Post on 12-Apr-2015
GMP
Dr. Mithilesh Trivedi
� 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.
Disclaimer Clause
� 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.
What is GMP?
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, one must comply to the auditing authorities requirements
� For e.g. WHO, US FDA, MHRA, TGA, PIC/S, ANVISA, MCC, MCA (Zimbabwe), NDA (Uganda), etc.
Customer’s Guideline
� One must comply to the Quality Agreement & requirements of customer.
� 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……….
Major International Codes of GMP
WHO Guideline for GMP
Basic Elements of GMP
� 1. Quality assurance
� 2. Good manufacturing practices for pharmaceutical products (GMP)
� 3. Sanitation and hygiene
� 4. Qualification and validation
� 5. Complaints
� 6. Product recalls
� 7. Contract production and analysis
� 8. Self-inspection and quality audits
� 9. Personnel
� 10. Training
� 11. Personal hygiene
� 12. Premises
� 13. Equipment
� 14. Materials
� 15. Documentation
� 16. Good practices in production
� 17. Good practices in quality control
WHO Guideline for GMP (contd.)
ICH Guideline for GMP – Q7
1. INTRODUCTION
1.1 Objective
1.2 Regulatory Applicability
1.3 Scope
2. QUALITY MANAGEMENT
2.1 Principles
2.2 Responsibilities of the Quality Unit(s
2.3 Responsibility for Production Activities
2.4 Internal Audits (Self Inspection)
2.5 Product Quality Review
3. PERSONNEL
3.1 Personnel Qualifications
3.2 Personnel Hygiene
3.3 Consultants
ICH Guideline for GMP – Q7 (Contd.)
4. BUILDINGS AND FACILITIES
4.1 Design and Construction
4.2 Utilities
4.3 Water
4.4 Containment
4.5 Lighting
4.6 Sewage and Refuse
4.7 Sanitation and Maintenance
5. PROCESS EQUIPMENT
5.1 Design and Construction
5.2 Equipment Maintenance and Cleaning
5.3 Calibration
5.4 Computerized Systems
ICH Guideline for GMP – Q7 (Contd.)
6. DOCUMENTATION AND RECORDS
6.1 Documentation System and Specifications
6.2 Equipment Cleaning and Use Record
6.3 Records of Raw Materials, Intermediates, API Labelling and Packaging Materials
6.4 Master Production Instructions (Master Production and Control Records)
6.5 Batch Production Records (Batch Production and Control Records)
6.6 Laboratory Control Records
6.7 Batch Production Record Review
7. MATERIALS MANAGEMENT
7.1 General Controls
7.2 Receipt and Quarantine
7.3 Sampling and Testing of Incoming Production Materials
7.4 Storage
7.5 Re-evaluation
ICH Guideline for GMP – Q7 (Contd.)
8. PRODUCTION AND IN-PROCESS CONTROLS
8.1 Production Operations
8.2 Time Limits
8.3 In-process Sampling and Controls
8.4 Blending Batches of Intermediates or APIs
8.5 Contamination Control
9. PACKAGING AND IDENTIFICATION LABELLING OF APIS AND INTERMEDIATES
9.1 General
9.2 Packaging Materials
9.3 Label Issuance and Control
9.4 Packaging and Labelling Operations
ICH Guideline for GMP – Q7 (Contd.)
10. STORAGE AND DISTRIBUTION
10.1 Warehousing Procedures
10.2 Distribution Procedures
11. LABORATORY CONTROLS
11.1 General Controls
11.2 Testing of Intermediates and APIs
11.3 Validation of Analytical Procedures - see Section 12
11.4 Certificates of Analysis
11.5 Stability Monitoring of APIs
11.6 Expiry and Retest Dating
11.7 Reserve/Retention Samples
ICH Guideline for GMP – Q7 (Contd.)12. VALIDATION
12.1 Validation Policy
12.2 Validation Documentation
12.3 Qualification
12.4 Approaches to Process Validation
12.5 Process Validation Program
12.6 Periodic Review of Validated Systems
12.7 Cleaning Validation
12.8 Validation of Analytical Methods
13. CHANGE CONTROL
14. REJECTION AND RE-USE OF MATERIALS
14.1 Rejection
14.2 Reprocessing
14.3 Reworking
14.4 Recovery of Materials and Solvents
14.5 Returns
ICH Guideline for GMP – Q7 (Contd.)
15. COMPLAINTS AND RECALLS
16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)
17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS
17.1 Applicability
17.2 Traceability of Distributed APIs and Intermediates
17.3 Quality Management
17.4 Repackaging, Relabelling and Holding of APIs and Intermediates
17.5 Stability
17.6 Transfer of Information
17.7 Handling of Complaints and Recalls
17.8 Handling of Returns
ICH Guideline for GMP – Q7 (Contd.)18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL
CULTURE/FERMENTATION
18.1 General
18.2 Cell Bank Maintenance and Record Keeping
18.3 Cell Culture/Fermentation
18.4 Harvesting, Isolation and Purification
18.5 Viral Removal/Inactivation steps
19. APIS FOR USE IN CLINICAL TRIALS
19.1 General
19.2 Quality
19.3 Equipment and Facilities
19.4 Control of Raw Materials
19.5 Production
19.6 Validation
19.7 Changes
19.8 Laboratory Controls
19.9 Documentation
20. GLOSSARY
US FDA 21 CFR 211
Subpart A – General Provisions
Subpart B – Organization and Personnel's
Subpart C – General Provisions
Subpart D- Equipment
Subpart E- Control of Components and Drug Product Containers and closures.
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
EU GMPVolume 1 - Pharmaceutical Legislation.
Medicinal Products for Human use.
Volume 2 - Notice to Applicants.Medicinal Products for Human use.
Volume 3 - Guidelines.Medicinal Products for Human use.
Volume 4 - Good Manufacturing PracticesMedicinal Products for Human and Veterinary use.
Volume 5 - Pharmaceutical Legislation.Veterinary Medicinal Products.
EU GMP (Contd.)Volume 6 - Notice to Applicants.Veterinary Medicinal Products.
Volume 7 - Guidelines.Veterinary Medicinal Products.
Volume 8 - Maximum residue limits.Veterinary Medicinal Products.
Volume 9 – Pharmaco vigilanceMedicinal Products for Human and Veterinary use.
Volume 10 - Clinical trialsMedicinal Products for human use in clinical trials (investigational medicinal products).Miscellaneous Good Distribution Practices
EU GMP – Volume 4
Contains the bulk of GMPs out of total 10 volumes.
Contains 9 Chapters in 2 parts and 19Annexure.
EU GMP – Volume 4, Part IChapter 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- going stability Programme, 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, Part II
Basic Requirements for Active Substances used as Starting Materials
Recently revised & made applicable from 31st
July 2010. Risk Management is incorporated in this revised guideline.
EU GMP – Volume 4, Annexure
Annex 1 : Manufacture of Sterile Medicinal Products
Annex 8 : Sampling of Starting and Packaging Materials
Annex 9 : Manufacture of Liquids, Creams and Ointments
Annex 11: Computerized Systems
Annex 13: Manufacture of Investigational Medicinal Products
EU GMP – Volume 4, Annexure (Contd.)
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
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
Interested:�Brazil�Bulgaria�Cyprus�Indonesia�Japan�Philippines�Slovenia�Taipei�Thailand
Requests:�Argentina�Israel�Oman�Russia�South Africa�USA
UNICEF WHOObserver:
PIC/S Guidelines
01-08-2005GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS
PE 009-5
01-07-2004EXPLANATORY NOTES FOR INDUSTRY ON THE PREPARATION OF A SITE MASTER FILE
PE 008-2
01-07-2004PIC/S GMP GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS
PE 007-2
Current Version
TitleNo.
TGA Interpretation for GMP
� For the purposes of this Code, the words “should” and “shall” appearing in each of the Chapters 1 to 9 inclusive in the Code, and in each of the Annexes 1 to 17 inclusive in the Code, mean “must” and the activities, descriptions or specifications accompanied by the word “should” or shall”are to be read as mandatory, unless the manufacturer is able to demonstrate that the activity, 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.
� Guide to interpretation of the Australian Code of Good Manufacturing Practice for Medicinal Products (16 August 2002) applicable to the manufacture of complementary medicines
Stand of EMEA on Interpretation of
GMP� “While EMEA welcomes questions on its
activities and the regulatory framework within which it operates, specific questions on the interpretation of GMP requirements should be addressed, ideally by the Qualified Person, directly to the relevant supervisory authority of the Member State in which the manufacturing authorisation holder is located. Manufacturers based in third countries should contact the authority supervising the authorised importer.”
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.
� GMP is concerned with both production and quality control.
Key areas for MHRA inspection in
GMP� Quality management system
– more than for ISO…
� Personnel
– Qualified Person (QP), training records, independence of QA from
production
� Premises
– Design, access & security, housekeeping
� Equipment
– Validation, calibration, fit for purpose?
� Documentation
– SOPs, methods, raw data
� Production testing & release
– raw materials, finished products & packaging materials
“People, Premises & equipment, Paper”
“3P’s”
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, assess the impact and justify your decision.
� Responsibilities� Be aware of your responsibilities, work to them &
provide the evidence you did what was expected!
How do GMPs of different countries
compare?
�At a high level, GMPs of various nations are very similar; most require proof for things like:
� equipment and facilities being properly designed, maintained, 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, premises and equipment to the training and personal hygiene of staff.
� Detailed, written procedures are essential for each process that could affect the quality of the finished product.
� There must be systems to provide documented proofthat correct procedures are consistently followed at each step in the manufacturing process - every time a product is made.
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
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.
� The system of documentation devised or adopted should have as its main objective to establish, monitor, and record “quality” for all aspects of the production, quality control and quality assurance
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.
� To be able to PREVENT mistakes from happening in the future.
• 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.
Purpose of Documentation
Levels Of Documentation
Quality Records
Supporting Documents or
Work Instructions
Quality Procedures
Quality
Manual
Broadly, all documents
relating to quality fall in to
the following categories: • Quality Manual• Quality Procedures• Supporting Documents or
Work Instructions• Quality Records
All levels are integrated to form a comprehensive and
cohesive documentation network via a system of cross
referencing
Quality
Procedures
The key document that outlines the organization’s system of quality
assurance to achieve customer satisfaction.
Objectives :• Describe the quality system structure• Declare the quality policy and organization goal• Describe how the organization meets the quality goal
Quality Manual
Quality Records
Supporting Documents
or Work Instructions
Quality
Procedures
Quality
Manual
Content of quality manual :• The quality policy declaration • The goal of quality;• The organisational structure including
responsibility and authority of each key personnel
• Procedures, instructions and resources for implementing the quality management.
User :• All personnel in the organization• Another parties, auditors, and customers
as applicable
The document that outlines the activities or operations of the organization
for implementation of the stated quality policies.
Quality Standard Procedures
Quality Records
Supporting Documents
or Work Instructions
Quality
Procedures
Quality
Manual
Objectives :Describe detail explanation how activities should be done, controlled and recorded in implementing the definite policy
Standard Operation Procedures explains: • What the process is and it’s purpose• Where activity is operating/carried out• Who is responsible for every activity• When activity to start & when to complete,
sequential of the activities, frequency, etc.• How activity can be finished by following • the work instruction design or other
reference documents • Reference to the other relevant documents
User :• All personnel who set up and run the
processes/activity/operation
The operational document containing instructions specifying how the
activities are performed or products are accepted.
Work Instructions
Quality Records
Supporting Documents
or Work Instructions
Quality
Procedures
Quality
Manual
Objectives :• It is an instruction document, step by step for
guideline to execute the daily activity or operation for personnel in every function
• It is used departmentally, for every activity/operation, every task &/or every line.
Content of work instructions : • Detailed explanation of instructions to • finish the job, detailed handling of
method, equipment and machine• Related to the technical matters with
stressing for operation, inspection & testing.
User :• All personnel who operates the certain task
Format :• Worksheet, sample, checklist• Audiovisual (tape, video, illustration, photo)
S.O.P. versus W.I.
• 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
QUALITY PROCEDURE/SOP
• Task oriented
• Describes detail instruction
• Operation guidance
• Dedicated to explain special task, method, 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
WORKING INSTRUCTION
Quality Records, including charts and data pertaining to design,
inspection, testing, survey, audit, review or related results, should be
maintained as important evidence to demonstrate:
• effectiveness of Quality System
Implementation;
� that products and services have been
developed and delivered appropriately
with the requirements.
All Quality Records should be :
� legible and clear;
� Dated;
� readily identifiable and retrievable;
� carry authorization status;
� retained for a designated period;
� protected from damage and
deterioration while storage.
Quality Records
Quality Records
Supporting Documents
or Work Instructions
Quality
Procedures
Quality
Manual
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, Intermediates, FG Labeling and Packaging Materials
� Master Production Instructions
� Batch Production Records
� Laboratory Control Records
� Batch Record Review
� Other Documents/Records (Preventative Maintenance, Calibration, Qualification, Validation etc.)
Documentation System and
Specifications
� Review, approval and distribution of documents
� Revision history
� Record retention
Should have procedures to describe:
• What should be written in the document (Title/Subject):
• Name of document (SOP, BMR, Protocol, Format, etc.)
• Name of company, 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
Content of Document
Entries
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
Correction
Corrections
Dated
Signed
Leave the original entry readable
XYZ 987
For e.g. ABC 123 MNTdd/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.
RECORDS MAINTENANCE
� Check whether control records are maintained for:
� Raw materials and primary packaging materials, documenting disposition of :
� released materials
� rejected materials.
� Manufacturing of batches, documenting the:
� kinds, lots and quantities of material used.
� processing, handling, transferring, holding and filling.
� sampling, controlling, adjusting and reworking.
� code marks of batches and finished products.
� Finished products, documenting sampling, individual laboratory controls, test results and control status.
� Distribution, documenting initial interstate shipment, code
marks and consignees.
Retention
Just what records need to be retained?
� Production, Quality Control and Distribution records
� At least 1 year after expiry date
� For APIs with retest date - at 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
�The basic requirements of all guidelines
�Compliance
�Proof
�Traceability
�These requirements can be demonstrated with the help of documents/records.
Overcoming the Challenge of Differing
Interpretations
Document, Document, Document!!!
In FDA-speak:
“If it is not documented . . .
it did not happen!”
or, it’s a rumor!”
Bottom Line
Industry Working V/s. Regulatory
Working
Industry works globally
vs. Regulators works locally
?Industry wishes regulators to recognise the necessity from a global system of
GMP
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, shift to ICH quality topics — Q8 (Quality by Design), Q9 (Risk Management), Q10 (Quality Systems)
Role of ICH for overcoming the
Challenges
� ICH quality topics — Q8 (Quality by Design), Q9 (Risk Management), Q10 (Quality Systems)
� After successful harmonization for API (Q7A), now working for harmonization for Formulations…
� ICH Q7B (future)…
� Quality Management
� Risk Management
� Development Pharmaceutics and Manufacturing Science
� Change Management
Mottos