Out of Specification SOP

SOP for Out of Specification (OOS) | Out of Specification as per ICH , MHRA , FDA Guidelines | Out of Specification Investigations |

Out of Specification (OOS) SOP covers below points:
- Out of Specification (OOS) definition
- Out of Specification Investigations
  - Phase I investigation
  - Phase-II investigations
  - Phase-III investigations
- Out of Specification (OOS) acceptance criteria
- Out of Specification (OOS) Reporting
- Out of Specification (OOS) Investigation Checklist
- Out of Specification (OOS) flow chart

1.0 OBJECTIVE :

This SOP defines the procedure for investigation of all Out of Specification (OOS) test results.

2.0 SCOPE :

This SOP is applicable to testing of Raw Materials, In-process Control Testing, Batch approval and Stability Testing when analysis results are outside of pre-defined specification in Quality Control department at the manufacturing facility.

3.0 RESPONSIBILITY :

Head of Quality Control shall be:
- Responsible for investigating the laboratory investigations.
- Reporting the OOS to Q.A. department and taking approval.
Quality Assurance shall be:
- Responsible for investigation of OOS.
- Review of OOS reported results.
- Initiation of “Failure Investigations” at Manufacturing.
- Evaluation of OOS test results and their Action plan.

4.0 ACCOUNTABILITY:

Q.A. Head and department head of concerned department

5.0 PROCEDURE :

5.1 The term OOS results include all test results that fall outside the established specifications or acceptance criteria.

5.2 Investigation of out of specification results shall be carried out in three different phases named as phase-I, phase-II and phase-III. Flowchart of investigation of different phases is mentioned in Out of Specification – Process Flow Chart of Investigation for different Phases (Refer Annexure No. 06).

5.3 When an out of specification test result is suspected, the analyst should immediately inform immediate (reporting) head. The immediate (reporting) head shall inform regarding OOS to QC Head / Designee.

5.4 The original samples, dilutions glass wares, aliquot of samples, reagents shall be preserved immediately once the OOS result is observed and shall be retained till the investigation for OOS complete.

5.5 Head of QC shall investigate the (OOS) as per this SOP.

Phase I investigation:
- Phase I investigation shall be carried out in two phases i.e. Phase I-A and Phase I-B.
  - Phase I-A investigation is to determine whether there has been a clear assignable cause due to external circumstances such as power failure or those that the analyst has detected prior to generating data such as spilling sample etc. that will negate the requirement of Phase I-B and Phase II investigation.
  - A Template for Laboratory Investigation Checklist cum Report of Phase I-A used during Phase I-A Investigation is attached as Annexure No. 01. Phase I Investigation should be completed within 2 working days. OOS should be report to be closed or proceed for further Investigation.
  - The concerned chemist and his respective (reporting) head shall annotate e.g. in-correct instrument parameter, calculation error etc., if any assignable cause found during phase I-A investigation, corrects the invalid result.
  - If any assignable cause is not found, repeat analysis must be carried out. The respective (reporting) head shall annotate on the respective document that “analysis to be repeated” on all associated analytical documentation.
  - The repeat analysis shall be carried out by same analysts by using original workings stock solutions but should not include another preparation from the original sample, however if the remaining quantity is insufficient for retesting then re-sampling, sample preparation and testing shall be followed, the retesting results shall be forwarded to Head QC for his review.
  - The results of repeat analysis as a repeat analysis report along with investigation report shall be sent to Q.A. Head or his designee who evaluates the results and if repeat analysis results are found satisfactory and within acceptance criteria as per respective product / material specification then the batch/material shall be approved.
- Note : Keep Original Results with Investigation Report and Repeat Analysis Report as part of Final Report.
- If initial investigation is not conclusive, the same shall be communicated to Q.A. by Head QC within two working days to initiate phase I-B investigation.
- Phase I-B investigation:
  - A Template for Laboratory Investigation Checklist cum Report of Phase I-B used during Phase I-B Investigation is attached as Annexure No. 03.
  - The analyst and respective (reporting) head, investigation during phase I-B should be restricted to data / equipment / analysis review only.
  - If any assignable cause found during phase I-B investigation then the original test data shall be invalidated with proper annotation of reason.
  - If the assignable cause is due to sampling error then re-sampling and retesting shall be done with prior approval of Q.A. Head/Designee.
  - Repeat analysis shall be carried out by two different analysts in duplicate by using original workings stock solutions but should not include another preparation from the original sample, however if the remaining quantity is insufficient for repeat analysis then re-sampling, sample preparation and testing shall be followed, the retesting results shall be forwarded to Head-QC for review.
  - The retests shall be performed by different analyst. The analyst shall be at least as experienced and qualified in the method as the original analyst.
  - If the result found after repeat analysis is satisfactory then record the results and inform to Q.A. Head / Designee shall review the results and if the results are found satisfactory and within the acceptance criteria then the batch/material shall be approved and investigation shall be closed.
  - All individual test results shall 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.
  - A CAPA shall be generated after finding of assignable cause but it shall not be limited to training of analyst and re-calibration of equipment.
- If Phase I-A and I-B investigation is not conclusive, the same shall be communicated to Q.A. by Head QC within two working days to initiate Phase-II investigation and simultaneously the notification to loan License Holder / Customer regarding the same shall be given.
Phase-II investigations:
The investigation consists of production process review and/or additional laboratory work.
- Q.A. Head shall initiate Phase II investigation as per respective SOP of “Failure Investigations (Refer Annexure No. 026)”.
- Q.A. Head shall thoroughly review documentation of Batch Manufacturing and Packing Records for the deviation, incident or change control which includes all steps of manufacturing like dispensing of raw materials, adherence to manufacturing steps and critical process parameters, results of in-process tests, yield, equipment or system malfunction etc. to determine the possible cause of OOS results.
- Q.A. Head shall review any deviation documented for the batch under investigation.
- Q.A. Head shall also take into account if the problem had occurred previously and effectiveness of corrective actions taken.
- If the investigation reveals a manufacturing defect, OOS result shall be validated and the batch shall be rejected and no further retesting shall be done and simultaneously the communication with loan License holder/customer shall be done.
- Q.A. Head shall evaluate impact of OOS on other batches or product associated with the failure.
- Q.A. Head shall summarize the aspects of the manufacturing process that may have caused the problem. Q.A. Head shall document the actual or probable cause and suggest corrective actions including revalidation of the manufacturing process.
- If the investigation does not reveal a manufacturing defect, Q.A. Head shall recommend for additional laboratory testing that should be based on a preapproved protocol/testing procedure.
- The additional laboratory testing shall include retesting a portion of original sample or re-sampling if the original sample is not sufficient for retesting.
- Retesting: Performed on the original sample not a different sample, can be a 2^nd aliquot from the same sample that was the source of the original failure. The sample used for the retesting should be taken from the same homogeneous material that was originally collected from the lot, tested, and yielded the OOS results.
- Re-sampling: 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 Q.A. / Supplier / loan License Holder. The process of obtaining the resample shall 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.
- Re-testing of sample shall be carried out by two different qualified analysts in triplicate, other than the original analyst who report the OOS. The analyst shall 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 shall be reviewed and documented.
- If there is any assignable cause found during additional laboratory testing (like sampling error) the original results shall be invalidate.
- Head-QC shall check whether the results are within OOS acceptance criteria and submit to Q.A. Head / Designee.
- The results of retest shall be evaluated by Q.A. Head / Designee and if results found satisfactory and within acceptance criteria as per respective product / material specification then the material/product shall be approved and investigation shall be closed.
- All individual test results shall 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.
If Phase-II investigation (Manufacturing and Laboratory investigation, (Refer Annexure No. 04) is not conclusive, then phase-III investigation shall be initiated to decide the fate of product.
Phase-III investigations (Refer Annexure No. 05):
This investigation has been carried out to determine the fate of product (approved /disposition) on the basis of investigation data of Phase-I and phase-II, if there is no any conclusive (assignable) reason of OOS.
The impact of OOS result on other batches, ongoing stability studies, validated processes and testing procedures shall be determined by Quality Control and Quality Assurance and shall be documented in the conclusion, along with appropriate corrective and preventive actions.
Batch Disposition: If no laboratory or calculation error are identified in the phase-I and Phase-II investigation and no scientific basis has been found to invalidate initial OOS, then all the results (passed and suspect) shall be documented to take decisions in regard of batch approval / rejection which shall be evaluated and approved by Q.A.
Any decision to approve a batch, in-spite of an original OOS result that has not been invalidated, shall only be done after complete investigation which reveals that the approved batch does not affect the quality of product / material.
Once the decision of rejection of batch has been taken, it cannot be reversed.
For Raw material OOS test result, Phase – I investigation shall be carried out up to laboratory error. In addition Q.A. Head shall communicate the results to vendor and request for joint analysis, if required. If OOS is valid, the initials results shall be considered for the rejection of material.
Stability OOS shall be evaluated if any results during stability study period has been observed.
If abnormal results found at any stability interval which predicts that the test results may be OOS, additional testing shall be carried out before the next scheduled testing interval with proper justification.
Stability study OOS investigation shall be carried out as per the instruction given for Phase-I and Phase-II investigation.
If the stability OOS leads to product recall the same shall be handled as per respective product recall procedure (Refer Product Recall SOP).

5.6 OOS acceptance criteria:

All reanalysis results should individually pass.
Overall RSD should be within limit as per table below.

Test	% RSD
Assay	NMT 2.0%
Residual solvent(if applicable)	NMT 15.0%
Impurity above 0.10 %	NMT 10.0%

In case of impurity level below 0.10%, the values shall individually pass.
In case of other test the values shall individually pass.
- In case any OOS result is observed in the test of Uniformity of content and Dissolution, this shall be handled as per current edition of USP as given in the chapter <711> for Dissolution and <905> for Uniformity of content.

5.7 Reporting:

Q.A. shall allocate OOS number in the OOS Register and will issue Report number. The OOS Register (Refer Annexure No. 02) shall be controlled by Q.A.
The OOS Report Number for In-process, Stability and Finished Product shall have prefixed ‘OOS’ and be assigned as per following example:
- Example: OOS / FP/ 22 / 001,
  - Where,
  - OOS : Out of Specification report
  - FP : Finished Product, in case of in-process write “IP” and in case of stability write “SS”
  - 22 : Year
  - 001 : Sequential number
In case of Raw Material OOS Report Number, numbering shall have prefixed ‘OOS’ and be assigned as per following example:
- Example: OOS / RM / 22 / 001,
  - Where,
  - OOS : Out of Specification report
  - RM : Raw Material
  - 22 : Year
  - 001 : Sequential number

5.8 OOS investigation shall be closed within 30 days of reporting. Further extension shall be justified and authorized after prior approval of Q.A.

5.9 Trending of OOS shall be done on yearly basis.

6.0 ABBREVIATIONS:

Abbreviation	Expanded form
SOP	Standard Operating Procedure
Q.A.	Quality Assurance
OOS	Out Of Specification
MHRA	Medicines And Healthcare Products Regulatory Agency
ICH	International Conference on Harmonization
FDA	Food And Drug Administration

7.0 ANNEXURES:

Annexure No.	Title
01	Format for Phase I-A Laboratory Investigation Checklist cum Report
02	Format for Out of Specification Register
03	Format for Phase I-B Laboratory Investigation Checklist cum Report
04	Format for Phase II Investigation Report
05	Format for Phase III Investigation Report
06	Format for Out of Specification- Process Flow Chart of Investigation for different Phases