Transcript Good Manufacturing Practices Purpose and Principles of GMP Tony Gould Why GMP?  Provides a high level assurance that medicines are manufactured in a.

Good Manufacturing Practices
Purpose and Principles of GMP
Tony Gould
Why GMP?
 Provides a high level assurance that medicines
are manufactured in a way that ensures their
safety, efficacy and quality
 Medicines are manufactured to comply with their
marketing authorization
 Quality is built in
– Testing is part of GMP, but alone does not provide a
good level of quality assurance
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Why inspect?
 Verify compliance with GMP
 Verify compliance with marketing authorization
– Dossier: "Dedicated equipment is used"
Inspection: Observation that this means "dedicated while used
for the product or not being used for another product"
– Dossier: "The vials are removed from the lyophilliser and
crimped in a grade A environment"
Inspection: Correct, but before crimping they are stored in an
uncontrolled corridor
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WHO GMP
Quality assurance of pharmaceuticals
A compendium of guidelines and related materials
Volume 2, 2nd updated edition
Good manufacturing practices
and inspection
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Guidelines and references
 GMP applies to both Active Pharmaceutical
Ingredients (APIs) and Finished Pharmaceutical
Products (FPPs)
– FPP:
WHO Good Manufacturing Practices for pharmaceutical
products: main principles. WHO Technical Report
Series, No. 908, 2003, Annex 4.
– API:
WHO good manufacturing practices for active
pharmaceutical ingredients - Annex 2, WHO
Technical Report Series 957, 2010 (Based on ICH
Q7)
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Other WHO GMP Guidelines
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Pharmaceutical excipients
Sterile pharmaceutical products
Biological products
Pharmaceutical products containing hazardous
substances
Investigational pharmaceutical products for clinical trials i
Herbal medicinal products
Radiopharmaceutical products
Water for pharmaceutical use
HVAC for non-sterile pharmaceutical dosage forms
Validation
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Good Manufacturing Practices (FPP):
1. Quality assurance
2. Good manufacturing practices for pharmaceutical
products
3. Sanitation and hygiene
4. Qualification and validation
5. Complaints
6. Product recalls
7. Contract production and analysis
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General
The contract giver
The contract accepter
The contract
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Good Manufacturing Practices (cont'd)
8. Self-inspection and quality audits
– Items for self-inspection
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Self-inspection team
Frequency of self-inspection
Self-inspection report
Follow-up action
Quality audit
Suppliers’ audits and approval
9. Personnel
– General
– Key personnel
10. Training
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Good Manufacturing Practices (cont'd)
11. Personal hygiene
12. Premises
– General
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Ancillary areas
Storage areas
Weighing areas
Production areas
Quality control area
13. Equipment
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Good Manufacturing Practices (cont'd)
14. Materials
– General
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Starting materials
Packaging materials
Intermediate and bulk products
Finished products
Rejected, recovered, reprocessed and reworked materials
Recalled products
Returned goods
Reagents and culture media
Reference standards
Waste materials
– Miscellaneous
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Good Manufacturing Practices (cont'd)
15. Documentation
– General
– Documents required:
• Labels
• Testing procedures
• Specifications for starting and packaging materials, for
intermediate and bulk products and for finished products
• Master formulae and Batch Processing Records
• Packaging instructions and Batch Packaging Records
• Standard Operating procedures (SOP's) and records
• Logbooks
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Good Manufacturing Practices (cont'd)
16. Good practices in production
– General
– Prevention of cross-contamination and bacterial
contamination during production
– Processing operations
– Packaging operations
17. Good practices in quality control
– Control of starting materials and intermediate, bulk and
finished products
– Test requirements
– Batch record review
– Stability studies
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GMP is actually Good Common Sense
Quality Management
Quality Assurance
GMP
Section 1 and 2
Production and Quality Control
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Quality management in the drug industry
Philosophy and essential elements:
 "The concepts of quality assurance, GMP, quality
control and quality risk management are
interrelated aspects of quality management, and
should be the responsibility of all personnel.
……their relationship and their fundamental
importance to the production and control of
pharmaceutical products."
Glossary
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Quality Management
 The basic elements are:
– An appropriate infrastructure or “quality system”
encompassing the organization structure,
procedures, processes and resources
– The systematic actions necessary to ensure adequate
confidence that a product (or service) will satisfy given
requirements for “Quality”
The totality of these actions is referred to as
“Quality Assurance”
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The five P's
 Premises
 Primary materials
 People
 Procedures
 Processes defined and recorded
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Quality Assurance
 Quality assurance is a management tool
 In contractual situations, it also serves to generate
confidence in a supplier
 QA, GMP and Quality Control are interrelated aspects
of Quality Management
– They are described on the following slides in order to
emphasize their relationship and their fundamental
importance to the production and control of
1.1
pharmaceutical products
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Quality Assurance
 Wide-ranging concept
– covers all matters that individually or collectively
influence the quality of a product
 Totality of the arrangements
– to ensure that the drug is continuously of the
right quality for the intended use
 Quality Assurance incorporates GMP
– and also includes product design and
development, with special focus on process
design
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1.1
The position of QA
Director
QA
Production
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QC lab
Other Depts
Quality Assurance means to assure:
 Products are designed and developed correctly
– Complying with, e.g. GMP, GCP, GLP
 Production and control operations are defined
 Managerial responsibilities are defined
– In job descriptions
 The manufacture, supply and use of correct starting
and packaging materials
1.1 a- d
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Quality Assurance means to assure:
(cont'd)
 Controls are performed, including
intermediates, bulk, calibration and validation
 Correct processing and checking of the
finished product
 Products are sold/supplied only after review
by the authorized person
– Complying with marketing authorization,
production and QC requirements
1.1 e - h
 Proper storage, distribution and handling
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Quality Assurance means to assure:
(cont'd)
 Procedures for self-inspection and quality
audits are applied
 Deviations are reported, investigated and
recorded
 System for change control is applied
 Regular evaluation of product quality to
1.1 i - l
verify consistency and continued
improvement
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Quality Assurance includes:
 Responsibility of the Manufacturer for the quality of the
product
– Fit for intended use
– Comply with marketing authorization
– Safety, efficacy and quality
 Commitment of senior management and involvement of all
staff
 Comprehensively designed and well implemented quality
system
 Full documentation and monitoring of effectiveness
 Competent personnel, sufficient premises, equipment and
facilities
1.3
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Good Manufacturing Practices
 That part of QA that ensures that products are
consistently produced and controlled
– Quality standards
– Marketing authorization
 Aim: Diminishing risks that cannot be controlled
by testing of product
– Contamination and cross-contamination
– Mix-ups (confusion)
2.1
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Basic requirements for GMP:
 Clearly defined and systematically reviewed
processes
 Qualification and validation is performed
 Appropriate resources are provided:
– Qualified and trained personnel
– Premises, space, equipment and services
– Materials, containers, labels
– Procedures, storage, transport
– Laboratories and in-process control
2.1 a - c
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Basic requirements for GMP:
(cont'd)
 Clear, written instructions and procedures
 Trained operators
 Records of actions, deviations and
investigations
 Records for manufacture and distribution
 Proper storage and distribution
 Systems for complaints and recalls
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2.1 d - j
GMP = continuous urge for improvement
 Involvement of the management
 Annual Product Quality Review
 Quality risk management
 Complaints handling
 Self-inspection
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Involvement of the management
 The senior management is responsible to attain the
company's quality objectives
 All different departments and all levels within
departments should be involved; and it's the senior
management who should facilitate this
 Also suppliers and distributors should be involved
 The senior management should make available the
required resources
 The basis of the quality system is the quality statement
and quality policy, by the senior management
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Product Quality Review
Objectives of Product Quality Review:
 To review and verify the consistency and
appropriateness of the existing process
 To identify and highlight any trends in the
process, e.g. in analytical results, yields etc.
 To identify any possible product or process
improvements
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Product Quality Review (cont'd)
 Review of starting materials/ packaging
materials, especially from new sources
 Review of in-process control results and finished
product analytical control results
 Amount of batches and packaging units
produced and their yields
 Reviews of:
– Out-of-spec situations, rejections, deviations, changes
– Plus investigations and analysis of causes
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Annual Product Quality Review (cont'd)
 Review of Marketing Authorization variations
submitted, granted or refused (incl. third countries)
 Review of stability programme and trends
 Review of adequacy of previous decisions on
changes or improvements or corrective actions
 For new Marketing Authorizations (plus new
variations) a review of post marketing commitment
 The qualification status of all relevant equipment
and utilities (like water, HVAC, gases, etc.)
 Review of Technical Agreements (if applicable)
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Complaints handling
Complaints: Principle
“All complaints and other information
concerning potentially defective products
must be carefully reviewed according to
written procedures and corrective action
should be taken.”
5.1
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Complaints Procedure
 Designated responsible person:
– To handle complaint
– Decide on measure to be taken
– May be authorized person - if not, must advise
authorized person of results
– Sufficient support staff
– Access to records
 Written procedure (SOP):
– Describes action to be taken
– Includes need to consider a recall (e.g. possible
product defect)
5.2 – 5.3
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Complaints Procedure – cont'd
 Thorough investigation:
– QC involved
– With special attention to establish whether
"counterfeiting" may have been the cause
– Fully recorded investigation – reflect all the details
 Due to product defect (discovered or suspected):
– Consider checking other batches
– Batches containing reprocessed product
5.4 – 5.6
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Complaints Procedure – cont'd
 Investigation and evaluation should result in
appropriate follow-up actions
– May include a "recall"
 All decisions and measures taken should be
recorded
 Referenced in batch records
 Records reviewed - trends and recurring problems
5.7 – 5.9
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Complaints - other actions
 Inform competent authorities in case of serious
quality problems such as:
– Faulty manufacture
– Product deterioration
5.10
– Counterfeiting
 Have a thorough recall procedure that is consistent
with the complaints handling procedure
 Trend complaints, their investigations and results
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Self-Inspection
 Purpose is to evaluate whether a company’s operations
remain compliant with GMP
 The programme should
– cover all aspects of production and quality control
– be designed to detect shortcomings in the implementation of
GMP
– recommend corrective actions
– set a timetable for corrective action to be completed
 Should be performed routinely
 Also on special occasions such as
– Recalls
– Repeated rejections
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8.1
Self-Inspection (cont'd)
 Performed by team appointed by management, with:
– authority
– sufficient experience, expertise in their own field.
knowledge of GMP
– may be from inside or outside the company
 Frequency should normally be at least once a year
– May depend on company requirements
– Size of the company and activities
8.3, 8.4
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Self-Inspection (cont'd)
 Report prepared at completion of inspection,
including:
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results
evaluation
conclusions
recommended corrective measures
 Follow-up action
– Effective follow-up programme
– Company management to evaluate both
the report and corrective actions
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8.5, 8.6
Summary and conclusions:
 GMP compliance is not an option
 Quality should be built into the product
 GMP's are very similar and are really
Good Common Sense
 Good Practices cover all aspects of
manufacturing activities prior to supply
 The role and involvement of senior
management is crucial
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http://www.who.int/prequal
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