Investigative process

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Investigative process

Investigative Procedures When

Incurred Sample Repeats (ISR) Fail

Dick Tacey


Why conduct ISR

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• ISR provide a measure of assay reproducibility in

individual subject samples and will quickly identify

analytical issues which lead to variability of results

• The conference report of the Third AAPS/FDA

Bioanalytical Workshop held in May 2006 (1) called for

incurred sample reanalysis to be conducted

• A follow up workshop held in February 2008 (2) provided

recommendations for conducting ISR and suggested

acceptance criteria

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What types of ISR failures do we observe

• Isolated random individual ISR failures

• Systematic multiple ISR failures

• Analyst performance related failures (i.e. pipetting,

diluting, mixing)

• Method issues (i.e. solubility, performance history)

• Sample issues (i.e. stability, matrix, properly labeled,

stored, handled)

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Evolution of Approach to Investigating ISR Failures

• The process must be uniform across studies

• To achieve uniformity and compliance we hired a QA Investigation

Specialist

- provides general oversight across all labs and

technologies

- issues controlled forms which are very detailed and record the

investigative process

- tracks and records activities

- ensures uniformity and compliance of

investigative approach

- looks for patterns or trends

- ensures completion in a timely manner

• Most laboratories have an SOP to define the ISR process. As we gain

more insight into the ISR process these SOPs continue to evolve.

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ISR - 2007

• Analyze 10% of study as ISR (~10% from each run)

• Selection of samples should be semi-random falling

in a concentration range of 2xLLOQ to


ISR - 2008

• Analyze 10% of study as ISR (~10% from each run)

• Selection of samples should be semi-random falling in a

concentration range of 2xLLOQ to


ISR - 2009

• Analyze 10% of study as ISR (2/3 runs must be represented)

• Selecting ISR – consideration should be given to choosing samples

with primary analyte concentrations at or near Cmax and toward the

elimination phase but >2x LLOQ

• ISR for a project are acceptable if 2/3 have an RPD of 20% for

chromatographic assays and 30% for immunoassays (failure

requires investigation)

• Any individual ISR quantitating 67% RPD requires duplicate

reanalysis with management approval. Report results per decision

tree.

• 2/3 of ISR supporting an original analytical run must meet the RPD

criteria (laboratory management determines if an investigation is

required)

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Investigative process

• Observation of anomalous results by analyst

- Notify the Bioanalytical Principal Investigator

- Confirm that the problem exists

- Identify and correct the problem

or

- Notify Manager and complete anomaly form if

anomaly cannot be immediately resolved

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Investigative process (continued)

• Analytical anomaly confirmed by Manager

- Resolve and close anomaly report, then

resume sample analysis

or

- Escalate and conduct Level I Investigation

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Investigative process (continued)

• Level I Investigation

- Review background

- Assess analytical process

- Write investigative plan including proposed

experiments

- Review results of experiments

- Document conclusion

- Determine extent of impact

- Complete Corrective and Preventative Action (CAPA)

- Close and resume sample analysis

or

- Escalate to Level II Full Scale Investigation

(Management decision)

- Notify Sponsor/Study Director

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Investigative process (continued)

• Level II Investigation

- Notify V.P. of Bioanalytical Laboratories

- Complete Level II Full Scale Investigation Form

• Reason for investigation

• General project information

• Historical review

• Additional analysis plan

• Additional analysis results and assessment

of impact

• Conclusion

• CAPA

• Close investigation

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ISR can also stand for …

“In Search of Relief”

In the next presentation Joe Bower will talk

about ways to avoid ISR failure, increase

success and hopefully provide some relief.

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Acknowledgements

• Bob Nicholson – VP Bioanalytical Labs

• Helen Lysy – Director, QA

• Donna Roney – Investigation Specialist

• Ed Tabler – Laboratory Manager

• Jim Gorman– Laboratory Manager

• Laura Schild Hay – Senior Research Scientist

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References

1. Viswanathan, et al, “Workshop/Conference

Report – Quantitative Bioanalytical Method

Validation and Implementation: Best Practices

for Chromatographic and Ligand Binding

Assays,” AAPS Journal, 9(1): E 30-42, 2007

2. Fast, et al, “Workshop Report and Follow-Up

– AAPS Workshop on Current Topics in GLP

Bioanalysis: Assay Reproducibility for Incurred

Samples – Implications of Crystal City

Recommendations,” AAPS Journal, 2009

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