Alert limits

Limits placed upon impurities that are carried along with the production of an API reflect upon the control of the manufacturing process. To ensure that control has been maintained during the process, a manufacturer may set alert limits for specified starting materials found in the drug substance. Alert limits are generally significantly lower than those required by an approved application. These limits are usually so low that they only indicate that the process should be closely monitored. 

If alert limits are in place, a manufacturer will typically also have action limits. These are limits that indicate that the manufacturer needs to intercede in some way to bring the process back under control before a lot fails the release specification. These limits are also usually lower than the acceptance criteria required by an approved application. 

Establish target and alert limits for chemical and microbial quality. 

SOP No. Val. 1400.1 C Type of Water 1 Alert Limit Effective date mm/dd/yyyy Approved by Action Limit... 

For each cleanliness class in the injectable preparation area (e.g., class 100, class 10,000, and class 100,000), alert limits will be half the number of particles allowed of 0.5 and 5.0 pm for each area. Area supervisors shall be immediately notihed verbally of particles exceeding the alert limit (in any of the three readings) in any area for corrective action. 

For continuous monitoring in the Riling area, particle counter probe will be positioned at a distance of not more than 12 in. from the filling nozzle (same identified position as used in the media fill runs for the vial and ampoule filling machine). Alert limits are as follows ... 

Type of Water Alert Limit Action Limit... 

Note It is appropriate to increase or decrease alert limit based on the trend performance. 

Room Activity/Works Area Position for Routine Monitoring Position for Intensive Monitoring Frequency Alert Limit Action Limit... 

Alert Limit Action Limit Results Remarks Alert Limit Action Limit Results Remarks... 

The viable count records of room air quality during media-filling mn 1, mn 2, and mn 3 were reviewed and found satisfactory, in accordance with the SOP. All the results were found within the alert limit. The microbes were identihed and represented the normal flora, indicating no new microbe introduced during the aseptic processing. 

The postmedia-fill run results for viable and nonviable count after cleaning and sanitation did not show any deviation and the results for the 3 consecutive days were found satisfactory and within alert limits. 

V. USING VALIDATION EXPERIENCE TO SET PRODUCT ALERT LIMITS... 

The recommendation to use control limits calculated as part of validation as alert limits is based on the expectation that test results from future production should normally fall within these limits. Indeed, this is the essence of retrospective validation. Furthermore, for a stable, centered process the control limits would fall within the release specification for the test. Exceeding an alert limit therefore would not necessarily delay product release but could precipitate an investigation into the cause. 

Quality assurance may request postapproval stability studies on specific batches of product to confirm that those batches have the same stability profile usually associated with that product. Special stability studies may be requested for batches that experienced manufacturing deviations, exceeded internal alert limits even if they passed regulatory specifications, exhibited... 

If results are over an alert limit, but not over the action limit, then enhance monitoring frequency for X cycles. (X is determined by the critical level of the area and process where the over-limit event occurred, but should provide an adequate interval to assure detection of a continued deterioration of process control.)... 

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