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Importance of Documentation in Importance of Documentation in GMP complianceGMP compliance

By:J.RamniwasDirector-Regulatory and Quality Affairs

Pharmaocean,Vadodara(India)

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Objective

• To review general requirements for documents

• To review specific requirements for each document

• To give general guidance how to create good documentation system

•A reliable evidence for GMP compliance.•Quality by design is the only solution to overcome the quality-related complaints in an organisation. •An essential element of quality assurance is good documentation practices. •The system of documentation devised or adopted should have as its main objective to establish, monitor, and record “quality” for all aspects of the production, quality control and quality assurance

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Purpose of Documentation

Clearly written documentation prevents errors that may arise in oral or casually written communication It provides assurance that quality related activities are carried out exactly the way they have been planned and approvedThe achievement of conformity and quality improvementPurpose of documentation :

To ensure that there are specifications for all materials and methods of manufacture and controlEmployees know what to doResponsibilities and authorities are identifiedEnsure that authorized persons have all information necessary for releaseProvide audit trailForms the basis for improvement.

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Quality Based Documentation System

Corporate Communication tool – internal and external

Integral part of corporate interactions

Corporate Policies – Rationale for responsible decision making

Currency of corporation

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Quality Policy and its Importance

Management commitment to quality•Customer FocusedSatisfy our customers' needs and expectations •Make commitments we fully understand and believe we can meet •Meet all commitments to customers on time

Performance Driven1. Verify that our products and services meet agreed requirements 2.Monitor, benchmark and continuously improve our business, products

and services, organization and employees' performance

Achieve Organisation's Mission and Goals1. Sustain and develop business growth and Intellectual Property

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Quality Manual

The strategic document that outlines the organization’s system of providing quality assurance to achieve customer satisfaction

Objectives :Describe the quality system structureDeclare the quality policy and organization goalDescribe how the organization meets the quality goal

Content of quality manual :The quality policy declaration The goal of quality;The organisational structure including responsibility and authority of each key personnelProcedures, instructions and resources for implementing the quality management.

User :All personnel in the organizationAnother parties, auditors, and customers

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Design of Documents

Useful

Flexible

Grow

Change

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Type of GMP Documents

1. Description Documents• Describe how to perform certain tasks• E.g.. SOPs, Protocols, Specifications, Master Production Records etc.

2. Data Collection Documents• Facilitate the timely and accurate documentation of tasks and events• E.g. Forms, Reports, Production Batch Records , Logbooks etc.

3. Numbering Systems• Serves to account for and track information and documents• E.g. Lot numbers, Part numbers, equipment numbers, Form numbers, SOP

numbers, Receiving codes etc.

4. Data Files• Serves to organize the data in to useful categories for review and to support

accountability and traceability requirements• E.g. Specification Files, Equipment Files, Equipment history files, Product files,

Facility Qualification files etc.

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• Establish, monitor and document Quality1. Description Documents

Define and establish the Quality of Raw materials, environment, production process and Finished Product

2. Data Collection DocumentsConfirm the materials ,environment , production processes or product routinely meet the established Quality characteristics.

3. Numbering SystemsControl and track the use of descriptive documents and data collection documents

4. Data FilesOrganize the data in to useful categories to facilitate review and retrieval

Function of GMP Documents

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Users

1. Bottom –up• Manufacturing, Laboratory or Operational personnel who interact with the detailed

steps of the system on a daily basis • Need to know what to do and how to do it2. Top-Down• Administrative personnel e.g. management, regulatory, development, finance,

marketing who must understand and interact with the system by reference• A good document is written both to inform and to educate• It must meet the needs of the line workers and the administrators

E.g. SOP on specification writing- describes the purpose of specifications, provide guidance on the decision making associated with writing specifications, numbering systems, change controls and responsible personnel, steps on generating and approving an SOP etc.

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A Well Designed Documentation System

Ensure Quality standards are met routinely

Minimize the potential for Error

Reduce downtime when deviations or failures occur by providing

immediate access to well organized data

Serve as a consistent training tool for line workers and administrators

GMP documents should be prepared, reviewed, approved, distributed

and archived according to written procedures.

A Poorly Designed System is a burden to all!

A simple system is always the most difficult to design.

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Manufacturer's Role

Comply with GMP regulations

Provide Quality medications to patientsProvide documentation to support the quality of the products from development to market and to product discontinuation

Producing documents is also part of the production

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Principles of Good Documentation

The heart of GMP is the establishment of well written procedures for each

step of our quality operations

Documentation is used for full traceability of events – cross reference all

related documents – audit

Written procedures provide the controls necessary to minimize the changes,

mix-ups and errors

Ensure compliance with GMP regulations but more importantly, we ensure

the consistent Quality of our products.

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Proof of Quality

• As a pharmaceutical company, your proof of success is found in the

documents records that you keep.

• Documentation is your proof that your products/ services are produced in

compliance with the GMP regulations and your company’s operating

procedures and standards.• Key Documents : Development Records, Clinical Trial Records, process

and method validation, production batch records, OOS, Deviations, Investigations, Equipment Calibration and preventive maintenance, Training Records, CAPA, Complaints, Change Control etc..

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Who Reads your Documents

Internal• Colleagues• Supervisors and managers• Data Reviewers• QA• Global Network Colleagues

External• Regulators – Local and Foreign • Customers – Local and Foreign• Lawyers• General Public

Write documents as though you are writing history.Write for future viewers

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Basics of Record Keeping

• Where your signature is required, write your name legibly and in ink – always use include the date of signing.

• Always document as soon as a task is performed• For all critical steps, a second person is required to verify the

entered data• Do not document someone else’s work unless you are

designated to do so.• Do not assume work has been properly documented without

seeing the work and / or the documents, e.g. blame for fraudulent action

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Real Time Formats and Dates

• Data entered directly as it occurs• Scratch paper or sticky notes must not be used• Records are signed and dated on the day (and time) the work

was performed• Consistent date format is important for a company e.g.

day/month/year or year/month/day• Alpha-numeric dating is preferred• 01 Nov 2008 is preferred over 01-11-2008• Each page should have the current date(s) – no back dating.

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Calculation and Numbers

Write down the formula and perform one sample calculation.

No calculation is required for simple math

e.g. 1+4 =5

Prevent using down arrow or ditto marks to show repetitiveness

e.g.

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Corrections

No over written

No use of white fluid

No out

Critical corrections or omissions must be addressed and signed by management on raw data record

Data on damaged pages should be re-entered for clarity, initial, date and explanationAll corrections must be initiated and dated by the analyst and reviewer when applikable

applicable John 01 Nov.2008

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Documentation Practices

Documentation requires that record, sign and date every step of the operations that we perform e.g. production batch recordsDocumentation should always be done promptly, accurately, legibly and in accord with our written procedures e.g. lab notebooksA check list serves as a check and double check against costly omissions, mix-ups and errors. It is used to avoid mistakes and ensure completeness of activitiesThere must be written procedures for process control activities i.e. SOP. These procedures including changes, must be reviewed and approved by the organizational unit and QA

Documentation Practices

Permanent ink – No pencil

All pages numbered and filled out consecutively. No blanks to b

e filled in later

Blank or unused pages voided with a line, initiated and dated

Small “fill in the blank” lined out with” “ or “N/A”.

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Control of Records

GMP DOCUMENTS shall not leave the company• Do not take them home

Do not throw away GMP documentsFull reconciliation of each piece of document e.g. sample labels, chromatograms, investigation reportArchive area

• Security Access• Document Withdrawal and Return Log • Smoke Alarms• Off-site back system for electronic files• Disaster recovery plan

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Electronic /Computerized Records

Records that are required to be maintained under predicate rule requirements• Maintaining in electronic format in place of paper format – Part 11 records• Maintain in electronic format in addition to paper format –rely on electronic record to

perform regulated activities ( Business practices) –Part 11 records• Document the business practices in an SOP

Audit trial for part 11 RecordsBackup records are maintained for electronic recordsElectronic data must be readily retrievable in a print formatElectronic signatures (e.g. approve, review and verify ) should be authenticated and secure. When used such a system must be evaluated and tested for security, validity and reliability, Records of those evaluations and tests must be maintained.During the retention period such records must be secured and accessible within 48

hours to manufacturer , packager, distributor and importer.

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GMP Numbering System

Some documents require two numbers to be identified completely,• A document number – tells what it is

• A revision number –tells which one it is

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SOP Numbers

Group SOPs by categories• Personnel• Quality Assurance• Quality Control• Records• Manufacturing• Packaging• Distribution• Building and facility• Equipment• Raw materials and packaging components• Development• Engineering

Recommend alphanumeric numbers and revision numbers e.g. QAD 123 v 03

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Lot Numbers

Lot numbers are assigned as• Receiving Lot numbers• Production / in-house lot numbers

To trace an item or a product from planning , staging, production, testing to marketTo identify an item completely, both the lot number and the partnumber are required

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Part Numbering System

Part number should be unique to each item

• Sodium Chloride USP Grade – Use in production

• Sodium Chloride ACS Grade – Use in laboratories

Consider grouping by SuppliersERP,SAP, or Manual Inventory System

• Numeric Numbering• Alpha-numeric numbering

Part number can be retired but never reassign Part numbers

A Simple Sample Part Numbering System

1000-1999 Raw Materials*2000-2999 Packaging Components*3000-3999 In-process Materials*4000-4999 Printed Materials and

Labels*5000-5999 Finished Products*6000-6999 Materials Prepared

In-house*7000-7999 Non-inventory chemicals*8000-8999 Non-inventory

Components** Inventory Items

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Document Numbers

Laboratory notebook numberEquipment logbook numberValidation Protocol NumberOOS numberCAPA numberComplaint numberChange number…… etc

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Types of Documents in Manufacturing

LabelsSpecifications and testing proceduresMaster formulae and instructionsBatch processing and batch packaging recordsStandard Operating Procedures (SOPs)LogbooksRecords

Stock control and distribution recordsOther documents …

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Standard Operating Procedures

Written commitments to regulators that describe the routine tasks

Descriptions on how to perform various routine operations

Step by step instructions that technicians in QC, Production,

maintenance, and material handling consult daily in order to

complete their tasks reliably and consistently

Effective periods and review frequency

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SOP Format

Informational Categories• Title• Purpose• Scope • Responsibility • Definitions• Reference/ Applicable Documents• Safety Considers• Procedural principles• Preliminary Operations• Procedures• Calculations• Documentation Requirements

Each Page – Title, SOP number, revision number ,paginations, company name, declaration of confidentialityFirst page –approval signatures, date of approval , issue date, next review date

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How to write good SOPs

SOP Numbering – simplify and group similar SOPs togetherReduce duplicate SOPs- facilitate training and improve complianceOutside the job – Use process flow diagramsWrite for the readers – i.e. operators, analysts, QA, Customers, Regulators

• Right language• Short, simple sentences• Familiar and short words• Write in conversational style• Explain the background, Do not assume people know / remember your processes

Use pictures to facilitate understanding, e.g. picture of an HPLCPut procedures in a good package

• Selling SOPs to employees so that they will follow procedures• Page design, instructions, table of contents , index , dividers, visual layout, right font

size, and types of binders used, intranet access etc.

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Specifications and Test Procedures

Primary source of information for an itemSpecification

• Specification number and version control• Description of each part numbered item

- Standard Naming convention• Name of company• Expiration date/ Re-test date• Chemical formula• Material• Dimensions• Sampling information e.g. size• Handling precautions• Storage conditions• Test requirements and method numbers• Acceptance Criteria

- Test before release- Release based on C of A and

concurrent testing- Release based on C of A and / or ID test

Pagination and approval signatures

Purchasing Information• List of approved vendors

• Local Supplier – name and address

• Manufacturer – Name and Address

• Minimum Order Quantity

• Quantity per Unit

• Palletization Information

• Certificate of analysis

• Contracts and Agreements

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Receiving Labels

Each item is labeled with its part number and receiving lot number• Quantity per unit• Total Quantity• Total Number of pallets/ skids• Responsible person – Initial and Date• Transportation conditions

Different colors for different types of labels• Quarantine Label – Yellow Color• Sampled Label – Blue Color• Under Hold Label – Orange Color• Release Label - Green Color• Rejection Label – Red Color

Barcode Labels Label issuance, usage, destruction and reconciliation document

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Process Development Report

The following exemplifies information to be contained in the development report. •Historical data of pharmaceutical development of new drug substances and

drug products at stages from early development phase to final application of

approval

•Raw materials and components

•Synthetic route

•Rational for dosage form & formula designs and design of manufacturing methods

•Rational and change histories of important processes and control parameters

•Quality Profiles of manufacturing batches ( including stability data)•Specifications and test methods of drug substances, intermediates, drug products, raw materials, and components, and their rationale( validity of specification range

of important tests such as contents impurities and dissolution, rational for selection of test methods, reagents and, columns, and traceability of raw data of those

information)

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Master Production Records

Prepare , sign and date by one person and independently check, sign and date by a person in the Quality unitProduct Description and item numberFull list of ingredientsAccurate statement of quantity or ratio of each raw material or intermediate to be usedProduction location, equipment and major utilitiesExpected production quantity, sample quantity, rejects, reprocessed quantity,% yield

Production instructions• Sequences to be followed• Critical steps have to be co-signed

by a second operator/ supervisor• Define the ranges of process

parameters• Sampling instructions and in-

process controls with acceptance criteria

• Time limits for completion of individual processing steps or total process

• Expected yield ranges at appropriate steps

• Special storage conditions including labeling and packing materials

• S special precautions

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Production Batch Records

Check batch record before issuance to assure the correct version is used- sign and date when issueOne batch record for one number ( unique number)For continuous production, the product code with the date and time can serve as the unique identifier until the final number is assignedFull traceability of records- dates, times , personnel, equipment, raw materials, actives, intermediates, packing components, labels, rejects, in-process and lab results, OOS, investigations, changes, release changes, stability results, environmental conditions etc…Investigation of critical deviations – extend to other batches that may have been associated with the specific failure or deviationDocument all deviations during manufacturing and cross reference to other documents if necessary e.g. OOS or unplanned deviationsAttach all process generated paper to product batch records e.g. raw material weighing records, tablet weight check, statistical process control charts, equipment print outs, equipment and room labels etc.Record production quantity, sample quantity, rejects, reprocessed quantity and % yield

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Production Record Review

Review and approve by the quality unit to determine compliance with all established , approved written procedures before a batch is released or distributedAny unexplained discrepancy or the failure of a batch or of its components shall be thoroughly investigated, whether or not the batch has already been distributedThe investigation shall extend to other batchesA written record of the investigation shall be made and shall include the conclusions and follow-up

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Packaging Instructions

Master packaging instruction – formally authorizedPackaging instruction• Strengths, dosage forms, size( by volume, weight or counts), packaging

materials, packaged lot number• Location of packaging line• Date, time and personnel• Labels and print components – keep samples coded with lot number and

expiry date, reconciliation and control• Line clearance checks – before and after • In-process controls from shift to shift• Samples control• Special precautions

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Equipment Records

Usage logs

• Product / Batch Number/ Person/ Date/ Time

Cleaning/ Sanitation/ Sterilization

Maintenance

• Person, date, time, results

Dedicate Equipment – One intermediate or one product

• Individual equipment records are not necessary if batches are traceable

sequence

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Laboratory Glassware

All in-process solutions, glassware, media tubes or plates, sample extracts and anything used in testing must be clearly labeledand identifiedLaboratory glassware with labels are kept until laboratory reports are reviewed and approved

Product : ABCLot Number : 130Sample : # 1Analyst initial & Date :

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External• Name(s) of manufacturer/distributor• Batch Number/ Item Number/ Labeling• Quantity of each shipment / Quantity per skid / Quantity per unit• Date of receipt/ expiry date• Certificate of analysis

Internal• Receiving Number / Item number/ Labeling• Sample Size• Test Specification, Identification/ Test Results and release decision• Packaging components, printed components and labels• Master approved labels and components for comparison• Inventory of each item, usage records for each material and rejection

Raw material and Packaging Component Records

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Laboratory Records

Complete lab data derived from all tests and lab equipmentCompliance with established specifications and standardsFull traceability – dates, time, samples, quantities , suppliers, personnel, equipment, reference standards, reagents, standard solutions, test methods, graphs, charts, spectra, chromatograms, calculations, conversion factors, test results, comparison to previous trends and validation batches, changes to methods, OOSSignature of the person who performed each test and the dates(s) the tests performedSignature and date of second person showing that the original records have been reviewed for accuracy, completeness and compliance with established standards.

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Laboratory Data

Raw data are necessary for support, reconstruction and

evaluation of test report

Raw data may include , but is not limited to , photographs,

microfilm, computer printouts, labels, magnetic media, including

dictated observations, and recorded data from automated

instruments

All raw data are kept with the test reports, unless there are

electronic records or other means of recording

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OOS FORM Plus all related documents

Initiate OOS investigation as soon as OOS is found

Any repeat testing or retesting due to laboratory error or instrument

problems must be approved by management prior to testing again

Only management has the authority to invalidate a result

Out of Specification and Re-testing

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Data Review

The raw data and lab records are very importantDocumentsBefore any product is released to the market, a complete check of production and laboratory records is made to make sure the product meets the quality standardsWhen you sign your name on the appropriate records, you are, in essence becoming an historian for that process.

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Stability Records

Demonstrate that the product meets its established specifications during the product shelf lifeTest product in its final package in which it is soldOn-going stability program: 0,3,6,9,12,18,24,36 …monthsTest with in the required time frame

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Deviation Records

Deviation Form + all related documents

Full investigation – Describe the background , the environment, personnel involved, root causes , risk assessment , conclusions,corrective and preventive actions(CAPA)

Write with short and simple sentences

Write for someone who does not know your procedures

Write for someone who will read this document few years from now.

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Regulations and Requirements - Change control as critical part of the

validation life cycle - How to set up Change Control,

Documentation Systems - Preparing Change Control SOPS & Forms - Processes involved to efficiently control

and document changes to:- Manufacturing processes- Facilities - Product - Elements of Change Control Management - Change Control process for computerized

systems - Change Control in API and Drug Product

industries - How to organize change documentation to

withstand regulatory queries during field inspections?

Change Control Records

-What functions a Change Control system must perform

- How the organizational culture can affect the successful implementation of Change Control

- Types of Changes - Different levels of change (major, minor, critical)

and distinguishing them - Types of reviews and approvals - Roles and Responsibilities

Signature meanings - How your Change Control system may be

examined by investigators - Change Control checklists - Personnel Training - Scale Up and Post Approval Changes – SUPAC- Bulk Actives Post Approval Changes - BACPAC

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Training Records

It is the responsibility of each employee/management to maintain their own and their department's training recordsYou can perform a test or task until you and your trainer have completed the training and signed -off on the procedure.Certain tests require performance assessment before QualificationMust document the training on new and revised SOPs issued throughout the year.Training Records should be reviewed during annual performance review between the manager and the employee. Document any additional training for the new year.For human errors on OOS or deviations – employee training records need to cross link to corrective and preventive actions.

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Organisation Charts

Dated and version controlName of all personnel involved in GMP activities and decision making.Provide information on full time, part time and contract staff.Provide global reporting structures for multinational organizations.

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Job Description

Job descriptions are written statements that describe the: • Duties, • Responsibilities, most important contributions and outcomes needed from a position, required qualifications of candidates, and reporting relationship and co-workers of a particular job.Job descriptions are based on objective information obtained through job analysis, anunderstanding of the competencies and skills required to accomplish needed tasks, and the needs of the organization to produce work.

Job descriptions clearly identify and spell out the responsibilities of a specific job. Job descriptions also include information about working conditions, tools, equipment used, knowledge and skills needed, and relationships with other positions. The best job descriptions are living, breathing documents that are updated as responsibilities change. The best job descriptions do not limit employees, but rather, cause them to stretch their experience, grow their skills, and develop their ability to contribute within their organization.

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Technology Transfer Documents

Like for like transfers.Levels of changes require for changes.Risk assessment for changes within the “Design Space”From one site to another site.From R&D to productionTransfer protocols – before and afterChange control or deviation during transferValidation status after transfersStability studies

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Validation Documentation

Validation Protocol – before validation• How validation of a particular process will be conducted• Specify the type of validation e.g. retrospective, prospective or concurrent and the number of

process runs• Specify critical process steps and acceptance criteria

- Important to put down the pre-determined specifications otherwise , any result can be claimed as ‘ validated’.

- Important to justify which are the priority parameters to be validated , since we may not be able to validate all combinations of results

Validation Report – After Validation• Cross reference the validation protocol• Summarize the results, deviations, changes and conclusions• Recommend changes to correct deficiencies• Justify any variations from the protocol• Review and approve by the designated units and QA

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Management Review Minutes

Attendance

Meeting Dates and Frequency

Discussions of Quality trends and issues• Identify responsible person(s) for CAPA

• Target dates for actions

Follow-up with previous minutes and actions

Escalation Process

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Documents involved External Stake Holders

Response to Regulatory InspectionsResponses to customer inspectionsComplaintsProduct RecallsAnnual Product Quality ReviewPost- market adverse drug events reportsWrite for the readersWrite for the future

Response to Regulatory Inspections

Respond on timeA cover letter and a separate on responsesUnderstand the GMP aspects of comments and respond to the commentsIdentify root causesProvide corrective and preventive actions with target datesInclude responsible department/function –names are not necessary

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Complaints

SOPs for handling of all written and oral complaintsTrain all employees on how to document complaintsComplaints involving the possible failure of drug product to meet any of its specifications – to be reviewed by the Quality Control UnitComplaint represent serious and unexpected adverse drug experience – require to be reported to FDAMaintain complaint records at least 1 year after the expiration date of the product or 1 year after the date that the complaint was received, whichever is longerWhere investigation is not conducted, the written record shall include the justification that an investigation was not necessary and the name of the responsible person making such a determination

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Product Recalls

Investigations, root cause analysis, CAPA Different levels of recalls have different regulatory requirements• Class- 1 – Recall from the market place• Class-2• Class-3

Distribution records – Full Traceability of Quantities distributed and the customers

• Includes sales records of drugs and professional samples• Enable a complete rapid recall of any lot or batch of a drug

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Health and Hygiene Records

Sanitation and hygiene should be practiced to avoid contamination of personnel and during manufacturing of products.It should cover all aspects of manufacturing:

PersonnelPremisesEquipment and apparatusProduction materials and containersProducts for cleaning and sanitationAll potential sources of contamination

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Pest and Rodent Control Records

Written pest control program Pest Control and Rodent Control Site mapLog book of Rodent and Insect TrapsInsect and Rodent Trap cleaning recordOutsourcing is recommendedUse of safe pest control agentsMSDS of all pest control agentsNo risk of contamination to the materials and productsProper records

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Regulatory Observation Related to Documentation Issues

There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality and purity they purport to possess.Written procedures have not been developed for the surveillance, and receipt of post marketing adverse drug events.Firm failed to follow their SOPs on OOS investigations. Samples were re-tested before any investigation was conducted.The operator who manufactured a batch of sterile product has no documented training onsterile production.Investigations fail to be conducted within a timely manner. The time frame for completion is required in SOP. The SOP places no limitations for the number of times a time frame may be extended, nor does it identify the number of days allowed to extend a timeframe.A portion of batch was rejected. The in-process solution made for the rejected portion of the batch was not reconciled .There was no record of the disposition of the excess quantity of the excess material.Lab records are deficient in that they do not include a complete record of all data generated during testing. There was no record on how many chromatograms were generated.The firm communicated GMP related information through electronic mails .Investigation and product decisions were made on emails. Contents of these emails are not archived or transcribed in to formalized records required by the regulations.

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Stock Control and Distribution Records

What should be recorded?Where should records be stored?Why are the records important?

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Design a Good Documentation System

Not a one size fits all approach

Unique operations and unique products

Complement the cultural environment of the corporation

Be the expert in your systems, operations, products and

services.

Do not create a system to satisfy one part of the corporation

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Revision and Renewal of Documents

Should be made periodically, or if neededObsolete documents should be retrieved from all relevant parties and its original copy should be archivedThe date of revision should be stated in the new documentsEvery revision should be approved by authorized person

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A Good Documentation Practice:A Life Style Approach

When you care enough to make GDP a life style and not just a regulation, you do more the signing documents – we put our name on job well done.Write it down – Keep good recordsIf it is not documented, it is a rumourThere can be no substitute for a clear commitment to entering data

• Correctly• Completely and • Chronologically

and right first time

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