Investigation and evaluation of Out of Specification

This Document describes (Standard Operating procedure) Sop for Investigation and evaluation of Out of Specification (OOS) results

Sop for Investigation and evaluation of Out of Specification (OOS) results

I. Purpose & Scope:

  • The Purpose of this SOP is to lay down the procedure for investigation and evaluation of Out of Specification (OOS) results
  • The procedure is applicable for investigation and evaluation of Out of Specification results in Laboratory during testing of finished product /Stability /Intermediate /Raw material /Packing material

II. Responsibilities:

• All Production, Quality Assurance, Quality Control, Warehouse personnel’s shall be responsible to follow and implement this SOP.

III : Introduction and Procedural Part :


  • Whenever any Out of Specification result is obtained during analysis in laboratory, Analyst shall inform the same to the Manager/Head QC. The Manager/Head QC promptly conduct a preliminary investigation. The Manager/ Head QC intimate Out of Specification results to QA. Quality Assurance assigns the OOS number and forms are issued to Quality Control for investigations.
  • Quality Assurance shall log OOS in the OOS Log register. (Refer Annex-III).
  • OOS number shall be numbered as per the following procedure: Unique alpha numeric number shall be given to each Out Of Specification form. Each serial number shall be broken down as follows:
OOS Code Space Material Category Space Current year Space Serial Number
Number 1 2 3 4 5 6 7 8 9 10 11 12 13
Type A A A S A A S N N S N N N
Example O O S / X X / Y Y / Z Z Z


Sample Code Sample Code
Raw Material/Packing Material RM/PM Intermediate IT
Finished Material FP Stability ST


  • In case of chemical testing, analyst shall retain all the test preparations, used glassware’s, portion of the test solution and sample under analysis for investigation purpose.
  • Findings on cause of Out Of Specification results shall be classified into two categories namely,
    • Phase-1: Laboratory error
    • Phase-2: Manufacturing/sampling related error
  • Following procedure shall be adopted for different types of materials.
    • Raw materials and Packing Materials: Only Phase I investigation as outlined in the subsequent sections shall be performed.
    • When the raw material is rejected, the details for the rejection of the raw material shall be provided to the manufacturer. An investigation report shall be requested from the manufacturer to include the root cause and the corrective and preventive actions taken to avoid the reoccurrence of the incidents in the failure.
    • Intermediates: Both Phase- I and Phase- II investigation as outlined in the subsequent sections shall be performed.
    • Finished Product and Stability samples: Both Phase I and Phase II  investigations shall be performed.

Phase-I investigation:

An occurrence of out of specification (OOS) result, Phase I   investigation can be performed in two categories,

  1. Obvious Error – Phase-Ia
  2. Assignable cause – Phase-Ib

Out Of Specification results with obvious error or Assignable causes include but are not limited to the following:   

  • Analyst error (wrong dilution, mistake in following the method of analysis, use of incorrect standard, Use of incorrect sample)
  • Calculation error: incorrect calculation formula in method of analysis, protocol, test specification or transcription error for calculating results
  • Weighing Errors
  • Instrumental Error/ malfunction
  • Testing error: spilling of sample, incomplete transfer, dilution error, interpretation error
  • Incorrect instrument parameters
  • Power failure: Power failure during the test
  • Handling or storage of sample
  • Any other explained errors
  • Phase- Ia investigation: It is to be performed by analyst, immediate superior / Head QC or relevant department head, as applicable.
  • If on review by Department Head / Designee, it is found to be an obvious error then the same shall be corrected and correct results shall be documented.
  • To correct obvious error, decision for recalculation / repeat testing shall be approved by Department Head. An appropriate justification shall be recorded in the investigation report. The justification shall be verified by QA.
  • Suitable corrective action shall be taken to eliminate assignable cause or obvious error.
  • Same sample shall be used for this testing i.e. analysis shall be done using the same sample that resulted in to out of specification observation.
  • Analysis / determination shall be done on a portion of the same sample previously collected for analysis after taking suitable corrective action.
  • If the entire quantity of sample is being consumed while performing the test, repeat testing shall be performed on separately sampled test specimen. The need for requirement of additional sample shall be clearly mentioned in the investigation report with appropriate justification; Head QA shall approve this requirement.
  • The test shall be repeated by same person, as per instructions in the test procedure. The testing shall be documented in the relevant test data sheet, or any other report recommended and issued by Department Head / Designee.
  • If the out of specification (OOS) is due to assignable cause or obvious error which does not involve re-testing, then Department Head shall invalidate the initial out of specification results and correct results shall be recorded in the analytical report. Reference of out of specification investigation shall be stated in analytical report / test record.
  • If the results are within specification the batch shall be approved.
  • Originally calculated results (i.e. OOS results) shall be invalidated with justification and correct results shall be recorded.
  • Phase-Ia investigation shall be ended here. No further investigation is required if the obvious error that led to out of specification (OOS) results is corrected. Appropriate remark shall be stated in the investigation report and the report shall be closed.
  • If there is no obvious error observed the investigation shall be extended to Phase- Ib.
  • out of specification (OOS) shall be communicated to client, as applicable and client concerns for guiding investigation procedure shall be requested. The OOS shall also be intimated to Production and ware house (if applicable) to explore the potential root cause, if any.
  • Initiating department shall record the relevant remarks in the checklist. Abbreviations may be used for remarks like ‘Y’ for Yes, ‘N’ for No, ‘ NA’ for Not Applicable etc.
  • On obtaining out of specification (OOS) results, the analyst shall immediately inform the immediate supervisor. investigation procedure is as follows:

Phase I b investigation:

    • Phase-Ib shall be carried out by analyst, immediate superior / Department Head / Designee and QA representative.
    • Phase-Ib investigation shall be carried out when there is no obvious error found in phase- Ia investigation.
    • Investigation shall involve review of data, instrument / equipment used for the test and analytical procedure followed.
    • Hypothesis testing shall be carried out to investigate other assignable cause, if any.

Hypothesis testing performed in order to find out root cause of out of specification (OOS) shall be justified by Department Head\Designee and shall be approved by Head QA\Designee. Based on sound scientific judgment hypothesis testing shall be proposed by Department Head. Department Head / Designee, based on investigation and assumptions shall request for testing considering factors such as instrument malfunction, air bubble in syringe / tubing / detector, fluctuation in column oven temperature, particular grade of chemical / solvent to be used etc. The justification shall also include number of testing to be performed and any additional sample quantity required to perform testing. Use of instruments other than that used earlier, or test to be performed by different analyst etc. shall be specifically included in the justification. Head QA shall approve hypothesis testing.

  • Based on outcome of hypothesis testing, if assignable cause is confirmed, retesting shall be carried by first analyst. Decision for retesting by initial analyst in Phase I b investigation shall be approved by Head QA.
  • If retest results of first analyst complies with specification, the results shall further be confirmed by second analyst.
  • Results obtained after repeat testing shall comply individually with test specification. Originally calculated results (i.e. out of specification OOS results) shall be invalidated with appropriate corrective and preventive actions.
  • Phase investigation details shall be noted in Annexure-I
  • Investigation shall be initiated to Phase-II (sampling process and Manufacturing process), if no any assignable cause obtained during Phase-I

Phase II investigation :

  • Investigation shall be extended to Phase II (sampling process and Manufacturing process), if no any assignable cause obtained during Phase I and if the retesting in phase I would lead to out of specification (OOS) results again.
  • The Phase II investigation shall consist of a review of manufacturing process and sampling process.
  • If assignable cause is confirmed during manufacturing and sampling procedure, re-sampling shall be done and retesting shall be carried by first analyst.
  • If retest results of first analyst complies with specification, the results shall further be confirmed by second analyst.
  • Results obtained after repeat testing shall comply individually with test specification. Originally calculated results (i.e. out of specification OOS results) shall be invalidated with appropriate corrective and preventive actions.
  • Production Department Head and QA shall co-ordinate with relevant department personnel like production, QC,IPQA, R& D\Developer\Client\ MA Holder , HR, Ware House ,Purchase , engineering, RA to review the manufacturing process ( wherever required) considering factors likely to impact out of specification (OOS) results.
  • Review of manufacturing documents, batch records, any other records like equipment usage logs, temperature/ RH records, previous product etc. shall be done.
  • Product history shall also to be considered in manufacturing investigation. Lag times while manufacturing process shall be investigated for impact on out of specification (OOS) results.
  • Investigation of manufacturing process shall be carried as per SOP for failure investigation SOP or SOP for incidence reporting if required.
  • If investigation of process reveals that error is related to manufacturing process, Department Head / Designee in consultation with concerned department shall record summary of investigation and appropriate corrective action shall be advised by Head QA/Designee with client consent, as applicable. SOP for corrective and preventive actions


    • In case of no assignable cause found in Phase I and Phase II investigation, retesting shall be performed in triplicate by two analysts.
    • If retesting results of two analysts are complying to specification, the out of specification (OOS) shall be invalidated and first re-test results shall be considered for reporting.
    • If any of the reanalysis results between two analysts does not complying with specification, then OOS shall be confirmed and initial out of specification (OOS) results shall be reported. In this case material/batch shall stands rejected with Client consent if required for the same.
    • If the batch is decided to be rejected, still further investigation is required to find out Impact on other batches / other products, to explore root cause, to identify and implement appropriate CAPA, the same shall be carried out with appropriate justification approved by client and Head QA.
    • Hypothesis testing to explore root cause shall be done in the manner as mentioned in Phase I investigation. Number of determinations to be performed, sample, analyst, instrumentation requirement shall be pre-decided. Hypothesis testing shall be based on sound scientific rationale, relevant data available, stability studies, method validation data or any other information, as applicable.
    • The requirement proposed by department head / designee shall be approved by Head QA after evaluation.
    • Data generated through hypothesis shall be clearly identified by appropriate remark.
    • A summary with conclusion of hypothesis testing shall be mentioned in investigation report
  • All the test results shall be recorded during investigations in Annexure-I
  • The impact of out of specification result shall be carried out for other succeeding and preceding batches of the same product.
  • Trending of out of specification (OOS) shall be done once in a year for the parameters like Equipment related, Method/Procedure related, Samples/Standards preparation Related error, Interpretation of data related, calculation related error, Product or analyst related error, Training related error, others etc.
  • Based on the trend evaluation, corrective and preventive action shall be planned. Complete investigation report copy shall be forwarded to the investigation team for decision and recommendation for disposal and further action to the batch.
  • Documentation- All documents related to the batch in question shall be compiled by Quality Assurance and reports of all such investigations shall be filled separately and maintained by the Quality Assurance Department, after disposition of out of specification (OOS) by Head QA.
  • Time Frame- Investigation and resolution of all Out-of-Specification test results in Phase-I investigation shall be completed within 10 days. In case of a confirmed out of specification (OOS) result, Phase-II investigation to identify the cause of failure shall be completed within 30 days and Action plan shall be circulated to all concerned departments.
  • Final conclusion shall be mentioned in out of specification (OOS) log register.

Annexure I

out of specification (OOS) Investigation Report

out of specification (OOS) No.          

[To be filled by QA]



Date:                                 [To be filled

by QA]



Name of the Intermediate / Material/Product : Batch No.


Mfg. Date : Exp./ Retest Date


A.R. No. : Pack size:                [If Applicable]


Description of out of specification (OOS) :












Test & date Observation Ref. Specification No:















Sign and Date



Sign and Date

(Head QC/ Designee)

Note: Attach Separate sheets, if required.


Category Sr. No Checklist item Yes No

Equipment / Instrument verification

1. Were equipment / instrument used for analysis in calibrated, qualified and maintained status?
2. Was there any evidence of malfunction of allied equipments?
3. Was appropriate balance used?
4. Glassware used is class A?
5. Correct pipette/volumetric flasks volumes used?
6. Was there any obvious evidence of the glassware contamination? (Visual)
7. Were the glassware used for analysis properly and legibly labeled?
Methods / Procedures verification 8. Was the correct method used and correct specification applied?
9. To ensure performance of method as per the standard expected based on method validation and historical data.
10. Validation status of the analytical method at the time of the test
11. Are the calculations correct and validated excel sheet used for calculation?
12. Correct wavelength used?
Standard verification 13. Is there any evidence of degradation of standards and / or samples
14. Were standards properly weighed and diluted?
15. Were standards, samples, reagents etc… are properly labeled?
16. Were standards, reagents and sample and their solutions within their expiration date?
17. Is the standard response the same as previous value?
18. Were the standards stored properly?
19. Were reagents properly standardized?
20. Reagents are within the shelf life.
21. Were reagents / chemicals used of recommended grade and prepared as per the analytical method?
Sample / Reagents verification 22. Is the sample weighed correctly?
23. Were the sampling quantity matching as per specification?
24. Were correct reagents, standards, glassware or other auxiliary equipments used?
25. Label of the sample verified-Correct
26. Sample integrity maintained, correct container and chain of custody
27. How were sample container stored prior to use
28. Correct sampling procedure followed


Category                                                                 Category Sr. No Checklist item Yes No
HPLC verification 29. System suitability was met as per STP?    
30. Column used as per STP?    
31. Leak observed?    
UV verification 32. Whether a peak maximum is at desired wavelength?    
33. Whether auto zeroing was done?    
34. Whether blank reading is taken & blank reading is subtracted from the standard and / or sample reading?    
Chromatograms verification 35. Peak shape is proper?
36. Peak integration is proper?
37. Retention time / relative retention time as per STP?
38. Base line is proper?
History 39. Is there a similar history with the product in the past?
40. Have there been similar errors in the past?
Other 41. Were environmental conditions (Temperature, Humidity, Light) are proper?
42. Was Analyst qualified for this test?
43. Were there any additional potential sources unique to the analytical procedure or laboratory preparation?
44. Interview analyst to assess knowledge of the correct procedure
45. Other potentially interfering testing/activities occurring at the time of the test.
Any other equipment 46.

[   ] Chromatographic data                                                     [   ] Calculation error

[   ] Sample preparation error                                                 [   ] Procedural error

[   ] Others

[   ] Assignable cause identified                                             [   ] Assignable cause not identified


Retesting of sample :                                     Required/Not required

If cause is  identified in this preliminary investigation, re testing from originally drawn sample to determine Analyst / Lab error may be permitted :


·       Re testing authorized by : Name_______________________, Signature  _______

Results Observation

Evaluation of Results :








If cause is not identified in this preliminary investigation:–


Conclusion of Phase-I Investigation: OOS result is invalidated / confirmed.

Phase-I Investigation Report Completed By:


Analyst 1                                 :                             Date:

Analyst 2 (if applicable)                 :                     Date:

Q.C. Manager                         :                             Date:


Phase-I Investigation Report Evaluated By:



Batch Status                                              :                                    APPROVED / REJECTED      




Recommendation by Head QA:




Requirement of Phase II Investigation:

(Manufacturing process review and additional laboratory testing)






Any other comment:


Quality Assurance Manager





[To be filled by QA]



Date:                                 [To be filled by QA]



Name of the Intermediate / Material/Product : : Batch No.


Mfg. Date : Exp./ Retest Date


A.R. No. : Pack size:                   [If Applicable]


Description of OOS













 Test & date Observation Ref. Specification No:
Phase II Investigation Started on  :

Investigation Assigned to                 :

Phase II Investigation
Batch record in line with the Original master formula document:



Raw Material (Active) used in the Batch and approved vendor status:



Dispensing errors: (If observed):



Any wrong entries in the BPR:



Errors in the Manufacturers and suppliers end: (For RM and PM)



Errors in In process testing:


Any equipment failure:


Any Utility failure       :



Any Equipment out of Calibration, Qualification and Validation status:



Environmental monitoring results, status of rooms/equipment and storage condition:
Cleaning and Validation status of equipment used:



Validation of the process



Evaluation of other related batches (if likely to have impact):



The critical steps during manufacturing to be witnessed by responsible supervisor:



Any deviations during process



Supervisor and Operator training:



Batch documentation (adequate, systematic and error free):



Performance of earlier batches of the same product (any abnormalities):



Any other observations:



Root cause identified / Not identified :

If root cause is identified:       APPROVED / REJECTED



If batch is rejected. Corrective action and preventive action on the failure investigations carried out by Quality Assurance Manager in consultation with manufacturing department:



Quality Assurance Manager


If root cause is not identified in this Phase-II investigation, re-sampling to be done only if investigation indicates sampling is an error or if the sampled quantity is insufficient/exhausted. Re-sampling to be carried out after taking approval from Head-QA.

Retesting of original sample or resample is permitted by Head-QA.


Re-testing to be performed in triplicate by two analysts :


·       Re-sampling / Re testing authorized by : Name____________ ,Signature  _______

·       Details of results observed after re testing of original sample / retesting of resample.

Results Observation
Analyst-1 Analyst-2





Evaluation of Results            :







Conclusion                       :  OOS result is invalidated / confirmed.



Corrective and Preventive Actions:





CONCLUSION: (Identified reason to be included)









Manufacturing  supervisor responsible person for the batch under investigation:

Manufacturing Operators involved:

R&D (if applicable)                       :

Investigation carried out by          :

Head Quality Assurance


Corrective action:









Preventive Action:










Production Manager                                                                           Head Quality Assurance

Date:                                                                                                   Date:

Final Review:

The above batch is released / rejected




Head Quality Assurance


Decision / Recommendation for disposal and further action to the batch:









Head Production / Date



Head QC / Date



Head QA / Date


Annexure II


Sr. No Date Name of

Product / Material

OOS No. Batch No. Brief Description of OOS Recorded by Reviewed by Final
















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