Out Of Specification Investigation Phase II (MHRA)

Out Of Specification Investigation Phase II (MHRA)

Conducted when the phase I investigations did not  reveal an assignable laboratory error.  Phase II investigations are driven by written and approved instructions against hypothesis.  Prior to further testing a manufacturing investigation should be started to determine whether there was a possible manufacturing root cause.

If not already notified the contract giver/MAH/QP (in accordance with the responsibilities in the TA) should be notified along with production and QA if a manufacturing site.

It is important when considering performing additional testing that it is performed using a predefined retesting plan to include retests performed by an analyst other than the one who performed the original test.  A second analyst performing a retest should be at least as experienced and qualified in the method as the original analyst.

If the investigation determines analyst error all analysis using the same technique performed by the concerned analyst should be reviewed.

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.

Re-Test

Performing the test over again using material from the original sample composite, if it has not been compromised and/or is still available. If not, a new sample will be used.

Re-sample

A new sample from the original container where possible, required in the event of insufficient material remaining from original sample composite or proven issue with original sample integrity.

Most probable cause

Scientifically justified determination that the result appears to be laboratory error.

Phase II Investigation  – Unknown Cause / No Assignable  Cause

Hypothesis Testing (Applicable to Phase Ia and Phase II):

Should be started as part of Phase Ia and continue into Phase II if no assignable cause found.

Description of the testing should be written, and then approved by QA/Contract Giver/QA equivalent prior to initiating investigational testing.  The requirements of investigational testing listed below:

The description must fully document

•The hypothesis to the test the root cause being investigated.

•What samples will be tested. 

•The exact execution of the testing.

•How the data will be evaluated

This Hypothesis testing may continue from the re-measurement of the original preparations.

Investigational testing may not be used to replace an original suspect analytical results.  It may only be used to confirm or discount a probable cause.

If no assignable cause that could explain the results can be identified during the manufacturing investigation or the assay failure investigation retesting may be considered.  Part of the investigation may involve retesting a portion of the original sample.

Retesting:

•Performed on the original sample not a different sample.

•Can be a 2nd aliquot from the same sample that was the source of the original failure.

•If insufficient quantity of the original sample remains to perform all further testing then the procedure for obtaining a resample must be discussed and agreed by QA/Contract Giver/QA equivalent.  The process of obtaining the resample should be recorded within the laboratory investigation.

•The decision to retest should be based on sound scientific judgement.  The  test plan must be approved before re testing occurs. The minimum number of retests should be documented within the procedure and be based upon scientifically sound principles.  Any statistical review  with regards to %RSD and repeatability should relate to the values obtained during method validation (accuracy, precision, and intermediate precision).  The number of retests should be statistically valid; papers have suggested 5, 7, or 9.

•The retests should be performed by a different analyst where possible.  The second analyst should be at least as experienced and qualified in the method as the original analyst.

Averaging:

•The validity of averaging depends upon the sample and its purpose. Using averages can provide more accurate results. For example, in the case of microbiological assays, the use of averages because of the innate variability of the microbiological test system.  The kinetic scan of individual wells, or endotoxin data from a number of consecutive measurements, or with HPLC consecutive replicate injections from the same preparation  (the determination is considered one test and one result), however, unexpected variation in replicate determinations should trigger investigation and documentation requirements.

•Averaging cannot be used in cases when testing is intended to measure variability within the product, such as powder blend/mixture uniformity or dosage form content uniformity.

•Reliance on averaging has the disadvantage of hiding variability among individual test results. For this reason, all individual test results should normally be reported as separate values. Where averaging of separate tests is appropriately specified by the test method, a single averaged result can be reported as the final test result. In some cases, a statistical treatment of the variability of results is reported. For example, in a test for dosage form content uniformity, the standard deviation (or relative standard deviation) is reported with the individual unit dose test results.

•In the context of additional testing performed during an OOS investigation, averaging the result (s) of the original test that prompted the investigation and additional retest or resample results obtained during the OOS investigation is not appropriate because it hides variability among the individual results. Relying on averages of such data can be particularly misleading when some of the results are OOS and others are within specifications. It is critical that the laboratory provide all individual results for evaluation and consideration by Quality Assurance (Contract Giver/QP).

All test results should conform to specifications (Note: a batch must be formulated with the intent to provide not less than 100 percent of the labelled or established amount of the active ingredient

Averaging must be specified by the test method.

•Consideration of the 95% Confidence Limits (CL 95% ) of the mean would show the variability when averaging is used.

Averaging continued: Consideration of using 95% Confidence Limits (CL 95% ) of the mean would show the variability when averaging is used.

The confidence interval is calculated from the formula:

CL= sample mean ± t 95% sample standard deviation/ √ n

–Where t is a value obtained from tables

–Where n is the sample size

–Table:

n t 95%
2 12.71
3 4.30
4 3.18
5 2.78
6 2.57
7 2.45
10 2.26
20 2.09
120 1.98
1.96

Re-sampling:

Should rarely occur, If insufficient quantity of the original sample remains to perform all further testing then the procedure for obtaining a resample must be discussed and agreed by QA/Contract Giver/QA equivalent.  The process of obtaining the resample should be recorded within the laboratory investigation. Re-sampling should be performed by the same qualified methods that were used for the initial sample. However, if the investigation determines that the initial sampling method was in error, a new accurate sampling method shall be developed, qualified and documented. It involves the collecting a new sample from the batch. Will occur when the original sample was not truly representative of the batch or there was a documented/traceable lab error in its preparation. Evidence indicates that the sample is compromised or invalid. Sound scientific justification must be employed if re-sampling is to occur.

Outlier test:

An outlier may result from a deviation from prescribed test methods, or it may be the result of variability in the sample. It should never be assumed that the reason for an outlier is error in the testing procedure, rather than inherent variability in the sample being tested. Statistical analysis for Outlier test results can be as part of the investigation and analysis.  However for validated chemical tests with relatively small variance and that the sample was considered homogeneous it cannot be used to justify the rejection of data.

• While OOS guidance is not directly intended for bioassay analysis, it can be used as a starting point for the investigation. Compendia such as the BP; PhEur and USP, provide guidance on outliers for these types of analysis

Reference :- MHRA OOS & OOT Investigation PPT.

Out Of Spesification Phase Ia & Ib ( MHRA)

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

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

Phase Ia Investigation

Definition:

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

Examples

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).