Investigating and Handling Of Out Of Specification (OOS) Test Results SOP

SOP for Out of Specification (OOS) | Out of Specification Pharma | Out of Specification as per MHRA & USFDA Guidelines |

• OOS SOP Covers below points:
  • Out of Specification meaning / Definitions
  • Investigation of Out of Specification
    • Preliminary OOS investigation procedure
    • Full scale OOS investigation procedure
  • Report formats
  • Checklist for Out of Specification investigation
  • Flow charts for Out of Specification investigation

1.0 OBJECTIVE :

• To lay down a procedure for investigating and handling of Out of Specification (OOS) test results.

2.0 SCOPE :

• This SOP is applicable for Out of Specification Test Results of Raw material, Packaging material, Finished Product and Stability samples in Quality Control Department.

3.0 RESPONSIBILITY :

• Analyst :
  • To perform the analysis and involve in investigation part as per the SOP.
• Section Head :
  • To co-ordinate with Head-QA regarding out of specification results and participate in Investigation for the same.
• QA authorized person
  • To participate in Investigation of OOS
  • To Evaluate OOS test results and action plan
  • To Initiate full scale OOS investigation.
• Head QA :
  • To Ensure that this SOP is followed during investigation of OOS results.

4.0 ACCOUNTABILITY:

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

5.0 PROCEDURE :

• 5.1 Definitions
  • OOS: The test result that does not comply with the pre determined acceptance criteria (Results that fall outside of established acceptance criteria which have been established in the specifications).
  • Hypothesis/Investigative Testing : It is testing performed to help confirm or discount a possible OOS 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 hypotheses can be explored.
  • Investigation : A formal documented process of collecting information in order to identify criticality, the extent of impact and risk, root cause and appropriate CAPAs.
  • Re-injection : Is defined as the re-chromatography of the original aliquot solutions as part of the OOS procedure.
  • 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 after authorization from QA Department.
  • Re-sample : 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 OOS results.
    • For example: Calculation error, Spillage of sample solution, incomplete transfer of sample, incorrect instrument parameters and sample preparation etc.,
  • Assignable cause: The initial justifiable cause for an issue. Action taken to address assignable cause will correct the issue however may not prevent reoccurrence.
  • No Assignable cause: No reason identified for obtaining an OOS result.

5.2 Investigations of “Out of Specification (OOS)” have to be done in cases of,

• 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.
• Previous approved batch used as reference sample in an OOS investigation showing OOS or suspect results.
• The unexpected, questionable, irregular, deviant or abnormal results that are still within specification (Significant change in result) to be investigated through OOS procedure.
• The abnormal results (Significant change in result) found at any stability interval which predicts that the test results may be OOS before the next testing interval

5.3 Out-of-Specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and /or adjusting the process.

5.4 Investigation of OOS will be carried out into two categories,

• Preliminary OOS investigation.
• Full scale OOS investigation.

5.5 On obtaining Out of Specification results, retain the test and standard preparations and any other solutions prepared and inform to section Head.

5.6 The analyst/section head who encounters OOS shall request to QA Department for issuance of the format for raising the OOS.

5.7 Authorized QA person will issue the format of OOS and enter the details of OOS in OOS log book as per Annexure No. 01.

5.8 Allocate OOS number in the OOS Register as given below,

• The OOS number for In-process, Stability and Finished Product shall have prefixed ‘OOS’ and be assigned as per following example:
• Example: OOS / FP/ XX / YY,
  • Where,
  • OOS      : Out of Specification report
  • FP         : Finished Product, in case of in-process write “IP” and in case of stability write “SS”
  • XX         : Last two digits of current year
  • YY         : Sequential number
• The OOS number for Raw Material shall have prefixed ‘OOS’ and be assigned as per following example:
• Example: OOS / RM / XX / YY,
  • Where,
  • OOS      : Out of Specification report
  • RM         : Raw Material
  • XX          : Last two digits of current year
  • YY          : Sequential number

5.9 OOS investigation shall be initiated by QC Department using the format “Out Of Specification Investigation Report – Preliminary Out Of Specification Investigation” as per Annexure No.02.

5.10 PRELIMINARY OUT OF SPECIFICATION INVESTIGATION

• Preliminary OOS Investigation is carried out into two different phases,
  • Phase- Ia Investigation
  • Phase- Ib Investigation
• Phase- Ia laboratory Investigation
  • Analyst should investigate himself as part of the Phase-Ia investigation as per checklist for Phase-Ia Investigation Annexure No. 04
  • After Phase-Ia investigation, he/she should inform the same to section Head.
  • In case if any obvious error (correctable error) identified during laboratory investigation, (Ex: Documentation error) the same shall be corrected and the investigation shall be closed by taking prior approval by Head-QC after evaluation of QA Department.
  • Investigation does not reveal any error then phase-Ib investigation shall be initiated.
• Phase-Ib Investigation
  • Phase-Ib Investigation shall be carried out by section head as per checklist for Phase-Ib Investigation Annexure No. 05
  • During the investigation, discuss with the analyst for;
    • Assessment of the possibility that the sample contamination has occurred during the testing / retesting procedure e.g. sample left open to air or unattended.
    • Assessment of the possibility for any occurrence of spillage of sample/standard solution.
    • Assessment of the possibility for incomplete transfer of sample composite.
  • If any assignable cause found during the investigation, invalidated the initial results.
  • If no any assignable cause found, hypothesis testing will be planned for further investigation to find out the root cause.
  • Hypothesis plan shall be defined by the Head of the department or designee.
  • The following will be considered for hypothesis testing for further investigation,
    • Solutions can be re-injected as part of investigation when a transient equipment malfunction is suspected. This could occur if bubbles were introduced during an injection on a chromatographic system such theories are difficult to prove, however a re-injection can provide strong evidence that the problem should be attributed to the instrument rather than sample or its preparation.
    • Investigational re-measurements on the original solution shall not be conducted prior to approval.
    • Injection from new vial from final dilution to evaluate vial contamination, vial crimping error or filtration error.
    • Use of other equipment is permitted, provided the rationale is fully documented.
    • Prepare new dilutions from a stock solution.
    • Additional extraction of sample solution to rule out the possibility of inadequate extraction such as sonication, shaking etc.
    • Preparing new sample preparations may be done in some situations, to examine the hypothesis of an improperly prepared sample composite or improperly handled initial sample preparation (e.g., original tablet grind).
  • The data from these investigations shall be used for investigation only and shall not be used as a valid test reportable result.
  • During hypothesis testing, if assignable cause found/ confirmed then the analysis shall be repeated with the same analyst.
  • In absence of the analyst who performed the original test, the same test will be performed by another qualified analyst after approval of head of department or designee.    
  • For investigation, previous released batch may be tested as reference sample in an OOS investigation to verify accuracy of re-analysis.
  • If an OOS or suspect result of previous released batch is observed during the OOS investigation, the same shall be investigated through OOS procedure.
  • If the repeated results are within the specification limit and the acceptance criteria, record and report the same.
  • Based on hypothesis analysis and repeated results, invalidate the initial results and close the OOS.
  • If the Initial assessment does not determine the laboratory error caused the OOS results, review the following data’s.
    • Cross reference of method by the trend data of previous batches.
    • Trend analysis /cross reference of analyst who has performed the analysis in OOS execution
  • The same shall be informed to QA Department in phase-Ib investigation.
  • Label the product as ‘HOLD’ and close preliminary investigation of OOS.
  • Inform the same to contract giver and F&D Department for further action, if required.
  • Based on the conclusion of Head-QA, conduct a full scale OOS investigation of Phase-II in co-ordination with Head-QA or his/her designee and Head-Production or his/her designee for Manufacturing Investigation.
  • Incase if the OOS results due to Dissolution / Content uniformity then the pharmacopoeial method shall be followed.

5.11 FULL SCALE OUT OF SPECIFICATION INVESTIGATION

• Full scale OOS investigation is carried out into two different phases,
  • Phase-II investigation
  • Phase-III investigation
• Full scale OOS investigation shall be initiated by QA using the format “Out of Specification Investigation Report – Full Scale Investigation” as per Annexure No. 03.

Phase-II Investigation (Manufacturing & Extended Laboratory Investigation)

• Manufacturing Investigation as Phase-II Investigation shall be carried out by Head QA or his/her designee and Head-Production or his/her designee as per checklist for Phase-II Investigation Annexure No. 06.
• If any assignable cause found during the manufacturing Investigation and the decision for the disposition of batch shall be taken by Head Quality Assurance.
• Extended Laboratory Investigation as Phase-II investigation shall be conducted when the phase-I Investigation did not reveal as assignable laboratory cause.
• Prior to further testing a manufacturing investigation should be started to determine whether there was a possible manufacturing root cause.
• If any/all of process parameters are found satisfactory in manufacturing investigation then conduct Hypothesis testing to find out the possibility of laboratory error as extended laboratory investigation.
• Retesting and re-sampling (if required) shall be decided jointly by Head-QC and Head-QA.
• Re-testing
  • The sample used for retesting should be taken from the same homogeneous material that was originally collected from the lot.
  • For a liquid, it may be from the original unit liquid product or composite of the liquid product.
  • For a solid, it may be an additional weighing from the same composite sample prepared for the original test.
• Re-sampling
  • Re-sampling shall be performed;
    • When there is not enough material left from the original sample to reform the retest.
    • The original sample is not representative i.e., degradation occurs in original sample.
    • When the original sample was not truly representative of the batch or there was a documented/traceable lab error in its preparation.
• If OOS results confirmed during the Extended Laboratory Investigation, no further retest is required and all the investigation details will be submitted to QA Department for OOS closure.
• In case of assignable cause found in hypothesis analysis, analysis shall be performed by the same analyst in triplicate.
• If all the results failing, no further retest is required and all the results will be submitted to QA Department for OOS closure.
• If any of the results failing or all the results passes, perform triplicate analysis by analyst-II.
• In case if non-assignable cause found in hypothesis analysis, analysis shall be performed by analyst-II in triplicate.
• The acceptance criteria between the two analysis results are as follows;
  • For Assay: 2%
  • For Related substances: 10%
  • For Dissolution: 5%  and
  • For Residual solvents: 15%
• If failing of the any of the results is obtained from triplicate analysis by Analyst-II, then there is no further retesting required and the same shall be discussed with Head-QA. The results can be declared as confirmed OOS and the batch or respective raw material shall be kept “HOLD” till further investigation is completed. The decision of disposition of such batch shall be taken by Head-QA and CAPA to be generated as per Corrective Action and Preventive Action SOP and close OOS.
• In case if the value reported by Analyst-II is within the specification Limit then the analysis shall be repeated with Analyst-III in triplicate to reconfirm the pass results and the repeated results of the Analyst-III passes to confirm the specification results then based on the Analyst-II and the Analyst-III results, the batch shall be released and the Analyst-I results shall be invalidated and CAPA to be generated as per Corrective Action and Preventive Action SOP and close OOS.
• If failing of the any of results is obtained from triplicate analysis by Analyst-III, then based on the Analyst-I and Analyst-III results, the Analyst-II results shall be invalidated and the decision of disposition of batch shall be taken by Head-Quality and CAPA shall be initiated as per Corrective Action and Preventive Action SOP for further investigation and close OOS.
• Based on the recommendations of Head-QA, phase-III Investigation shall be performed.

Phase-III Investigation

• Phase-III investigation involves in the manufacturing investigation for the other batches or products affected for the said non conformity.
• Investigation of method validations, stability data and testing procedures shall be evaluated.
• A confirmed OOS result indicates that the batch does not meet established standards or specifications and should result in Batch’s rejection and proper disposition.
• The disposition decision will be taken by the Head-QA.
• Label the Non- Conformity product as ‘REJECTED’ as per SOP.
• Segregate the non-conformity product in a separate designated area to avoid any unintended use.
• In case of Raw and packaging material, not confirming to establish standards/specifications, move them to the designated rejected area and inform Purchase department regarding the rejection.
• It should be identified that the raw /packaging material of same batch number was not received earlier and approved.
• If any consignment of same batch number was approved earlier, it should be investigated.
• Further decision of rejected raw and packaging materials to be decided based upon discussion from supplier and subsequently from Purchase department.
• The next supply shall be accepted based on the acceptance of CAPA report provided by the vendor within 15 working days.
• The Out of specification results observed for the tests of physical parameter shall be investigated though OOS procedure.
• The Out of specification results observed for packaging materials shall be investigated though OOS procedure.
• The procedure of OOS is not applicable for the tests of validations and standardizations.
• In case of In-process product, finished product, stability samples, further decision of rejection to be decided jointly by Head-Production, Head-QC, Head-QA and Head Quality/Technical.
• In case of stability samples it needs to give the information to F&D Department and Regulatory affairs department for necessary corrective actions.
• Necessary corrective action to be taken by QA Department.

5.12 The OOS should be closed out with all supportive documentations within 30 days from the OOS occurred.

5.13 In case of any Out of Specification results found during contract analysis at Public Testing Laboratory, then the Public Testing Laboratory should follow their in-house OOS investigation procedure.

5.14 Public Testing Laboratory should convey its data, finding and supporting documentation to Contract giver.

5.15 If in case excess of samples require for Investigation then Contract giver should provide the quantity as required by the external laboratory for further investigation.

5.16 In case of confirm OOS is Preliminary OOS investigation at contract laboratory, contract giver should initiate.

5.17 Trend of OOS shall be prepared on yearly basis based on number of OOS against categorization of OOS such as analyst error, document error, manufacturing error, confirm OOS etc.

 6.0 ABBREVIATIONS:

Abbreviation	Expanded form
SOP	Standard Operating Procedure
No.	Number
QC	Quality Control
QA	Quality Assurance
F&D	Formulation & Development
OOS	Out of specification
Dept	Department
MHRA	Medicines and Health Care Product Regulatory Agency
USFDA	United States Food and Drug Administration
CDER	Center for Drug Evaluation and Research
CAPA	Corrective action and Preventive action
%	Percentage

7.0 ANNEXURES:

Annex. No.	Title
01	Out of Specification (OOS) log book
02	Out of Specification Investigation Report – Preliminary Out Of Specification Investigation
03	Out of Specification Investigation Report – Full Scale Investigation
04	Checklist for Phase-Ia Investigation
05	Checklist for Phase-Ib Investigation
06	Checklist for Phase-II Investigation
07	Checklist for Phase-III Investigation
08	Flow chart for the OOS investigation – Preliminary OOS Investigation
09	Flow chart for the OOS investigation – Full Scale OOS Investigation
10	Flow chart for investigating and reporting of OOS results of Dissolution
11	Flow chart for investigating and reporting of OOS results of Content Uniformity of finished dosage.

8.0 SOP REFERENCES

• MHRA : Out Of Specification Investigation
• USFDA-CDER : Guideline for industry-Investigating Out Of Specification (OOS) test results for pharmaceutical production- October 2006

END OF THE SOP

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ANNEXURES :

Annex. No. 01 Out of Specification (OOS) log book

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Annex. No. 02 Out of Specification Investigation Report – Preliminary Out Of Specification Investigation

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Annex. No. 03 Out of Specification Investigation Report – Full Scale Investigation

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Annex. No. 04 Checklist for Phase-Ia Investigation

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Annex. No. 05 Checklist for Phase-Ib Investigation

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Annex. No. 06 Checklist for Phase-II Investigation

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Annex. No. 07 Checklist for Phase-III Investigation

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Annex. No. 08 Flow chart for the OOS investigation – Preliminary OOS Investigation

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Annex. No. 09 Flow chart for the OOS investigation – Full Scale OOS Investigation

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Annex. No. 10 Flow chart for investigating and reporting of OOS results of Dissolution

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Annex. No. 11 Flow chart for investigating and reporting of OOS results of Content Uniformity of finished dosage.

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