The Overview• Introduction• Requirements• Types of GMP Documentation• Purposes of GMP Documentation• The Structure of Document Management• Evaluation of the Documentation System• The Document Management Cycle• Tips to good documentation practices• Warning letters and observations• Summary & conclusion
What is Documentation ? To Document each Activity you perform Documentation is a Process, which comprises of the following :- Recording of Data- Review of Documents- Approval of Documents- Issuance and Disposal of Documents- Retrieval of Documents- Presentation of Documents
What are the Definitions ?• GMP Documentation can be defined as: Any procedure, instruction, logbook, record, raw data, manual, or policy associated with the development, manufacture, testing, marketing, and distribution of a product required to demonstrate compliance with the GMPs and other regulatory requirements• Or more shortly: A GMP document is any written record associated with the manufacture, control and distribution of the API or pharmaceutical product
WHY GMP DOCUMENTATION ?“If it hasnt been documented, then it hasnt done or happened!” “If it is not documented, it is a rumour!” This is the FDA Inspection AttitudeThe product considered as “Adulterated” if the procedure not followed/ not documented properly.
WHY DOCUMENTATION ? Cost for Good DocumentationCost for Poor/NoDocumentation THEREFORE, DOCUMENTATION BRINGS BUSINESS
GDP references21 CFR 58 GLP: All data generated during performing of a study, (except automated data collection systems), shall be recorded directly, promptly, and legibly in ink. All data entries shall be dated on the date of entry and signed or initialed by the person entering the data. Any change in entries shall be made so as not to obscure the original entry, shall indicate the reason for such change, and shall be dated and signed or identified at the time of the change.
GDP references21 CFR 211.188 (a) : Control & issue of production batch records.21 CFR 211.194 (a) Verification of laboratory test data for “Accuracy, Completeness compliance with established standards”ICH Q7 : Chapter–6 & other GMP guidelines Documentation and Records
Comments at the beginning• GMP documentation is one critical aspect of our business and it is a legal requirement too!• Inspection or audit observations frequently on poor documentation practices, outdated documents and inadequate version control,• Quality can not be assured in a regulated industry without good documents and good documentation practices Keep in mind, after the product is distributed to the customer, what remains with us is documents.
Comments at the beginningWhy do people sometimes fail to document activities or events properly?• People don’t understand the legal requirement of documentation.• People do not relate records to auditing.• People don’t clearly understand what , how or when to document.• Procedures may not be completely understood or followed.• People aren’t always held accountable.• People will make mistakes.• People don’t always make corrections properly.
Key Features of Good Documentation• Careful design of documents should make them easy to read, easy to understand and easy to complete properly• Just creating documents is not enough; must follow specific standards when doing so. Ensure user reads and understand exactly what it means.• Master documents must be subject to appropriate controls to ensure that only one version is current. Such documents must be approved, signed and dated• Modifications to master documents must be managed through change control• There must be a periodic review of GMP documents to ensure that they are compliant with current regulatory files and GMP requirements.
Key Features of Good Documentation• Original documents should be easily distinguishable from photocopies, and should have clear and concise information• Good documents should have sufficient space for entries, to record variable information and signature and to attach print-outs etc.• Data entries must be made or completed at the time the action is performed• Entries in logbooks should be done in chronological order.• It is necessary to document anything that directly impacts a product. Record every procedure you write, form you fill out, and test you perform. Using a standard format eliminates discrepancies between documents from different sources.
What should be recorded ?• All important information that is generated during an operation or process must be recorded by who performed the operation and when it was carried out.• Such information should be legible, accurate, dated, traceable, and accessible. “All documentation should be legible, clean, readily identifiable, retrievable and maintained in facilities that provide a suitable environment to minimize deterioration or damage and to prevent loss”• This information should reflect the complete history of the manufacture, packaging and control of the product.
Where documentation ?Documentation during Project Design, Construction Phase Commissioning and start-up Qualification and Validations Commercial Production, Testing and Release, Distribution Implementation of Quality system Regulatory submissions. And beyond…………
Types of GMP Documentation (1)• This Documentation includes, but is not limited to the following Batch Related Records:o Master Batch Records (e.g. Processing & Packaging Instructions)o Batch Records (e.g. Batch manufacturing Records)o Raw Data Records (charts, chromatograms, etc.)o Laboratory Recordso Distribution Recordso Standard Operating Procedures (SOPs)o Specifications and Test Methodso Records of Raw Materials, Intermediates, Labelling and Packaging Materials
Types of GMP Documentation (2)• Non Batch related Recordso Qualification and Validation Documentso Change Control Documentationo Engineering Drawingso Maintenance and Calibration Recordso Complaint, Returns and Recalls Recordso Environmental Monitoring Recordso Utility Monitoring Recordso Line and Equipment Logso Personnel Training Recordso Quality Agreements (i.e. Technical Agreements)o Stability Records
Types of GMP Documentation (3) Non Batch related Records (continued):o Failure Investigation and Reporting Recordso Cleaning and Sanitization Recordso Entry Records for Controlled Areaso Pest Control Recordso Audit and Regulatory Inspection Reportso Regulatory FilesOther documentation that must be ensured :o SOP Annexeso Computer fileso Process Flow and other Diagrams, pictorial displays (e.g. gowning )o Technical Reportso Labels (room and equipment status, sampling, material status)
Purposes of GMP Documentation (1)• There are three main purposes for GMP documentation:• To meet legal requirements including all GMP expectations• To meet our business requirements• To form the basis of good scientific decision making• Any type of product is developed and produced, it must be safe, effective and fit for its intended use.• Quality characteristics are established in documents.• Documents declare product standards and describe how to monitor, test and judge for compliance with these standards.
Purposes of GMP Documentation (2)• To understand what needs to be done (the process)• To understand how to do it (the method)• To understand why it needs to be done (the context)• To understand who must do it (the responsibility)• To understand when to do it (frequency, close out)• …. At the end: to ensure that there is an adequate record of who did what, when, how and why!
Purposes of GMP Documentation (3)• If you cannot answer all of the questions from the previous slide, then the documentation (system) has somehow failed• PROCEDURES SHALL BE WRITTEN AND FOLLOWED• It is a concern if an SOP has not been in place• But it is a violation of the GMP requirements, if the SOP is present, but not followed.
Purposes of GMP Documentation (4) Documenting Decisions and Rationales• The regulators expect things to occasionally go wrong during manufacturing or testing• However, we must ensure that we clearly document and sign off our decisions with a rationale behind• In reality, this is one area of a general weakness• During many audits, people can explain precisely why an action was taken, but rationale or justification was never documented/signed off at the time.
Strengths of Good DocumentationClear Objective and scope of the documentWho should prepare ? Should know ?Layout of the documentExplain the activity performed logicallyUse short, simple, easy to understand sentencesMaintain flow of scriptMatch script to the sequence of events of the activityUse correct data formatDraw neat and correct inferenceConclusion & SummaryGet your document edited by an expert
Document Management• Document Administration Department – Centralized better than de-centralized? – Reporting Relationship• Document Numbering System – Logical and easy to understand – Identifies revisions – No duplication• Document Management Procedures – Writing, reviewing, and approving – Numbering and version control – Issuing – Retrieving – Retention and Archiving
Document Retention and Archiving21CFR 211.180(d) …These records or copies…shall besubject to photocopying or other means ofreproduction as part of such inspection.Records that can be immediately retrieved fromanother location by computer or other electronicmeans shall be considered as meeting therequirements of this paragraph.”
Document Management Retention and Archiving• 21CFR 211.180(d)…..• Require clear procedures for archiving of documents Defined Retention Periods No loss of Information during retention (thermal printers) Fire and waterproof archives Access and Control of document archives Readily Retrievable (in case of compliant, recall, audit) Periodic Checks of archive Electronic Archives to be Qualified and Validated Document destruction
Evaluate the Documentation System• Review whether our documentation system is working correctly or not• It is easy to find out and classify the issues; “nobody fills out the documents correctly” “there are always problems with the documentation” “the particular system does not work”• Collect and analyse real data – Area of poor documentation – Classify the type of issues – Evaluate is it person dependent, system dependent – Training or change required – Monitor the improvement• Improvements will occur If we are monitoring & measuring (people know some one is watching)
Evaluate the Documentation System• Some examples of what we can review and evaluate: % SOP’s not reviewed within the required time frame % Batch Records with missing information during review % of logbooks not reviewed within the correct time frame % of outdated versions of SOPs versus the master copy % of superseded documents not retrieved• Identify the priorities and the reasons Are there certain issues within specific departments? Are some systems badly out of control? Make the data transparent Ask users why they believe current system is not working Compare systems that work well with those that do not
The Documentation Management Cycle FOLLOW-UP / MONITOR REVIEW AGAIN MAKE EFFECTIVE DRAFT TRAINING REVIEW VERSION CONTROL APPROVAL
The Documentation Management Document preparation• Written procedures to be drafted to avoid errors/discrepancy: clear instructions written in sufficient detail well understandable defining the responsibilities easy to implement.• The document is only useful if the person who should use it, actually understands it• Therefore consider the following aspects; educational level cultural background linguistic ability comprehension ability Readability 13 words per sentence.
The Documentation Management Document Review• What can be reviewed and evaluated when checking individual documents? the information that is stated the information that is not stated/missing steps scientifically incorrect information/requirements conflicting requirements safety issues legal/regulatory issues the rationale for the document (is the document serving a useful purpose).
The Documentation Management Document Approval• GMP Documentation is normally signed by the following persons: Author: a knowledgeable and trained person in the relevant topic within the relevant department (QA author for QA document) Reviewer: who is someone equally proficient as the author Approver: an appropriate level of management (QA manager).• Quality Assurance main role is to review and approve that all GMP documents are in compliance with regulatory files and meets the GMP requirements.
Documentation Management: Training• When New/Updated documents made: ensure that relevant people are informed/trained before the document becomes effective• The document can be trained on a one to one basis or as group.• The document can be read by the relevant people• In some cases, there may be some short questions to answer to ensure that key aspects are understood.• Training of documented could be s built into the system• The documentation system must ensure that absentees are also trained upon their return to work• Ensure that the training is recorded.
Tips to Good Documentation Practices/ Recordkeeping procedures:
Tips to Good Documentation Practices When portions of a page or a complete page remain unused, a single line must be drawn angularly across the unused portion. Sign and date the crossed out section and provide an explanation Eg- Not applicable; Remining pages not used refer new note book Ensure the pagination (all pages to be numbered; could be page X of Y for loose sheets and page x.. For bound books) Make the required entries on the record as the work is performed. Do not record information on a separate piece of paper /temporary entry and enter on the record later
Tips to Good Documentation Practices •Use only black or blue permanent ink.The ink should not run or smear if therecord is splashed with liquid. All entriesmust be permanent and able to bephotocopied. •Don’t use pens like gel pens, ink pensfor making entries. Don’t use pens like red,green color ink. • Pencil writing is not acceptable,
Tips to Good Documentation Practices Use correct rounding off procedures and significant figures When a comment or explanation is required, make all statements objective. Avoid personal comments and opinions. When dating a signature, use the actual day the signature was signed. If the activity being recorded occurs on more than one day, the record must clearly indicate where the "break" occurred. This can be accomplished by drawing a horizontal line through the procedure at the break" and indicating the new date or making entries that are initiated and dated appropriately.
Tips to Good Documentation Practices• Never sign your name for performance of a job for work actually performed by someone else.• When one or more person complete a task, all must sign.• When spaces or cells do not contain information, EACH must contain the appropriate “not applicable” entry.• Spaces and cells cannot be left “blank”!• Do not use titto, bracket/brace, arrow to link• Don’t remove any pages or portions from a note book• Do not change the paper size/quality/colour• Use polyvinyl alcohol base gum or white glue for pasting of graphs etc
Tips to Good Documentation Practices BMRs are important documents reviewed by regulators, so ensure to fill correctly: Missing signatures & dates Over-writing without correction, sign, date No remarks for correction Control Number not recorded correctly Time/Date and PC Number recorded in BPR not matching with in-process production Log Books Every person must be trained to complete documents properly; improper use of the documents can lead to inaccurate, inadequate or incomplete documents
Tips to Good Documentation Practices/ Recordkeeping procedures: Data may be attached to the page, however, it must be firmly attached. Label, sign and date the attachment. If a record becomes messy and extremely difficult to read or damaged, do not discard. Inform QA/supervisor and transcribing the data to a clean record sheet and attaching the original record sheet. Provide an explanation for the transcription. Use clear transparent tape for mending (patch-up). Computer print outs taken on thermal paper or easily fading inks should be photocopied and maintained.
Tips to Good Documentation Practices Review of records• Proper review will prevent the Non-compliances/ observation;• Sincere and effective review shall be done; not just signing as reviewer;• The following shall be reviewed but not limited to; – Incomplete entries, signature – missing records and out-prints – Illegible entries / unacceptable corrections – Traceability of relevant records /cross references – Deviations, if any investigation the impact on the product – Valid calibrations and service intervals of test equipment – Compliance with specifications, – Calculations
GDP:Filling of BPR Missing signatures & dates Over-writing without correction, sign, date No remarks for correction Control Number not recorded correctly Time/Date and PC Number recorded in BPR not matching with in-process production Log Books Every person must be trained to complete documents properly; improper use of the documents can lead to inaccurate, inadequate or incomplete documents BPRs are major documents reviewed by regulators
Tips to Good Documentation Practices Clearly Record the DataWhat’s that number?Is it 27? 29? 24? 2%Hmmmm. What do we do now?
“ I swear to follow the good documentation practice and document the actual information and on line…..”
Observations on poor documentation practices• Document error correction not signed/dated, and didn’t include a reason for the correction• Write-overs, multiple line-through and use of "White-out" or other masking device• Sample sequence table and audit trail not documented (if its not documented, it didn’t happen)• SOP related to production, calibration, storage and maintenance not authorized by the QA head• The delegation for the batch release, in case of absence of the QA manager, not recorded / documented• Out-of-specification (OOS) procedure not detailed enough; flow chart and /or check-list not available .
Observations on poor documentation practicesUse of signature stamp• US FDA Warning Letter UCM075960 to Scott A. Spiro, MD, 28-Jun-06. • US FDA Warning Letter UCM066113 to Medtronic, Inc., DEC 2 1997. Obscured original data• US FDA Warning Letter UCM076246 to Gynetics Medical Products NV, JAN 16 2007Use of pencilInaccurate records• US FDA Warning Letter 320-01-02 to SOL Pharmaceuticals Limited, NOV 21, 2000Hand changes not dated• Form FDA 483 issued to L. Perrigo Co., NOV 7, 2008. 
Observations on poor documentation practices• The records did not contain the complete raw data for all the laboratory testing performed.• The periodic calibration of the laboratory instruments was not documented completely in the laboratory records.• The records did not include the reason for the modification of a test method.• The laboratory records did not include a statement on the identity of the reference standards used and on the method with which these were produced.• The laboratory records did not include the initials or signature of a second person showing that the original records had been reviewed for accuracy, completeness, and compliance with established methods.
Summary and Conclusions (1)• GMP Documentation is one critical aspect of our business.• Documentation must be consistent and systematic• Documentation practices must assure that records meet GMP requirements• Documentation process must be controlled to minimize redundancies in the work flow• Inspections and audits regularly identify issues with documentation system.
Summary and Conclusions (2)• Document management system needs to be clear and logical Use a top down approach (QA must take the lead!) Use flow chart and other tools to define documentation needs Includes all types of documentation (including electronic) Ensure a robust document cycle from drafting to archiving• Review and evaluate the performance of documentation system.