OOS SOP is a basic requirement in the pharma industry to investigate Out of Specification (OOS) results.
Introduction of OOS SOP
“Out Of Specification” (OOS) result investigation is a key GMP requirement in Pharmaceutical Industry. Hence, Out of Specification Standard Operating Procedure (OOS SOP) is prepared here to be in line with USFDA and MHRA OOS guidelines.
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The objective of OOS SOP
To describe a procedure for the investigation of the reported test results, that does not meet the predetermined specification.
Scope of Out of Specification SOP
This SOP is applicable for the analytical results of Raw-materials, Packaging materials, Intermediate stages, finished products (Drug Substances/ Drug Products), and Stability study samples, at the Quality Control Laboratory of Pharma Units.
This OOS SOP will not apply under the following circumstances (depending on the Organization’s Quality policy).
- In-process samples.
- Analyst qualification.
- Additional tests based on the Customer requirement specifications.
- Monograph evaluations/ Analytical Method Transfer analysis.
- Further study of stability sample for data collection which is OOS at a previous station in the same condition.
- Photo Stability & Transportation study (Stress Stability).
OOS SOP Responsibilities / Accountability
| Responsible Person | OOS SOP Responsibility / Accountability |
| Analyst – Quality Control | Immediate information to the laboratory supervisor by reporting the results. |
| Laboratory Supervisor | To review the documents and to perform the OOS investigation with the coordination of other departments. |
| QA Designee | To issue the OOS forms on the request and inward the reported OOS. To review and coordinate with other departments for OOS investigation. To lead the investigation team & to initiate Phase III. |
| Responsible Person | OOS SOP Responsibility / Accountability |
| Head Quality control/ Designee | To ensure the compliance of Phase-I and Phase-II/A investigation (Laboratory investigation) as per OOS SOP. To support the cross-functional Teams for better investigation. To propose the appropriate Preventive measure and implementation. |
| Concerned Head of the Department | To support the cross-functional investigation (Phase-II & Phase-III investigations). |
| Site-Quality Head/ Designee | To ensure compliance as per OOS SOP. To ensure the evaluation/ assessment and completion of the OOS investigation. To ensure the batch disposition of the material. |
Definitions
The terms and Definitions shall be included in the OOS SOP.
Out of Specification: Test results that fall outside of established acceptance criteria that have been established in specifications.
Assignable cause: Clear evidence, scientifically justified and documented as the cause of an OOS result.
Corrective Action: Corrective Action is an action(s) taken to eliminate the cause of nonconformity in order to avoid reoccurrence.
Preventive Action: Preventive Action is an action(s) taken to eliminate the potential nonconformity, defect, or undesirable situation in order to avoid occurrence.
Reporting of OOS Results
Reporting of OOS Results procedure as part of the investigation shall be included in the Out of Specification SOP.
OOS shall report within 24 hours of observation by the Analyst through the “Investigation of Out Of Specification Results” form.
The supervisor shall review the OOS form which will submit to the Quality Assurance department for allotment of the OOS reference number.
Designee–QA shall enter the OOS details in the Out Of Specification log as per the format.
OOS numbering system
The procedure for the numbering system shall be incorporated into OOS SOP. OOS number shall assign as per the below numbering system.
OOS/XX/YY/ZZZZ
Where,
OOS: Out of Specification
XX: Unit code (for Unit-I A1, Unit-II A2 & for Unit-III A3)
YY: Two-digit year code (ex: for the year 2022: 22)
ZZZZ: Four-digit serial number (0001, 0002, etc. for a particular year)
Ex: OOS/A1/22/0001
OOS SOP – Points to consider
In case of multiple batch failures in a single analysis set, one OOS number shall assign for all the batches however separate OOS forms shall use. These points shall be elaborated in OOS SOP for better Clarity.
In case of multiple test parameter failures reported for a single batch, the same OOS number shall assign.
In case of OOS occurred at an outside testing laboratory, the OOS number shall assign & investigation form shall be sent to the respective laboratory for investigation purposes. Alternatively, the investigation report shall accept and considered for OOS investigation/ necessary CAPA using the vendor’s format as well.
Notify the OOS results to the customer, as per the quality agreement.
Preliminary Laboratory Investigation (Phase-I)
The Out of Specification SOP shall elaborate the Phase I investigation procedure.
Laboratory investigation shall carry out by the Quality Control department Supervisor as per the OOS investigation checklist available in OOS form (but not limited to).
Phase-I (a) Investigation
- If any obvious error is found [Transcriptional / Calculation / Method parameter errors / Instrument breakdown / Power failures / (not limited to)], further investigation may not be required. The results shall correct and document with appropriate CAPA.
Retesting (Triplicate analysis) shall perform if applicable.
Phase-I (b) Investigation
If an obvious error is not identified, further laboratory investigation shall be carried out.
Analyst Interview: Conduct the Interview with the persons who performed the critical steps during the analysis, to understand the practices & to find out the assignable root cause. Capture the Interview details in the OOS form.
During the investigation, make sure that all the solutions associated with OOS shall remain till the completion of the preliminary phase-I investigation by the supervisor. Original samples (Including Standards & Impurities) shall retain until the completion/ conclusion of the reported OOS investigation.
Evaluate/ discuss the status of impacted batches.
Based on the checklist review any reportable observations notified, and then the same shall discuss for further evaluation. The impact shall assess and a conclusion shall draw.
As a part of the investigation, re-measurement shall carry out with retained solutions (same-vial/ same-solution/ re-dilution) unless otherwise justified (for applicable tests).
Hypothesis analysis (remeasurement procedure)
The Out of Specification SOP shall elaborate the Hypothesis procedure.
Re-measurement testing shall perform to verify probable errors regarding what might have happened (E.g. Instrument malfunction, dilution errors & contamination/ etc).
The re-measurement shall perform under the supervision of QC/QA with the same analyst or second analyst as mentioned below.
| Analysis to be done as a part of Remeasurement Testing | Suspected Laboratory Error if the Remeasurement is confirmed |
| Re-injection of the same vial of standard and test solution | Transient Instrument malfunction |
| Re-filling of the vial with the same test preparation | Contamination due to vial in case of OOS results in Impurities |
| Re-dilution of the test and/or standard preparation from the stock solution | Dilution error during final dilution of test and/or standard preparation |
Note: The obtained results shall not consider for reporting purposes.
Applicability of remeasurement
The Out of Specification SOP shall elaborate on the remeasurement/hypothesis investigation analysis procedure.
Remeasurement is applicable for the techniques like chromatography where the Same vial and Original solutions are intact and possible for remeasurement (In the case of GC-HS, the same vial may not be required). Whereas the techniques like non-chromatography (WC, LOD, IR, XRD & Potentiometry Assay), remeasurement can skip and justification shall document.
- If an assignable cause is identified during the Laboratory investigation (re-measurement), QA Head/ Designee shall allow for retesting of the original sample (Three measurements) preferably by the second analyst.
- If an assignable cause is not identified during the Preliminary Laboratory investigation, QA Head/ Designee shall recommend for Full-scale investigation (Phase II – Parallel investigation of Manufacturing & extended Laboratory investigation).
Note: Phase-IIA investigation shall initiate, whereas the remeasurement is not applicable. In such cases, the parallel investigation may not require and Phase-IIB investigation shall initiate based on the outcome of Phase-IIA.
- For extended laboratory investigation (Phase-IIA), an OOS form shall follow, and for Mfg investigation (Phase-IIB), notify the Manufacturing department for further investigation.
Note: Phase-II B (Manufacturing) Investigation is not applicable in the case of Raw-materials.
Extended Laboratory Investigation (Phase-IIA)
The Out of Specification SOP shall elaborate on the Phase-IIA investigation procedure.
Extended Laboratory Investigation shall carry out with approved protocol to find out the assignable cause/ most probable causes.
The protocol shall prepare by QC as per Annexure-V and approved by QA.
During the extended laboratory investigation (Hypothesis/ Simulation study), the below points shall consider.
The study shall be carried out with the available Standard unless otherwise justified.
If any suspected cause is identified, then only the original sample measurement shall perform.
In the case of Solution, stability places a role in reported OOS; it should be proved by using Standard only.
If any ambiguity in sample storage condition or doubt in sample integrity, in such cases resampling shall be done upon QA approval (with justification).
An extended hypothesis study shall perform until the most probable causes are identified.
If an assignable root cause is identified (during Phase-IIA), invalid the initial OOS results then propose CAPA & proceed for further retesting (Three measurements) followed by results reporting and impact-assessment.
If an assignable root cause is not identified during Phase-IIA/ Phase-IIB then based on the most suspected cause retesting (Triplicate analysis) shall be done with two different analysts.
Note: If the first retesting analysis failed, the second retesting analysis can skip.
Further retesting will not be allowed, if OOS results were confirmed (OOS confirmed).
Note: If extended investigation remains unclear (No assignable cause), report the results, and Phase-III investigation can carry out.
Manufacturing Investigation (Phase-IIB)
The Out of Specification SOP shall elaborate the Phase-IIB investigation procedure.
Phase-IIB investigation shall carry-out by the manufacturing department, upon the conclusion of the Preliminary Laboratory Investigation (Phase-I).
Based on the notification received from QA as per Annexure-VI, the Concerned manufacturing person shall start the investigation by process review including preliminary checkpoints. Based on the Phase-IIB investigation as per Annexure-VIII, observations shall document by the Designee-Production.
If an assignable cause is identified during Phase-IIB investigation, then appropriate corrective & preventive action shall be taken along with impact assessment followed by batch disposition.
In case the assignable cause/ probable cause is identified as a sampling error, resampling can be performed based on the QA approval.
If an assignable cause is not identified during the preliminary investigation, further retesting (Triplicate) with the original sample can be proposed based on rationale (Refer to Phase-II A).
OOS SOP – Resampling procedure
The Out of Specification SOP shall elaborate on the investigative resampling procedure.
Before proceeding with the re-sampling activity, ensure/consider the below points.
Sound scientific justification must be provided for re-sampling and shall occur rarely.
In case of an insufficient quantity of the original sample whereas other test parameters to perform with further testing of OOS, hence then resampling can perform with approval from QA.
Evidence indicates that the sample is compromised or invalid.
The process of resample activity shall document (Refer to Annexure).
Re-sampling shall perform by the same sampling methods used for the initial sample. However, if the investigation determines that the initial sampling method was in error, a new accurate sampling method shall develop, qualify, and documented.
The analysis shall perform in duplicate measurements, upon resample.
Retesting & Reporting of Analytical Results
The Out of Specification SOP shall elaborate on the retesting and reporting procedure.
If an assignable cause is identified – Retesting shall be carried out in Three (3) measurements (3 different preparations).
If an assignable cause is not identified – Retesting shall be carried out on Three (3) measurements with Two analysts (Second analyst and most preferably first analyst). Total 6 measurements.
Impacted batches (Other than OOS batch within the same analysis set) retesting analysis shall be carried out and assessed (Single measurement/ as per STP).
Based upon the retesting analysis conclusion, the initial OOS analysis set (all batch results) shall be invalidated, and the ‘Not considered’ stamp shall be affixed.
The original Sample shall be used for retesting analysis until justified (QA will decide in case of re-sampling).
Note: Retesting of three measurements is not applicable for the test parameter of Description/ Appearance, where a Single measurement is sufficient.
Follow us below, for the final result reporting.
Average results shall be considered for reporting in the case of quantitative analysis (All individual results shall comply).
Note: For the Assay test parameter, %RSD shall be NMT-2.0%. If % RSD does not comply, further investigation shall be based on QA recommendation/evaluation.
Phase-III Investigation
The Out of Specification SOP shall elaborate the Phase-III investigation procedure.
If an assignable cause is not identified during the Phase-II investigation, then report all the results (Confirmed OOS) and initiate Phase-III investigation. As part of Phase-III investigation, review the manufacturing investigation and combine laboratory investigation. The OOS results shall escalate to PDL/ ADL for further investigation to find out the root cause and preventive measures. The impact of OOS results on other batches shall evaluate.
Stability Specific Procedure
Out of Specification (OOS) procedure shall be the same as regular analysis. However, Cross Functional Investigation (Phase II & Phase-III) shall be led by QA.
Additional samples can be withdrawn for investigative analysis based on the pre-approved protocol with proper justification (Phase-IIA), protocol shall approve by QA Head/ Designee.
During the investigation, further station Stability samples can test if the product is bound to fail. This activity can be done with pre-approved protocol only.
In case of confirmed OOS in stability study, further study (upcoming station analysis) may continue for data collection purposes and OOS shall not report for the same batch at the same condition.
Batch Disposition – OOS Conclusion
The Out of Specification SOP shall elaborate the Batch disposition procedure.
All test results, shall report and considered in batch release decisions.
If an assignable cause is not identified and OOS is found invalid, a batch disposition decision shall take by QA. Considering the most probable cause determined once after completion of the full-scale investigation (Phase-II) (Where the OOS result not reflecting the quality of the batch).
Upon the batch disposition decision, the OOS investigation shall close with reference CAPA number by QA Head/ Designee (if applicable). Hence, further implementation of proposed Corrective actions & preventive actions shall track.
Raw Materials / Packing Materials Specific procedure
The Out of Specification SOP shall elaborate the Rawmaterial investigation procedure.
Any batch rejected either due to non-conformance to the Quality standards, OOS shall inform the Purchase department (as per Annexure-X) for further notification to the respective vendor.
QA Designee shall log vendor non-conformance as per Annexure.
Vendor non-conformance shall be numbered as ‘VNC/AA/YY/XXX’.
Where,
VNC – stands for Vendor non-conformance.
AA – stands for location Code (Unit-I A1, Unit-II A2 & Unit-III A3).
YY – stands for the last two digits of the current calendar year (22 for 2022).
XXX – stands for a serial number starting from 001, 002, 003…
E.g. First vendor non-conformance of the year 2022 for Unit-I, shall be numbered as VNC/A1/22/001.
Based on the above notification (Annexure), the QA designee shall be taken follow-up for the response of said non-conformance w.r.t. the KSM.
After getting a response from the vendor, an evaluation of the response shall be done by the Head QA/Designee.
If vendor response is not received within 60 days, then the non-conformance form shall be closed with recommendations for upcoming lots monitoring.
In case of any quality issues, reanalysis/ joint analysis shall be decided by the Head QA/Designee.
The decision of batch disposition shall be taken by the Head QA/Designee.
For Packing material, Phase-I investigation shall be carried out as per Annexure.
Timelines for OOS investigation completion
OOS investigation shall be completed within 30 calendar days from the date of OOS reported, unless otherwise justified (Phase-I & Phase-II).
Phase-I Investigation (Laboratory) shall be completed within 3 calendar days from the date of OOS reported unless otherwise justified.
Designee of Laboratory/ Mfg. shall request Quality Assurance with proposed timelines for further extension. An extension request shall be made before its actual timelines.
The phase-III investigation shall be completed within 30 calendar days from the date of Phase-III initiation.
Evaluation of OOS Investigation
The OOS SOP shall elaborate on the Investigation evaluation procedure.
- A summary of OOS shall be prepared by Quality Assurance on a half-yearly basis for the effectiveness of the investigations and impact evaluation.
- Investigation/ report shall be amended in case of customer / regulatory observations.
- The investigation report shall contain the following information (but not limited to).
- General information including OOS details
- Product/ Batch history
- Investigation with Root cause analysis
- Root cause/Conclusion
- Correction/ Impact assessment
- Corrective action
- Preventive action
- Report approval details
Reference to OOS SOP
The reference to the OOS SOP is “USFDA & MHRA OOS Guidelines”. The website links are given below.
Refer latest & never-before Pharma Guidelines at PharmaeliX Latest ICH Guidelines for Pharmaceuticals 2023
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