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05.Apr.2013

Atypical or Aberrant Results: OOS/OOT scenario with inglasia suggested answers

(scenarios originally published within inglasia Linkedin group: GMP/GDP Quality Management Documents and Training for Pharmaceutical Companies)

Consider the following scenarios and review them in light of FDA and EU requirements. Note: they may not contain all the information you need to form a reasonable judgement. Answer the following questions in your response:
a. What are the key issues?
b. What further information do you need?
c. What further investigation or actions would you have taken?
d. What documented evidence would you require?
e. Do you agree with the decisions taken in the scenario?
 Scenario 1


An assay result on a final product, measured on a sample of a bulk injection, is 20% low. The laboratory investigation suggests a 20ml pipette was used instead of a 25ml pipette. However, the technician did not record which item of equipment was used as he was not required to. The analytical solutions and the original test sample were discarded but the laboratory sample had been retained. No production errors were recorded in the manufacturing records and a reconciliation of the active ingredient stocks confirmed that the correct amount of API had been used in the batch manufacture. The original laboratory sample was re-tested by two separate, more experienced technicians. Both produced results which were within specification and close to each other. It was therefore concluded that an analytical error had been made and the batch was passed by QC.
inglasia Suggested Answers:
a) What are the key issues?
1) Why were the analytical solutions and the original test samples discarded before the results were checked?
2) Are requirements – for the recording of equipment and apparatus used – appropriately specified?
3) Why was retesting done before the investigation had been completed?
4) Was the technician competent and properly trained?
5) Is the analytical method description detailed enough?

b. What further information do you need?
1) Were 20ml pipettes readily available in the laboratory?
2) Training records of the technicians
3) Analytical method review
4) Confirmation of absence of calculation errors
5) Sample usage reconciliation

c. What further investigation or actions would you have taken?
1) Review control of volumetric glassware
2) Review of raw data
3) Consider other possibilities (e.g. 200ml/250ml flask)
4) Try to reproduce the error
5) Retesting with control samples
6) Trend analysis of previous product batches
7) Original technician to retest alongside two experienced analysts
8) Documented CAPA for remedial actions.

d. What documented evidence would you require?
1) OOS SOP
2) Training record of the technician involved
3) Raw data/worksheets
4) Retest data
5) Investigation report addressing the entire investigation

e. Do you agree with the decisions taken in the scenario?
Inadequate failure investigation. Assignable analytical cause of error and release of the batch.

Scenario 2


An HPLC assay for a topical preparation had an RSD based on single assay of 2.7%. This was shown, as part of a method validation, to be due to a difficult extraction procedure. In order to reduce this RSD the method requires the assay to be carried out in triplicate i.e. three separate portions of the laboratory sample taken through the procedure. The assay value is taken to be the average of the three determination and acceptance criteria for the maximum spread of results. An inspector was of the opinion that the company should not accept a batch if any of the three individual results was out of specification. The firm countered by saying that what they are doing is scientifically sound and that they were correct in passing batches on this basis.
inglasia Suggested Answers:
a) What are the key issues?
1) What is the reportable value?
2) What is an analytical result?
3) What is to be compared with the specification?
4) What are the analytical process capabilities?
5) What are the regulatory requirements?

b. What further information do you need?
1) Method Validation report
2) Statistical justification for the reportable result approach?
3) What has been registered?

c. What further investigation or actions would you have taken?
1) Review method validation reports
2) Revision of the analytical method/SOP if insufficiently clear in defining and justifying the reportable value.

d. What documented evidence would you require?
1) Clear concise definitions of reportable values and their generation
2) Briefing paper giving full statistical approach justification

e. Do you agree with the decisions taken in the scenario?
Data integrity and compliance issue not an OOS issue.

Scenario 3
A company carried out stability tests on three batches of product per year. Long term storage tests (ICH Q1A(R)) are carried out at 6 months, 12 months, 2 years and 3 years. One sample gave a low assay result (OOT) at 12 months but the other two batches tested earlier in the programme were satisfactory. The decision was to wait for the next stability time point. This was satisfactory and no action was taken.
inglasia Suggested Answers:
a) What are the key issues?
1) What was the basis for the decision to wait till 24 months?
2) Quality Management failure?
3) Why were the ICH time points (3 & 9 months) not performed?
4) Is there a data review SOP?
5) Who reviewed the analytical records?
6) Why was an OOT investigation not carried out?

b. What further information do you need?
1) Additional storage condition/temperature data?
2) Review of other tests at this time point e.g. related substances
3) Were the samples stored correctly?
4) Was the primary packaging damaged?
5) Equipment calibration/performance records
6) Detailed review of the analytical raw data
7) Review original manufacturing records.

c. What further investigation or actions would you have taken?
1) Review analytical method development and validation reports
2) Re-analysis solutions if available
3) Re-test immediately if sufficient samples permit with increased replication
4) Re-test at 18 months if sufficient samples permit with increased replication.

d. What documented evidence would you require?
1) Storage condition records
2) Stability history of product
3) Batch manufacturing and testing records
4) Investigation report

e. Do you agree with the decisions taken in the scenario?
Not compliant with ICH/FDA stability testing requirements. Quality Management failure with potential recall situation.