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Pharma&Biotech
Conducting Effective OOS or OOT Investigations for Unexpected Results from the BET Assay
Dealing with Unexpected Results in Routine Testing
In a well controlled aseptic production process, the likelihood of product adulteration by endotoxin should be minimal
This means that the vast majority of results generated in the BET should be either below the Endotoxin Release Limit (ERL) for the product or undetectable i.e. below the detection limit of the assay
However, unexpected results can and do occur with some frequency in QC laboratories, worldwide 2 Jun-13
FDA Guidelines on OOS & OOT Results
OOS (Out of Specification) “All suspect results that fall outside the specification or acceptance criteria established in new drug applications, official compendia, or by the manufacturer”
OOT (Out of Tolerance) Consideration should equally be applied to results which are atypical and could constitute an increased risk
Source
FDA Guidance for Industry. Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production. http://www.fda.gov/cder/guidance/index.htm
3 Jun-13
Initial Assessment
There should be an objective and timely assessment to:
Establish likelihood of laboratory error
OR
Confirm there is an indication of manufacturing process / product problems Assess significance of the result in overall QA program
The process for making the decision on these key questions must be documented in an approved SOP
4 Jun-13
BET Assay Assessment Flow Chart Test passes
Assay criteria met %CV standard correlation Y-INT/slope Blank reaction < Lowest standard
Sample criteria met %CV standard Single well reaction PPC recovery
Assay criteria NOT met Assay invalid
Sample criteria NOT met Sample invalid
Retest whole assay
Retest invalid samples
Endotoxin recovery within limits
Result OOS Test fails
OOS investigation
Not OOS but INVESTIGATE if REPEATED 5 Jun-13
If an OOS Investigation Is Merited
Report suspect result to QA/Regulatory for assessment
Notify production of need to investigate process
An investigation team should be formed
Start a documented investigation process, as soon as possible
Make preliminary assessment of effects
Inform customer services / production of potential consequences
6 Jun-13
Can the Result Be Attributed to Laboratory Error ?
Supporting historical data with trend analysis will help
Justify the decision making process Suggest Corrective And Preventative Actions (CAPA)
Working with paper-based reports or excel spreadsheets can be cumbersome
As kinetic BET assays generate large volumes of data, a database approach is recommended with Structured Query Language capability
Training records Contamination during dilution Retest originals Retest new samples
Test equipment Test reagents Test consumables
OOS result
Any unusual events during testing?
Contamination in other tests? 8 Jun-13
A Logical Approach Can Focus the Investigation
When investigating potential laboratory error, use logic to narrow the field of investigation
I usually classify issues with kinetic assays into one of three types
Likely to cause individual well variations, i.e. one well in error in a pair Likely to cause multiple replicate errors, i.e. duplicate wells are in error Likely to cause multiple well variations (all or several wells on the same plate in error)
Similarly, you can identify factors that are likely to only affect the standard curve or only likely to affect sample results.
Doing this will narrow the field of search, when asking questions of the database. 9 Jun-13
PPC Out-Of-Trend – Situation
The following example illustrates the ease and efficiency of investigating OOS or OOT results using trend analysis:
Company ‘XYZ’ makes an antibiotic ‘Polymegacillin’
PPC recovery percentages are normally consistent but recent assays show a sharp upward trend, with OOS & OOT results
Endotoxin results for the unspiked samples appear normal and follow previous trend
10 Jun-13
Potential Sources of Error in PPC Recovery
What could be the possible cause(s)?
Technician Error?
Glucans?
Sample contamination?
Accessories?
Change in product formulation?
Plan of action?
Data Analysis & Trending using the built-in Trend Analysis module of the WinKQCL™ Software
11 Jun-13
Query qualifiers used
Sharp upward trend for PPC results from assay 31 onwards
Query qualifiers used 5 analysts involved
Query qualifiers used
Nearly all OOT PPCs performed by PJONES Faulty technique? Contamination?
Isolate items most likely to be involved
e.g. P20 pipettor
Only two P20 units in active use One unit PIP782 only used by technician PJONES
Query qualifiers used
P20 with ID 782 is associated with all high PPC values
Query qualifiers used in this case to highlight the evidence
Evidence clearly indicates a problem with the P20 unit PIP 782 is the culprit and not technique
Conclusions
Use of a SQL-database trending program can help identify the cause of unexpected OOS or OOT results
Such a database should be designed to automatically collect this data, as in the case in Lonza’s WinKQCL™ Endotoxin Detection and Analysis Software
The ability to cross-examine and trend data using query qualifiers helps to rapidly uncover the source(s) of error
Use of such an integral database can save both time and money, whilst providing documentary evidence for decision processes
