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Dr. Mithilesh Trivedi

Disclaimer Clause
The information contained in this Publication is provided solely for the purpose of providing General information and convenience to interested parties about “GMP”. This publication has been compiled in good faith by Publisher but no representation is made or warranty given (either express or implied) as to the completeness or accuracy of the information it contains. Viewers are therefore requested to verify this information before they act upon it. In no event Publisher of this Bulletin be liable for any kind of damage resulting from any cause or reason, arising out of or in connection with the use or performance of information available from the Publication. By accessing this Publication you agree that Publisher will not be liable for any direct or indirect loss arising from the use of the information and the material contained in this Publication.

What is GMP?
The acronym "GMP" (Good Manufacturing Practice) is used internationally to describe a set of principles and procedures which, when followed by manufacturers of therapeutic goods, helps ensure that the products manufactured will have the required quality. Good Manufacturing Practices (GMPs) are regulations that describe the methods, equipment, facilities, and controls required for producing:
human and veterinary products medical devices processed food

Usually see “cGMP” – where c = current, to emphasize that the expectations are dynamic A basic tenet of GMP is that quality cannot be tested into a batch of product but must be built into each batch of product during all stages of the manufacturing process. It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product.

GMP Different Guidelines Interpretation By Regulatory Authorities Interpretation by Auditor How to address this issue .

Applicable Different Guidelines Local Government GMP Guideline Exporting Country’s GMP Guideline Other Applicable GMP Guideline .

.Local Government GMP Guidelines As the law of land. one must comply to the requirements of this guidelines.

Exporting Country’s GMP Guideline One must comply to the GMP requirements of the country where the product is exported. .

Other Applicable GMP Guideline As applicable. MCC. US FDA. WHO.g. etc. MCA (Zimbabwe). TGA. MHRA. one must comply to the auditing authorities requirements For e. NDA (Uganda). PIC/S. . ANVISA.

Customer’s Guideline One must comply to the Quality Agreement & requirements of customer. .

.Major International Codes of GMP World Health Organization (WHO) – 1992 WHO is the default guideline Many countries have formulated their own requirements for GMP based on WHO GMP EU Guide to Good Manufacturing Practice – 1997 United States – FDA CFRs 21 CFR 211 for Drugs – current GMPs 820 Quality Systems for Medical Devices – current GMPs Australian Code GMP Medicines – 1990 ISO 9001/EN 46001 – Medical devices Canadian cGMP – 1999 PIC/S cGMP Guidelines……….

Sanitation and hygiene 4.WHO Guideline for GMP Basic Elements of GMP 1. Product recalls 7. Good manufacturing practices for pharmaceutical products (GMP) 3. Self-inspection and quality audits . Complaints 6. Qualification and validation 5. Quality assurance 2. Contract production and analysis 8.

Personal hygiene 12. Equipment 14. Good practices in production 17. Materials 15. Documentation 16. Premises 13. Training 11. Personnel 10.) 9. Good practices in quality control .WHO Guideline for GMP (contd.

2 Responsibilities of the Quality Unit(s 2.1 Principles 2.5 Product Quality Review 3. PERSONNEL 3. QUALITY MANAGEMENT 2.3 Scope 2. INTRODUCTION 1.2 Regulatory Applicability 1.3 Responsibility for Production Activities 2.1 Personnel Qualifications 3.2 Personnel Hygiene 3.1 Objective 1.4 Internal Audits (Self Inspection) 2.3 Consultants .ICH Guideline for GMP – Q7 1.

ICH Guideline for GMP – Q7 (Contd.6 Sewage and Refuse 4.4 Containment 4.1 Design and Construction 5.2 Utilities 4.7 Sanitation and Maintenance 5.) 4.1 Design and Construction 4.4 Computerized Systems .3 Calibration 5. BUILDINGS AND FACILITIES 4.5 Lighting 4. PROCESS EQUIPMENT 5.3 Water 4.2 Equipment Maintenance and Cleaning 5.

DOCUMENTATION AND RECORDS 6.4 Master Production Instructions (Master Production and Control Records) 6.) 6.1 General Controls 7. MATERIALS MANAGEMENT 7.ICH Guideline for GMP – Q7 (Contd. Intermediates. API Labelling and Packaging Materials 6.3 Records of Raw Materials.6 Laboratory Control Records 6.5 Re-evaluation .3 Sampling and Testing of Incoming Production Materials 7.2 Equipment Cleaning and Use Record 6.1 Documentation System and Specifications 6.4 Storage 7.7 Batch Production Record Review 7.5 Batch Production Records (Batch Production and Control Records) 6.2 Receipt and Quarantine 7.

4 Blending Batches of Intermediates or APIs 8.2 Time Limits 8.) 8. PRODUCTION AND IN-PROCESS CONTROLS 8. PACKAGING AND IDENTIFICATION LABELLING OF APIS AND INTERMEDIATES 9.3 Label Issuance and Control 9.4 Packaging and Labelling Operations .2 Packaging Materials 9.1 General 9.3 In-process Sampling and Controls 8.ICH Guideline for GMP – Q7 (Contd.1 Production Operations 8.5 Contamination Control 9.

3 Validation of Analytical Procedures .6 Expiry and Retest Dating 11.7 Reserve/Retention Samples .5 Stability Monitoring of APIs 11. STORAGE AND DISTRIBUTION 10.4 Certificates of Analysis 11.) 10. LABORATORY CONTROLS 11.ICH Guideline for GMP – Q7 (Contd.2 Testing of Intermediates and APIs 11.1 Warehousing Procedures 10.2 Distribution Procedures 11.see Section 12 11.1 General Controls 11.

REJECTION AND RE-USE OF MATERIALS 14. VALIDATION 12.1 Validation Policy 12.3 Reworking 14.7 Cleaning Validation 12.4 Approaches to Process Validation 12.ICH Guideline for GMP – Q7 (Contd.4 Recovery of Materials and Solvents 14.6 Periodic Review of Validated Systems 12.5 Process Validation Program 12.) 12.5 Returns .2 Validation Documentation 12.2 Reprocessing 14.8 Validation of Analytical Methods 13. CHANGE CONTROL 14.1 Rejection 14.3 Qualification 12.

3 Quality Management 17.) 15. REPACKERS. COMPLAINTS AND RECALLS 16. Relabelling and Holding of APIs and Intermediates 17. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) 17. AGENTS.ICH Guideline for GMP – Q7 (Contd. TRADERS.8 Handling of Returns .2 Traceability of Distributed APIs and Intermediates 17.5 Stability 17.7 Handling of Complaints and Recalls 17. BROKERS.6 Transfer of Information 17. AND RELABELLERS 17.4 Repackaging.1 Applicability 17. DISTRIBUTORS.

1 General 18.2 Quality 19.ICH Guideline for GMP – Q7 (Contd.3 Cell Culture/Fermentation 18.6 Validation 19.) 18. GLOSSARY .5 Viral Removal/Inactivation steps 19.4 Harvesting.4 Control of Raw Materials 19.2 Cell Bank Maintenance and Record Keeping 18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18.3 Equipment and Facilities 19.7 Changes 19.1 General 19.9 Documentation 20.8 Laboratory Controls 19.5 Production 19. Isolation and Purification 18. APIS FOR USE IN CLINICAL TRIALS 19.

Control of Components and Drug Product Containers and closures.US FDA 21 CFR 211 Subpart A – General Provisions Subpart B – Organization and Personnel's Subpart C – General Provisions Subpart D. Subpart F – Production Subpart G – Packaging and Labeling Control Subpart H – Holding and Distribution Subpart I – Laboratory Controls Subpart J – Records and Reports Subpart K – Returned and Salvaged Products .Equipment Subpart E.

EU GMP Volume 1 . Volume 2 .Guidelines. Volume 3 . Volume 5 .Good Manufacturing Practices Medicinal Products for Human and Veterinary use.Pharmaceutical Legislation.Pharmaceutical Legislation. . Medicinal Products for Human use. Volume 4 . Medicinal Products for Human use.Notice to Applicants. Veterinary Medicinal Products. Medicinal Products for Human use.

Veterinary Medicinal Products. Miscellaneous Good Distribution Practices .) Volume 6 .Notice to Applicants.Maximum residue limits. Volume 8 .Clinical trials Medicinal Products for human use in clinical trials (investigational medicinal products). Volume 7 . Veterinary Medicinal Products.Guidelines. Volume 9 – Pharmaco vigilance Medicinal Products for Human and Veterinary use. Veterinary Medicinal Products. Volume 10 .EU GMP (Contd.

.EU GMP – Volume 4 Contains the bulk of GMPs out of total 10 volumes. Contains 9 Chapters in 2 parts and 19 Annexure.

going stability Programme.EU GMP – Volume 4. Part I Chapter 1 :Quality Management (revision October 2005) Chapter 2 :Personnel Chapter 3 :Premise and Equipment Chapter 4 :Documentation Chapter 5 :Production Chapter 6 :Quality Control (Revised version (October 2005) including on. came into operation on 1 June 2006) Chapter 7:Contract Manufacture and Analysis Chapter 8:Complaints and Product Recall Chapter 9:Self Inspection .

EU GMP – Volume 4. Risk Management is incorporated in this revised guideline. Part II Basic Requirements for Active Substances used as Starting Materials Recently revised & made applicable from 31 July 2010. st .

Creams and Ointments Annex 11: Computerized Systems Annex 13: Manufacture of Investigational Medicinal Products . Annexure Annex 1 : Manufacture of Sterile Medicinal Products Annex 8 : Sampling of Starting and Packaging Materials Annex 9 : Manufacture of Liquids.EU GMP – Volume 4.

) Annex 15: Qualification and validation (July 2001) Annex 16: Certification by a Qualified person and Batch Release (July 2001) Annex 17: Parametric Release (July 2001) Annex 18: Good manufacturing practice for APIs [requirements for active substances used as starting materials from October 2005 covered under part II] Annex 19: Reference and Retention Samples .EU GMP – Volume 4. Annexure (Contd.

Stand of PIC/S for Interpretation of GMP PIC/S is working for International GMP Harmonisation The PIC/S Committee is promoting for uniform interpretation of GMP & Quality System .

PIC/S Working The Pharmaceutical Inspection Co-operation Scheme (PIC/S) Cooperation established between inspectorates Quality assurance of inspections Framework for exchange of information and experience Coordinate mutual training for inspectors Harmonisation of standards for inspection Extend the cooperation to competent authorities Requests: Argentina Israel Oman Russia South Africa USA Interested: Brazil Bulgaria Cyprus Indonesia Japan Philippines Slovenia Taipei Thailand Observer: UNICEF WHO .


and in each of the Annexes 1 to 17 inclusive in the Code. descriptions or specifications accompanied by the word “should” or shall” are to be read as mandatory. Guide to interpretation of the Australian Code of Good Manufacturing Practice for Medicinal Products (16 August 2002) applicable to the manufacture of complementary medicines . mean “must” and the activities. the words “should” and “shall” appearing in each of the Chapters 1 to 9 inclusive in the Code. description or specification is inapplicable or can be replaced by an alternative which must be demonstrated to provide at least an equivalent level of quality assurance. unless the manufacturer is able to demonstrate that the activity.TGA Interpretation for GMP For the purposes of this Code.

specific questions on the interpretation of GMP requirements should be addressed. Manufacturers based in third countries should contact the authority supervising the authorised importer.” . directly to the relevant supervisory authority of the Member State in which the manufacturing authorisation holder is located.Stand of EMEA on Interpretation of GMP “While EMEA welcomes questions on its activities and the regulatory framework within which it operates. ideally by the Qualified Person.

GMP is concerned with both production and quality control.MHRA Definition of GMP Good Manufacturing Practice (GMP) Definition of Good Manufacturing Practice (GMP) Good Manufacturing Practice (GMP) is that part of quality assurance which ensures that medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation (MA) or product specification. .

raw data Production testing & release – raw materials. fit for purpose? Documentation – SOPs. calibration. independence of QA from production Premises – Design. access & security. Premises & equipment. finished products & packaging materials “People.Key areas for MHRA inspection in GMP Quality management system – more than for ISO… Personnel – Qualified Person (QP). Paper” “3P’s” . training records. housekeeping Equipment – Validation. methods.

View of MHRA for GMP When working in the “Pharma” world… Documentation you may have to explain your workbook or results many years after performing the work – how will you remember everything if not written down? Deviations (planned or unplanned changes) If anything deviates from the standard process then document it. Responsibilities Be aware of your responsibilities. work to them & provide the evidence you did what was expected! . assess the impact and justify your decision.

How do GMPs of different countries compare? At a high level. maintained. GMPs of various nations are very similar. most require proof for things like: equipment and facilities being properly designed. and cleaned Standard Operating Procedures (SOPs) be written and approved an independent Quality unit (like Quality Control and/or Quality Assurance) well trained personnel and management .

GMP covers… ALL aspects of production. from the starting materials. Detailed. . There must be systems to provide documented proof that correct procedures are consistently followed at each step in the manufacturing process .every time a product is made. written procedures are essential for each process that could affect the quality of the finished product. premises and equipment to the training and personal hygiene of staff.

What is GMP? ON the Lighter Side The full form of GMP Varies department wise For Quality – Good Manufacturing Practice For Production – Give More Production For HR – Give More People For Marketing – Give More Product For Finance & MD – Give More Profit For Workman – Give More Pay .

GMP as per QA perspective GMP – Generate More Proof To generate more proof Generate More Paper .

Proof – Paper/Documents/Records More paper means more documents/records As per MHRA Guidelines also Evidence (i.e. Proof/Document/Paper) is more important for GMP .

monitor.Importance of Documentation There should be document for each operation one carry out A reliable evidence for GMP compliance. An essential element of quality assurance is good documentation practices. and record “quality” for all aspects of the production. The system of documentation devised or adopted should have as its main objective to establish. quality control and quality assurance .

To be able to PREVENT mistakes from happening in the future.Why is so much paperwork required? To make sure we know exactly what we did. . and when we did it. To be able to correct mistakes if they happen.

Purpose of Documentation • To ensure that there are specifications for all materials • and methods of manufacture and control • Employees know what to do • Responsibilities and authorities are identified • Ensure that authorized persons have all information • Necessary for release • Provide audit trail • Forms the basis for improvement. .

all documents relating to quality fall in to the following categories: • Quality Manual • Quality Procedures • Supporting Documents or Work Instructions • Quality Records Quality Records All levels are integrated to form a comprehensive and cohesive documentation network via a system of cross referencing .Levels Of Documentation Quality Manual Quality Procedures Quality Procedures Supporting Documents or Work Instructions Broadly.

User : Quality Records • All personnel in the organization • Another parties.Quality Manual The key document that outlines the organization’s system of quality assurance to achieve customer satisfaction. Quality • The organisational structure including Procedures responsibility and authority of each key personnel Supporting Documents • Procedures. auditors. instructions and resources or Work Instructions for implementing the quality management. Objectives : • Describe the quality system structure • Declare the quality policy and organization goal • Describe how the organization meets the quality goal Content of quality manual : Quality • The quality policy declaration Manual • The goal of quality. and customers as applicable .

frequency. controlled and recorded in implementing the definite policy Standard Operation Procedures explains: • What the process is and it’s purpose Quality • Where activity is operating/carried out Manual • Who is responsible for every activity • When activity to start & when to complete. Procedures • How activity can be finished by following • the work instruction design or other Supporting Documents reference documents or Work Instructions • Reference to the other relevant documents Quality Records User : • All personnel who set up and run the processes/activity/operation . etc.Quality Standard Procedures The document that outlines the activities or operations of the organization for implementation of the stated quality policies. Quality sequential of the activities. Objectives : Describe detail explanation how activities should be done.

inspection & testing. for every activity/operation. step by step for guideline to execute the daily activity or operation for personnel in every function • It is used departmentally. Objectives : • It is an instruction document. or Work Instructions User : • All personnel who operates the certain task Quality Records Format : • Worksheet. illustration. every task &/or every line. video. detailed handling of Procedures method. Quality Manual Content of work instructions : • Detailed explanation of instructions to Quality • finish the job. photo) . sample. checklist • Audiovisual (tape. equipment and machine • Related to the technical matters with Supporting Documents stressing for operation.Work Instructions The operational document containing instructions specifying how the activities are performed or products are accepted.

method.S. versus W. QUALITY PROCEDURE/SOP • • • • Process oriented Describes steps of procedure Supporting the Quality Manual Explains general description on certain process and give systematic action to ensure product quality Procedure guideline which involve several departments and/or sections During implementation need other supported documents Guideline at organization level • • • • WORKING INSTRUCTION Task oriented Describes detail instruction Operation guidance Dedicated to explain special task.P. machine or technique which should be done to achieve target quality Instruction guidance which dedicated for certain department or section only During implementation can stand alone Guidance at operational level • • • • • • .I.O.

inspection. retained for a designated period. that products and services have been developed and delivered appropriately with the requirements. should be maintained as important evidence to demonstrate: • Quality Manual Quality Procedures Supporting Documents or Work Instructions effectiveness of Quality System Implementation. review or related results. readily identifiable and retrievable. Dated. Quality Records All Quality Records should be : legible and clear. . including charts and data pertaining to design. audit. survey. testing. carry authorization status. protected from damage and deterioration while storage.Quality Records Quality Records.

) . Calibration. Qualification. FG Labeling and Packaging Materials Master Production Instructions Batch Production Records Laboratory Control Records Batch Record Review Other Documents/Records (Preventative Maintenance.Documentation and Records Quality manual Site Master File Validation Master Plan/Master Validation Plan Documentation System and Specifications Equipment Cleaning and Use Record Records of Raw Materials. Validation etc. Intermediates.

Documentation System and Specifications Should have procedures to describe: Review. approval and distribution of documents Revision history Record retention .

etc. Protocol.) Name of company. Format.Content of Document • • • • • • • • • • • • • • What should be written in the document (Title/Subject): Name of document (SOP. department or division of the maker Document number Page and number of pages of document Number of revision Date of approved Next due Date for revision Procedure/Details Name and signature of the person who prepared the document Names and signatures of the person who reviewed Name and signature of person who approved the document Document receiver History . BMR.

Entries in records should
• Be legible • Be indelible (incapable of being removed, erased or washed away) • Made in spaces provided • Made directly after performing the activity • Identify the person making the entry

Corrections Dated Signed Leave the original entry readable
XYZ 987 For e.g. ABC 123
MNT dd/mm/yy

• Signature can be • initials • full handwritten signature • personal seal, or • authenticated and secure electronic signature

Don’ts for Documentation

No erasures.

No correction fluid.

No “Post-it” notes.

documenting disposition of : released materials rejected materials. code marks of batches and finished products. controlling.RECORDS MAINTENANCE Check whether control records are maintained for: Raw materials and primary packaging materials. handling. adjusting and reworking. holding and filling. Distribution. documenting initial interstate shipment. test results and control status. transferring. Finished products. documenting the: kinds. lots and quantities of material used. code marks and consignees. individual laboratory controls. . processing. documenting sampling. Manufacturing of batches. sampling.

Quality Control and Distribution records At least 1 year after expiry date For APIs with retest date .Retention Just what records need to be retained? least 3 years after complete distribution of the batch .

Retention Records may be retained as originals or true copies (accurate reproductions) Originals or copies should be available at the establishment where the activity occurred Prompt retrieval from another location by electronic or other means is acceptable If reduction techniques (microfilm) or electronic records are used. suitable retrieval equipment and means to produce hard copy should be readily available .

What are the challenges? If not complied During Audit Critical Non compliance Major Non compliance Minor Non compliance Suggestions/Recommendations During Production Rejection of batch Impurities Contamination .

Overcoming the Challenge of Differing Interpretations The ultimate aim of all GMP Guidelines is that the product must have Quality Safety Efficacy .

Overcoming the Challenge of Differing Interpretations The basic requirements of all guidelines Compliance Proof Traceability These requirements can be demonstrated with the help of documents/records. .

Bottom Line Document. it did not happen!” or. it’s a rumor!” . . . Document!!! In FDA-speak: “If it is not documented . Document.

Regulators works locally ? Industry wishes regulators to recognise the necessity from a global system of GMP .Industry Working V/s. Regulatory Working Industry works globally vs.

Q9 (Risk Management). shift to ICH quality topics — Q8 (Quality by Design).Recommendation from Industry Any inspectorate should accept PIC/S and ICH inspections as the standards Joint development of global guidelines with industry Develop global guidelines / interpretations (such as ICH Q7A/Q9) Rather than GMP. Q10 (Quality Systems) .

Role of ICH for overcoming the Challenges ICH quality topics — Q8 (Quality by Design). now working for harmonization for Formulations… ICH Q7B (future)… Quality Management Risk Management Development Pharmaceutics and Manufacturing Science Change Management . Q9 (Risk Management). Q10 (Quality Systems) After successful harmonization for API (Q7A).

Mottos .