STANDARD OPERATING PROCEDUREPage 1 of 7
Document Number: S-115 Ver. 1.xx
Handling Out-of-Specification Results
Standard Operating Procedure
Handling Out-of-Specification Results
This is an example of a Standard Operating Procedure. It is a proposal and starting point only. The type and extent of documentation depends on the process environment. The proposed documentation should be adapted accordingly and should be based on individual risk assessments. There is no guarantee that this document will pass a regulatory inspection.
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Superseded Document / N/A, new
Reason for Revision / N/A
Effective Date / February 1, 2012
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Author / I indicate that I have authored or updated this SOP according to applicable business requirements and our company procedure: Preparing and Updating Standard Operating Procedures.
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Approver / I indicate that I have reviewed this SOP, and find it meets all applicable business requirements and that it reflects the procedure described. I approve it for use.
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Reviewer / I indicate that I have reviewed this SOP and find that it meets all applicable quality requirements and company standards. I approve it for use.
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1.PURPOSE
The FDA requires that an investigation be conducted whenever an Out-of-Specification (OOS) result is observed. This SOP defines the requirements for dealing with OOS results. Even if a batch is rejected based on an OOS result, the investigation is necessary to determine if the result is associated with other batches of the same drug product or other products.
2.SCOPE
Results that fall outside the specifications or acceptance criteria established in new drug applications, official compendia, or by the manufacturer and suspect within test results. The SOP applies to OOS as a result of analytical errors, process errors and manufacturing errors.
3.GLOSSARY/DEFINITIONS
Item / ExplanationOOS / Out-of-Specification. OOS results include those that fall outside the specifications or acceptance criteria established in New Drug Applications (NDAs), official compendia or by the manufacturer.
OOT / Out of trend
Retesting / Repeated testing of a portion of the original sample. The sample is taken from the same homogeneous material used for the original test.
Resampling / Collection and testing of a new sample from the batch. Resampling is conducted if the investigation concludes that the original sample was prepared improperly and was therefore not representative for the batch.
CA / Corrective Action
CAPA / Corrective and preventive action
Suspect Results / Test results that fall outside historical, expected or previous trends.
Note: For other definitions, see
4.REFERENCE DOCUMENTS
4.1.FDA Guidance for Industry: “Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production”, 2006.
4.2.SOP S-530: “Laboratory Failure Investigations”
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4.3.SOP S-114: “Corrective and Preventive Actions”
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4.4.Checklist E-116: “Out-of-Specification Situations (OOS)”
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4.5.SOP S-118 “Investigating Manufacturing Incidents”
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5.RESPONSIBILITIES
5.1.Laboratory Staff
5.1.1.Perform analysis correctly and check results for specifications.
5.1.2.Retain test preparations
5.1.3.Report failed results to laboratory supervisor.
5.1.4.Initiate out of failure investigation.
5.1.5.Prepare initial and final investigation report.
5.2.Laboratory Supervisor
5.2.1.Assesses failure investigations together with laboratory staff
5.2.2.Reviews and accepts or rejects test results.
5.2.3.Reviews and approves initial and final laboratory failure investigation report.
5.3.Quality Control Unit
5.3.1.Performs a batch failure investigation
5.3.2.Reviews test results and releases batch
5.4.Quality Assurance Department
5.4.1.Performs a batch failure investigation
5.4.2.Reviews test results and releases batch
5.4.3.Reviews and accepts or rejects failure investigation reports
5.4.4.Checks if processes and documentation are in compliance with internal policies and regulations/guidelines
5.4.5.Reviews and approves initial and final investigation report.
6.FREQUENCY OF USE
6.1.After each analysis, before final approval of the result.
7.OOS, FAILURE INVESTIGATION AND CAPA
The flow chart below illustrates the management of OOS Situations. According to the FDA draft guide, the identification of an OOS Result should be followed by an investigation with the purpose of trying to determine the cause of the OOS result. If an assignable cause was defined, either as a lab error or mfg error, CAPA is required to mark the closure of quality loop.
The figure below illustrates the link between an out-of-specification situation (OOS) a laboratory failure investigation and on corrective action and a preventive action.
Raw materials, active pharmaceutical ingredients (API) and finished products are tested against product specifications, e.g., amount of individual impurities should be below 0.1%. When the results are within specifications, they are reported, reviewed by the laboratory supervisor and by the responsible person in quality control and the batch is released. When the test results are outside the predetermined specifications, a laboratory failure investigation is initiated to identify the source of the problem. If a laboratory failure cannot be identified, it is assumed that there is a product problem and the batch cannot be released. A manufacturing or batch failure investigation is initiated to identify the source of the batch problem.
If the source of the batch problem is identified a corrective action is initiated to make sure that next production run is in specification. Simultaneously a plan is developed to prevent occurrence of the same problem at similar processes. This is called CAPA which stands for Corrective and Preventive Action. A CAPA is a subpart of a quality system and should always be conducted whenever there is a quality problem which can be identified as part of an audit, as a result of a failure investigation or as a results of a customer compliant, deviations assessment, other quality problems.
8.PROCEDURE
8.1.Upon completion of the analysis the analyst checks the results for specifications
8.2.If there is a deviation the analyst reports the deviation to the laboratory supervisor and initiates an informal investigation report
8.3.If the source of the deviation can be identified and well explained, errors should be corrected and the sample retested again by the same analyst. If the new result is in specification the original result can be invalidated. A formal investigation is not required. Initiate a corrective and preventive action plan according to the SOP “Corrective and Preventive Actions” in reference 4.3
8.4.If the source of the deviation cannot be identified and explained by the informal investigation this means it is not a lab error, a retest protocol should be initiated. A retest from the original sample container must be performed together with a retest from a different sample container, if necessary.
8.5.If the OOS result is confirmed, and the batch is rejected, QA Director or Manager initiates a cross functional investigation that involves Mfg, Eng/Maintenance, Technical Dept, etc to determine if the cause of the failure was a manufacturing error. Investigations must be completed within 20 business days following the deviation. Follow SOP “Investigating Manufacturing Incidents” in Reference4.5
8.6.If a manufacturing error is identified, investigation of other batches is required. CA will be proposed according to the SOP “Corrective and Preventive Actions” in reference 4.3.
8.7.If the cause of the failure is not a manufacturing error, the OOS is not confirmed and the result is considered not representative for the batch. Based on product investigation results and product history, QA/QU Dir or Manager would make the decision on batch disposition.
8.8.Document each step and the outcome of the investigation.
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