MICLAB-135 Documentation Requirement For Micro Test Method Validation

Test methods must be developed documented and have sufficient detail so that a qualified analyst can accurately perform the test in the manner in which it was validated. Method validation and compendial method verification is to be performed by qualified personnel. All compendial methods (e.g. BP, EP) are considered validated but must be verified under actual use conditions. The information outlined in this procedure can be used to perform method validation or verification.

5.1. Purpose/Use of Templates

 5.1.1. Test Method Development Protocols

The purpose of test method development is to establish the testing parameters required for a particular product or material. Test method development is not required and is only performed when there is insufficient information about a product or material to allow the assignment of a particular test method in the test method validation protocol.

5.1.2. Test Method Validation/Verification Protocols

The purpose of the validation/verification protocol is to document the validation/verification of the specific test method chosen for the testing and release of a particular product or material.

5.1.3. Validation/Verification Summary Reports

Summary reports are generated at the completion of a validation/verification study. The summary memo may provide the justification for the use of a particular test method for the release testing of a product or material.

5.2. Required Content and Format for Development Protocols

The following sections are required, additional sections may be added based on technology specific requirements.

5.2.1. Header

Contains: company name, template type, page number, protocol title and protocol version number, document code. The version number reflects the version of the document being generated with the template, not the version of the template.

5.2.2. Footer None

5.2.3. Approval page

5.2.4. Table of contents

Listing, at minimum, the title and page number of all sections.

5.2.5. Revision History

The protocol may need to be revised at some point during the performance of the validation. This section allows the tracking of all approved and in-process versions of a protocol.

5.2.6. Definitions, Acronyms and Abbreviations Section

The definitions of all terms, acronyms, and abbreviations required to properly interpret the protocol requirements must be provided in this section.

5.2.7. Objective Section

States the purpose of the validation study. Identify the product(s) or material(s) that is to be the subject of the protocol. Identify whether it is a validation or revalidation.

5.2.8. Scope Section

Summarise the principles and boundaries of the validation or verification studies.

5.2.9. Protocol Deviations Section

Documents and details any deviations identified during the execution of an approved protocol. All Deviations are reported in the final summary report. See Section 5.9 of this procedure for more information on Deviations.

5.3. Required Content and Format for Validation/Verification Protocols

All requirements listed in Section 5.2 above must also be met for the validation protocol. In addition the following sections are required.

5.3.1. Lot Identification Section

5.3.1.1. Identify the lot number(s) of the product or material being evaluated.

5.3.1.2. In cases when the lot number(s) are not available at the time of protocol origination, a comment can be made indicating that the lot numbers are “To Be Determined”.

5.3.1.3. The lot numbers are to be filled in prior to execution of the approved protocol.

5.3.2. Prerequisites Section

5.3.2.1. Identify all prerequisites as defined by technology specific validation procedures (ex. media evaluation, instrument calibration status).

5.3.2.2. Identify all relevant controlled procedures (including version number) necessary for the execution of the defined development of validation studies.

5.3.2.3. Identify any related reports used to support the development or validation studies. This may include development protocols, past validation summary reports, literature review, etc.

5.3.2.4. Identify any training required prior to execution of the approved protocol. This should include, but is not limited to, any procedures being used in draft format.

5.3.3. Execution Section

5.3.3.1. Provides any additional general information related to performing the method development or validation.

5.3.3.2. Provides the specific instructions for the performance of the method development or validation studies. Include directions for how many replicates of each test are required.

5.3.3.3. Provides references to specific SOPs for instruction where appropriate.

5.3.3.4. Identifies all quantitative and/or qualitative acceptance criteria for each test performed.

5.3.3.5. Provides directions for recording and record checking of all primary data generated as part of executing the protocol.

5.3.4. Deviations

Provide directions on how to document deviations that occur during the execution of the approved protocol.

5.3.5. Signature List Section

Documents all personnel involved in the validation of a test method including record checkers. Documents printed name, signature, initials, company / department and date.

This section also verifies that each person involved in the validation studies has been trained on all procedures listed in the Prerequisites Section.

5.3.6. References Section

Lists any references used for the validation studies. This may include, but is not limited to, reference to compendia for the establishment of acceptance criteria.

5.4. Required Content and Format for Summary Reports

All requirements listed in Section 5.2 above must also be met for the validation summary report. In addition, the following sections are required.

5.4.1. Data Transcription Checker

All data transcribed into a final report must be checked against the primary data for completeness and accuracy. The person responsible for this check signs and dates the final report prior to routing for approval. The data transcription checker can be anyone other than the person responsible for data transcription.

5.4.2. Deviations Provide a list of all deviations, a brief description of the deviation, and the corrective action (if required) associated with each.

5.4.3. Discussion/Results

5.4.3.1. Validation Conclusion – Provide a clearly stated conclusion that confirms the successful or unsuccessful completion of the validation.

5.4.3.2. Pre-requisites Verification – List all pre-requisites listed in the protocol and whether they were met. This can be done in table format.

5.4.3.3. Results – Provide a list of all tests performed, whether they passed the predetermined acceptance criteria and whether they were performed without deviation.

5.4.4. Additional Content

Additional sections may be used in validation templates based on technology specific requirements.  Additional sections may also be added at the time of protocol generation.  These additional sections should be noted in the SCOPE section of the protocol. Examples of addition sections may include, but are not limited to.

5.4.4.1. Supporting Documentation Section

Lists any supporting documentation used during the validation studies. All supporting documents are attached to the executed protocol.

5.4.4.2. Appendices Section Contain any tables used to record information referred to in the main text of the protocol (ex. a list of calibrated equipment used for validation studies).

5.4.4.3. Attachment Section Contains any supporting documentation referred to in the main text of the protocol (ex. A calibration status report for all equipment used for validation studies). When attaching memos or articles, it may be acceptable to attach only the title and/or approval pages.

5.5. Generating Protocols and Summary Reports

Requirements

Originator:

5.5.1. Accesses the current version of the appropriate template.

5.5.2. Saves template to personal drive for modification. It is recommended that the template be saved using a unique identifier, such as the assigned document number.

5.5.3. Modifies relevant template sections and saves draft on hard drive or network drive. Modifies all highlighted selections within protocol or report.

5.5.4. Ensures that the version numbers of all controlled procedures listed in the protocol or report are correct.

5.5.5. Adds product specific information in appropriate sections.

5.5.6. Adds specific test method information where appropriate.

5.5.7. Lists all sections added to the protocol or report and an explanation for the addition in the Scope section.

5.5.8. Lists all sections deleted from the protocol or report and an explanation for the deletion in the Scope section. The headers for all deleted sections should be left in the protocol.

5.5.9. Route for approval prior to protocol execution.

5.6. Approval of Protocols and Summary Reports

Requirements

5.6.1. Test Method Development Protocols

5.6.1.1. Originator and Laboratory Management

5.6.2. Test Method Validation/Verification Protocols

5.6.2.1. Originator and Laboratory management

5.6.3. Validation/Verification Summary Memos

5.6.3.1. In general, those parties responsible for approval of a validation protocol should also approve the final summary report. In the event that one or more approvers are not available, an alternate approver at the same level may approve the summary report.

5.6.3.2. In addition, a quality authority review, independent of the Lab Manager, should review the final report.

Responsibilities – Originator

5.6.4. Verifies that all relevant information has been added to the protocol and is correct.

5.6.5. Signs and dates the protocol and routes it to Laboratory Management for approval.

5.6.6. If a mistake is noted prior to gaining all required approvals, corrects mistake, prints a new hard copy protocol and routes for management approval. A new version number is not necessary if the mistake was corrected prior to collection of all approvals. Discard the draft of the protocol containing the mistake.

5.6.6.1. If a mistake is noted after receiving all required approvals, corrects the mistake, increases the version number by one, fills out the revision history section of the revised protocol indicating why the revision was necessary and routes the revised protocol for the appropriate signatures. Keeps all previous versions of the protocol with the most current version.

Responsibilities – Laboratory Management

5.6.7. Verifies that the content of the protocol or report meets all internal and external requirements for method development or validation.

5.6.8. If approving a subsequent version of a protocol or report, verifies that all previous versions are present.

5.6.9. If the protocol meets all requirements, signs and dates the protocol and either routes it to the next approver or sends it back to the originator for further routing.

5.6.10. If the protocol or report does not meet all requirements, returns the unsigned protocol to the originator for corrections.

Responsibilities – Quality Authority Reviewer

5.6.11. Reviews and approves the report for completeness and accuracy.

5.7. Executing Protocol

Executor

5.7.1. Obtains the approved protocol from the originator. Only fully approved protocols are to be executed.

5.7.2. Reads entire protocol and familiarises him/herself with all requirements of the protocol.

5.7.3. Contacts the originator if additional information is required.

5.7.4. Executes the protocol exactly as written. In the event that a mistake is noted in the protocol, contacts the originator to discuss the necessity of issuing a corrected version of the protocol.

5.7.5. For Validation/Verification Protocols never generates additional pages for data entry. Typically the need for additional data pages is considered a deviation from the approved protocol and is addressed accordingly. If additional data pages are generated under a deviation report, they are filed as attachments to the approved protocol. All additional pages must be initialled and dated by the laboratory analyst executing the protocol as well as laboratory management.

5.7.6. Reports all deviations to originator and/or laboratory management within 2 business days of discovery.

5.7.7. Completes all requirements of the protocol. Upon completion provides the protocol to an appropriate Record checker.

Record Checker

5.7.8. Second checks all data for accuracy and completeness.

5.7.9. Returns executed protocol to analyst for corrections if necessary. Does not approve any incomplete data.

5.8. Deviations 

The following guidelines can be used to aid in determining whether a deviation report is needed. These guidelines apply only to deviations related to validation protocols. Deviations associated with the execution of development protocols are handled at the discretion of laboratory management.

5.8.1. A deviation report is not required if:

5.8.1.1. The entire protocol must be re-executed following a failure requiring additional method development.

The protocol, containing the revised test method, is reissued with an increased version number.  If a new protocol template is needed, a validation termination report is issued describing the protocol failure. This incident should be addressed in the final summary report.

5.8.1.2. A new protocol is needed because the original protocol was physically destroyed. The protocol should be reissued with an increased version number. If data was generated in the destroyed protocol and can be salvaged, it is transcribed into the new protocol after approval. The transcription must be record checked for accuracy. If data was generated but cannot be salvaged, the studies must be repeated. This incident should be addressed in the final summary report.

5.8.1.3. A validation study is terminated for reasons outside the control of the laboratory (ex. validation is cancelled by requestor). A validation termination report is issued to close out the protocol.

5.8.1.4. A typographical or editorial error is noted after approval but prior to execution of the protocol. An assessment is to be made as to whether the protocol can be corrected with a lineout or if a new version of the protocol needs to be issued. The originator of the protocol, with the assistance of laboratory management, will decide whether a new protocol is to be issued.

5.8.1.5. A typographical or editorial error is noted during or after execution of the protocol that will not impact the validity of the data generated (ex. incorrectly listed lot number). An assessment is to be made as to whether the protocol can be corrected with a lineout or if a new version of the protocol needs to be issued. The originator of the protocol, with the assistance of laboratory management, will decide whether a new protocol is to be issued. If a new version is issued, previously generated data can be transcribed into the newly approved protocol. The transcription must be record checked for accuracy. This incident should be addressed in the final summary report.

5.8.2. A deviation report is required for the following:

5.8.2.1. The approved protocol is lost or misplaced. All studies must be repeated.

5.8.2.2. Any situation in which the data generated cannot be reported (ex. analyst error, failed system suitability, failed equipment, etc.).

5.8.2.3. Any situation that will require additional data pages; In this case, addition pages are obtained from the protocol template and attached to the deviation report for approval. Laboratory management must initial each additional data page.

5.8.2.4. A typographical or editorial error that could have potentially impacted the validity of data already generated. An assessment (with the aid should be made as whether the data is acceptable and whether a new version of the protocol should be issued.

5.9. When a deviation report is necessary

Originator

With the help of laboratory management, completes the deviation report within the protocol and includes the following information:

5.9.1. “Deviation Description” – describes the deviation, including the conditions, sequence of operations, etc. observed at the moment of the deviation.

5.9.2. “Type of Deviation” – classifies the deviation into one of the following categories:

5.9.2.1. Editorial – a deviation that documents changes made to a test due to formatting, switching instruction step sequences, clarification or typographical errors.

5.9.2.2. DNR – Analyst Error – a deviation that results in data that cannot be reported and can be directly attributed to an analyst error.

5.9.2.3. DNR – Failed System Suitability – a deviation that results in data that cannot be reported and can be directly attributed to a failed system suitability control.

5.9.2.4. DNR – Instrument Failure – a deviation that results in data that cannot be reported and can be directly attributed to an instrument failure.

5.9.2.5. Other – a deviation that cannot be classified by the above categories. A full explanation of this is required. This may include (but is not limited to) assay variability, suspected laboratory contamination, etc.

5.9.2.6. “Root cause analysis” – describes why the deviation occurred. The explanation should support the type of deviation selected.

5.9.2.7. “Impact” – describes the impact of the deviation on existing validation plans, protocols, requirements, specifications, product quality, completed tests, and/or other manufacturing concerns.

5.9.2.8. “Corrective action” – outlines all corrective actions and a rationale for the said corrective actions. If the corrective action requires retesting or additional testing, attach the appropriate test section from the qualification protocol with any required modifications.

5.9.3. Signs and dates the report as the originator.

5.9.4. Brings the deviation report to laboratory management for approval.

Laboratory management/designee

5.9.5. Reviews the disposition of the deviation prior to execution of any proposed corrective actions, additional testing, or modified testing and determine if the specified activities are appropriate and if additional review by QA is required.

5.9.6. For deviations where a change or a modification to the protocol is required

5.9.6.1. If the change does not impact previously completed tests, document the change in the deviation report.

5.9.6.2. If the change impacts previously completed tests, the deviation report must address all previously completed sections that have been impacted by the change.

5.9.6.3. If, based on the impact of the deviation, it is determined that re-execution of the entire protocol is required (as determined by Microbiology Support Management): Revise the protocol (increment version number) and route for approval prior to execution.

5.9.6.4. Approves the deviation report.

5.9.6.5. Returns the approved deviation report to the laboratory analyst.

Laboratory Analyst

5.9.7. After approval of the corrective actions, completes all outstanding work necessary to resolve the deviation.

5.9.7.1. Completes any necessary corrective action approved by Microbiology Support Management.

5.9.7.2. Completes any necessary additional testing required on the original copy of the deviation.

5.9.7.2.1. Testing results must be included in the Additional Testing / Results section of the deviation report. Attach all raw data or related information required to verify successful completion of the testing (i.e., screen shots, reports, charts, etc.) to the deviation report.

5.9.7.2.2. If no testing will be executed, cross out the Additional Testing / Results section of the deviation report.

5.9.8. Attaches all approved deviation reports and any additional data to the protocol.

5.9.9. If necessary, revises protocol and routes for approval.

5.9.10. Proceeds with validation studies.

5.10. Document Storage – Hard Copy and Electronic

5.10.1. Upon completion of a validation study, all hard copy data and reports are stored in the records cabinet in the Microbiology Lab.

5.10.2. Electronic copies of any protocols and/or reports can be submitted to the Team Leader for electronic storage.

6.0. Definitions / Acronyms

Deviation – Any planned or unplanned discrepancy from approved procedures, formulas, specifications, trends, equipment or parameters that occurs during testing, validation or verification.

DNR  – Data Not Reported Final Summary Report – A report issued at the conclusion of a validation study outlining all results obtained.

GM – General Method

MLT – Microbial Limits Test Protocol – A written plan of action designed to gather documented evidence that will support or refute a stated premise or meet an objective.

SOP – Standard Operating Procedure

Validation – Establishing documented evidence that provides a high degree of assurance a specific test method will consistently produce results meeting its predetermined quality characteristics.

Validation Termination Report – A report issued when the activities associated with an approved validation protocol cannot be completed. Verification – Confirmation that a compendial test method can be performed and will provide expected results under actual use conditions in the laboratory.  NOTE: For the purposes of this procedure, the term validation can be replaced with verification at any time.