Transcript Slide 1

Basic Principles of GMP
Good Practices in
Production and Quality
Control
Section 16 and 17
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Good Practices
Objectives
 Discuss aspects of good practices in production
 Discuss aspects of good practices in quality control
 Group session
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Good Practices
Manufacture

WHO Definition: All operations of purchase of materials and
products, production, quality control, release, storage and
distribution of pharmaceutical products, and the related controls

GMP applies to production and QC

Separate training module on QC
Glossary
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Good Practices
 All activities in accordance with written SOPs
 Records made at the time of action – and maintained
 Deviations avoided – when occur, follow SOP
– Quality unit involved
 Checks on yields - reconciliation
 One product at a time in an area
16.2 – 16.5
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Good Practices
 All containers, equipment and areas labelled
 Access to areas controlled
 No non-medicinal products in the areas
 In process controls performed
 Prevention of mix-ups, contamination and crosscontamination kept in mind
16.6 – 16.9
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Good Practices
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

Protection from insects, birds, vermin and weather
12.2, 12.3, 12.7, 12.9, 12.29
 from receipt of raw materials to dispatch of released product
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Basic Principles of GMP
 Walls, floors, ceilings –
smooth and easy to clean
 No ledges or areas where
dust can accumulate
 Prevention of build-up of dirt
and dust to avoid
unnecessary risks of
contamination
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Good Practices
Avoidance of Cross-Contamination I
 Special precautions to prevent generation and dissemination of dust
 Proper air control – supply and extraction, suitable quality
 Risk assessment
 Avoid contamination by :
 dust, gas,
 particles, clothing, skin,
 vapours, sprays,
 organisms, residue,
 insects
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16.10 - 11
Good Practices
Avoidance of Cross-Contamination II
 Technical or organizational measures taken
 Dedicated and self-contained areas for:
 Live vaccines
 Live bacterial preparations
 Certain other biological materials
 Penicillin products
16.12(a)
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Good Practices
Avoidance of Cross-Contamination III
 Campaign production:
 Separation in time
 Followed by appropriate cleaning
 Validated cleaning procedure
16.12(b)
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Good Practices
Avoidance of Cross-Contamination IV
 Ventilation systems and airlocks
 Appropriately designed ventilation system with air supply and
extraction systems (See HVAC module)
 Supply or incoming air should be filtered
 Filtered recirculation of air or 100% fresh air supply
 Proper airflow patterns
 Pressure differentials
 Appropriately designed airlocks
16.12 (c and d)
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Good Practices
Avoidance of Cross-Contamination V
 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
16.12(e)
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Good Practices
Avoidance of Cross-Contamination VI
 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
 Environmental monitoring (particles and micro)
 Effectiveness of systems checked
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16.12(f, h and i), 16.13,
16.14
Good Practices
Avoidance of Cross-Contamination -VII
 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)
16.12(g)
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Good Practices
Processing operations
 Always ensure the work area is ready for the process
(e.g. line opening)
 Environmental and in-process controls done and
recorded
 Deviations and failures recorded
 Cleaning performed within specified (validated) time
limits
16.15 – 16.20
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Good Practices
Processing operations
 Use clean containers
 All pipes, equipment, instruments are:
– suitable for use, integrity checks
– calibrated and verified / checked
– in good state of repair
– correct connections
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16.21 – 16.24
Good Practices
Packaging operations
 No risk of mix-ups, contamination and cross-contamination
 Preferrably physical separation between lines
 Area indicates product under process
 Filling followed by sealing and labelling- no delays
 Correct performance e.g. overprinting, labels, leaflets
– Automated checks preferred
16.25 – 16.30
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Good Practices
Production Operations – Sanitation – IV
Area clearance checks
 The area clearance check should be carried out by two people
 between batches of same product, acceptable for both
checks to be carried out by production personnel
 for product changeover, second check carried out by QC staff
 all checks carried out in accordance with written SOP and
results recorded on the batch documentation.
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Basic Principles of GMP
Line opening:
 Includes checks on
materials and components
 Batch number
 Expiry date
 Printed packaging material
including cartons, leaflets,
foil . . .
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Good Practices
Packaging operations
 Online control during packaging should include at least checks on:
– general appearance of the packages;
– whether the packages are complete;
– whether the correct products and packaging materials are
used;
– whether any overprinting is correct;
– the correct functioning of line monitors.
 Samples taken away from the packaging line should not be
returned.
16.32
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Good Practices
Packaging operations
 Reintroduction - only after special inspection, investigation and
approval. Detailed records of this operation.
 Discrepancy in reconciliation investigated and recorded before
release.
 Unused batch-coded packaging materials destroyed.
 Returning of unused materials to stores – SOP followed
 Batch records reviewed as part of batch release
 Investigation in case of discrepancies
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16.33 – 16.36
Good Practices
Production Operations – Sanitation – I
 Work-flow
 designed to avoid potential contamination , mix-ups and errors
 Access
 restricted to authorized personnel
 direct operators, QC staff, warehouse staff, maintenance
personnel, cleaners
 the more critical the area - fewer number of persons there
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Good Practices
Production Operations – Sanitation – VII
 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
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Good Practices
Good Practices in Quality Control (QC)
 Complete module on Quality Control Laboratories. This
section only reflects some aspects of good practices in QC
labs
 QC concerned with sampling, testing, specifications
 QC should be independent from production
17.1. – 17.2.
 Involved in various areas – not confined only to the laboratory
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Good Practices
Each manufacturer should have a QC “function”
 Supervised by a person with qualification and experience
Resources should include:
 Adequate facilities
 Trained personnel
 Approved procedures for all activities
 Specifications and test procedures
 Pharmacopoeia
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17.3(a)
Good Practices
Basic Requirements for Quality Control – II
1. Sampling inspecting and testing of materials, bulk, finished
products
2. Monitoring environmental conditions
3. Qualification and validation
4. Maintaining records of actions, deviations, investigations
5. Ensure ingredients and finished products are of the required
quality and comply with marketing authorization
6. Keeping retention samples
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17.3 .
Good Practices
Other responsibilities include
1. Establish, validate and implement QC procedures
2. Evaluate, store and maintain reference standards
3. Correct labelling of containers and materials and products
4. Monitor stability of APIs and products
5. Participate in complaint investigations
6. Participate in environmental monitoring
7. Participate in Quality Risk Management programs
17.4
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Good Practices
QC Access
 QC personnel must have access to production
and other areas
 Sampling e.g. water system, steam,
environmental monitoring
 For investigations
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17.5
Good Practices
Sampling
 Avoid contamination, cross-contamination and
mix-ups during sampling - no adverse effects
 Sampled containers labelled and re-sealed
 Clean sampling equipment used - stored
separately from other laboratory equipment
17.8 – 17.10
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Good Practices
Control of starting materials and intermediate, bulk and
finished products – and printed packaging material
 Each lot/batch examined following receipt
 Samples taken - representative of the batch
 Samples tested according to test procedures
 Results checked by supervisor prior to release or
17.6 – 17.7, 17.15
rejection
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Good Practices
Each sample container should bear a label indicating:
(a) the name of the sampled material;
(b) the batch or lot number;
(c) the number of the container from which the sample was taken;
(d) the number of the sample;
(e) the signature of the person who has taken the sample;
(f) the date of sampling.
17.11
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Good Practices
Out of specification results
 SOP for OOS investigation followed
 OOS reported without delay
 Investigated
 Action taken – see also guidelines from stringent regulatory
authorities)
17.12
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Good Practices
Test requirements: Starting and packaging materials
 Materials tested prior to release
 Results checked by QC manager (meet specification)
 An identity test on a sample from each container normally
required
 Reduced sampling and testing subject to certain
17.13-17.14
conditions in supplier qualification
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Good Practices
Reduced sampling: A validated procedure
 Consider the nature and status of the manufacturer and supplier
(GMP);
 QA system of the manufacturer of the starting material;
 Manufacturing conditions;
17.14
 nature of the starting material and products in which it will be used
– coming from a single product manufacturer or plant;
– coming directly from a manufacturer, or in the manufacturer’s sealed container where
there is a history of reliability, and regular audits of the manufacturer’s QA system
are conducted by the purchaser (the manufacturer of the medicinal product) or by an
officially accredited body.
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Good Practices
Not applicable normally to:
 starting materials supplied through agents and
brokers where the source of manufacture is
unknown or not audited;
 starting materials for use in parenteral products
17.14
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Good Practices
Can results be taken from the Certificate of Analysis (from the
supplier?)
 Subject to appropriate periodic validation
 Reliability of the supplier’s analysis
 On-site audits of the supplier’s capabilities
 Original COAs (not photocopies) or authenticity assured
 COAs must contain relevant information such as name and address
of supplier; signatures, qualifications, materials, batch number,
specifications, results, dates
17.16
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Good Practices
 In-process control records – keep as part of the
batch records
 Each batch of finished product – confirm
compliance with specification before release
 If a product does not meet the specification –
rejected
17.17 – 17.19
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Good Practices
Review of Records
 QC records reviewed as part of batch approval process
 Batch failure should be thoroughly investigated - written record of
the investigation – extend to other batches if needed
 Retention samples kept of finished product
– in their final packaging
– stored under the recommended conditions
– Samples of active starting materials and excipients also kept
17.20- 17.21
 Sufficient quantity to permit at least two full re-examinations.
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Good Practices
Stability studies
 QC to evaluate the quality and stability of finished pharmaceutical
products and, when necessary, of starting materials and
intermediate products
 Establish expiry dates and shelf-life specifications on the basis of
stability tests related to storage conditions
 Stability determined prior to marketing
 Significant changes in processes, equipment, packaging
materials,
17.2217.23,
17.25
etc. – stability testing.
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Good Practices
Written programme for ongoing stability consisting of:
(a) complete description of the medicine involved in the study;
(b) testing parameters and methods;
(c) provision for the inclusion of a sufficient number of batches;
(d) the testing schedule for each medicine;
(e) provision for special storage conditions;
(f) provision for adequate sample retention
17.24
(g) data summary, evaluation and the conclusions of the study.
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Good Practices
Quality Control - summary
 QC is part of GMP - refer to the handout
 sampling
 authorization
 specifications
 definition of product quality
 testing
 laboratory operations
 release procedures
 release decisions
 recalls and complaints
 investigation and reporting
 decision-making in all
quality matters
2.1, 17.1 - 17.3
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