2The Overview General Aspects and Requirements Types of GMP DocumentationPurposes of GMP DocumentationThe Structure of Document ManagementEvaluation of the Documentation SystemThe Document Management Cycle
3Some Remarks at the Beginning GMP documentation is one critical aspect of our business and it is a legal requirement too!Inspection or audit observations frequently identify outdated documents, inadequate version control, and poor documentation practicesAs the Quality Unit is responsible for designing and operating the GMP documentation systems on site, such audit observations reflect on QA either directly or indirectly.
4What 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 medicinal product required to demonstrate compliance with the GMPs and other regulatory requirementsOr more shortly:A GMP document is any written record associated with the manufacture, control and distribution of the API or pharmaceutical product.
5What are the Responsibilities ? The site Quality Manager is responsible for ensuring that:the systems to manage and control GMP documentation are available and comply with GMP requirementsall GMP documents in the documentation management system are in compliance with the regulatory files and GMP requirements.The site functional Information Solution (IS) Head is responsible for:supporting systems that assure integrity and availability of any electronic GMP documentation.
6General Aspects and Requirements The System Approach Each site or facility handling GMP documentation must have systems and procedures for their management and control.These systems and procedures must be compliant with company policies and GMP requirements.Documentation subject to company policies must be identified and defined within the documentation management system.
7General Aspects and Requirements What should be recorded ? All important information that is generated during an operation or process must be recorded together with who performed the operation and when it was carried out.Such information should be legible, accurate, dated, traceable, and accessible.This information should reflect the complete history of the manufacture, packaging and control of the product.
8General Aspects and Requirements Key Features of Good Documentation Careful design of documents should make them easy to read, easy to understand and easy to complete properlyOriginal documents should be easily distinguishable from photocopies, and should have clear and concise informationGood documents should have sufficient space for entries, to record variable information and signature and to attach print-outs etc. Unused empty fields should be crossed-out.
9General Aspects and Requirements What else is relevant? GMP documentation must clearly state title and content and must possess a site unique identifying numberGMP documentation must be formally approved, issued and version controlledData entries must be made or completed at the time the action is performedEntries in logbooks should be done in chronological order.
10General Aspects and Requirements What else is relevant? Master documents must be subject to appropriate controls to ensure that only one version is current. Such documents must be approved, signed and datedModifications to master documents must be managed through change controlThere must be a periodic review of GMP documents to ensure that they are compliant with current regulatory files and GMP requirements.
11General Aspects and Requirements What else is relevant? All information contained within GMP documentation that is stored and maintained electronically must be made available in both electronic and human readable formatsAll SA product and system related documents are considered the intellectual property of SA and must be maintained and distributed in a confidential manner.
12Types of GMP Documentation (1) This Documentation includes, but is not limited to the following Batch Related Records:Master Batch Records (e.g. Processing Instructions,(Packaging Instructions)Batch Records (e.g. Batch Production Records)Raw Data RecordsLaboratory RecordsDistribution RecordsStandard Operating Procedures (SOPs)Specifications and Test MethodsRecords of Raw Materials, Intermediates, Labellingand Packaging Materials
13Types of GMP Documentation (2) Non Batch related RecordsQualification and Validation DocumentsChange Control DocumentationEngineering DrawingsMaintenance and Calibration RecordsComplaint RecordsRecalls and ReturnsEnvironmental Monitoring RecordsUtility Monitoring RecordsLine and Equipment Logs
14Types of GMP Documentation (3) Non Batch related Records (continued):Personnel Training RecordsQuality Agreements (i.e. Technical Agreements)Failure Investigation and Reporting RecordsCleaning and Sanitization RecordsEntry Records for Controlled AreasPest Control RecordsStability RecordsAudit and Regulatory Inspection ReportsRegulatory Files
15Types of GMP Documentation (4) Some other examples of documentation thatmust not be forgotten:SOP AnnexesComputer filesProcess Flow and other Diagrams (e.g. gowning diagrams)Raw Data Sheets (charts, chromatograms, etc.)Technical ReportsLabels (room and equipment status, sampling, material status)
16Purposes of GMP Documentation (1) There are three main purposes for GMP documentation:To meet legal requirements including all GMP expectationsTo meet our business requirementsTo form the basis of good scientific decision making
17Purposes of GMP Documentation (2) “If it is not documented, it is a rumour!”This is the FDA Inspection Approach
18Purposes of GMP Documentation (3) 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!
19Purposes of GMP Documentation (4) If you cannot answer all of the questions from the previous slide, then the documentation (system) has somehow failedRemember, documentation should equally be for our own benefit as it is for the regulatorsAnd: inspections normally provide good feedback for improvement.
20Purposes of GMP Documentation (5) PROCEDURES SHOULD BE WRITTEN ANDFOLLOWEDIt is a concern if an SOP has not been in placeBut it is a violation of the GMP requirements, ifthe SOP is present, but not followed.
21Purposes of GMP Documentation (6) Documenting Decisions and Rationales The regulators expect things to occasionally go wrong during manufacturing or testingHowever, we must ensure that we clearly document and sign off our decisions with a rationale behindIn reality, this is one area of a general weaknessDuring many audits, people can explain precisely why an action was taken. Although the decision may have been the correct one and documented, the rationale was never documented/signed off at the time.
22The Structure of Document Management Taking a Logical Approach There should be one “umbrella” document (SOP) that defines the management of GMP documentation, our approach to documentationFor example:What type of documents are covered by GMPWhat is raw data and what notWho is responsible for each GMP documentationWho can author, review, and approve GMP documentsHow working copies are controlledHow the documents are archivedWhen the documents are reviewed for changes
23The Structure of Document Management Control of Working Copies It is important to have the most up to date working copy of a document issued to a department. But how can we stop uncontrolled copies being photocopied (e.g. replacement page of BMR)It is easier now for people to make uncontrolled copies as they have general access to photocopy machines.Apart from rigorous training, many different methods are used to help control documentationBatch number punched through all pages of BMR copyBMR Copy stamped in red with batch number and dateSOP’s red stamped with controlled copy and the number of the copy.
24The Structure of Document Management Document Administration DepartmentCentralized better than de-centralized?Reporting RelationshipMust be audited like all other GMP related departmentsDocument Numbering SystemLogical and easy to understandIdentifies revisionsNo duplicationDocument Management ProceduresWriting, reviewing, and approvingNumbering and version controlIssuingRetrievingRetention and Archiving
25The Structure of Document Management Retention and Archiving Require clear rules and procedures about archiving of superseded documentsDefined Retention PeriodsNo loss of Information during retention (thermal printers)Fire and waterproof archivesAccess and Control of document archivesReadily Retrievable (in case of compliant, recall, audit)Periodic Checks of archiveElectronic Archives to be Qualified and ValidatedDocument destructionNote the archived documents are the property of the company. Even if the site is sold, and documents must be transferred to another site and secured in a storage area
26The Structure of Document Management Document Retention Rules The retention period for all quality documentation must meet legal and regulatory requirements of all relevant markets.It is the responsibility of each department to ensure the control and retention of GMP Documents in accordance with the systems and procedures.
27Evaluate the Documentation System (1) We need to review whether our documentation system is working correctly or notIt is easy to make general statements to the effect that:“nobody fills out the documents correctly”“there are always problems with the documentation”“the system does not work”As with any other process, we need to collect and analyse real data to see if there is a problem or not, or to identify whether performance is improving or not.It is a well known phenomenon that improvements will occur just because people know that we are measuring it.
28Evaluate the Documentation System (2) Some examples of what we can review and evaluate:% SOP’s not reviewed within the required time frame% Batch Records with missing information at review time% of logbooks not reviewed within the correct time frame% of uncontrolled technical drawings% of outdated versions of SOPs versus the master copy% of superseded documents not retrievedIdentify the priorities and the reasonsAre there certain issues within specific departments?Are some systems badly out of control?Make the data transparentAsk users why they believe current system is not workingCompare systems that work well with those that do not
30The Documentation Management Cycle (2) Document Drafting Written procedures need to be drafted in a way that will help avoid errors:clear instructionswritten in sufficient detailwell understandableversion controlledwritten with a view for trainingdefining the responsibilitieseasy to implement.
31The Documentation Management Cycle (3) Document Drafting The document is only useful if the person who should use it, actually understands itTherefore consider the following aspects when drafting documents:educational levelcultural backgroundlinguistic abilitycomprehension abilityreadability Index for average English:13 words per sentence.
32The Documentation Management Cycle (4) Document Review What can be reviewed and evaluated when checking individual documents?the information that is statedthe information that is not stated/missing stepsscientifically incorrect information/requirementsconflicting requirementssafety issueslegal/regulatory issuesthe rationale for the document (is the document serving a useful purpose).
33The Documentation Management Cycle (5) Document Approval GMP Documentation is normally signed by the following persons:Author: a knowledgeable and trained person in the relevanttopic within the relevant department (QA only author their own documents!)Reviewer: who is someone equally proficient as the authorApprover: an appropriate level of management (normally theQA 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.The QA signature is therefore the last one to be added.
34The Documentation Management Cycle (6) Version Control Effective Version Control is an essential part of the GMP document management systemThere must be a high level of confidence that only the latest versions of documents exist as working copiesThere are two ways of dealing with superseded versionsPassive retrieval (not recommended)The new document is issued and the recipient is asked to destroy all copies of the superseded one (rarely happens)Active retrieval (recommended)The new document is exchanged for the superseded version
35The Documentation Management Cycle (7) Training New/Updated documents have been written for a reason, and it is essential that relevant people are informed/trained as appropriate before the document becomes effectiveThe document can be trained on a one to one basis or within a group. The document can be read by the relevant peopleIn some cases, there may be some short questions to answer to ensure that key aspects are understood.
36The Documentation Management Cycle (8) Training People can generally have different preferences in their way of learning, but the most important thing is that the time for training is built into the cycle, and properly documentedThe documentation system must ensure that absentees are also trained upon their return to workThe system must also ensure that the proof of training can be retrieved easily.
37The Documentation Management Cycle (9) Make Effective The effective date of the document (e.g. SOPs, protocols) should permit enough time for training of relevant personnelProcedures, once effective, should be as working documents, and treated as suchThe best procedure is of no value in the supervisor’s locked office!And then: Follow up and monitor!
38Summary and Conclusions (1) GMP Documentation is one critical aspect of our business.All documentation required by GMP regulations must be issued, managed, and controlled by a document management system.QA have a major role to play in managing GMP documentation.Inspections and audits regularly identify issues with documentation system.
39Summary and Conclusions (2) Document management system needs to be clear and logicalUse a top down approach (QA must take the lead!)Use flow chart and other tools to define documentation needsIncludes all types of documentation (including electronic)Ensure a robust document cycle from drafting to archivingReview and evaluate the performance of documentation system.