Out Of Specification Investigation Phase Ia & Phase Ib (MHRA)

Out Of Specification Investigation Phase Ia & Phase Ib (MHRA)

Phase Ia Investigation


Out of Specification Investigation 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 Phase 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


Calculation 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, annotate “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 the detector at the wrong wavelength, analyst and supervisor document the event, annotate “incorrect instrument parameter”; analysis to be repeated” on all associated analytical documentation .

If no error was noted, and none of the above conditions were met Phase Ib investigation must take place.

Phase Ib Investigation

Specification –

A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests described.  It establishes the set of criteria to which a drug substance, drug product or materials at other stages of its manufacture should conform to be considered acceptable for its intended use.  “Conformance to specification” means that the drug substance and drug product, when tested according to the listed analytical procedures, will meet the acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval.

Regulatory Approved Specification

Specifications for release testing.  If no release specifications have been established then the internal specification becomes the release specification.

Acceptance Criteria –

Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures which the drug substance or drug product or materials at other stages of their manufacture should meet.

Internal Specification –

Are also action limits within regulatory specifications.

Phase Ib Investigation – Definitions

Assignable Cause –

An identified reason for obtaining an OOS or aberrant/anomalous result.

No Assignable Cause  –

  When no reason could be identified.

Invalidated test –

  A test is considered invalid when the investigation has determined the   assignable cause. •

Reportable result –

Is the final analytical result. This result is appropriately defined in the written approved test method and derived from one full execution of that method, starting from the original sample.

Warning Level or Trend excursions

If two or more consecutive samples exceed warning (alert), or if an increasing level of counts, or same organisms identified, over a short period was identified consideration should be given to treat the results as action level excursions.

Hypothesis/Investigative Testing

  Is testing performed to help confirm or discount a possible root cause i.e what might have happened that can be tested:- for example it may include further testing regarding sample filtration, sonication /extraction; and potential equipment failures etc. Multiple hypothesis can be explored.

Investigation by Analyst and Supervisor

Phase Ib Investigation – Initial Investigation conducted by the analyst and supervisor using the Laboratory Investigation Checklist

Contact Production/Contract Giver/QP/MAH as appropriate

For microbiological analysis where possible once a suspect result has been identified ensure all items related to the test failure are retained such as other environmental plates, dilutions, ampoules/vials of product, temperature data, auto-pipettes, reagents – growth media.  No implicated test environmental plates should be destroyed until the investigation has been completed.

The Analyst and Supervisor investigation should be restricted to data / equipment / analysis review only

On completion of the Analyst and Supervisor investigation re-measurement can start once the hypothesis plan is documented and is only to support the investigation testing.

This initial hypothesis testing can include the original working stock solutions but should not include another preparation from the original sample (see: re-testing)

The checklist may not be all-inclusive, but should be a good guideline to cover the pertinent areas that need to be covered in any laboratory investigation:-

-Correct test methodology followed e.g.. Version number.

-Correct sample(s) taken/tested (check labels was it taken from a correct place).

Sample Integrity maintained, correct container and chain of custody (was there an unusual event or problem).

How were sample containers stored prior to use

Correct sampling procedure followed e.g. version number

Assessment of the possibility that the sample contamination has occurred during the testing/ re-testing procedure (e.g. sample left open to the air or unattended).

All equipment used in the testing is within calibration date.

-Review equipment log books. -Appropriate standards used in the analysis. -Standard(s) and/or control(s) performed as expected.

System suitability conditions met (those before analysis and during analysis).

-Correct and clean glassware used.

-Correct pipette / volumetric flasks volumes used. -Correct specification applied.

-Media/Reagents prepared according to procedure.

•Items were within expiry date

•A visual examination (solid and solution) reveals normal or abnormal appearance

Data acceptance criteria met

-The analyst is trained on the method.

Interview analyst to assess knowledge of the correct procedure.

Examination of the raw data, including chromatograms and spectra; any anomalous or suspect peaks or data.

Any previous issues with this assay.

-Other potentially interfering testing/activities occurring at the time of the test.

-Any issues with environmental temperature/humidity within the area whilst the test was conducted.

-Review of other data for other batches performed within the same analysis set.

Consideration of any other OOS results obtained on the batch of material under test.

Assessment of method validation.

Additional considerations for microbiological analysis:

-Are the isolates located as expected

on glove dab marks, SAS ‘dimples’, filter membrane, etc.

-Was the sample media  integral

i.e. no cracks in plates.

Was there contamination present in other tests (or related tests) performed at the same time, including environmental controls.

-Were negative and positive controls satisfactory.

Were the correct media/reagents used?

Were the samples integral (not leaking)

Were the samples stored correctly (refrigerated)

Were the samples held for the correct time before used for the test?

Was the media/reagent stored correctly before use

Were the incubation conditions satisfactory?

Take photographs to document the samples at the time of reading (include plates, gram stains and anything else that may be relevant).

If still investigation is not closed then investigation should go in Phase II

Reference:- MHRA OOS & OOT PPT.

Out of Specification Investigation Phase II (MHRA).

Out Of Specification & Out Of Trend Investigation (MHRA).

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