Good Manufacturing
Practices
in the manufacture of
medicines
The World Health Organization (WHO) GMP
rules are the subject of the course
1
I am afraid, the
industrial drug
manufacture is a
bit more
complicated
than this…
2
starting
already
outside, in
the yard
3
active substance
4
manufacture
dosage-form
manufacture
5
computer-aided
manufacture
6
control lab
7
GMP
certificate
issued by the
national GMP
compliance
monitoring
authority
8
GMP
• Basic Principles
• Specific rules
9
GMP: „soft” and „hard” law
„The manufacturer should possess
adequate…
• number of personnel...
• with adequate qualification...
• manufacturing area…”
Impossible to specify the values in a
law!
The inspector will decide on the spot
whether the requirement is met!
10
Basic Principles of GMP
Introduction
to the Training Course
11
Programme Overview – I
Basic Principles of GMP
1.
2.
3.
4.
Quality Management
Sanitation and hygiene
Validation
Complaints and recalls
12
Programme overview II
Basic Principles of GMP
5. Contract production and
analysis
6. Self Inspection
7. Personnel
8. Premises
9. Equipment
13
Programme overview - III
Basic Principles of GMP
10. Materials
11. Documentation
12. Sterile production
13. Active pharmaceutical
ingredients
14
Programme overview - IV
GMP Inspection Process
14. Introduction
15. The role of the inspector
16. Preparation for the inspection
17.Types of GMP inspection
18. The inspection
15
Basic principles of GMP
in more detail
16
1. Quality Management
17
European Union Directive
„The manufacturer shall establish and
implement an effective
pharmaceutical QA system,
involving the active participation of
the management and personnel of
the different services involved”
18
The Quality Management
• The first, introductory chapter of the
WHO GMP
• Having defined some concepts and
terms, it summerises what is also
detailed in other chapters (do not be
surprised if its parts are also reproduced
elsewhere)
19
Quality Management
Objectives
• To understand/identify key issues in
quality assurance/quality control
• To understand/identify specific
requirements on organization,
procedures, processes and
resources
• To develop actions to resolve your
current problems
20
Quality Management
• Determines and implements the
“quality policy”
• The basic elements are:
– an appropriate infrastructure or “quality
system” encompassing the 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 termed
“Quality Assurance”
21
Quality Management
• Terminology may differ (e.g. from
ISO)
– “Quality System” is said to be rarely
used in drug manufacturing
• The concepts of 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 pharmaceutical products
22
Quality Management
Principles of Quality Assurance
• Wide-ranging concept
– covers all matters that individually or collectively
influence the quality of a product = responsibility
of everyone
• Totality of the arrangements
– to ensure that the drug is of the right quality for
the intended use
• Quality Assurance incorporates GMP
– and also product design and development which
is outside the scope of this module
23
Requirements for QA Systems
Think over what should be done
properly during drug manufacture!
Quality Management
Requirements for QA Systems – I
1.Ensure products are developed correctly
2.Identify managerial responsibilities
3.Provide SOPs for production and control
Standard Operating Procedures
4.Organize supply and use of correct starting
materials
5.Define controls for all stages of manufacture
and packaging
25
Quality Management
Requirements for QA Systems – II
6. Ensure finished product correctly
processed and checked before release
7. Ensure products are released after
review by authorized person
8. Provide storage and distribution
9. Organize self-inspection
26
Quality Management
GMP
• Ensure that products are
consistently produced and
controlled
• Diminishes risks that cannot be
controlled by testing of product
– Cross-contamination the most lifethreatening
– Mix-ups
mistakes!
27
Quality Management
Basic Requirements for GMP – I
1. Clearly defined and systematically
reviewed processes
2. Critical steps validated
3. Appropriate resources: personnel,
buildings, equipment, materials
4. Clearly written procedures
5. Trained operators
28
„Clearly defined and systematically
reviewed manufacturing processes”
• = all relevant quality specifications, SOPs
and batch documentation must be
prepared in harmony with each other
• It also means that the Departments
involved know each other’s task to
eliminate discrepancies
• Also: QC/QA staff is acting as coordinator
and is involved in all decisions
29
„Critical steps validated”
• There is a variability in the quality of incoming
materials and in the performance of the
equipment, we need to check whether the
process works with all varibaility that can arise
• The process of checking and documenting
variability = validation
• if validation, we have sufficient knowledge of
materials, equipment and process = what
variables arelikely to arise.
• Then we carry out controlled experiments to
ensure that whatever variables cab occur, the
product still meets the specification
• Validation is also needed when there is any
change in materials, process or equipment
30
„Appropriate resources: personnel,
buildings, equipment and materials”
• These all should be available to
produce a quality product.
• Thus, the company should evaluate
all of the elements it needs to
produce a drug to see that it has
sufficient resources
31
„Manufacture is based on
clearly written procedures”
• Procedures:
– batch manufacturing instructions
– testing instructions
– SOPs needed for all departmants
• Preparing these documents is very
important task (see Documentation)
32
„Trained operators”
• Documentation, instructions, etc.
are not enough if the operators can
not work with them properly
• Training includes also follow-up
training
33
Quality Management
Basic Requirements for GMP – II
6. Complete records, failure
investigations
7. Proper storage and distribution
8. Recall system
9. Complaint handling
34
„Complete records, failure
investigations”
• (We have just seen there are
manufacturing, packaging, QC, etc.
instructions how to perform the work)
• Also records are needed to show what
and how was actually done each time, by
whom, etc.
• If there is a reason later to come back to
check what happened with a given batch,
the only possibility is to check the records
• E.g. when failures are found later
35
„Proper storage and
distribution”
• When a new drug is developed,
stability studies determine the
storage conditions and its shelf-life
• However, the storage conditions
should be met!
• Also during distribution!
36
„Recall system”
• If quality problems detected when the
product is already on the market, there
should be a system to recall them (from
wholesalers or from pharmacy level)
• System, for there can be different ways
anddegress of severity, depending upon
the reasons for the recall
Simple circular information by letter<by fax<TV and press
warning if life threatening, etc.
Involvement of national regulatory
authorities – according to local law
37
Complaint handling
• If the complaint of a purchaser or
consumer is possibly related to
manufacturing defects, it is worth of
investigation
• This way its re-occurrence can be
prevented
38
Quality Management
Cascade
Quality relationships
Quality Management (overall policy)
Quality Assurance (concept ensuring
that the policy is achieved)
GMP (how to do it)
including
Quality Control
39
Quality Management
Quality Control (QC) Department
• Each holder of a manufacturing authorization
should have a QC Department
• Independence from production and other
departments is considered to be fundamental
• Under the authority of an appropriately
qualified and experienced person with one or
several control laboratories at his or her
disposal.
40
Quality Management
Basic Requirements for Quality
Control
Resources
•
•
•
Adequate facilities
Trained personnel
Approved procedures
41
Quality Management
Basic Requirements for Quality
Control
Tasks
•
•
•
•
Sampling
Inspecting
Testing
Monitoring (materials, environmental
conditions)
•
Releasing/rejecting
42
Basic Requirement for Quality
Control - I
Objects
•
•
•
•
•
•
Starting materials
Packaging materials
Intermediates
Bulk products
Finished products
Environmental conditions
43
Basic Requirements for QC - II
1. Sampling approved by QC department not
necessarily done by them, but ensuring samples are
representative
2. Validated test methods accurate, precise, robust,
specific, linear…
3. Records of sampling, inspecting, testing, of incoming
materials, intermediates, bulk and packaged finished products
4. Review and evaluation of production
documentation for release: not only test results
5. Failure investigations for all deviations
6. Ingredients comply with the marketing
authorization
44
Basic Requirements for QC III
7.
8.
9.
Ingredients are of the required purity
Proper containers compatibility!
Correct labelling mislabelling = life-threatening
error
10. Release of batches by the authorized
person who has the right – predetermined persons
with adequate qualification and experience
11. Retained samples of starting materials
and products
45
Other Duties of the QC
Department
1. Establish QC procedures and
validation in the first time then its „release”
2. Reference standards and their storage!
Mainly test results rely on the comparison with
the reference standards…
3.
4.
5.
6.
Correct labelling
Stability testing
Complaint investigations
Environmental monitoring
46
Assessment of Finished
Products
Should embrace all relevant factors (not
only the QC test results!). For example:
• production conditions
• in-process test results
• manufacturing documentation
• compliance with finished product
specification
• examination of the finished pack
47
QC Access
• QC Personnel MUST have access to
production areas for sampling and
investigation
• As appropriate! E.g. not appropriate:
entering in aseptic filling suites, or where highly
potent dangerous materials are present…
48
QC - Summary
QC is part of GMP
–
–
–
–
–
–
sampling
specifications
testing
release procedures
recalls and complaints
decision-making in all
quality matters
– authorization
– definition of product
quality
– laboratory
operations
– release decisions
– investigation and
reporting
49
Quality management
also means:
• identification
• assessment
• cotrol (keeping under control)
• presentation (to all interested
persons)
of any risk factor that may affect the
quality of the medicine
50
Quality Management
Group session II
• Imagine you are inspecting a
pharmaceutical company for
compliance with GMP
• Consider the situations in the
next slides which may impact on
a company’s quality management
programme
• Describe the action to be taken in
each case
51
Quality Management
Issues 1
• Quality Management manual not
established in writing
• Limited human resources
• Lack of qualified people
• Processes not properly validated
• Poor SOPs or standard batch
documentation
• More consideration to cost than quality
• Family members in key positions of
authority
52
Quality Management
Issues 2
• Substandard materials deliberately
purchased
• Technical staff not involved in
purchasing
• Inability to re-export substandard
materials
• Owner insists on selling rejects
• Corruption
53
• No commitment to training
Before starting:
definitions
54
Definitions 1
• In-process control IPC: QC during
the production
• Campaign working: separated in
time
• Quarantine: separation of the the
incoming or newly manufactured
product until the release
55
Definition 2
• Release: decision on a batch: whether it
meets the requirement (or not), based on
both QC results and batch production
records
• Key persons: head of production, head
of QC/QA + the qualified person QP if
different from the latter
56
Definitions 3
• Standard Operating Procedure SOP:
description of a technological procedure
• Intermedier product: product between
the starting materials and the final
product
• Bulk: starting materials and intermediates
as well as final products e.g. in barrels
57
Definitions 4
• Yield in synthesis: based on the chemical
formulas, molecular weights, the reaction
equation and the measured-in quantities
• Yield in dosage-form production: based
on the measured-in quantities and the
quantitative composition of one tablet
Never 100%!
58
2. Sanitation and Hygiene
59
Sanitation and Hygiene
Objectives
• Review measures to ensure good
sanitation in:
– premises
– equipment
– processes
• To review measures to ensure good
personnel hygiene
60
Sanitation and Hygiene, scope
All aspects of manufacturing
• Personnel who enter the manufacturing area
• Premises the level of attention will depend on the nature of
the operation carried out there
• Equipment
• Apparatus
• Production materials and container if not handled
properly can contribute to dirt
• Products for cleaning and disinfection but
cleaningagents also controlled = they do their job but do not
contaminate the product. Also cleaning tools e.g. brushes
• All potential sources of cross-contamination
61
Design of Premises - I
• 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 (e.g. cleaning a warehouse differs from
cleaning a sterile area), its frequency, cleaning
records
62
Design of Premises - II
• Effective cleaning and disinfection
– choice of materials and chemicals,
validation
• Drains no back-flow, in sterile areas: at a minimum,
• Protection from insects, vermin and
weather
– from receipt of raw materials to despatch
of released product
63
Design of Premises:
avoidance of cross-contamination
Definitions:
• Contamination: by a foreign matter
• Cross-contamination: by a material
also manufactured there
64
Avoidance of Crosscontamination - I
•
•
•
•
•
Segregated areas
Ventilation systems and airlocks
Clothing
Closed processing systems
Cleaning and decontamination
65
Avoidance of Crosscontamination - II
• Segregated areas and separate
facilities for
– live vaccines and other biological
materials
– penicillin products
– campaign processing
66
Avoidance of Crosscontamination - III
Ventilation systems and airlocks
– design of ventilation system
– incoming air should be filtered
– pressure differentials and air
extraction positive pressure
– airlocks
– airflow patterns and equipment
design
– recirculation versus 100% fresh air
supply
67
Avoidance of Crosscontamination - IV
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
68
personnel in different coloured garments
69
Avoidance of Crosscontamination - V
Closed processing systems, i.e.
– totally enclosed water purification
systems
– tanks fitted with appropriate
filtration - without
removable lids
– present special cleaning difficulties,
sometimes use
70
clean-in-place (CIP)
Avoidance of Crosscontamination - VI
Cleaning and decontamination
– procedure for removing soil and dirt
– remove all cleaning chemical
residues or disinfectant residues
– must remove or reduce microorganisms
71
Product Operations – Sanitation 1
• Work-flow
– designed to avoid potential contamination
– access restricted to authorised persons
exclusively
• operators
• QC staff
• warehouse staff
• maintenance personnel
• cleaners
the more critical the more restriction!
72
Production Operations –
Sanitation 2
Simultaneous operations
• not permissible to process different
products in different areas with a
common ventilation system
• permissible to carry out secondary
packaging activities for different
products within a packing hall with
adequate physical separation
73
Production Operations –
Sanitation 3
Area clearance checks
• Process of checking
– all materials and documentation from
the previous batch removed
– all plant and equipment thoroughly
cleaned and appropriate status
labelling
– checklist useful
74
Production Operations Sanitation 4
Area clearance checks a)
• 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 it
is the first manufacturing/packaging step!
75
Production Operations –
Sanitation 5
Area clearance checks b)
• The area clearance check should be
carried out by two people
– 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
76
Production Operations Sanitation 6
• Cleaning and cleaning validation
– degree of cleaning depends on whether
consecutive batches are of same or
different product
• Check cleaning agent is fully removed
• If possible hot water alone used for cleaning
– all cleaning and disinfecting solutions
carefully prepared and expiry dated
• Final rinse with purified water, or water for
injection (for sterile products)
• Full records kept
77
Production Operations –
Sanitation 7
• Water systems
• Water - major constituent of most
products
• SOP for cleaning and sanitisation of the
water purification system should
include distribution pipework
• Validation and removal of disinfectant
before reuse
78
Production Operations –
Sanitation 8
• 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
79
Personnel Hygiene 1
• Health examinations
– On recruitment for direct operators ,
repeated on regular basis
• Training - check
!
– induction training for new operators
includes basic personal hygiene training
– written procedures - to wash hands before
entering a manufacturing area
– signs in changing rooms to reinforce hand
washing
80
Personnel Hygiene 2
• Illness
– staff with illness or open lesions
should not handle starting materials,
intermediates or finished products
81
Personnel Hygiene 3
• Adverse conditions
– operators trained to recognize risks
– willingness to report illness to the
area supervisor easy? What happens?
People can be motivated to the opposite!
82
Personnel Hygiene 4
• Contact between product and
operator
– avoid direct contact
– if direct handling unavoidable,
gloves should be worn
– check glove disinfection (for
sterile production) and disposal
83
Personnel Hygiene 5
• Clothing and changing facilities a)
– check changing rooms
(handwashing, towels or hot air
hand dryers) opening taps
– check if used clothing stored in
separate closed containers while
awaiting cleaning
84
85
Personnel Hygiene 6
• Clothing and changing facilities b)
– laundering of clean area clothing
must be to SOP and in
appropriate facility
– check for procedure for sterilizing
and storing clothing for use in
sterile area
86
Personnel Hygiene 7
• Smoking, eating and drinking should
not be allowed in any manufacturing
area, including laboratories and
storage rooms
• Chewing of gum should be banned
87
Personnel Hygiene 8
• There should be no plants kept
inside any factory areas.
• Rest and refreshment areas should
be separate from manufacturing
areas.
• Toilets should not open directly into
production or storage areas.
88
Sanitation and Hygiene
Group Session
You are inspecting a new factory.
What are the key issues for
sanitation and the key issues for
personnel hygiene that the
company should have in place?
89
Sanitation and Hygiene
•
•
•
•
•
Possible Issues – Sanitation 1
Mixed production
Penicillins
Product versus batch changeovers
Water systems
How long should a “cleaned” status last
for?
90
Sanitation and Hygiene
Possible Issues – Sanitation 2
• What should happen if a clearance check
is required when no QC personnel are on
duty?
• Procedures and records
91
Sanitation and Hygiene
•
•
•
•
•
•
Possible Issues – Hygiene
Personal hygiene
Health checks
Dealing with health problems
Personal responsibility
Training records
Frequency of handwashing
92
Exam topic
93
Sanitation and hygiene in GMP
• Design of premises (walls, ceilings, floors, drains,
cleaning programme, protection from external
factors)
• Avoidance of cross-contamination (mention
measures)
• Campaign working versus dedicated manufacture
areas for certain drugs (examples!).
• Clothing
• Health measures
• Cleaning
94