What are the most common pitfalls and mistakes to avoid in drug product specification development?

When setting specification limits, ensure that the limit aligns with contemporary regulatory expectations and process capability and that they align with the expected dosage and route of administration of the product. Setting a tighter specification than required may result in lot failures for products that would actually be suitable for the intended use of the product.

Great suggestions by all and germane. I suggest that the reason for the need to update specs originates with inadequate characterization of the subject material, or resulting from a method that wasn’t properly deemed fit for purpose, resulting in aberrations in data points. I propose that analytical methods should follow ICH Q14 principles to minimize this. Additionally, specs were set inappropriately for the subject material that is not fit for the stage of development- often times there is temptation to assign a spec pertinent to later stage development in the early development stages on a false sense of confidence in understanding the material and/process. A simple report results is acceptable.

1) Not having a robust assay for the CQA and the process, is by far the most dangerous pitfall. Not only could the CQA be over or under-estimated, but it could also result in inability to understand the process and critical process steps. 2) Setting a spec with data obtained at a different lab then where routine testing is intended to occur (e.g. tech transfer situations, due to differences in instruments, techniques, etc.) 3) Not understanding the process and making frequent process changes w/o understanding process/product impact. 4) Not understanding the relationship between the attribute, and its impact on patient safety and efficacy - i.e. need to ensure the attribute is indeed a Critical one before being considered for spec setting.

Make sure that ranges are established with equipment tolerances and calibrations in mind. Oftentimes, process specifications are established based on successful development runs without testing the true limitations of "success" and "failure". Without that understanding, a process can be at risk of "hidden" variability as equipment naturally drifts within acceptable tolerance limits.

It is important to understand the difference in specifications for release (EMA) and expiry (US & EMA). Tighter release specifications ensure the product will meet the regulatory/shelf-life specification. All other data should support the quality criteria.

Establecer especificaciones que no le aportan a la calidad de la forma farmacéutica, y, definir especificaciones cuya determinación no es posible realizar en los laboratorios locales.

Pay careful attention to aligning the product specifications with the specifications of incoming raw materials and the capability of the process to change them. If a final product has a very low specification for a residual impurity, it may not be possible to achieve this if raw materials have high levels of it or are used at high levels in processing or formulation.