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GMP { Good manufacturing Practices }

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Karthik Penamala

Good Manufacturing Practices (GMP) are regulations and guidelines for manufacturing drugs, medical devices, and food to ensure product quality and safety, enforced globally by regulatory agencies like the FDA and equivalent bodies. GMP emphasizes high sanitation standards, qualified personnel, and thorough documentation across all stages of manufacturing, including production, equipment maintenance, and hygiene practices. The document details specific requirements for personnel qualifications, cleanliness, and the avoidance of cross-contamination to maintain product integrity.

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Good Manufacturing Practices Karthik Penamala
What is GMP?  Good Manufacturing Practice is a set of regulations, codes, and guidelines for the manufacture of drug substances and drug products, medical devices, in vivo and in vitro diagnostic products, and foods. Fig.4 GMP handbooks for every industry
 Good Manufacturing Practices are enforced in the United States by the FDA  In the United Kingdom by the Medicines and Healthcare Products Regulatory Agency  GMPs are enforced in Australia by the Therapeutically Goods Administration  In India by the Ministry of Health, multinational and/or foreign enterprises  Many underdeveloped countries lack GMPs Good Manufacturing Practices Worldwide Enforcement
1941 Initiation of GMP  Sulfathiaziole tablets contaminated with phenobarbital  1941 - 300 people died/injured  FDA to enforce and revise manufacturing and quality control requirements  1941 - GMP is born Fig. 5 1906 Certificate of Purity signed by doctor
Provisions 21 CFR Parts 210 and 211 (Drug Industry) 21 CFR Parts 600 (Biological Products: General) 21 CFR Parts 601 (Licensing) 21 CFR Parts 600, 601, 610 (Biological Products standard)
Part 211 –Selected cGMP For Finished Pharmaceuticals  Subpart B-Organization and Personnel  Responsibilities of quality control unit.  Personnel Qualifications.  Personnel responsibilities.  Subpart C-Buildings and Facilities  Ventilation, air filtration, air heating and cooling sanitization, maintenance, sewage and refuge, plumbing.  Maintenance  Subpart D-Equipment  Equipment design, size, and location.  Equipment construction.  Equipment cleaning and maintenance.  Automatic, mechanical, and electronic equipment.  Filters.  Subpart E-Control of Components and Drug Product Containers and Closures  General requirements.  Receipt and storage of untested components, drug product containers, and closures.  Testing and approval or rejection of components, drug product containers, and closures.  Use of approved components, drug product containers, and closures.  Subpart F-Production and Process Controls  Written procedures; deviations.  Charge-in of components.  Calculation of yield.  Equipment identification.  Sampling and testing of in process materials and drug products.  Time limitations on production.  Control of microbiological contamination  Reprocessing.
Part 211 –Selected cGMP For Finished Pharmaceuticals  Subpart G-Packaging and labeling control  Material examination and usage criteria.  Labeling issuance  Packaging and labeling operations.  Drug product inspection  Expiration dating.  Subpart H-Holding and distribution  Warehousing procedures  Distribution procedure  Subpart I-Laboratory control  General requirement  Testing and release for distribution  Stability testing  Special testing requirement  Reserve sample  Laboratory animals  Subpart J-Records and reports  General requirements.  Equipment cleaning and use log  Component, drug product container, closure and labeling records.  Master production and control records  Production control record review  Laboratory records  Distribution records  Complaint files  Subpart K-Returned and salvaged drug products  Returned drug products.  Drug product salvaging
Part 610 –General Standard for Biological product  Subpart A:- Release Requirement  Subpart B-General provision  Subpart C-Standard preparation s and limit of potency  Subpart D- Mycoplasma  Subpart E- testing requirement for communicable disease Agent  Subpart F- Dating period limitations  Subpart G- Labeling standards
3.1 Scope High level of sanitation and hygiene practised – in every aspect of manufacturing. It covers: Personnel Premises Equipment and apparatus Production materials and containers Products for cleaning and disinfection All potential sources of cross-contamination Sanitation and Hygiene
Personal Hygiene (1)  Health examinations:  Before and during employment  Periodic eye examinations for those who do visual inspections  Training:  Practices in personal hygiene  Written procedures and instructions  Signs in areas Sanitation and Hygiene 11.1 - 2
Basic Principles of GMP  Written procedures and instructions - to wash hands before entering production areas  Some also use disinfectants 11.1 - 2
Basic Principles of GMP  Wash hands before entering production areas  Signs in areas (e.g. changing rooms) 11.1 - 2
11.2 - 5 Personal Hygiene (2)  Illness or open lesions:  May affect the quality of products  Should not handle starting materials, intermediates or finished products, etc.  Instruction and encouragement to report to supervisors  Direct contact between product and operator:  Should be avoided  Starting materials, primary packaging materials, intermediate and bulk product Sanitation and Hygiene
Personnel Hygiene (3)  Protection of product from contamination:  Clean clothes appropriate to personnel activities  Including hair covering (e.g. caps)  Check change rooms/changing facilities  Hand washing, signs, drying of hands  Used clothing stored in separate closed containers while awaiting cleaning  Laundering of clean area clothing according to an SOP and in an appropriate facility  Procedure for disinfecting and sterilizing when required Sanitation and Hygiene 11.6
Personnel Hygiene (4)  Smoking, eating and drinking not allowed in production areas, laboratories and storage areas  No chewing (e.g. gum), or keeping food or drinks allowed  No plants kept inside these areas  Rest and refreshment areas should be separate from manufacturing and control areas Sanitation and Hygiene 11.7, 12.11
Basic Principles of GMP  Toilets should not open directly into production or storage areas TOILETS AIR LOCK CANTEEN FACTORY CHANGE ROOM 12.12
Personnel Hygiene (5)  Personal hygiene procedures including wearing protective clothing apply to all persons entering into production areas:  Full-time employees  Temporary workers  Contractor's employees  Visitors  Managers  Inspectors Sanitation and Hygiene 11.8
Design of Premises  Design  Walls, floors, ceilings, ledges, drains, air supply, dust extraction  Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination  Cleaning programme, appropriate cleaning, cleaning records  Effective cleaning and disinfection  choice of materials and chemicals, validation  Drains – prevent backflow Sanitation and Hygiene 12.2, 12.3, 12.7, 12.9, 12.29
Basic Principles of GMP  Protection from insects, birds, vermin and weather  from receipt of raw materials to dispatch of released product 12.9
16.10 - 11 Avoidance of Cross-Contamination (1)  Special precautions should be taken to prevent generation and dissemination of dust  Proper air control – supply and extraction, suitable quality  Due to uncontrolled release of:  dust, gas, particles, vapours, sprays, organisms, residue, insects Sanitation and Hygiene
Basic Principles of GMP Measures that can be taken to prevent cross-contamination also include:  Segregated areas  Ventilation systems  Airlocks  Clothing  Closed processing systems  Cleaning and decontamination
16.12(a) Avoidance of Cross-Contamination (2)  Dedicated and self-contained areas for:  Live vaccines  Live bacterial preparations  Certain other biological materials  Penicillin products Sanitation and Hygiene
16.12(b) Avoidance of Cross-Contamination (3)  Campaign production:  Separation in time  Followed by appropriate cleaning  Validated cleaning procedure Sanitation and Hygiene
16.12 (c and d) Avoidance of Cross-Contamination (4)  Ventilation systems and airlocks  Appropriately designed ventilation system with air supply and extraction systems  Supply or incoming air should be filtered  Recirculation of air versus 100% fresh air supply  Proper airflow patterns  Pressure differentials  Appropriately designed airlocks Sanitation and Hygiene
16.12(e) Avoidance of Cross-Contamination (5)  Clothing  Protection of operator and product  Highly potent products or those of particular risk - need for special protective clothing  Personnel should not move between areas producing different products  Garments need to be cleaned Sanitation and Hygiene
16.12(f, h and i) Avoidance of Cross-Contamination (6)  Cleaning and decontamination  Procedure for removing soil and dirt  Remove all cleaning chemical residues or disinfectant residues  Remove and/or reduce micro-organisms  Validated (known effectiveness of the procedure)  Use cleanliness status labels  Test for residues Sanitation and Hygiene
16.12(g) Avoidance of Cross-Contamination (7)  Closed processing systems  For example: totally enclosed water purification systems  Tanks fitted with appropriate filtration - without removable lids  Present special cleaning difficulties, sometimes use clean-in-place (CIP) Sanitation and Hygiene
Production Operations – Sanitation (1)  Cleaning and cleaning validation  Degree of cleaning depends on whether consecutive batches are of same or different product  Check cleaning agent is fully removed  If possible hot water alone used for cleaning  all cleaning and disinfecting solutions carefully prepared and expiry dated  Final rinse with purified water, or water for injection (for sterile products)  Full records kept Sanitation and Hygiene
Production Operations – Sanitation (2)  Full records kept  Water systems  Water - major constituent of most products  SOP for cleaning and sanitization of the water purification system should include distribution line  Validation and removal of disinfectant before reuse Sanitation and Hygiene
Production Operations – Sanitation (3)  Maintenance and repair  activities inevitable in manufacturing area  Should present no risk to product  Whenever possible, all planned maintenance outside normal operating hours  Emergency work in working area followed by thorough clean down and disinfection before manufacturing recommences  Area clearance by QC Sanitation and Hygiene
Personnel Basic Principles of GMP 9
9.1 Principle  Establishment and maintenance of satisfactory system of QA, manufacture and control of products and actives rely on people.  Must be sufficient qualified personnel to carry out tasks  Individual responsibilities must be clearly defined and understood by individuals concerned  Written job descriptions  All personnel should be aware of the principles of GMP that affect them Personnel
9.2 General (1) Personnel requirements:  Adequate number of persons  With necessary qualifications  With practical experience  An individual’s responsibilities should not be so extensive as to present a risk to quality Personnel
9.3 General (2)  All responsible staff should have specific duties recorded in individual written job descriptions  Have adequate authority to carry out responsibilities  May delegate to designated deputies with qualifications  No gaps or unexplained overlaps  Organization chart Personnel
Basic Principles of GMP Organization chart  This is NOT what it should look like
9.4 General (3)  All personnel should be aware of GMP  Must receive training in GMP:  initial training  continuing training  including hygiene standards  Motivated to  support the establishment  maintain high-quality standards Personnel
9.5 General (4)  Prevent unauthorized access  To production areas  Storage areas  Quality control  Stop personnel who do not work in these areas using them as passageways Personnel
9.6 Key Personnel (1) Key personnel (which normally should be full-time) positions include:  Authorized person  Head of Production  Head of Quality Control  May delegate functions – not responsibility  Heads of Production and Quality Control should be independent of each other Personnel
9.7 Key Personnel (2) Should posses appropriate qualifications  Scientific education such as:  chemistry or biochemistry  chemical engineering  microbiology  pharmaceutical sciences and technology  pharmacology and toxicology  physiology; or  other related science subjects relevant to the responsibilities to be undertaken Personnel
9.7 Key Personnel (3) Should posses appropriate experience  Practical experience  Manufacture and quality assurance  Preparatory period under professional guidance sometimes needed  Education and experience should enable personnel to take difficult decisions in an independent, professional and scientific way  resolve the problems encountered in manufacturing and QC Personnel
Shared Responsibilities (1) Heads of Production and Quality Control may share/jointly exercise some responsibilities relating to quality:  authorization of written procedures (SOPs) and other documents, including amendments  monitoring and control of manufacturing environment  plant hygiene  process validation and calibration  training, including application and principles of QA  approval and monitoring of suppliers and contract acceptors Personnel 9.8
Shared Responsibilities (2)  Designation and monitoring of storage conditions for materials and products  Performing and evaluating in-process controls  Retention of records  Monitoring compliance with GMP  Inspection, investigation, and taking of samples to monitor factors which may affect quality Personnel 9.8
Head of Production: Responsibilities (1)  Product production and storage according to appropriate documentation  Approval and implementation of production instructions, in-process QC and ensure strict implementation  Ensures that production records are evaluated and signed by designated person Personnel 9.9
Head of Production: Responsibilities (2)  Checks maintenance of production department, premises and equipment  Ensures process validation and calibration performed, recorded, and reports are made available  Ensures initial and continuous training of production personnel Personnel 9.9
Head of Quality Control: Responsibilities (1)  Approval or rejection of materials, e.g. packing materials, intermediates, bulk and finished products, in accordance with specifications  Evaluation of batch records  Ensures carrying out of necessary testing  Approval of quality control procedures, e.g. sampling and testing; specifications Personnel 9.10
Head of Quality Control: Responsibilities (2)  Approval and monitoring of all contract analysis  Checks maintenance of quality department, premises and equipment  Ensures validation (including analytical procedure validation) and calibration of control equipment  Ensures initial and continuous training of QC personnel Personnel 9.10
Authorized person: Responsibilities (1)  Compliance with technical and regulatory requirements  Approval of the release of finished product for sale  Establishment and implementation of quality system  Development of quality manual  Supervision of self-inspections and quality audits Personnel 9.11
Authorized person: Responsibilities (2)  Oversight of the QC department  Participation in external audits and vendor audits  Participation in validation programmes  May delegate approval of release of product through approved procedure  Normally by QA by means of batch review Personnel 9.12, 9.13
Person releasing the batch should ensure: (1)  Each batch meets manufacturing and marketing authorization requirements  Principles and requirements of GMP are met  All checks and tests have been performed  Production conditions and manufacturing records  Planned changes and deviations reported - including where necessary to drug regulatory authority Personnel 9.14 a - e
Person releasing the batch should ensure: (2)  Additional sampling, inspection, checks and tests had been done when required  All production and control documents are completed and endorsed  Audits, inspections and spot-checks were done  QC approval has been given  All other relevant factors have been considered Personnel 9.14 f - j
Training (1)  Training, in accordance with a written, approved programme  all personnel whose duties take them into production areas; or  into control laboratories; and  for others whose activities could affect the quality of the product including technical, maintenance and cleaning personnel  Induction and continuing training  on theory and practice of GMP and their duties  training records should be kept  practical effectiveness checked  training before undertaking any new task Personnel 10.1, 10.2
Training (2)  Specific training for staff in special areas, e.g.  Where contamination is a hazard  Including clean areas; or  Areas where highly active, toxic, infectious, sensitizing materials are handled  The concept of QA should be fully discussed during training to facilitate proper understanding to ensure its implementation Personnel 10.3, 10.4
10.5 Visitors or Untrained Personnel Preferable not to enter production and control areas. If this is unavoidable then:  They must be given information in advance, particularly about  personal hygiene  protective clothing requirements  Must be accompanied and closely supervised at all times Personnel
10.6 Consultants and contract staff  Should be qualified for the services provided  Training records maintained  Records should prove qualifications Personnel
Premises Part One Basic Principles of GMP 12
12.1 Principle Important aspects to be kept in mind to ensure the suitability of the operations to be carried out for different dosage forms and product range:  Location  Design  Construction  Adaptation  Maintenance Premises
12.1, 12.4 Location  Geography, climate, noise and economic factors  Neighbours  What do they do?  What impact can they have on the business?  Pollution/effluent control  Minimum risk for contamination of products and materials Premises
12.4 Principle  Premises must be located to minimize risks of cross- contamination, e.g. not located next to a malting factory with high airborne levels of yeast Premises
12.2 General The layout and design should aim to:  Minimize risks of errors  Permit effective cleaning  Permit effective maintenance  Avoid cross-contamination, build-up of dirt and dust  Avoid any adverse effect on the quality of products Premises
Design Principles Keep in mind:  Material flow  People flow  Process flow Ensure logical flow Premises 12.10
Q C Offices Gowning Canteen Incoming goods Corridor Corridor Shipping Corridor Packaging Weighing Processing Filling Raw Materials & Packaging Storage Washing Machine Shop Finished Products Storage Corridor Utilities and Services Waste Treatment Example of Materials and People Flow Arrival of goods Entrance for visitors Entrance for Workers Shipment of goods Material Flow People Flow Zone: Clean Zone: Packaging Zone: Controlled Premises
12.5, 12.7, 12.9 Design  Suitable design and construction to facilitate good sanitation  Cleaning and disinfecting according to detailed written procedures – records maintained  Maximum protection against entry of insects, birds and animals  Procedure for rodent and pest control Premises
12.8, 12.32 Construction  Suitable materials  Electrical supply  Suitable lighting (especially for visual on-line checks)  Temperature and relative humidity control  Appropriate and effective ventilation These may affect products during manufacture or storage as well as functioning of equipment Premises
Basic Principles of GMP  The temperature and relative humidity should be controlled, monitored in accordance with an SOP, and the results recorded. The limits should be appropriate according to the materials stored and product processed
12.3 Construction  Dust generating operations  e.g. during sampling, weighing, mixing, packing of powders, etc.)  Measures should be taken to prevent cross-contamination  Measures to facilitate cleaning Premises
Basic Principles of GMP Design of areas for weighing of materials  Proper air supply  Dust control measures (including extraction of dust and air)  Easily cleanable surfaces  No areas for dust accumulation  Protection of material, product and operator
12.6 Maintenance  Careful maintenance done  Repairs and maintenance should not present any hazard to the quality of the products Premises
12.11 – 12.36 Specific areas Review some recommendations for specific areas in the following slides (Part 2):  Ancillary areas  Storage areas  Weighing areas  Production areas  Quality control areas Premises
Basic Principles of GMP Cleaning of incoming containers  Cleaning with a cloth, or duster  Cleaning by using a vacuum cleaner  Use of air curtains and air tunnels
12.15, 12.16 Storage areas - 1  Storage areas of sufficient capacity  Orderly storage of categories of materials and products  Separate and segregated areas: starting materials, packaging materials, intermediates, bulk, finished products, quarantined, released, rejected, returned and recalled products and materials Premises
Basic Principles of GMP
Basic Principles of GMP
12.16, 12.17 Storage areas - 2  Appropriate temperature and relative humidity conditions within defined limits  Provided, controlled, monitored and recorded  Good storage conditions: clean, dry and appropriate lights Premises
12.18 – 12.20, 12.22 Storage areas - 3  Quarantine area: clearly marked and access restricted  A separate sampling area is the norm: no risk for contamination or cross-contamination  Segregated areas for rejected, recalled and returned materials and products  Safe and secure areas for highly active, radioactive materials, narcotics and other materials (risk of abuse, fire, explosion) Premises
Basic Principles of GMP
12.21 Storage areas – 4 Printed packaging materials  Critical to ensure compliance with correct labelling of products  Special attention to sampling  Special attention to safe and secure storage  Ensure compliance with specifications, prevent mix-ups Premises
12.23 Weighing areas  Weighing operations – in separated areas  Appropriate design (see also training material on HVAC)  Provision for dust control  Smooth, impervious, durable, easy-to-clean finishes  Cleaning procedures and records  Documentation, e.g. SOPs, logs and records Premises
Basic Principles of GMP
12.24 Production areas - 1 Minimize risk of cross-contamination:  Dedicated and self-contained facilities for some products such as highly sensitizing materials (e.g. penicillins) or biological preparations (e.g. live microorganisms)  Separate facilities for other products such as some antibiotics, hormones, cytotoxic substances  Non-pharmaceuticals normally not in the same facility, e.g. pesticides, herbicides Premises
12.32, 12.26, 12.31 Production areas -2  Layout in accordance with sequence of production  Appropriate cleanliness level  Adequate work and in-process storage space  Orderly and logical positioning of equipment minimizes risk of contamination, mix-ups and missing production steps  Specially designed areas for packaging  Layout to avoid mix-ups and cross-contamination Premises
12.27 Production areas - 3  Starting and packaging materials, intermediates and bulk exposed to environment: Interior surfaces (walls, floors, ceilings) – smooth, free from cracks and open joints No shedding of particles Easy and effective cleaning permitted  Disinfection if needed Premises
12.28, 12.29 Production areas - 4  Design of pipework, light fittings, and ventilation points – no recesses that are difficult to clean  Access for maintenance from outside production areas  Drains of adequate size, and equipped to prevent back-flow  Open channels avoided Premises
Basic Principles of GMP
12.30 Production areas - 5  Effective ventilation with air control facilities  Including filtration of air to a sufficient level to prevent contamination and cross-contamination – also external environment  Control of temperature and relative humidity where necessary  Regular monitoring of conditions during production and non- production periods Premises
12.33, 12.34 Quality Control areas - 1  QC laboratories should be separate from production areas  Separate areas for biological, microbiological and radioisotope methods  Suitable design with sufficient space to avoid mix-ups and cross-contamination  Suitable space for storage samples, reference standards, solvents, reagents and records Premises
Basic Principles of GMP
12.35, 12.36 Quality Control areas - 2  Suitable construction materials  Prevention of fumes  Ventilation  Separate air supply (production and QC)  Separate rooms for some instruments to protect them from interference (e.g. electrical, vibration, moisture, etc.) See supplementary training on QC laboratories Premises
90 DOCUMENTATION “A GOOD documentation is an ESSENTIAL part of Quality Assurance System and relates to ALL aspects of G.M.P.” Clearly written documentation prevents error from spoken communication and permits tracing of back history.
 It provides assurance that quality related activities are carried out exactly the way they have been planned and approved  The achievement of conformity and quality improvement  Responsibilities and authorities are identified  Ensure that authorized persons have all information necessary for release 91 PURPOSE
 Forms the basis for improvement  Uniformity & consistency in carrying out activities  Audit trail (traceability).  Written instructions/guidance/forms to all personnel to know WHAT’,WHEN and ‘HOW’ to carry out an activity. •Evidence to regulatory agencies and customers for conformance to G.M.P •A defense in an event of legal matters. 92 PURPOSE
“GOOD Documentation is the PROOF of what You Do” 93 WHAT IS DOCUMENTATION ?
94 Not documented = NOT DONE! In God we trust, all others show documented evidence". •Can you reconstruct an experiment after 6 months by your note? * Is your work obvious and clear for your supervisor? * Make sure nothing is suspicious!
 Document is : complete history of each batch from starting materials to finished products Records the activities for :  maintenance  storage  quality control  primary distribution  specific matter related to GMP 95 WHAT IS DOCUMENTATION ?
 Documentation is the key to operating a company in compliance with GMP requirements.  All the elements, requirements and provisions adopted by company for its quality system should be documented in a systematic, orderly and understandable manner in the form of policies and procedures. 96 WHAT IS DOCUMENTATION ?
97 WHY DOCUMENTS ARE SO IMPORTANT? What is being made? Most of us when attempting a task need some sort of documentation
98 WHY DOCUMENTS ARE SO IMPORTANT?
“If You Didn't Document It, You Didn't Do It.” -FDA 99 WHY DOCUMENTS ARE SO IMPORTANT?
100 WHY DOCUMENTS ARE SO IMPORTANT? • DOCUMENTATION IS A CORNER STONE OF GMP • Communication - everyone must understand what they have to do - PROVIDES INSTRUCTION • Cost - the business must know how much things cost. • Audit trail-We must be able to find out what happened- PROVIDES FULL TRACEABLE HISTORY • CONTROLS DEVELOPMENT AND CHANGE.
101 DOCUMENTATION - Should be: • DESIGNED • PREPARED • REVIEWED • APPROVED • DISTRIBUTED WITH CARE • REVIEWED PERIODICALLY • CLEAR • WRITTEN IN SHORT SENTENCES • IMPERATIVE FOR INSTRUCTIONS • REMOVED IF OBSOLETE • CHANGED WITH APPROVAL • SECURED BY BACK UP FOR ELECTRONIC VERSIONS • RETRIEVEABLE
Broadly, all documents relating to quality fall in to the following categories:  Quality Manual  Quality Procedures  Supporting Documents or Work Instructions  Quality Records 102 TIERS OF DOCUMENTATION Quality Records Supporting Documents or Work Instructions Quality Procedures Quality Manual
TYPES OF GMP DOCUMENTS 103 Record • It is a Dead Paper • Dependent Variable • Generated at the end of performance • Never to be changed • Require review and no revision • Approved after completion • Identified by the Format Number Document • It is Live Paper • Independent Variable • Referred during performance • Subject to change • Require review or revision • Approved before use. • Identified by Issue Number
1) PROCEDURES:  Proper instruction/explanation of Handling an operation/activity that consist of: − explanations − flowchart − charts/photos 104 TYPES OF GMP DOCUMENT
2) RECORDS :  Written records of the operations or activities  Type of record;  hard copy; stock cards, logbooks  soft copy 105 TYPES OF GMP DOCUMENT
 Each document should be suitable for all users  In general, all quality documents can be written in the following format :  narrative  flowchart  combination narrative and flowchart  electronic / computerized system 106 FORMATTING OF DOCUMENT
 Every document should have a number For traceability.  Document numbering system should be made as per the procedure. 107 NUMBERING SYSTEM
108 HOW SHOULD I USE DOCUMENTS ? • Read them • Make sure you understand what you have to do! • Ask if you are not sure
HOW TO CREATE GOOD DOCUMENTATION SYSTEM 109
 Documents should be designed, prepared, reviewed and distributed with care  Documents should be dated and authorized  approved, signed and dated by appropriate authorized persons  no document should be changed without authorization •All relevant GMP documents (such as associated records of actions taken or conclusions reached) and SOPs are approved, signed, and dated by the Quality Assurance department. Records may be maintained in electronic format provided that backup copies are also maintained. 110 HOW TO CREATE GOOD DOCUMENTATION SYSTEM
 Documents should have unambiguous contents-title, nature and purpose should be clearly stated.  Documents should be laid in an orderly fashion and easy to check.  Reproduced documents should be clear and legible.  The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process. 111 HOW TO CREAT GOOD DOCUMENTATION SYSTEM
 Documents should be regularly reviewed and kept up- to-date.  When a document has been revised, systems should be operated to prevent inadvertent use of superseded documents.  Documents should not be handwritten; although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space should be provided for such entries. 112 HOW TO CREATE GOOD DOCUMENTATION SYSTEM
 When correction on document is needed, please do the following actions :  original entry not lost (draw a line across the original entry)  close to original entry  initialed / dated for correction  dedicated person • Documents are not altered without the approval of the Quality Assurance department. Any alteration made to a document is signed and dated; the alteration permits the reading of the original information. Where appropriate, the reason for the change is recorded. 113 HOW TO CREAT GOOD DOCUMENTATION SYSTEM
 Wherever required, reason for rectification shall be given very briefly.  In records or documents such as executed BMRs, executed chromatograms/spectra/computerized printouts, executed QC records, and other production related computerized print outs, rectification of errors shall be done with due care. This shall be done after proper consultation with QA and concerned department head.  The records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal product are traceable. 114 HOW TO CREAT GOOD DOCUMENTATION SYSTEM
 Name of document  Name of company, department or division of the maker  Document number  Page and number of pages of document  Number of revision  Date of approved  Name and signature of the person who prepared the document  Name and signature of the person who has reviewed and approved the document  Body of document  Document receiver 115 CONTENT OF DOCUMENT
 All document records should be completed as the process proceeds.  Distribution list of documents should be recorded  Obsolete documents should be :  taken from users , based on distribution list  marked “obsolete”, archived  Create a list of running documents , centralized .  Use only updated and Approved documents 116 “Do” Rules
 Prepared Documents should be checked or reviewed by competent person .  Documents should be approved, signed and dated by appropriate and authorized persons.  Distribution list of documents should be recorded  Obsolete documents should be :  taken from users , based on distribution list  marked “obsolete”, archived 117 “Do” Rules
 A written certification that a document has been  Generated  Reviewed  Approved  …and found to contain information that is  Complete  Accurate  Factual  Representative of an action  Truthful 118 What is the meaning of a signature
119 Don’t write things on unapproved documents or a piece of paper. Always record your activities Always record your activities when you do them. Never sign for anything you have not done yourself. “Do Not” Rules
120 • Remember there are two 6 o’clock in a day! Always record timings as per procedure. • Don’t just write “N/A” (unless you are instructed to). Always explain why? • Never use ditto marks or flower brackets. • If you make a mistake, always correct as per the procedure. • Corrections should not be done on the approved documents. “Do Not” Rules
121 DO NOT scribble out mistakes (obscures entry) DO NOT write correct entries over incorrect entries (writing over obscures original entries) DO NOT forget to enter all required info DO NOT forget to initial and date entry DO NOT use coloured ink/pencil DO NOT leave mistakes uncorrected (check your entries) DO NOT use white fluid to erase any entry. “Do Not” Rules
122 “Do Not” Rules Bring your ideas to your superior DO NOT deviate the Approved Procedures !!!
123 5. DON’Ts (cont’d) NEVER FRAUDE! Signature Date Manual change, after date… = illegal
 Sign after completion of each activity (Online documentation) “Basic cGMP requirement is that…the operations, instructions are being followed in effective and timely manner”.  Dates and times for major steps in process  Instrument/Equipment numbers and process.  In put weights and measurements  Reference number and quantity of materials used in the batch.  In process instructions.  Yield statement.  Complete labelling control.  Sampling instructions.  Parameter recording sheets. 124 Remember !!!
1. Record concurrently as process progress. 2. Sign only after thorough review. 3. Keep the records neat and clear. 4. If there is a mistake, cross it with a single line, initial and date. 125 Remember !!!
 Document control and identification should apply to all documentation that is created, distributed and retained for information. 126 CONTROL OF DOCUMENTS  Master copy  Controlled copy  Reference copy  Superseded copy  Obsolete copy
 Distribution of documents should be the up-to-date documents  Copy of documents should be distributed to relevant department.  The list of distribution should be made  Document Data Control Division of QA can distribute the document  All system documents should be received by all Department  All Supporting document is distributed to related division only 127 DISTRIBUTION DOCUMENT
Review and revision to ensure relevancy and accuracy  Documents should be regularly reviewed and kept up-to-date.  When a document has been revised, systems should be operated to prevent inadvertent use of superseded documents. 128 REVIEW AND RENEWAL OF DOCUMENTS
 Obsolete documents shall be retrieved from all relevant department and its original copy shall be archived  The date of revision shall be stated in the new documents  Any revision shall be approved by authorized person. 129 REVIEW AND RENEWAL OF DOCUMENTS
 Records should be retained for sufficient period to satisfy regulatory/customer requirement as per the procedure.  All documentation must be organized into files which must be maintained for specified periods of time after the expiry date of the product. DOCUMENT RETENTION TIME 130
 Records may be maintained in electronic format provided that backup copies are also maintained.  Electronic data must be readily retrievable in a printed format. During the retention period, such records must be secured and accessible within 48 hours to the fabricator, packager/labeller, distributor, or importer. 131 DOCUMENT RETENTION TIME
SUMMARY 132 DOCUMENTATION Creation Checking Approval Training Control & Issue Review Retention
133 Thank you for your attention

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GMP { Good manufacturing Practices }

  • 2. What is GMP?  Good Manufacturing Practice is a set of regulations, codes, and guidelines for the manufacture of drug substances and drug products, medical devices, in vivo and in vitro diagnostic products, and foods. Fig.4 GMP handbooks for every industry
  • 3.  Good Manufacturing Practices are enforced in the United States by the FDA  In the United Kingdom by the Medicines and Healthcare Products Regulatory Agency  GMPs are enforced in Australia by the Therapeutically Goods Administration  In India by the Ministry of Health, multinational and/or foreign enterprises  Many underdeveloped countries lack GMPs Good Manufacturing Practices Worldwide Enforcement
  • 4. 1941 Initiation of GMP  Sulfathiaziole tablets contaminated with phenobarbital  1941 - 300 people died/injured  FDA to enforce and revise manufacturing and quality control requirements  1941 - GMP is born Fig. 5 1906 Certificate of Purity signed by doctor
  • 5. Provisions 21 CFR Parts 210 and 211 (Drug Industry) 21 CFR Parts 600 (Biological Products: General) 21 CFR Parts 601 (Licensing) 21 CFR Parts 600, 601, 610 (Biological Products standard)
  • 6. Part 211 –Selected cGMP For Finished Pharmaceuticals  Subpart B-Organization and Personnel  Responsibilities of quality control unit.  Personnel Qualifications.  Personnel responsibilities.  Subpart C-Buildings and Facilities  Ventilation, air filtration, air heating and cooling sanitization, maintenance, sewage and refuge, plumbing.  Maintenance  Subpart D-Equipment  Equipment design, size, and location.  Equipment construction.  Equipment cleaning and maintenance.  Automatic, mechanical, and electronic equipment.  Filters.  Subpart E-Control of Components and Drug Product Containers and Closures  General requirements.  Receipt and storage of untested components, drug product containers, and closures.  Testing and approval or rejection of components, drug product containers, and closures.  Use of approved components, drug product containers, and closures.  Subpart F-Production and Process Controls  Written procedures; deviations.  Charge-in of components.  Calculation of yield.  Equipment identification.  Sampling and testing of in process materials and drug products.  Time limitations on production.  Control of microbiological contamination  Reprocessing.
  • 7. Part 211 –Selected cGMP For Finished Pharmaceuticals  Subpart G-Packaging and labeling control  Material examination and usage criteria.  Labeling issuance  Packaging and labeling operations.  Drug product inspection  Expiration dating.  Subpart H-Holding and distribution  Warehousing procedures  Distribution procedure  Subpart I-Laboratory control  General requirement  Testing and release for distribution  Stability testing  Special testing requirement  Reserve sample  Laboratory animals  Subpart J-Records and reports  General requirements.  Equipment cleaning and use log  Component, drug product container, closure and labeling records.  Master production and control records  Production control record review  Laboratory records  Distribution records  Complaint files  Subpart K-Returned and salvaged drug products  Returned drug products.  Drug product salvaging
  • 8. Part 610 –General Standard for Biological product  Subpart A:- Release Requirement  Subpart B-General provision  Subpart C-Standard preparation s and limit of potency  Subpart D- Mycoplasma  Subpart E- testing requirement for communicable disease Agent  Subpart F- Dating period limitations  Subpart G- Labeling standards
  • 9. 3.1 Scope High level of sanitation and hygiene practised – in every aspect of manufacturing. It covers: Personnel Premises Equipment and apparatus Production materials and containers Products for cleaning and disinfection All potential sources of cross-contamination Sanitation and Hygiene
  • 10. Personal Hygiene (1)  Health examinations:  Before and during employment  Periodic eye examinations for those who do visual inspections  Training:  Practices in personal hygiene  Written procedures and instructions  Signs in areas Sanitation and Hygiene 11.1 - 2
  • 11. Basic Principles of GMP  Written procedures and instructions - to wash hands before entering production areas  Some also use disinfectants 11.1 - 2
  • 12. Basic Principles of GMP  Wash hands before entering production areas  Signs in areas (e.g. changing rooms) 11.1 - 2
  • 13. 11.2 - 5 Personal Hygiene (2)  Illness or open lesions:  May affect the quality of products  Should not handle starting materials, intermediates or finished products, etc.  Instruction and encouragement to report to supervisors  Direct contact between product and operator:  Should be avoided  Starting materials, primary packaging materials, intermediate and bulk product Sanitation and Hygiene
  • 14. Personnel Hygiene (3)  Protection of product from contamination:  Clean clothes appropriate to personnel activities  Including hair covering (e.g. caps)  Check change rooms/changing facilities  Hand washing, signs, drying of hands  Used clothing stored in separate closed containers while awaiting cleaning  Laundering of clean area clothing according to an SOP and in an appropriate facility  Procedure for disinfecting and sterilizing when required Sanitation and Hygiene 11.6
  • 15. Personnel Hygiene (4)  Smoking, eating and drinking not allowed in production areas, laboratories and storage areas  No chewing (e.g. gum), or keeping food or drinks allowed  No plants kept inside these areas  Rest and refreshment areas should be separate from manufacturing and control areas Sanitation and Hygiene 11.7, 12.11
  • 16. Basic Principles of GMP  Toilets should not open directly into production or storage areas TOILETS AIR LOCK CANTEEN FACTORY CHANGE ROOM 12.12
  • 17. Personnel Hygiene (5)  Personal hygiene procedures including wearing protective clothing apply to all persons entering into production areas:  Full-time employees  Temporary workers  Contractor's employees  Visitors  Managers  Inspectors Sanitation and Hygiene 11.8
  • 18. Design of Premises  Design  Walls, floors, ceilings, ledges, drains, air supply, dust extraction  Prevention of build-up of dirt and dust to avoid unnecessary risks of contamination  Cleaning programme, appropriate cleaning, cleaning records  Effective cleaning and disinfection  choice of materials and chemicals, validation  Drains – prevent backflow Sanitation and Hygiene 12.2, 12.3, 12.7, 12.9, 12.29
  • 19. Basic Principles of GMP  Protection from insects, birds, vermin and weather  from receipt of raw materials to dispatch of released product 12.9
  • 20. 16.10 - 11 Avoidance of Cross-Contamination (1)  Special precautions should be taken to prevent generation and dissemination of dust  Proper air control – supply and extraction, suitable quality  Due to uncontrolled release of:  dust, gas, particles, vapours, sprays, organisms, residue, insects Sanitation and Hygiene
  • 21. Basic Principles of GMP Measures that can be taken to prevent cross-contamination also include:  Segregated areas  Ventilation systems  Airlocks  Clothing  Closed processing systems  Cleaning and decontamination
  • 22. 16.12(a) Avoidance of Cross-Contamination (2)  Dedicated and self-contained areas for:  Live vaccines  Live bacterial preparations  Certain other biological materials  Penicillin products Sanitation and Hygiene
  • 23. 16.12(b) Avoidance of Cross-Contamination (3)  Campaign production:  Separation in time  Followed by appropriate cleaning  Validated cleaning procedure Sanitation and Hygiene
  • 24. 16.12 (c and d) Avoidance of Cross-Contamination (4)  Ventilation systems and airlocks  Appropriately designed ventilation system with air supply and extraction systems  Supply or incoming air should be filtered  Recirculation of air versus 100% fresh air supply  Proper airflow patterns  Pressure differentials  Appropriately designed airlocks Sanitation and Hygiene
  • 25. 16.12(e) Avoidance of Cross-Contamination (5)  Clothing  Protection of operator and product  Highly potent products or those of particular risk - need for special protective clothing  Personnel should not move between areas producing different products  Garments need to be cleaned Sanitation and Hygiene
  • 26. 16.12(f, h and i) Avoidance of Cross-Contamination (6)  Cleaning and decontamination  Procedure for removing soil and dirt  Remove all cleaning chemical residues or disinfectant residues  Remove and/or reduce micro-organisms  Validated (known effectiveness of the procedure)  Use cleanliness status labels  Test for residues Sanitation and Hygiene
  • 27. 16.12(g) Avoidance of Cross-Contamination (7)  Closed processing systems  For example: totally enclosed water purification systems  Tanks fitted with appropriate filtration - without removable lids  Present special cleaning difficulties, sometimes use clean-in-place (CIP) Sanitation and Hygiene
  • 28. Production Operations – Sanitation (1)  Cleaning and cleaning validation  Degree of cleaning depends on whether consecutive batches are of same or different product  Check cleaning agent is fully removed  If possible hot water alone used for cleaning  all cleaning and disinfecting solutions carefully prepared and expiry dated  Final rinse with purified water, or water for injection (for sterile products)  Full records kept Sanitation and Hygiene
  • 29. Production Operations – Sanitation (2)  Full records kept  Water systems  Water - major constituent of most products  SOP for cleaning and sanitization of the water purification system should include distribution line  Validation and removal of disinfectant before reuse Sanitation and Hygiene
  • 30. Production Operations – Sanitation (3)  Maintenance and repair  activities inevitable in manufacturing area  Should present no risk to product  Whenever possible, all planned maintenance outside normal operating hours  Emergency work in working area followed by thorough clean down and disinfection before manufacturing recommences  Area clearance by QC Sanitation and Hygiene
  • 32. 9.1 Principle  Establishment and maintenance of satisfactory system of QA, manufacture and control of products and actives rely on people.  Must be sufficient qualified personnel to carry out tasks  Individual responsibilities must be clearly defined and understood by individuals concerned  Written job descriptions  All personnel should be aware of the principles of GMP that affect them Personnel
  • 33. 9.2 General (1) Personnel requirements:  Adequate number of persons  With necessary qualifications  With practical experience  An individual’s responsibilities should not be so extensive as to present a risk to quality Personnel
  • 34. 9.3 General (2)  All responsible staff should have specific duties recorded in individual written job descriptions  Have adequate authority to carry out responsibilities  May delegate to designated deputies with qualifications  No gaps or unexplained overlaps  Organization chart Personnel
  • 35. Basic Principles of GMP Organization chart  This is NOT what it should look like
  • 36. 9.4 General (3)  All personnel should be aware of GMP  Must receive training in GMP:  initial training  continuing training  including hygiene standards  Motivated to  support the establishment  maintain high-quality standards Personnel
  • 37. 9.5 General (4)  Prevent unauthorized access  To production areas  Storage areas  Quality control  Stop personnel who do not work in these areas using them as passageways Personnel
  • 38. 9.6 Key Personnel (1) Key personnel (which normally should be full-time) positions include:  Authorized person  Head of Production  Head of Quality Control  May delegate functions – not responsibility  Heads of Production and Quality Control should be independent of each other Personnel
  • 39. 9.7 Key Personnel (2) Should posses appropriate qualifications  Scientific education such as:  chemistry or biochemistry  chemical engineering  microbiology  pharmaceutical sciences and technology  pharmacology and toxicology  physiology; or  other related science subjects relevant to the responsibilities to be undertaken Personnel
  • 40. 9.7 Key Personnel (3) Should posses appropriate experience  Practical experience  Manufacture and quality assurance  Preparatory period under professional guidance sometimes needed  Education and experience should enable personnel to take difficult decisions in an independent, professional and scientific way  resolve the problems encountered in manufacturing and QC Personnel
  • 41. Shared Responsibilities (1) Heads of Production and Quality Control may share/jointly exercise some responsibilities relating to quality:  authorization of written procedures (SOPs) and other documents, including amendments  monitoring and control of manufacturing environment  plant hygiene  process validation and calibration  training, including application and principles of QA  approval and monitoring of suppliers and contract acceptors Personnel 9.8
  • 42. Shared Responsibilities (2)  Designation and monitoring of storage conditions for materials and products  Performing and evaluating in-process controls  Retention of records  Monitoring compliance with GMP  Inspection, investigation, and taking of samples to monitor factors which may affect quality Personnel 9.8
  • 43. Head of Production: Responsibilities (1)  Product production and storage according to appropriate documentation  Approval and implementation of production instructions, in-process QC and ensure strict implementation  Ensures that production records are evaluated and signed by designated person Personnel 9.9
  • 44. Head of Production: Responsibilities (2)  Checks maintenance of production department, premises and equipment  Ensures process validation and calibration performed, recorded, and reports are made available  Ensures initial and continuous training of production personnel Personnel 9.9
  • 45. Head of Quality Control: Responsibilities (1)  Approval or rejection of materials, e.g. packing materials, intermediates, bulk and finished products, in accordance with specifications  Evaluation of batch records  Ensures carrying out of necessary testing  Approval of quality control procedures, e.g. sampling and testing; specifications Personnel 9.10
  • 46. Head of Quality Control: Responsibilities (2)  Approval and monitoring of all contract analysis  Checks maintenance of quality department, premises and equipment  Ensures validation (including analytical procedure validation) and calibration of control equipment  Ensures initial and continuous training of QC personnel Personnel 9.10
  • 47. Authorized person: Responsibilities (1)  Compliance with technical and regulatory requirements  Approval of the release of finished product for sale  Establishment and implementation of quality system  Development of quality manual  Supervision of self-inspections and quality audits Personnel 9.11
  • 48. Authorized person: Responsibilities (2)  Oversight of the QC department  Participation in external audits and vendor audits  Participation in validation programmes  May delegate approval of release of product through approved procedure  Normally by QA by means of batch review Personnel 9.12, 9.13
  • 49. Person releasing the batch should ensure: (1)  Each batch meets manufacturing and marketing authorization requirements  Principles and requirements of GMP are met  All checks and tests have been performed  Production conditions and manufacturing records  Planned changes and deviations reported - including where necessary to drug regulatory authority Personnel 9.14 a - e
  • 50. Person releasing the batch should ensure: (2)  Additional sampling, inspection, checks and tests had been done when required  All production and control documents are completed and endorsed  Audits, inspections and spot-checks were done  QC approval has been given  All other relevant factors have been considered Personnel 9.14 f - j
  • 51. Training (1)  Training, in accordance with a written, approved programme  all personnel whose duties take them into production areas; or  into control laboratories; and  for others whose activities could affect the quality of the product including technical, maintenance and cleaning personnel  Induction and continuing training  on theory and practice of GMP and their duties  training records should be kept  practical effectiveness checked  training before undertaking any new task Personnel 10.1, 10.2
  • 52. Training (2)  Specific training for staff in special areas, e.g.  Where contamination is a hazard  Including clean areas; or  Areas where highly active, toxic, infectious, sensitizing materials are handled  The concept of QA should be fully discussed during training to facilitate proper understanding to ensure its implementation Personnel 10.3, 10.4
  • 53. 10.5 Visitors or Untrained Personnel Preferable not to enter production and control areas. If this is unavoidable then:  They must be given information in advance, particularly about  personal hygiene  protective clothing requirements  Must be accompanied and closely supervised at all times Personnel
  • 54. 10.6 Consultants and contract staff  Should be qualified for the services provided  Training records maintained  Records should prove qualifications Personnel
  • 56. 12.1 Principle Important aspects to be kept in mind to ensure the suitability of the operations to be carried out for different dosage forms and product range:  Location  Design  Construction  Adaptation  Maintenance Premises
  • 57. 12.1, 12.4 Location  Geography, climate, noise and economic factors  Neighbours  What do they do?  What impact can they have on the business?  Pollution/effluent control  Minimum risk for contamination of products and materials Premises
  • 58. 12.4 Principle  Premises must be located to minimize risks of cross- contamination, e.g. not located next to a malting factory with high airborne levels of yeast Premises
  • 59. 12.2 General The layout and design should aim to:  Minimize risks of errors  Permit effective cleaning  Permit effective maintenance  Avoid cross-contamination, build-up of dirt and dust  Avoid any adverse effect on the quality of products Premises
  • 60. Design Principles Keep in mind:  Material flow  People flow  Process flow Ensure logical flow Premises 12.10
  • 61. Q C Offices Gowning Canteen Incoming goods Corridor Corridor Shipping Corridor Packaging Weighing Processing Filling Raw Materials & Packaging Storage Washing Machine Shop Finished Products Storage Corridor Utilities and Services Waste Treatment Example of Materials and People Flow Arrival of goods Entrance for visitors Entrance for Workers Shipment of goods Material Flow People Flow Zone: Clean Zone: Packaging Zone: Controlled Premises
  • 62. 12.5, 12.7, 12.9 Design  Suitable design and construction to facilitate good sanitation  Cleaning and disinfecting according to detailed written procedures – records maintained  Maximum protection against entry of insects, birds and animals  Procedure for rodent and pest control Premises
  • 63. 12.8, 12.32 Construction  Suitable materials  Electrical supply  Suitable lighting (especially for visual on-line checks)  Temperature and relative humidity control  Appropriate and effective ventilation These may affect products during manufacture or storage as well as functioning of equipment Premises
  • 64. Basic Principles of GMP  The temperature and relative humidity should be controlled, monitored in accordance with an SOP, and the results recorded. The limits should be appropriate according to the materials stored and product processed
  • 65. 12.3 Construction  Dust generating operations  e.g. during sampling, weighing, mixing, packing of powders, etc.)  Measures should be taken to prevent cross-contamination  Measures to facilitate cleaning Premises
  • 66. Basic Principles of GMP Design of areas for weighing of materials  Proper air supply  Dust control measures (including extraction of dust and air)  Easily cleanable surfaces  No areas for dust accumulation  Protection of material, product and operator
  • 67. 12.6 Maintenance  Careful maintenance done  Repairs and maintenance should not present any hazard to the quality of the products Premises
  • 68. 12.11 – 12.36 Specific areas Review some recommendations for specific areas in the following slides (Part 2):  Ancillary areas  Storage areas  Weighing areas  Production areas  Quality control areas Premises
  • 69. Basic Principles of GMP Cleaning of incoming containers  Cleaning with a cloth, or duster  Cleaning by using a vacuum cleaner  Use of air curtains and air tunnels
  • 70. 12.15, 12.16 Storage areas - 1  Storage areas of sufficient capacity  Orderly storage of categories of materials and products  Separate and segregated areas: starting materials, packaging materials, intermediates, bulk, finished products, quarantined, released, rejected, returned and recalled products and materials Premises
  • 73. 12.16, 12.17 Storage areas - 2  Appropriate temperature and relative humidity conditions within defined limits  Provided, controlled, monitored and recorded  Good storage conditions: clean, dry and appropriate lights Premises
  • 74. 12.18 – 12.20, 12.22 Storage areas - 3  Quarantine area: clearly marked and access restricted  A separate sampling area is the norm: no risk for contamination or cross-contamination  Segregated areas for rejected, recalled and returned materials and products  Safe and secure areas for highly active, radioactive materials, narcotics and other materials (risk of abuse, fire, explosion) Premises
  • 76. 12.21 Storage areas – 4 Printed packaging materials  Critical to ensure compliance with correct labelling of products  Special attention to sampling  Special attention to safe and secure storage  Ensure compliance with specifications, prevent mix-ups Premises
  • 77. 12.23 Weighing areas  Weighing operations – in separated areas  Appropriate design (see also training material on HVAC)  Provision for dust control  Smooth, impervious, durable, easy-to-clean finishes  Cleaning procedures and records  Documentation, e.g. SOPs, logs and records Premises
  • 79. 12.24 Production areas - 1 Minimize risk of cross-contamination:  Dedicated and self-contained facilities for some products such as highly sensitizing materials (e.g. penicillins) or biological preparations (e.g. live microorganisms)  Separate facilities for other products such as some antibiotics, hormones, cytotoxic substances  Non-pharmaceuticals normally not in the same facility, e.g. pesticides, herbicides Premises
  • 80. 12.32, 12.26, 12.31 Production areas -2  Layout in accordance with sequence of production  Appropriate cleanliness level  Adequate work and in-process storage space  Orderly and logical positioning of equipment minimizes risk of contamination, mix-ups and missing production steps  Specially designed areas for packaging  Layout to avoid mix-ups and cross-contamination Premises
  • 81. 12.27 Production areas - 3  Starting and packaging materials, intermediates and bulk exposed to environment: Interior surfaces (walls, floors, ceilings) – smooth, free from cracks and open joints No shedding of particles Easy and effective cleaning permitted  Disinfection if needed Premises
  • 82. 12.28, 12.29 Production areas - 4  Design of pipework, light fittings, and ventilation points – no recesses that are difficult to clean  Access for maintenance from outside production areas  Drains of adequate size, and equipped to prevent back-flow  Open channels avoided Premises
  • 84. 12.30 Production areas - 5  Effective ventilation with air control facilities  Including filtration of air to a sufficient level to prevent contamination and cross-contamination – also external environment  Control of temperature and relative humidity where necessary  Regular monitoring of conditions during production and non- production periods Premises
  • 85. 12.33, 12.34 Quality Control areas - 1  QC laboratories should be separate from production areas  Separate areas for biological, microbiological and radioisotope methods  Suitable design with sufficient space to avoid mix-ups and cross-contamination  Suitable space for storage samples, reference standards, solvents, reagents and records Premises
  • 87. 12.35, 12.36 Quality Control areas - 2  Suitable construction materials  Prevention of fumes  Ventilation  Separate air supply (production and QC)  Separate rooms for some instruments to protect them from interference (e.g. electrical, vibration, moisture, etc.) See supplementary training on QC laboratories Premises
  • 88. 90 DOCUMENTATION “A GOOD documentation is an ESSENTIAL part of Quality Assurance System and relates to ALL aspects of G.M.P.” Clearly written documentation prevents error from spoken communication and permits tracing of back history.
  • 89.  It provides assurance that quality related activities are carried out exactly the way they have been planned and approved  The achievement of conformity and quality improvement  Responsibilities and authorities are identified  Ensure that authorized persons have all information necessary for release 91 PURPOSE
  • 90.  Forms the basis for improvement  Uniformity & consistency in carrying out activities  Audit trail (traceability).  Written instructions/guidance/forms to all personnel to know WHAT’,WHEN and ‘HOW’ to carry out an activity. •Evidence to regulatory agencies and customers for conformance to G.M.P •A defense in an event of legal matters. 92 PURPOSE
  • 91. “GOOD Documentation is the PROOF of what You Do” 93 WHAT IS DOCUMENTATION ?
  • 92. 94 Not documented = NOT DONE! In God we trust, all others show documented evidence". •Can you reconstruct an experiment after 6 months by your note? * Is your work obvious and clear for your supervisor? * Make sure nothing is suspicious!
  • 93.  Document is : complete history of each batch from starting materials to finished products Records the activities for :  maintenance  storage  quality control  primary distribution  specific matter related to GMP 95 WHAT IS DOCUMENTATION ?
  • 94.  Documentation is the key to operating a company in compliance with GMP requirements.  All the elements, requirements and provisions adopted by company for its quality system should be documented in a systematic, orderly and understandable manner in the form of policies and procedures. 96 WHAT IS DOCUMENTATION ?
  • 95. 97 WHY DOCUMENTS ARE SO IMPORTANT? What is being made? Most of us when attempting a task need some sort of documentation
  • 96. 98 WHY DOCUMENTS ARE SO IMPORTANT?
  • 97. “If You Didn't Document It, You Didn't Do It.” -FDA 99 WHY DOCUMENTS ARE SO IMPORTANT?
  • 98. 100 WHY DOCUMENTS ARE SO IMPORTANT? • DOCUMENTATION IS A CORNER STONE OF GMP • Communication - everyone must understand what they have to do - PROVIDES INSTRUCTION • Cost - the business must know how much things cost. • Audit trail-We must be able to find out what happened- PROVIDES FULL TRACEABLE HISTORY • CONTROLS DEVELOPMENT AND CHANGE.
  • 99. 101 DOCUMENTATION - Should be: • DESIGNED • PREPARED • REVIEWED • APPROVED • DISTRIBUTED WITH CARE • REVIEWED PERIODICALLY • CLEAR • WRITTEN IN SHORT SENTENCES • IMPERATIVE FOR INSTRUCTIONS • REMOVED IF OBSOLETE • CHANGED WITH APPROVAL • SECURED BY BACK UP FOR ELECTRONIC VERSIONS • RETRIEVEABLE
  • 100. Broadly, all documents relating to quality fall in to the following categories:  Quality Manual  Quality Procedures  Supporting Documents or Work Instructions  Quality Records 102 TIERS OF DOCUMENTATION Quality Records Supporting Documents or Work Instructions Quality Procedures Quality Manual
  • 101. TYPES OF GMP DOCUMENTS 103 Record • It is a Dead Paper • Dependent Variable • Generated at the end of performance • Never to be changed • Require review and no revision • Approved after completion • Identified by the Format Number Document • It is Live Paper • Independent Variable • Referred during performance • Subject to change • Require review or revision • Approved before use. • Identified by Issue Number
  • 102. 1) PROCEDURES:  Proper instruction/explanation of Handling an operation/activity that consist of: − explanations − flowchart − charts/photos 104 TYPES OF GMP DOCUMENT
  • 103. 2) RECORDS :  Written records of the operations or activities  Type of record;  hard copy; stock cards, logbooks  soft copy 105 TYPES OF GMP DOCUMENT
  • 104.  Each document should be suitable for all users  In general, all quality documents can be written in the following format :  narrative  flowchart  combination narrative and flowchart  electronic / computerized system 106 FORMATTING OF DOCUMENT
  • 105.  Every document should have a number For traceability.  Document numbering system should be made as per the procedure. 107 NUMBERING SYSTEM
  • 106. 108 HOW SHOULD I USE DOCUMENTS ? • Read them • Make sure you understand what you have to do! • Ask if you are not sure
  • 107. HOW TO CREATE GOOD DOCUMENTATION SYSTEM 109
  • 108.  Documents should be designed, prepared, reviewed and distributed with care  Documents should be dated and authorized  approved, signed and dated by appropriate authorized persons  no document should be changed without authorization •All relevant GMP documents (such as associated records of actions taken or conclusions reached) and SOPs are approved, signed, and dated by the Quality Assurance department. Records may be maintained in electronic format provided that backup copies are also maintained. 110 HOW TO CREATE GOOD DOCUMENTATION SYSTEM
  • 109.  Documents should have unambiguous contents-title, nature and purpose should be clearly stated.  Documents should be laid in an orderly fashion and easy to check.  Reproduced documents should be clear and legible.  The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process. 111 HOW TO CREAT GOOD DOCUMENTATION SYSTEM
  • 110.  Documents should be regularly reviewed and kept up- to-date.  When a document has been revised, systems should be operated to prevent inadvertent use of superseded documents.  Documents should not be handwritten; although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space should be provided for such entries. 112 HOW TO CREATE GOOD DOCUMENTATION SYSTEM
  • 111.  When correction on document is needed, please do the following actions :  original entry not lost (draw a line across the original entry)  close to original entry  initialed / dated for correction  dedicated person • Documents are not altered without the approval of the Quality Assurance department. Any alteration made to a document is signed and dated; the alteration permits the reading of the original information. Where appropriate, the reason for the change is recorded. 113 HOW TO CREAT GOOD DOCUMENTATION SYSTEM
  • 112.  Wherever required, reason for rectification shall be given very briefly.  In records or documents such as executed BMRs, executed chromatograms/spectra/computerized printouts, executed QC records, and other production related computerized print outs, rectification of errors shall be done with due care. This shall be done after proper consultation with QA and concerned department head.  The records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal product are traceable. 114 HOW TO CREAT GOOD DOCUMENTATION SYSTEM
  • 113.  Name of document  Name of company, department or division of the maker  Document number  Page and number of pages of document  Number of revision  Date of approved  Name and signature of the person who prepared the document  Name and signature of the person who has reviewed and approved the document  Body of document  Document receiver 115 CONTENT OF DOCUMENT
  • 114.  All document records should be completed as the process proceeds.  Distribution list of documents should be recorded  Obsolete documents should be :  taken from users , based on distribution list  marked “obsolete”, archived  Create a list of running documents , centralized .  Use only updated and Approved documents 116 “Do” Rules
  • 115.  Prepared Documents should be checked or reviewed by competent person .  Documents should be approved, signed and dated by appropriate and authorized persons.  Distribution list of documents should be recorded  Obsolete documents should be :  taken from users , based on distribution list  marked “obsolete”, archived 117 “Do” Rules
  • 116.  A written certification that a document has been  Generated  Reviewed  Approved  …and found to contain information that is  Complete  Accurate  Factual  Representative of an action  Truthful 118 What is the meaning of a signature
  • 117. 119 Don’t write things on unapproved documents or a piece of paper. Always record your activities Always record your activities when you do them. Never sign for anything you have not done yourself. “Do Not” Rules
  • 118. 120 • Remember there are two 6 o’clock in a day! Always record timings as per procedure. • Don’t just write “N/A” (unless you are instructed to). Always explain why? • Never use ditto marks or flower brackets. • If you make a mistake, always correct as per the procedure. • Corrections should not be done on the approved documents. “Do Not” Rules
  • 119. 121 DO NOT scribble out mistakes (obscures entry) DO NOT write correct entries over incorrect entries (writing over obscures original entries) DO NOT forget to enter all required info DO NOT forget to initial and date entry DO NOT use coloured ink/pencil DO NOT leave mistakes uncorrected (check your entries) DO NOT use white fluid to erase any entry. “Do Not” Rules
  • 120. 122 “Do Not” Rules Bring your ideas to your superior DO NOT deviate the Approved Procedures !!!
  • 121. 123 5. DON’Ts (cont’d) NEVER FRAUDE! Signature Date Manual change, after date… = illegal
  • 122.  Sign after completion of each activity (Online documentation) “Basic cGMP requirement is that…the operations, instructions are being followed in effective and timely manner”.  Dates and times for major steps in process  Instrument/Equipment numbers and process.  In put weights and measurements  Reference number and quantity of materials used in the batch.  In process instructions.  Yield statement.  Complete labelling control.  Sampling instructions.  Parameter recording sheets. 124 Remember !!!
  • 123. 1. Record concurrently as process progress. 2. Sign only after thorough review. 3. Keep the records neat and clear. 4. If there is a mistake, cross it with a single line, initial and date. 125 Remember !!!
  • 124.  Document control and identification should apply to all documentation that is created, distributed and retained for information. 126 CONTROL OF DOCUMENTS  Master copy  Controlled copy  Reference copy  Superseded copy  Obsolete copy
  • 125.  Distribution of documents should be the up-to-date documents  Copy of documents should be distributed to relevant department.  The list of distribution should be made  Document Data Control Division of QA can distribute the document  All system documents should be received by all Department  All Supporting document is distributed to related division only 127 DISTRIBUTION DOCUMENT
  • 126. Review and revision to ensure relevancy and accuracy  Documents should be regularly reviewed and kept up-to-date.  When a document has been revised, systems should be operated to prevent inadvertent use of superseded documents. 128 REVIEW AND RENEWAL OF DOCUMENTS
  • 127.  Obsolete documents shall be retrieved from all relevant department and its original copy shall be archived  The date of revision shall be stated in the new documents  Any revision shall be approved by authorized person. 129 REVIEW AND RENEWAL OF DOCUMENTS
  • 128.  Records should be retained for sufficient period to satisfy regulatory/customer requirement as per the procedure.  All documentation must be organized into files which must be maintained for specified periods of time after the expiry date of the product. DOCUMENT RETENTION TIME 130
  • 129.  Records may be maintained in electronic format provided that backup copies are also maintained.  Electronic data must be readily retrievable in a printed format. During the retention period, such records must be secured and accessible within 48 hours to the fabricator, packager/labeller, distributor, or importer. 131 DOCUMENT RETENTION TIME

Editor's Notes