Whenever results are OOS or out-of-trend, a formal investigation must be undertaken. The investigation invariably starts with
a thorough review of the raw data. Assuming no errors are noted, then the CAL should contact the client to discuss the next
course of action.
It may be that no further action is required. Clients may occasionally (and without notice to the CAL) request the analysis
of known OOS samples to test the competency of the CAL, or to confirm an in-house result. Clearly in these two cases, the
OOS result is to be expected.
However, when the OOS is unexpected, further investigations will be required.
FDA's Guidance on OOS Results
The FDA's most recent guidance on investigating OOS test results provides some significant additions to previous guidance.1 Its most significant changes from previous guidance are the following;
- the scope and background was revised to clarify the applicability of the document
- the section on investigating OOS results, averaging, and concluding the investigation was reorganized
- specific guidance on certain issues was added or clarified.
The guidance addresses investigations of OOS results in the laboratory phase, including responsibilities of the analyst and
supervisor, and when indicated, the expansion of an investigation outside of the laboratory to include production processes
and raw material, as appropriate.
The new guidance is a bit confusing in certain parts, however, and from the perspective of the CAL, there are one or two surprising
omissions. In the FDA guidance, an OOS result is defined as,
"all test results that fall outside the specifications or acceptance criteria established in new drug applications, drug
master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests
that are outside of established specifications."
Interestingly, Section II of the FDA guidance states, "The responsibility of a contract testing laboratory in meeting these
requirements is equivalent to that of a manufacturing firm." Later, in Section III it is stated, "For contract laboratories,
the laboratory should convey its data, findings, and supporting documentation to the manufacturing firm's quality control
unit (QCU), who should then initiate the full-scale OOS investigation."
These two statements appear to contradict each other, suggesting on the one hand that the CAL has equal responsibility with
the manufacturer, and on the other that it is only responsible to the manufacturer. In practice, of course, investigating
OOS results is usually a mutual decision, prompted by the reporting of results by the CAL, proposal of follow-up investigation
by one or both parties, and agreement of the contractual basis on which the work is being carried out.
Corrective or Preventative
The new guidance is surprisingly lacking in detail as to how OOS results should be classified and followed up. It merely notes
that, "the source of the OOS result should be identified either as an aberration of the measurement process or an aberration
of the manufacturing process."
From the laboratory's perspective, it is far more useful to drill down to the detail and assign the error more specifically
(e.g., dilution error or wrong sample weight used). Our own laboratories would always seek to assign a conclusion to any investigation
(i.e., calculation error, method error, equipment error, technician fault, or genuine OOS). This affords the opportunity to
analyze OOS results for specific trends to highlight potential weaknesses in our own quality system, and also provides greater
assurance to the client that an OOS result reported as arising from manufacturing error is indeed genuine.
Section III of the guidance states that, "corrective action to prevent recurrence" should occur whenever laboratory error
is identified as being the cause of an OOS result. However, this author is in favor of the term "preventive action," which
is used later in the section.
Leaving aside the semantics, where the laboratory has shown that there has been a fault in the production process rather than
the testing process, there is more investigative analysis that the laboratory can undertake to establish the root cause of
the OOS result.
It helps if there has been a history of good communication between the CAL and client. Investigating an OOS result may necessitate
the client disclosing sensitive, proprietary information to the CAL so that they can make sense of what has gone wrong. It
may be necessary to open up manufacturing facilities to the CAL so that samples can be taken and processes be understood.