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Module 13 | Slide 1 of 43 2013
Good Practices in Production and Quality Control
Basic Principles of GMP
Section 16 and 17
Module 13 | Slide 2 of 43 2013
Good PracticesGood Practices
Objectives
Discuss aspects of good practices in production
Discuss aspects of good practices in quality control
Group session
Module 13 | Slide 3 of 43 2013
Good PracticesGood 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
Module 13 | Slide 4 of 43 2013
Good PracticesGood 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
Module 13 | Slide 5 of 43 2013
Good PracticesGood 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 cross-contamination kept in mind
16.6 – 16.9
Module 13 | Slide 6 of 43 2013
Good PracticesGood 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
from receipt of raw materials to dispatch of released product
12.2, 12.3, 12.7, 12.9, 12.29
Module 13 | Slide 7 of 43 2013
Basic Principles of GMPBasic 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
Module 13 | Slide 8 of 43 2013
16.10 - 11
Good PracticesGood 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
Module 13 | Slide 9 of 43 2013
16.12(a)
Good PracticesGood 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
Module 13 | Slide 10 of 43 2013
16.12(b)
Good PracticesGood Practices
Avoidance of Cross-Contamination III
Campaign production:
Separation in time
Followed by appropriate cleaning
Validated cleaning procedure
Module 13 | Slide 11 of 43 2013
16.12 (c and d)
Good PracticesGood 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
Module 13 | Slide 12 of 43 2013
16.12(e)
Good PracticesGood 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
Module 13 | Slide 13 of 43 2013
16.12(f, h and i), 16.13, 16.14
Good PracticesGood 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
Module 13 | Slide 14 of 43 2013
16.12(g)
Good PracticesGood 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)
Module 13 | Slide 15 of 43 2013
16.15 – 16.20
Good PracticesGood 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
Module 13 | Slide 16 of 43 2013
16.21 – 16.24
Good PracticesGood 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
Module 13 | Slide 17 of 43 2013
16.25 – 16.30
Good PracticesGood 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
Module 13 | Slide 18 of 43 2013
Good PracticesGood 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.
Module 13 | Slide 19 of 43 2013
Basic Principles of GMPBasic Principles of GMP
Line opening:
Includes checks on materials and components
Batch number
Expiry date
Printed packaging material including cartons, leaflets, foil . . .
Module 13 | Slide 20 of 43 2013
16.32
Good PracticesGood 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.
Module 13 | Slide 21 of 43 2013
16.33 – 16.36
Good PracticesGood 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
Module 13 | Slide 22 of 43 2013
Good PracticesGood 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
Module 13 | Slide 23 of 43 2013
Good PracticesGood 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
Module 13 | Slide 24 of 43 2013
Good PracticesGood 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
Involved in various areas – not confined only to the laboratory
17.1. – 17.2.
Module 13 | Slide 25 of 43 2013
17.3(a)
Good PracticesGood 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
Module 13 | Slide 26 of 43 2013
Good PracticesGood 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 17.3 .
Module 13 | Slide 27 of 43 2013
17.4
Good PracticesGood 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
Module 13 | Slide 28 of 43 2013
Good PracticesGood Practices
QC Access
QC personnel must have access to production and other areas
Sampling e.g. water system, steam, environmental monitoring
For investigations17.5
Module 13 | Slide 29 of 43 2013
Good PracticesGood 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
Module 13 | Slide 30 of 43 2013
Good PracticesGood 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 rejection 17.6 – 17.7, 17.15
Module 13 | Slide 31 of 43 2013
Good PracticesGood 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
Module 13 | Slide 32 of 43 2013
Good PracticesGood 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
Module 13 | Slide 33 of 43 2013
Good PracticesGood 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 conditions in supplier qualification 17.13-17.14
Module 13 | Slide 34 of 43 2013
Good PracticesGood 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;
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.
17.14
Module 13 | Slide 35 of 43 2013
Good PracticesGood 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
Module 13 | Slide 36 of 43 2013
Good PracticesGood 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
Module 13 | Slide 37 of 43 2013
Good PracticesGood 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
Module 13 | Slide 38 of 43 2013
Good PracticesGood 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
Sufficient quantity to permit at least two full re-examinations.
17.20- 17.21
Module 13 | Slide 39 of 43 2013
Good PracticesGood 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, etc. – stability testing.
17.22- 17.23, 17.25
Module 13 | Slide 40 of 43 2013
Good PracticesGood 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
(g)data summary, evaluation and the conclusions of the study.
17.24
Module 13 | Slide 41 of 43 2013
Quality Control - summary
QC is part of GMP - refer to the handout sampling specifications testing release procedures recalls and complaints decision-making in all
quality matters
2.1, 17.1 - 17.3
Good PracticesGood Practices
authorization definition of product quality laboratory operations release decisions investigation and reporting
