Out of Specification - Out of Trend Investigation

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1.0 Purpose 
 
 This procedure documents the steps necessary for investigating all analytical Out-of-
 Specification (OOS), Out-of-Trend (OOT) and unusual results, including stability results. The
 
 investigation is conducted to determine the root cause of the non-conforming result.
 
 2.0 Scope 
 
 This procedure applies to release and stability test results that fail to meet pre-established
 
 specifications. This procedure may be applied to, but is not required for, test results that meet
 pre-established specifications but are out of trend with historical data or are otherwise aberrant.
 
 This procedure does not apply to results generated during non-commercial testing activities such
 as research and development testing, validation, and method suitability studies. This procedure
 
 does not apply to microbiological results. 
 
 3.0 Definitions 
 
 3.1 OOS — Out of Specification; designation which indicates that the result for the test
 
 performed does not meet the established acceptance criteria. 
 
 3.2. OOT — Out of Trend; designation which indicates that the result for the test performed
 
 meets specification but is not statistically consistent with historical trends.
 
 3.3 UR — Unusual Result; a result that meets specification but is considered atypical,
 
 abnormal, anomalous, deviant, irregular, questionable, or unexpected.
 
 3.4 AR- Associated Result; a result generated during the analysis of an OOS, OOT, and/or
 
 
 

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 Out of Specification/Out of Trend Investigation D-105 2 of 17 
 
 unusual result that may be effected by the outcome of an investigation, but that on the
 surface are not suspect. 
 
 3.5 HPLC — High Performance Liquid Chromatography; analytical technique used to
 separate a mixture of compounds with the purpose of identifying and quantifying the
 
 individual components of the mixture 
 
 3.6 INV — an abbreviation for “Investigation” subject to this procedure and subject to formal
 
 documentation using the forms and documentations requirements of this procedure.
 
 3.7 Effectiveness Plan — a defined plan that will be used to evaluate if a root cause and/ or
 corrective action is effective. 
 
 3.8 Effectiveness Check — the verification that the root cause and/ or corrective action was
 remediated and the quality objectives were met. 
 
 3.9 QC — Quality Control 
 
 3.10 QA — Quality Assurance 
 
 3.11 DC — Document Control 
 
 3.12 GDP — Good Documentation Practice 
 
 3.13 GMP — Good Manufacturing Practice 
 
 3.14 RM — Raw Material 
 
 3.15 ITP — Investigative Test Protocol 
 
 3.16 TLC — Thin Layer Chromatography 
 
 3.17 FTIR — Fourier Transform Infrared Spectroscopy 
 
 3.18 MRB — Material Review Board 
 
 
 

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 3.19 NCR — Non-Conformance Report; a report documenting the details on a confirmed
 failure that needs further assessment by the material review board
 
 3.20 SME — Subject Matter Expert 
 
 4.0 Responsibility 
 
 4.1 It is the responsibility of all QC Laboratory personnel to report INV results to laboratory
 
 management and to complete the required sections of the investigation form.
 
 4.2 It is the responsibility of QC Laboratory Management to authorize and approve
 
 investigations. 
 
 4.3 It is the responsibility of QC Laboratory Management or designee to review the INV test,
 
 approve additional laboratory testing, and ensure completion of the investigation.
 
 4.4 It is the responsibility of Quality Systems Management (DC) or designee to review and
 
 approve the final investigation forms and associated log for consistency.
 
 4.5 External laboratories may be employed to investigate their results.
 
 4.6 External laboratories may be employed for confirmation testing. 
 
 4.7 The production group will provide support for batch record reviews.
 
 5.0 References 
 
 5.1 D-105-F1, Form, Laboratory Investigation Form 
 
 5.2 D-105-F2, Form, Investigative Test Protocol and Report 
 
 5.3 C-202, SOP, Material Review Board 
 
 5.4 QS-111, SOP, Root Cause Analysis (RCA) 
 
 
 

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 Standard Operating Procedure SOP No Rev No Page 
 Out of Specification/Out of Trend Investigation D-105 4 of 17 
 
 5.5 QS-112, SOP, Core Quality Systems and Quality Events 
 
 5.6 QS-108, SOP, Corrective and Preventative Action (CAPA) 
 
 5.7 C-501, SOP, Document Control 
 
 5.8 C-502, Record Storage, Retention, and Destruction 
 
 5.9 Guidance for Industry, Investigating Out-of-Specification (OOS) Test Results for
 Pharmaceutical Production — Level 2 revision, May 2022 
 
 5.10 Guidance for Industry, Statistical Techniques for Data Analysis, John Keenan Taylor,
 1990 Lewis Publishers ISBN 0-87371-250-1 
 
 6.0 Overview 
 
 6.1 See SOP QS-112 Core Quality Systems and Quality Events for an overview on the core
 required structure for documenting and tracking quality events at Ion Nutritional Labs.
 
 7.0 Results to Investigate 
 
 7.1 This procedure applies to Phase I, Phase I], Phase III Investigations and Investigative
 Test Protocols for laboratory test results that are OOS. 
 
 7.2 This procedure applies to testing associated with raw materials, manufactured bulk
 products, components, intermediate and finished products, and cleaning validation
 
 samples to that extent that cGMP regulations apply. 
 
 7.3 This procedure is used for OOT and/or UR tests when laboratory management agrees to
 
 investigate OOT / UR tests. 
 
 7.4 This procedure may be used to investigate results that are “Exempt” from this procedure
 
 if Quality Management decides to use this structured process. 
 
 
 

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 8.0 Exemptions from Investigation 
 
 8.1 Calculation Errors — Calculation errors should be corrected by GDP.
 
 8.2 No Established Specifications — If a specification is not in place then a result cannot be
 out of specification and this procedure does not apply. 
 
 8.3 Research and Development Activities 
 
 8.3.1 For data generated as a part of research and development but not associated with
 raw material or finished product testing for release, which includes components
 
 of validations, method’s development, exploratory testing and other types of non-
 GMP testing, an INV is not required for an out of specification result. All results
 
 and explanations will be documented. 
 
 8.3.2 When method verification or qualification is being performed on a new
 
 formulation, all results are experimental and don’t require an investigation.
 
 8.4 Method suitability can be performed on a new product matrix to determine specificity,
 accuracy and precision without the requirement of an investigation when OOS results are
 
 generated. This also applies when suitability is performed by comparing the performance
 of multiple methods. A description of testing and data must be documented.
 
 8.5 For qualitative assays such as TLC, FTIR, optimization testing is permitted as per
 respective SOP without investigation. 
 
 Examples: 1) To optimize sample / standard loading using TLC. 
 
 2) Recrystallizing sample and standard (ex. FTIR). 
 
 3) Tableting standard material (ex. FTIR). 
 
 8.5.1 Document the inconclusive conditions and the final conditions.
 
 
 

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 8.6 Alert Limits Not Met — Alert limits are not considered specifications and do not require
 a formal investigation under D-105. 
 
 8.7 Testing covered by protocol — If a protocol provides directions for handling results that
 do not meet acceptance criteria, then those directions supersede this SOP.
 
 8.8 Staged Testing — An investigation is not required for early “stages” of testing if that stage
 of testing dictates next steps. For example, a USP <905> “Uniformity of Dosage Units”
 
 does not require an investigation if it fails to meet the S1 limits associated with testing of
 
 the first 10 units. The test may move on to S2 and test the additional 20 units. If test
 results are UR or if they would fail S2 regardless of the results of S2 additional testing,
 
 an investigation may be initiated. 
 
 8.9 Failure to meet test suitability requirements — Certain analytical methods have system
 
 suitability requirements, and results from systems not meeting system suitability
 requirements should not be used. 
 
 9.0 Investigation Number Assignment 
 
 9.1 DC will assign each INV an investigation number then enter the investigation into the
 electronic INV Log. The INV number shall be referenced on all data and attachments
 
 associated with the INV. 
 
 10.0 Data and Sample Handling 
 
 10.1. Under no circumstances may incomplete or erroneous data be deleted.
 
 10.2. Analysts should not continue with an experiment if errors are obvious, such as the spilling
 of a sample solution, the incomplete transfer of a sample composite, or system suitability
 
 is not met. The analyst should document what happened and discontinue the experiment.
 
 
 

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 11.0 Investigation Forms 
 
 11.1 Laboratory investigations are documented using a single form, D-105-F1. Investigative
 
 Test Protocols use a separate form, D-105-F2 and multiple copies of the form can be used
 
 in a single investigation. 
 
 11.2. INV #- the number assigned to the investigation. 
 
 11.3. Investigation Rev # - This field should initially be “0”. The revision field is used to
 document revisions to the investigation. This is rare, but if after the investigation is
 
 closed and the need for revision is identified, this field provides a mechanism to document
 the process. The previous form may be lined out using Good Documentation Practices,
 
 kept in DC and the revised form numbered sequentially by revision should be placed in
 
 the place of the lined out form. 
 
 11.4 Attachments should be placed at the end of the investigation. 
 
 11.5. DC will review the documentation for completeness and sign on the indicated forms.
 
 12.0 Investigation Procedure 
 
 12.1 Investigation Principles / Tools described in this and referenced SOP’s should be
 followed during the investigation process. 
 
 12.2. Upon the occurrence or discovery of an OOS result, the Chemist performing the test must
 
 notify Laboratory Management immediately. 
 
 12.2.1. Laboratory Management will evaluate unusual results prior to initiating an OOT
 
 investigation. 
 
 12.3. The analyst must immediately preserve any and all materials, chemicals, solutions, and
 
 equipment used in performing the analysis. 
 
 
 

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 12.4 A preliminary evaluation must be completed by a qualified investigator to include the
 Phase I- Accuracy Assessment and Phase I— Confirmatory analysis prior to the expiration
 
 of any standards, samples or reagents, when possible. 
 
 12.4.1 The limited testing (re-analysis, re-injection, re-dilution, etc.) of the original test
 
 samples will be conducted when available and appropriate to confirm a laboratory
 
 error. 
 
 12.4.2 Re-analyze as per the Test Method. 
 
 12.4.3 Sample preparations that are known to be past their stability, unstable, or depleted
 will not be re-analyzed. 
 
 12.4.4 Data generated during re-analysis cannot be used to release material.
 
 12.4.5 If the results for the confirmatory analysis confirm the original results obtained
 
 then further investigation is necessary in determining the root cause of the original
 result obtained. 
 
 12.4.6 If the results for the confirmatory analysis do not confirm the original results
 obtained, and if the root cause is determined to be sample preparation error or
 
 instrument error, then the original results may be invalidated. Further
 
 investigation may still be necessary in determining the root cause of the original
 result obtained. 
 
 12.5 If a definitive root cause is found the original test result can be invalidated with proper
 scientific justification. Laboratory error is the assigned cause and a new sample is
 
 prepared and tested according to the test method and documented in the conclusion of the
 
 investigation. 
 
 12.6 Laboratory management and SME’s will evaluate the root cause of the laboratory error
 
 to determine whether a CAPA is required to correct and prevent the error from
 
 
 

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 reoccurring. CAPA’s will be documented using QS-108, Corrective and Preventative
 Action (CAPA). 
 
 12.7. When there is no scientific basis for determining there was a laboratory error, a full-scale
 investigation is initiated upon QA or designated review of the data and confirmation of
 
 the result. 
 
 12.8 A Phase I historical review of the material will be performed to determine if there are any
 
 trends in the test results that would help determine the root cause of the OOS result.
 
 Examination of other factors such as RM inputs, new material status, and formulation
 accuracy can be assessed to help determine root cause. 
 
 12.9 A formal root cause analysis tool such as the 6M, 5Y, Fishbone, etc. can be used to help
 identify the root cause of the OOS result. Refer for SOP QS-111 Root Cause Analysis
 
 (RCA) for additional guidance. 
 
 12.10 To aid in the determination of root cause, Investigative Test Protocols (ITP)’s can be
 
 executed using D-105-F2 to generate data to confirm or refute a hypothesis.
 
 12.10.1 Three main components are required for an ITP protocol, a hypothesis
 statement, a hypothesis test plan which includes an experimental design which
 
 can prove or refute the hypothesis and an outline of how to interpret the results
 of the data. 
 
 12.10.2 An ITP requires QA approval prior to execution. 
 
 12.10.3. The ITP results, discussion and conclusion will be documented on Page 2 of
 
 form D-105-F2, the report form. 
 
 12.10.4 The results from an ITP study cannot be used to release a product.
 
 12.11 A Phase II Investigation is initiated after the Phase I investigation including ITP testing
 
 is complete. 
 
 
 

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 12.12 A hypothesis statement is required to initiate Phase II triplicate retest of the original
 sample. The hypothesis statement will address the root cause of the original result.
 
 12.12.1 Ifthe sample is implicated as the root cause or there is insufficient sample for a
 triplicate retest, then a replacement sample can be used in the Phase II
 
 investigation. 
 
 12.13 Document any changes in method execution that differ from the original test conditions
 
 to support root cause determination. Changes should be within the allowed scope of the
 
 method. 
 
 12.14 Re-test will be conducted by an SME for the test being performed.
 
 12.15 In the event that the initial OOS result is confirmed, a Phase III investigation can be
 initiated to evaluate potential root causes originating external to the laboratory.
 
 12.16 The Phase III investigation uses the same format as the Phase II investigation. However,
 the focus of the investigation moves from the laboratory as a potential source of the OOS
 
 to all other potential sources of the OOS. 
 
 12.17 The Material Review Board should be notified and provide direction for the Phase III
 
 activities of the investigation and corrective actions, especially if the OOS involves
 
 actions from other departments. 
 
 13.0 Investigation Principles / Tools 
 
 13.1 Rules for Re-Testing: 
 
 13.1.1 Original results must be considered valid until proven to be invalid. If a re-test
 
 result generates data that does not agree with the suspect result under
 
 investigation, that fact alone does not invalidate the original result. Justification
 for invalidating a result must be scientifically justified and supported by
 
 investigation. 
 
 
 

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 13.1.2 Re-test must have a purpose: 
 
 13.1.2.1 The number of re-tests allowed is limited because re-testing must have
 
 a purpose. For example, a re-test may be conducted to confirm the
 original result. If the result is confirmed under the retest plan, it does
 
 not make sense to try to confirm the result again. 
 
 13.1.2.2 It is permissible to re-test under protocol using an ITP to collect
 
 evidence to support a theory. The ITP plan must define the purpose of
 
 the experiment and define the criteria by which the theory would be
 proven or disproved. 
 
 13.1.2.3 For example, a protocol written to test a theory about the validity of
 original results of product to be tested for release may generate re-test
 
 data as part of that investigation. This data may be defined in the
 protocol to only be used to test that theory. Regardless of whether the
 
 re-test results meet required specifications or not, they cannot be used to
 
 release the product if defined this way. The results would be used to
 either prove or disprove the theory. 
 
 13.1.3 Appropriate samples must be used: The sample used for the re-testing or
 investigative testing should be taken from the same homogeneous material that
 
 was initially tested and yielded the suspect result. For example, the original liquid
 
 sample solution that was injected into the chromatographic system may be used,
 while a solid sample may require an additional weighing from the same sample
 
 composite that had been prepared by the analyst. If a sample cannot be taken from
 the same homogeneous material that was initially tested, then the re-test would
 
 also be considered re-sampling. The rules for re-sampling would apply.
 
 13.2. Rules for Re-Sampling: 
 
 13.2.1 Re-sampling should be avoided if at all possible. The suspect result was generated
 
 
 

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 from the original sample, and that sample may be the cause of the result. Re-
 sampling unnecessarily could hide the true cause of the result and impair the
 
 investigation. This is especially true for content uniformity or blend uniformity
 samples where the purpose of the test is to look for variability of the samples. The
 
 following criteria must be met when re-sampling is used: 
 
 13.2.1.1 Re-testing criteria apply: Since re-sampling will require re-testing to
 generate data, the rules for re-testing also apply to re-sampling with the
 
 exception of the sample used. 
 
 13.2.1.2 Invalid Sample: It is appropriate to re-sample if it can be shown that the
 
 original sample was obtained, stored, or handled improperly in such a
 way as to cause the sample integrity to be compromised. If this can be
 
 proven, it will invalidate not only the sample, but also the original
 
 suspect result. Re-sampling may be necessary to prove or disprove a
 theory about the validity of the original sample. 
 
 13.2.1.3 Shortage of sample: It may be appropriate to re-sample if there is not
 enough sample to complete an investigation. If the original sample
 
 expires or is too small to continue an investigation, re-sampling will be
 necessary. This does not negate the need to evaluate the impact that re-
 
 sampling may have on the result. 
 
 13.2.1.4 Impact must be considered: The impact that re-sampling may have on
 the ability of the investigation to identify the true cause must be
 
 considered. If re-sampling has occurred, it must be able to be defended
 in the scientific evaluation of the suspect result. 
 
 13.3. Reportable Results: 
 
 13.3.1 If a laboratory error was discovered in the investigation, the results associated
 
 with the error must be invalidated and followed with valid results as directed in
 
 
 

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 the investigation protocols. 
 
 13.3.2 If no error could be identified in the original test results, and there is not scientific
 
 basis for invalidating the results under investigation, then the test result being
 investigated must be reported. 
 
 13.4 Averaging: 
 
 13.4.1 Averaging, though it can be a rational and valid approach, generally is a practice
 
 that should be avoided. This is because averages hide the variability among
 
 individual test results. The phenomenon is particularly troubling if testing
 generates both OOS and passing individual results which, when averaged, yields
 
 a result that is within specification. Here, relying on the average calculated figure
 without examining and explaining the individual OOS results through an
 
 investigation process is highly misleading and unacceptable. 
 
 13.4.2 Dosage form content uniformity results or powder blend/mixture uniformity
 
 never should be averaged to obtain a passing uniformity value. Nor should
 
 equipment cleaning validation/verification results from multiple swab sites be
 averaged. In the former case the tests are intended to measure variability; in the
 
 latter case it may obscure a localized high level of impurity in a specific swab
 
 area. 
 
 13.4.3 It should be noted that a test might consist of replicates to arrive at a result. For
 instance, an HPLC assay result may be determined from the average value of the
 
 peak responses from a number of consecutive replicate injections from the same
 
 sample preparation. The assay result for each sample would be calculated using
 the peak response average. This determination is considered one test and one
 
 result. This is a distinct difference from the analysis of different portions from a
 lot, intended to determine variability within the lot. 
 
 13.5 Outlier Test- Criteria 
 
 
 

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 Standard Operating Procedure SOP No Rev No Page 
 Out of Specification/Out of Trend Investigation D-105 14 of 17 
 
 13.5.1 An outlier is a value in a data set which appears to deviate markedly from other
 members of the same sample in which it occurs, and has low statistical probability
 
 of belonging to the same population. Outlier’s tests can indicate a test error when
 used with re-measurement or retesting of samples that are expected to be
 
 homogenous (i.e. crushed tablets, solutions). Under no circumstances may an
 
 outlier test be used to disqualify a test where uniformity is being tested (..e.
 content uniformity and dissolution). 
 
 13.5.2 The preferred method for outlier analysis is the Q-Test. 
 
 13.5.2.1 Rank the data points in order of increasing value X1 < X2 <...Xn.
 
 13.5.2.2 Decide whether X1 or Xn is suspect. 
 
 13.5.2.3 Calculate the sample average (A) and standard deviation (s) using all of
 
 the data for the moment. 
 
 13.5.2.4 Calculate Q as follows using equation 1 if X1 is suspect or equation 2 if
 
 Xn is suspect: 
 
 Ro ~ Ky GO = Ay Ray 
 
 Xp 4 Bry om Ry 
 
 13.5.2.5 90% is the accepted confidence level for risk of false rejection.
 
 N Qcrit Qcrit Qcrit 
 (CL: 90%) | (CL: 95%) | (CL: 99%) 
 3 0.941 0.970 0.994 
 4 0.765 0.829 0.926 
 5 0.642 0.710 0.821 
 6 0.560 0.625 0.740 
 7 0.507 0.568 0.680 
 
 8 0.468 0.526 0.634 
 9 0.437 0.493 0.598 
 10 0.412 0.466 0.568 
 
 
 

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 13.5.2.6 If the calculated value exceeds the Qcrit value, the data point is a
 statistical outlier; otherwise the data is not a statistical outlier.
 
 13.5.2.7 If the original data does not contain a statistical outlier or combined
 initial and secondary data does not contain a statistical outlier based on
 
 the Q-Test, the raw original data will be combined with the secondary
 
 test data then averaged. The averaged result will be the reported value.
 
 14.0 Documentation Requirements 
 
 14.1. All documentation will be distributed and maintained as outlined in SOP C-501
 
 Document Control and SOP C-502 Record Storage, Retention, and Destruction.
 
 15.0 Revision History 

| Rev | Date | Description of Changes | CCR # | By |
|-----|----------|------------------------|-------|----|
| 0 | 03/04/10 | New - - Clarified and reorganized SOP, changed format, created OOS log and l LOM 8/12 revised OOS form : - Changed “QC Manager” to “Lab Manager’, changed in section 5.1.4 & > 07/08/13 5.1.4.2 “QC Analyst” to “DC”, section 5.5.5 “QC Laboratory” to "DC 13-593 B. Johns office”, changes in section 5.4.6.6, 5.5.6. Clarified process for determining outlier using Q Test. Added Out of Trend Investigation criteria. Added a new section on Data Handling. Clarified form data entry. Added new section of exploratory testing for root cause. Changed minimum signature requirements for test | - | - |
| 3 | 03/25/14 | approval. Phase II investigation controlled by QA / Production. Expanded corrective action responsibilities. Changed outlier criteria to 90% confidence level. Changed form D-105-F1 to include Exploratory Testing section, adjusted format, reduced signature requirements. | 14-0277 | B. Johns |
| 4 | 01/13/16 | Removed paper log; expanded responsibilities | 16-0030 | D. Popp |
| 5 | 08/01/17 | Added impact assessment requirements during investigation. | 17-0762 | S. Millar |
| 6 | 12/29/18 | Complete rewrite. | 18-0450 | D. Herd |
| 7 | 09/03/19 | Added reference to QS-112 Quality Events SOP. g 03/28/22 Added requirements for short-term and long-term monitoring of CC-22-0140 J. Sassman effectiveness check. Reduced investigation forms from ten to two, form for investigation, form2 for investigation test protocols. Restructured investigation process to three Phases, Phase I- Preliminary investigation, Phase II — retest to challenge | 19-0605 | A. Roxbury |
| 9 | 06/13/24 | laboratory issue, Phase II]- retest to challenge non-laboratory root causes. CC- Made CAPA structure external using SOP QS-108. Added additional detail to improve clarity of instruction. Added the use of a root cause analysis tool for determining root cause, referencing SOP QS-111. Updated flow chart to reflect new process | 24-0278 | B. Johns |

 
 

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 Standard Operating Procedure SOP No Rev No Page 
 Out of Specification/Out of Trend Investigation D-105 16 of 17 
 
 16.0 Attachments 
 
 16.1 Attachment 1 - Lab Investigation Flow Chart 
 
 
 

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 Standard Operating Procedure SOP No | Rev No Page 
 Out of Specification/Out of Trend Investigation D-105 9 17 of 17 
 
 Attachment 1 — Lab Investigation Flow Chart 
 (1) (2) (3) End 
 0OS/OOT/ Conducta Phase Confirm that 
 UR y results are within 
 Test result assessment and the scope of SOP 
 confirmatory 
 ; D-105 
 testing as needed (6) 
 Complete applicable 
 (8) sections of the Phase |
 (9) Update the investigation investigation with 
 Definitive Log and obtain an (7) (4) documentation to 
 root cause Investigation #. Include this Complete Phase | Yes In invalidate data or
 determined number on all Form D-105 investigation Scope discard if not
 documents applicable 
 No t 
 (10) 
 (11) 
 --Yes————_ Invalidate original result and 
 retest. Result confirms specification (5) 
 If applicable correct
 calculations and re- 
 NI evaluate result. DO 
 Ce econ eeenaeeneneeeeeoeeeenaneeneenneos . NOT Acquire an 
 Investigation Loop <¢__________—_———_No : Investigation number 
 (18) 
 {13) : (19) 
 Complete Form F2, Assignable cause . Phase II investigation 
 page 2 to document y (22) 
 determined and reportable 
 the results of the test values available? : Is a Phase Ill 
 protocol defined in to Investigation —— 
 Step 15 No e Required? 
 : (20) 
 No : Proceed to 
 : Retest 
 ° Yes 
 ; (23) 
 : (21) Alert the Material 
 (17) There is a hypothesis to evaluate, . Hy pothesis Review Board for Input
 Protocol confirmatory testing needed, and/or No# confirmed and and Direction on the
 Results testing required to generate reportable reportable test investigation.
 results? 
 values available? 
 (24) 
 Continue the Investigation Loop
 "] (13-18) with focus on non- 
 laboratory sources of the OOS.
 Use Form F2 as necessary to
 (16) document investigation 
 Execute the protocol (15) activities 
 defined in form F2, Complete form F2, page 1 to document a | 
 protocol for the next investigation step. 
 page 1. 
 (29) (27) 
 (25) 
 Update Investigation Log a Assemble all documents, forms and 
 Complete Form F1 
 See SOP (9.4) attachments.. Ensure that all 
 collected documents are complete 
 (28) 
 with all necessary signatures. (26) 
 Paginate the 
 documents and }¢ Summarize the 
 investigation on Form F1, 
 have DC review and 
 End sign. Page 1