Abstract

Producing APIs (active pharmaceutical ingredients) in multi-purpose or shared equipment or facilities, respectively, involves the danger of cross-contamination (contamination of the considered API by another) through space, through infrastructure systems and through production equipment. The latter is usually the most relevant. It is controlled by equipment cleaning, depends on the definition of adequate carry-over limits and becomes demanding when producing APIs of strongly differing potency. Engineering measures and working technique determine cross-contamination through infrastructure systems and the efficacy of containment, which impacts on the protection of patients and workers. The toxicological facts to be considered in view of these two populations are similar, resulting in converging regulatory developments and a trend to increasingly comparable, differentiated risk management approaches. This is particularly important for highly potent APIs.

INTRODUCTION

There is old regulatory history of addressing the avoidance of cross-contamination and the safety of workers in the same context. In 1834 the following had already been published on the subject of the legally required inspections of pharmacies (translated from German) (1): “The laboratory for the production of medicines has to ensure comfortable, safe and uninhibited working… and … it goes without saying that one has all the right to in the first place ask for installations and equipment which are orderly, clean and allowing for speed.” The mention of speed was mainly targeting the avoidance of bio-burden and the resulting deterioration of the almost exclusively natural products. This aspect was only heuristically understood at the time, is controlled in much more sophisticated terms today, and will not be further addressed in the present publication.
Since these early days, production of drugs in pharmacies has become a minor aspect of the whole healthcare system, and industrialisation has led to high standardisation and strongly increased storability of drugs, thanks to far reaching specialisation of their manufacturing an ...