gmp by dr. mithilesh trivedi calyx

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


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


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


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


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



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



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



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