled storage conditions are permitted and which necessitate material destruction or return. PDA Technical Report 53 provides guidance on the requirements for stability testing of new drug products to support distribution conditions.

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