Responses to Infringements of Limits

Environmental standards and limits have been addressed. Manufacturers of sterile products may adopt published limits, or they may develop their own based on the performance of their facilities, or they may apply limits that are a combination of the two.This is not easy: but it is far more difficult to relate whatever limits have been decided to courses of appropriate action.

In most circumstances, environmental monitoring data should confirm that the environment is in satisfactory control. Infringements of limits should be fairly rare events. But what should be done when they do occur?

Wherever possible a two-tier approach of alert and action limits should be taken to quantitative microbiological data.

There is also a decisional element more evident in microbiology than in other quantitative sciences, as to whether a limit has in reality been breached. Where a limit has been set at, for example, no more than 5 cfu, actual counts of 6 cfu ought to be seen as infringements if the actual pattern of data is along the lines of 0 or 1 cfu, but should not be seen as an infringement if the actual pattern of data is along the lines of 4 or 5 cfu. This is a serious dilemma for QA microbiologists in the pharmaceutical industry. There is no easy answer. Education and communication with personnel responsible for general management, production, engineering and nonmicrobiological QA are probably key. However, whereas a history of reasonable flexibility ought to stand a QA microbiologist in good stead on the rare occasions when he is obliged to "draw a line in the sand," in practice he is more likely to face allegations of inconsistent application of standards.

Excursions beyond alert limits but not exceeding the action limit should initiate informal or semiformal communication with the personnel in charge of the facility or equipment, with the intention of stimulating whatever steps are necessary to avoid subsequent infringements of the action limit. Oversensitive alert limits are counterproductive.

Infringements of action limits should genuinely require action. Communication with personnel in charge of the facility or equipment must be formal. It must be in writing, elicit a written response, and the documentation must be available for inspection by the regulatory agencies. "Action" should not be interpreted as merely the "action" of documenting the infringement. Infringement of action limits must result in meaningful action from the personnel in charge of the facility or equipment.

Actions must be corrective (as indicated by satisfactory data from remonitoring) and should preferably be preventive. Repeated infringements of action limits, resulting in actions only along the lines of "operators were counselled and retrained, the affected part of the facility was cleaned and disinfected" should not be tolerated. Repeated infringements of action limits indicate that the limits have been set too severely, or that the process (in its broadest sense) is not suited to manufacture of sterile pharmaceutical products.

There are a variety of processes appropriate to infringements of action limits. They are specific to particular situations. Some generalisations are, however, possible.

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