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1、Out Of Specification Investigations. How to Use The Investigation of Out Of Specification Flowchart Navigation: This file should be viewed using the Slideshow View. Clicking on those Process Step boxes with a heavy border in a process flow slide will take you to a new slide with further detail about
2、 that step. Each step has a link to return to the Overview Slide. This moves the slide upwards This moves the slide downwards to the next slide Laboratory Analysis Satisfactory OOS (OOT) Result Phase Ib Investigation Phase II Investigation Manufacturing Investigation Product Impact Assessment Phase
3、III Investigation Batch Disposition Phase la Investigation Satisfactory Laboratory Analysis Investigations of “Out of Specification (OOS) / Out of Trend (OOT)/ Atypical -results“ have to be done in cases of: Batch release testing and testing of starting materials. In-Process Control testing: if data
4、 is used for batch calculations/decisions and if in a dossier and on Certificates of Analysis. Stability studies on marketed batches of finished products and or active pharmaceutical ingredients, on-going / follow up stability (no stress tests) Previous released batch used as reference sample in an
5、OOS investigation showing OOS or suspect results. Batches for clinical trials. All solutions and reagents must be retained until all data has been second person verified as being within the defined acceptance criteria. Pharmacopoeia have specific criteria for additional analyses of specific tests (i
6、.e. dissolution level specification for S1, S2 Uniformity of dosage units specification for testing of 20 additional units; Sterility Testing). However if the sample test criteria is usually the first level of testing and a sample has to be tested to the next level this should be investigated as it
7、is not following the normal trend. The OOS process is not applicable for In-process testing while trying to achieve a manufacturing process end-point i.e. adjustment of the manufacturing process. (e.g. pH, viscosity), and for studies conducted at variable parameters to check the impact of drift (e.g
8、. process validation at variable parameters). OOS / OOT Result Out-of-Specification (OOS) Result Test result that does not comply with the pre-determined acceptance criteria (i.e. for example, filed applications, drug master files, approved marketing submissions, or official compendia or internal ac
9、ceptance criteria). Test results that fall outside of established acceptance criteria which have been established in official compendia and/or by company documentation (i.e., Raw Material Specifications, In-Process/Final Product Testing, etc.). Out of Trend (OOT) Result Is generally a stability resu
10、lt that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study. However the trends of starting materials and in-process samples may also yield out of trend data. The result is not necessarily OOS bu
11、t does not look like a typical data point. Should be considered for environmental trend analysis such as for viable and non viable data (action limit or warning limit trends) Atypical / Aberrant / Anomalous Result Results that are still within specification but are unexpected, questionable, irregula
12、r, deviant or abnormal. Examples would be chromatograms that show unexpected peaks, unexpected results for stability test point, etc. No Error found Phase la Investigation No Further Investigation Required Obvious Error Document and Correct Invalid Result Initiate Phase Ib Laboratory Investigation P
13、hase la Investigation Definition: Phase la investigation is to determine whether there has been a clear obvious errors due to external circumstances such as power failure or those that the analyst has detected prior to generating data such as spilling sample that will negate the requirement of a Pha
14、se Ib investigation. For microbiological analysis this may be after the analysis has been completed and reviewed during reading of the samples. It is expected that these issues are trended even if a laboratory investigation lb or ll was not raised. Phase la Investigation - Obvious Error Examples Cal
15、culation error analyst and supervisor to review, both initial and date correction. Power outage analyst and supervisor document the event, annotate “power failure; analysis to be repeated” on all associated analytical documentation. Equipment failure analyst and supervisor document the event, annota
16、te “equipment failure; analysis to be repeated” cross reference the maintenance record. Testing errors for example, spilling of the sample solution, incomplete transfer of a sample; the analyst must document immediately. for microbiology it could be growth on a plate not in the test sample area, negative or positive controls failing. Incorrect Instrument Parameters for example setting
