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STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

/
Author

Date

Dept. Head Approval

Date

QA
Approved by QA

Date

Distribution:

QA, QC OOTOOS Analytical results obtained could be atypical (out of trend, OOT) or out-of-specification (OOS). These aberrant results require verification and, if verified, investigation into their root cause. This procedure provides detailed instructions for consistent and thorough evaluation and investigation of such analytical results. OOS OOT This procedure covers handling of data, investigation and documentation of final results. QC laboratory has responsibility for the evaluation of all investigations of laboratory data associated with potential OOS or OOT results. This procedure applies to all testing against approved specification. It applies, but not limited to, analytical and physical testing of the following materials: Incoming raw materials Intermediates, In-process samples and final products Stability samples Process and cleaning validation samples This procedure does not apply to: OOS/OOT Potential OOS/OOT results obtained during process development (includes stress or accelerated study), where some results are expected to fall outside of established limits. Method validation and verification Method transfer

PURPOSE:

SCOPE:

SCOPE: (Cont.)

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2/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

Analyst qualification / Equipment qualification/calibration

REFERENCE AND ATTACHMENT:

SOP/ SOP/TITLE 1-3002 Deviation Investigation

// FORMS/ATTACHMENTS/TITLE 1 Attachment 1: Laboratory Investigation Flow Chart 2 Attachment 2: Aid to Analyst/Supervisor Review in Initial Laboratory Investigation F-03-001 Laboratory Investigation Report --Initial Investigation by QC Laboratory F-03-002 Laboratory Investigation Report --Further Investigation by QC Laboratory F-03-003 Laboratory Investigation Report Distribution Log F-03-004 KLE Known Laboratory Error Log F-03-005 OOS Laboratory OOS Log

N/A Any laboratory test result (including individual data point when replicate are determined) that fails a stated specification limit, either descriptive or numerical limit. An unusual, atypical or unexpected test result within specification limit, which, on inspection and in consideration of previous testing results, may not be reasonably expected to occur. OOT OOS Note: Analytical results arising from description mentioned above are also known as aberrant results until these results are investigated and classified as either OOT or OOS.

DEFINITIONS:

OOS Out-ofSpecification Result (OOS) OOT Out of Trend (OOT)

:
DEFINITIONS: (Cont.)

Established Specification

A value or range of values that define the acceptance criteria for a given test, material or product.

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3/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

Assignable Cause Sample Original Sample Preparation

A detailed and scientifically sound explanation of laboratory error or other cause that lead to occurrence of aberrant result. A representative quantity of material taken from a defined bulk (by a known method), clearly identified and logged into laboratory for analysis. Aliquot of sample prepared according to test method for analysis, which includes dilution and any solution prepared from the ORIGINAL sample.

Original Result Test value obtained on analysis of original sample preparation according to specified test method. Invalid Result Result found to be incorrect following a documented investigation based on sound scientific evidence, which indicates that the result produced under incorrect condition or from an improper sample. Examples of data considered invalid are: Incorrect start and stop integration locations Failure to properly follow instructions as required in test methodology Error in preparation HPLC Instrument malfunction, e.g. HPLC auto sampler miss-injection Sample deterioration is suspected due to long queue time before testing is completed. Sample exceeds storage time as per methodology (Includes sample solution preparation as well as bulk raw material sample) / Incorrect storage of sample/standard

:
DEFINITIONS: (Cont.)

Invalid Result

/ Note: When data/results are invalidated due to a factor that affects a number of analytical results tested at the same time using the same method, all data that are affected by that factor must be invalidated. Invalid data/results should be crossed out.

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4/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

Investigation

A systematic documented process by which the potential causes for error are identified and the appropriated follow-up work that may be undertaken (e.g. scientifically sound and justifiable experiments, gathering of evidence from other sources) to enable the identification of assignable or most probable cause of error. Any scientifically sound and justifiable experiments undertaken, as part of an investigation, must be described in an approved protocol. An error occurring in the testing process, caused by an analyst, a piece of equipment, the test materials, etc. that can be proven through investigation, that enables the invalidation of the result to be declared. Examples of Known Laboratory Error includes: Calculation error Measurement error (weights, volumes, etc.) Use of incorrect, expired, or otherwise defective standards Manipulation error (pipetting, transferring, etc.) Failure to follow test method as written Use of non-validated or inadequately validated method Use of unapproved method or modified method

KLE Known Laboratory Error (KLE)

:
DEFINITIONS: (Cont.)

Additional replicate analysis performed using an aliquot or additional portion of material from the original analytical sample.

Retest

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STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

Note: Retest may not always be possible, e.g. testing a sample from a dynamic process (in-process testing of a reaction mixture), where testing is destructive of the material tested, or where testing is compromised by previously opened container e.g. determination of moisture of a hygroscopic material. QA A further sample taken from the same batch or lot of material from which the original sample was taken. Note that resample is not taken from the same sample originally submitted to the laboratory. Resample should be taken in compliance with a clearly defined sampling procedure or an approved investigation protocol, to provide a new sample for analysis. Resample is only allowed when original analytical sample used for testing is shown, by investigation, to be: --- Not representative of the batch or lot --- Or because it has been used up --- Or compromised in some manner Note: A retained sample is not considered a resample. There must always be a documented rationale, QA approved, for resample. Control Sample A sample of material that has been previously characterized and tested and results obtained been found to be consistent with similar historical results for that material. Any product that has previously been well characterized may also be used; typically, a stability sample with a prior historical trend is a good source of control samples. Process Error OOS/OOT An error occurred in or related to the manufacturing process, where root cause is known or determined or attributed to the process, which may result in OOS / OOT results.

Resample

:
DEFINITIONS: (Cont.)

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6/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

Re-dilution

Repeating any dilution or treatment of original sample and its accompanying standard solution for repeating the analysis or test measurement to confirm result obtained. This is used to identify a possible sample preparation problem and is not considered a retest. A re-aliquot is justified when an intermediate step in the sample preparation is suspect (e.g. dilution, digestion, pipetting etc.). Note: Re-dilution is dependant upon suitable solution/sample stability from the time of preparation and its storage.

/ Re-injection / Re-read

OOS/OOT / Re-examination of the same aliquot or dilution that produced OOS / OOT result in order to confirm the actual result obtained. Note: As above, this may not be possible where the prepared aliquot or dilution is known to be unstable after a given time period.

Valid Result

A result from testing carried out under approved, scientifically suitable conditions, whether within specification or outside, and there is no sound scientific grounds for invalidating this result.

ACTION

PROCEDURE:

RESPONSIBILIT Y

1. Analyst 1.1

INITIAL INVESTIGATION BY QC LABORATORY

Immediately notify Supervisor when an aberrant result is obtained Note that notification should be done after calculations have been checked.

RESPONSIBILIT Y

ACTION

QC

1.2

QC QC

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7/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

Analyst & QC Supervisor

When the reason for aberrant result is easily and completely explained, e.g. calculation, clerical, or transcription error, and the Supervisor is satisfied that the reason is valid and no further practical work needs to be carried out, then the analyst should enter the reason for the error and the correct value(s) in the notebook. Supervisor countersigns these entries. 1.3 QC LIR When calculation of result is found to be accurate, a formal investigation is required and this initial investigation should be recorded in the Laboratory Investigation Report (LIR) Form - Initial Investigation by QC Supervisor. QC LIR LIR First, analyst should obtain the next sequential LIR Number from the Logbook and obtain an authorized copy of the LIR Initial Investigation Form from QC Supervisor or designee. 1.4.1 The initial Laboratory Investigation involves investigating, within the laboratory, for known errors during testing of the sample. This Initial Laboratory Investigation should be completed within one work-day when aberrant result is reported. LIR 2005 LIR 2005-001 Assign unique LIR Number using numeric full year designation followed by a sequential number corresponding to the occurrence in that year. For example, the first occurrence of 2005 would be assigned an LIR Number of 2005-001.

QC QC Supervisor

Analyst

1.4

1.4.2 1.4.3

QC Analyst & QC Supervisor

1.5

QC LIR Working together with Supervisor, analyst should perform a preliminary assessment of the data and result(s) obtained (including a visual check on pipettes, flasks used, weights, numbers calculations, equipment used, etc.) to establish whether there is any identifiable laboratory or clerical error (Known Laboratory Error, KLE). Analyst and Supervisor should complete the LIR Initial Investigation Form as they undertake this phase of the investigation.

RESPONSIBILIT Y

ACTION

QC Analyst & QC Supervisor

a QC 2 / Notes: Analyst and Supervisor shall use checklist given in Attachment 2 (Aid to Analyst / Supervisor Review in Initial Laboratory Investigation) as an aid to undertake this initial investigation.

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8/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

b HPLC/GC 1.2 When investigating an aberrant result involving a HPLC/GC auto sampler and it is clearly obvious that there is a stable system and that one injection of replicate injection is clearly miss-inject, it is permissible, in this case, to re-inject the original solution to confirm results. However, this re-injection needs to be clearly documented and signed by the Supervisor as in 1.2 above. 2. Analyst & Supervisor 2.1
REVIEW OF INITIAL INVESTIGATION

If the conclusion of the Initial Investigation is that the aberrant results was due to laboratory error, then: 2.1.1 2.1.2 2.1.3 2.1.4 2.1.5 2.1.6 No further investigation needs to be performed The original results are invalided The analysis must be repeated either by re-dilution or in its entirety according to assigned cause. LIR / Complete the Initial Investigation Review section of the LIR Initial Investigation Form, sign and date. New results should be reported. Record laboratory error in the KLE logbook

2.2

LIR / The LIR Initial Investigation Form should be filed with each Data Recording Sheet/laboratory notebook, or stability file covering the product analysis in question. KLE QA Notify QA at the end of the Initial Laboratory Investigation if no KLE could be found, and the result considered valid.

Analyst & Supervisor

RESPONSIBILIT Y

2.3

ACTION

QA

2.4

Note:

a KLE QC QAQA In the case of new incoming raw material analysis, at the end of the Initial Laboratory Investigation and if analytical result is confirmed as not being due to a KLE, QC should notify QA. QA should then Reject the batch of raw material, notify Purchasing and arrange for material to be returned to the supplier.

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STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

bQA SOP 1-3002 In the case of retested raw material that have been stored at site, QA may decide to undertake further investigation. In such case, SOP 1-3002 should be followed. 3. QA 3.1
CROSS FUNCTIONAL MEETING

QC QA Upon receiving the notification from QC, QA should notify the relevant Production, Engineering and Material to alert people to possibility of a product quality problem. QA QA 3 Note: QA may decide to call a cross functional meeting to discuss the aberrant result and require Production, Engineering or Material Management to undertake investigations in their respective areas to identify potential causes of aberrant result. This meeting to initiate further investigation must be undertaken within 3 work days from the date event reported to QA.

QC QA

3.2

QC If aberrant result is due to a potential processing error and this is confirmed by Production, then no further investigation needs to be carried out by the laboratory. Then QC reports the results. The batch shall be rejected. LIR / The LIR Initial Investigation Form should be filed with each Data Recording Sheet/laboratory notebook, or stability file covering the product analysis in question.

RESPONSIBILIT Y

ACTION

QC

3.3

LIR If it is decided that further QC work is required, this must be documented in a LIR --- Further Investigation. QC If it is decided that no further QC work is required, then QC reports the results, and Deviation Investigation procedure shall be initiated. QA

QC QA

3.4

QA

3.5

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10/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

QA should write meeting minutes or memo, the investigation report of relevant department shall be attached to the minutes or memo. 3.6 LIR The minutes or memo should be attached to the LIR Investigation Protocol or Deviation Investigation Report (if applicable).
FURTHER QC INVESTIGATION

4. QC 4.1

QC LIR If further work is required, analyst should obtain an authorized copy of the LIR Further Investigation by QC Laboratory from QC Supervisor or designee. These documents are to be regards as the minimal level of documentation required for Further Investigation. / A more comprehensive protocol / report may need to be developed on additional pages to these Forms as required. QC QA Note: QA must approve all protocols before QC carries out any additional work.

QC

4.2

QC Using the Further Investigation form, QC Supervisor and analyst must define possible causes for the problem and design an investigation protocol aimed at determining the assignable or most probable cause of the aberrant result via available data.

RESPONSIBILIT Y

ACTION

QC

4.3

Using the protocol, a pre-defined number of retests should be documented using scientifically sound judgment and rationale, and should be approved PRIOR to any testing activity. Note: Retesting may not be necessary if all of the results outside of the specification are expected (e.g. a stability interval result obtained after batch expiration or on accelerated stability).

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11/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

QC Analyst & QC Supervisor

4.4

Each investigation needs to be evaluated on a case-by-case basis and documented in the protocol using scientifically sound justification. The applicability of a Second Analyst should be evaluated. A second analyst is not always required. A second analyst could however be an effective tool in finding an assignable cause and could improve the power of the retest data. The use of a control sample could assist in finding the likely root cause and when used, acceptance criteria for the control should be pre-defined. A control sample could be a stability sample or previously well-characterized material. QC The QC Supervisor should always ensure that any further analyses are undertaken in accordance with the defined and approved investigational protocol, and assess if results meet acceptance criteria of the protocol. If the results meet the acceptance criteria of the protocol, then a decision could be taken with respect to compliance to specification and the data reported. LIR If not, further investigational work may be carried out in accordance with additional approved protocols and these should be cross-referenced to the original LIR Number. The protocols must clearly state at what point testing will be stopped, and a decision reached on whether or not the material under test complies with specification.

4.5

QC QC Supervisor

4.6

4.7

RESPONSIBILIT Y

ACTION

5. QC QC Supervisor 5.1

EVALUATIONS AND REPORTING OF RESULTS

LIR Investigational reports must be generated using the issued LIR Further Investigation by QC Laboratory for each completed protocol, minimally describing: 5.1.1 5.1.2 Clear chronology of the investigation and determination of the assignable cause Corrective and preventative actions

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12/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

5.1.3 5.1.4 5.1.5 5.1.6

The final result to be taken as the reported value The justification for invalidating any data and QC QA Appropriate approvals --- QC Supervisor, QA Manager - as necessary. 30 QA QA These reports must be completed within 30 calendar days from date aberrant result is found. If investigational work requires longer time, QA should be notified. If appropriate, QA could a grant extension to the investigation underway. a / When averaging results for reporting purpose, careful consideration should be given to this process. Any re-injection / re-reads of a preparation should be treated as sub sets of a preparation. Redilutions may also be treated as a sub set of a preparation. All Retests should be weighted the same as the original preparation. The documentation should clearly present the averaging process used in reporting results. b/ Use of averaging depends on sample / purpose. If the sample could be assumed to be homogenous and a number of discrete measurements are taken (e.g. in Specific Rotation tests), then the average of all valid data points could be reported as test result.

Note:

RESPONSIBILIT Y

ACTION

c SD RSD Unless the test method or Investigational Protocol specifies averaging, all individual test results should be reported; it may be appropriate to report an assessment of the variability of the data such as the Standard Deviation and Relative Standard Deviation. d To use averaged results for assay or related substances reporting, all individual test results must conform to specification. QC QA 5.2 QA

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13/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

QC Supervisor QA

Ensure that the Investigation is complete and that all data has been documented in the Investigation Report in compliance with the procedure. If a Deviation is initially raised, QA may need to close the Report through the Site Deviations Procedure. QA Ensure clear conclusions are reached including the status and / or fate of the batch(es) in question (production batch testing only) and pass the Report to QA for final approval. QC QA LIR On periodic basis (but a least annually), QC Supervisor and the QA Manager should formally review all LIRs for trends with respect to analyst, product, method, and equipment. This review should be reported as part of the notification to Senior Management. OOS OOT SOP In the event that an aberrant result is confirmed as an OOS or OOT, the material must be rejected using the relevant SOPs. OOS OOS In the event that an aberrant result is confirmed as an OOS, it should assign the OOS Number and document in the logbook. 5.6.1 OOS OOS 2005 OOS OOS 200501 Assign unique OOS Numbers using the numeric full year designation followed by a sequential number corresponding to the occurrence in that year. For example, the first occurrence of 2005 would be assigned an OOS Number of 200501.
SUMMARY OF CHANGES

5.3 QC QA QC Supervisor QA 5.4 QC QA QC Supervisor QA Manager

QA

5.5

QC QA 5.6 QC Supervisor QA

CC No. Revision No. Effective Date Summary

N/A 2006-0034 .00 .01

2005.12.1 2006.7.20

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14/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

Aberrant Result

Easily and completely explained?

Y
Record in Data Recording Sheet/Notebook

N
Initial Investigation

Review of Initial Investigation

KLE

No KLE can be confirmed or No assignable cause is found

KLE

Invalidate Original Result

QA
Notify QA

Repeat Test

Cross Functional Meeting

1 Attachment 1: Laboratory Investigation Flow Chart Complete Initial Investigation Review

Production

Engineering

QC

Material

Other relevant Department

Confirmed process error

Further QC investigation required?

Report Original results

Complete Initial Investigation Review

Y LIR
LIR Investigation Protocol

Close the Report through Deviation procedure

LIR
LIR result of Investigation Protocol

Evaluations and reporting of results

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15/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

21 Attachment 2: Aid to Analyst/Supervisor Review in Initial Laboratory Investigation (1) This guide is provided to aid analyst and supervisor in investigating the validity of analytical test results. This list is NOT all-inclusive; other parameters should be evaluated as needed. General Items Analyst training Testing procedure Calculations Reagents Standards Environment Lab equipment Instrument performance Filters Volumetric flasks Shakers Instrument calibration HPLC HPLC Items System suitability Peak shape Tailing Shoulders Baseline trend Peak integration Retention times Mobile phase Lamp energy Wavelength Column ID Column pressure / UV/VIS Items Raw data information Spectra ID Baseline correction Blank reading Cell quality Wavelength Lamp energy Bubble Performance record

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16/17 3-0002.01 2006.7.20 2005.12.1

STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

Balance used Pipettes

Seal leak Bubble Injection time

22 Attachment 2: Aid to Analyst/Supervisor Review in Initial Laboratory Investigation (2) The following (which are not exclusive) are example of questions that should be considered during deviation investigation of the QC Microbiological Laboratory following a deviation: 1 Date unacceptably high microbiological results were recorded? 2 Sample reference and Date sample taken? 3 Batch numbers / material impacted by or in production at time of high results being recorded. 4 Did sampler observe anything different when taking the sample for analysis? 5 SOP Reference of SOP(s) used by sampler. 6 SOP SOP in date and current? 7 SOP Sampler trained in the sampling technique / SOP requirements? 8 Microbiological Laboratory Aspects: 1 Expiry date of media used? 2

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STANDARD OPERATING PROCEDURE

Title

OOS
INVESTIGATION OF OUT-OF-SPECIFICATION RESULTS

Correctly stored? 3 Media receipt and media preparation logs satisfactory? 4 Are media preparation records satisfactory? 5 Growth promotion on batch of media used satisfactory? 6 Are incubators used operating correctly? 7 Are incubators within calibration date? 8 Have temperature monitoring charts been checked. 9 Any additional information relevant to the investigation.