Investigating and Handling of Out Of Trend (OOT) Test Results SOP

SOP for Out of Trend in pharma | Out of Trend as per MHRA Guidelines | Out of Trend as per USP |

OOT SOP covers below points:
- Out of trend in pharma
- Definitions
- Investigation procedure
  - Preliminary Laboratory Investigation
  - Manufacturing Investigation
  - Extended Laboratory Investigation
  - Closure of OOT
  - OOT Formats
    - Investigation report for Out of Trend results
    - Checklist for Laboratory Investigation of OOT results
    - Out of Trend (OOT) log book
    - Criteria for Identifying OOT Results in Long Term Stability Study
    - Criteria for Identifying OOT Results in Accelerated Stability Study
    - Justification for extension of OOT
    - Flow Chart for the OOT Investigation

1.0 OBJECTIVE :

To lay down a procedure for investigating and handling of Out of Trend (OOT) results during testing of Active materials, In-process, Finished product and Stability samples.

2.0 SCOPE :

This procedure is applicable to Critical chemical tests such as Assay, Related substances, Loss on drying, Water by KF, Dissolution and Content Uniformity / Uniformity of Dosage units performed for all types of samples in Quality Control Department.

3.0 RESPONSIBILITY :

Analyst :
- To inform and initiate the OOT results for samples.
Section Head / Head –QC :
- To conduct the investigation, review and implementing necessary CAPA.
Head QC :
- To ensure that this SOP is followed during Investigation of out of trend results.

4.0 ACCOUNTABILITY:

Quality Control Head, Quality Assurance Head and Head of concerned Department.

5.0 PROCEDURE :

5.1 Definitions
- OOT : An analytical result that whilst being in specification, falls outside of expected normal or pre-defined for that particular test parameter. This shall be identified during analysis by comparing against trend and results obtained at the extreme of specification. In general, Out of Trend can be described as a result or sequence of results that are within specification limits, but are unexpected and not in line with the routine.
- Hypothesis/Investigative Testing : It is testing performed to help confirm or discount a possible root cause from assumptions made 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 hypotheses can be explored.
- Reinjection : Is defined as the re-chromatography of the original aliquot solutions as part of the OOT procedure.
- Retest : 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 after authorization from QA.
- Resample : A new sample from the original container where possible, required in the event of insufficient material remaining from the original sample composite or proven issue with original sample integrity.
- Obvious error : An evident/apparent/clear reason for obtaining an OOT results.
  - Examples: Calculation error, Spillage of sample solution, incomplete transfer of sample, incorrect instrument parameters and sample preparation etc.
- Assignable cause: An identified reason for obtaining an OOT result.
- No Assignable cause: No reason identified for obtaining an OOT result.
- Typical Result: Those that are unusual on the basis of experience, trending, or data review but still are within specification.

5.2 Investigations of “Out of Trend (OOT)“ have to be done in cases of :

Batch approval testing and testing of starting materials.
In-process control testing: if data is used for batch calculations/decisions and if in a dossier and on certificates of analysis.
Stability studies on marketed batches of finished products and or active pharmaceutical ingredients, on –going / follow up stability (no stress tests).
Previous approved batch used as reference sample in an OOT/OOS investigation showing OOT or suspect results.

5.3 After the results are obtained in stability batches for critical tests such as Assay, Related substances (test for impurities) , Dissolution, Content Uniformity tests, Loss on drying and Water by KF, analyst shall determine whether the obtained results are (OOT) out of trend based on the criteria defined in relevant attachment.

5.4 Analyst shall refer Annexure No. 04 for long term stability samples.

5.5 Analyst shall refer the Annexure No. 05 for accelerated stability samples.

5.6 In case of commercial batches, unexpected or typical results, questionable, irregular, deviant or abnormal results i.e., significant change in result, which are within the limit shall be considered as OOT results and investigated.

5.7 The analyst/section head who encounters the OOT shall request to QA Department for issuance of the format for raising the Out of Trend (OOT).

5.8 Authorized QA person will issue the format of OOT and enter the details of OOT in Out of Trend (OOT) log book as per Annexure No. 03.

5.9 OOT investigation shall be initiated by QC using the format “Investigation report for Out of Trend results” as per Annexure No. 01.

5.10 The number shall be given as below:

OOT/XXX/YY,
- Where,
- OOT = Out Of Trend
- XXX = Three digit running sequence number generated through the register.
- YY = Last two digits of running year.

5.11 Preliminary Laboratory Investigation

On obtaining Out of Trend results, Analyst shall inform any OOT, as soon as possible to the Section Head or Head of the department.
To the extent possible, analyst shall retain aliquots of original solutions, and / or portions of samples used for analysis under suitable storage conditions to facilitate investigation.
The summary of results shall be indicated in the space provided in the “Investigation report for Out of Trend results’’ form.
Investigation shall be carried out along with section head and findings shall be elaborated in to the “Investigation report for Out of Trend results’’ form.
As a tool for investigation, section head shall use relevant checklist as per Annexure No. 02, but not necessarily in the sequential order in which the check points are listed.
During the initial investigation, Hypothesis testing shall be done as follows (but not limited to):
- Re-injection from same vial of standard and test solutions.
- Re-filtration / re-centrifugation of the original test solution.
- Re-dilution from original stock solution.
- Additional sonication/shaking of the same solution.
Hypothesis testing results may not be used to replace original suspected analytical results. It may only be used to confirm or discount a probable cause.
If assignable cause identified, then the analysis shall be repeated using original solutions / sample portion by the 1^st Analyst (If 1^st Analyst is not available then analysis can be performed by an equal competent Analyst by taking prior approval of QC Head) taking care to omit all errors identified during the investigation.
If original solutions / sample portions are found to be not suitable, then freshly prepared solutions / fresh portion from the original sample shall be used.
- If the above repeat analysis results are not fall under OOT criteria, the initial results shall be made invalid.
- A review of the reasons for Analyst/ laboratory errors shall be assessed with respect to Training needs, Procedural revisions, impact on other batches analysis done during the same run, impact on previous analysis done by the Analyst shall be put in place.
- Report the re-analysis results as final result and forward the investigation report to QA Department for comment.
- In case of no assignable cause identified during preliminary investigation, then QC or QA Department shall inform to relevant functional department (Production, F&D) for further investigation.

5.12 Manufacturing Investigation

QA Head or designee and Concerned Department Head or designee shall investigate the manufacturing and packing process to identify the possible error. Investigation can be extended to the other departments, if necessary such as Manufacturing, Engineering, and F&D.
The investigation shall include but not restricted to review of Batch manufacturing record, to verify any deviation/ incident from manufacturing procedure or equipment operation procedure or environment monitoring parameter and yield at different stages.
In case of stability OOTs review, following points shall be verified but not limited to,
- Time delay in stability initiation from the day of manufacturing.
- Review of initial analytical data.
- Change in source of input materials if any.
Trend of results of starting materials, stability data and impact of the trend on related quality attribute etc. Trend data of past batches, equipment maintenance record, changes in facility/equipment/process shall be reviewed.
Record the investigation along with OOT form.
If any assignable cause is identified from the manufacturing investigation then complete investigation report along with CAPA shall be forwarded to QA for review and comments.

5.13 Extended Laboratory Investigation

In case of no assignable cause identified from the manufacturing investigation, then QC may retest by 2^nd Analyst in triplicate using original samples.
If the repeated results are within the OOT acceptance criteria then the first measurement in case of Related substances / Impurities shall be reported as final result, wherever applicable.
If the repeated results are within the OOT acceptance criteria then the average of triplicate measurements other than Related substances / Impurities shall be reported as final result, wherever applicable.
If the repeat analysis results are not within the trend, then report the original result as confirm OOT.
All results obtained along with conclusion of investigation shall be forwarded to QA Department for review and comments.
If original sample not sufficient to complete the investigation testing or sample is compromised or sample integrity is suspected, re-sampling may be performed with proper justification and approved by QA Department.
If the repeat analysis result is found to be ‘Out of Specification’, then the same shall be investigated by following the SOP for Investigating and handling of Out-of-Specification (OOS) test results.

5.14 When OOT is investigated and concluded as OOT is not due to laboratory error, then QA Department shall inform to contract giver / customer and F&D Department for further course of action.

5.15 If OOT is confirmed, previous approved batches data & stability data of the same product is evaluated for impact on quality of product till expiry of the product.

5.16 Based on evaluation of stability data and trend of previous approves batches, impact on product quality of the same batch is found less, Generate the CAPA and the batches shall be approved by reporting same OOT result as outlier results and the same batch is charged for further stability study.

5.17 If impact on product quality of the same batch is found high, the batch shall be disposed and documented.

5.18 Closure of OOT

OOT investigation shall be closed within 25 working days from date of reporting including manufacturing and further laboratory investigation.
In case if the OOT is not closed within 25 working days, it is recommended to extend the closure of OOT for 50 working days with proper justification.
Justification for extension of OOT investigation shall be documented as per Annexure No. 06 and it should be approved by head QC and head QA.

5.19 All Investigations regarding Out of Trend results should be documented and preserved for one year after batch expiry.

6.0 ABBREVIATIONS:

Abbreviation	Expanded form
SOP	Standard Operating Procedure
No.	Number
QC	Quality Control
QA	Quality Assurance
OOS	Out of specification
MHRA	Medicines and Health Care Product Regulatory Agency
KF	Karl Fischer
CAPA	Corrective action and Preventive action
%	Percentage
F&D	Formulation and Development
USP	United State Pharmacopeia

7.0 ANNEXURES:

Annex. No.	Title
01	Investigation report for Out of Trend results
02	Checklist for Laboratory Investigation of OOT results
03	Out of Trend (OOT) log book
04	Criteria for Identifying OOT Results in Long Term Stability Study
05	Criteria for Identifying OOT Results in Accelerated Stability Study
06	Justification for extension of OOT
07	Flow Chart for the OOT Investigation

8.0 SOP REFERENCES

MHRA-Guidance for Out of Specification investigation.
An article “Identification of Out of Trend stability results” released on April 2003 by Members of the PhRMA CMC Statistics and Stability Expert.
USP General Chapter <1010> Analytical Data – Interpretation and Treatment.

END OF THE SOP

ANNEXURES :

Annex. No. 01 Investigation report for Out of Trend results