Good Manufacturing Practices in the manufacture of medicines

1
Good Manufacturing Practicesin the manufacture
of medicines
The World Health Organization (WHO) GMP rules are
the subject of the course
2
I am afraid, the industrial drug manufacture is a
bit more complicated than this
3
starting already outside, in the yard
4
active substance manufacture
5
dosage-form manufacture
6
computer-aided manufacture
7
control lab
8
GMP certificate issued by the national GMP
compliance monitoring authority
9
GMP

• Basic Principles
• Specific rules

10
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!

11
Basic Principles of GMP
Introduction to the Training Course
12
Programme Overview I

• Basic Principles of GMP
• 1. Quality Management
• 2. Sanitation and hygiene
• 3. Validation
  
• 4. Complaints and recalls

13
Programme overview II

• Basic Principles of GMP
• 5. Contract production and analysis
• 6. Self Inspection
  
• 7. Personnel
  
• 8. Premises
  
• 9. Equipment
  

14
Programme overview - III

• Basic Principles of GMP
• 10. Materials
  
• 11. Documentation
• 12. Sterile production
• 13. Active pharmaceutical ingredients

15
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

16
Basic principles of GMPin more detail
17
1. Quality Management
18
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

19
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)

20
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

21
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

22
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

23
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

24
Requirements for QA Systems

• Think over what should be done properly during
  drug manufacture!

25
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

26
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

27
Quality Management

• GMP
• Ensure that products are consistently produced
  and controlled
• Diminishes risks that cannot be controlled by
  testing of product
• Cross-contamination
• Mix-ups

the most life-threatening mistakes!
28
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

29
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 others task to eliminate discrepancies
• Also QC/QA staff is acting as coordinator and is
  involved in all decisions

30
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

31
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

32
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)

33
Trained operators

• Documentation, instructions, etc. are not enough
  if the operators can not work with them properly
• Training includes also follow-up training

34
Quality Management

• Basic Requirements for GMP II
• 6. Complete records, failure investigations
• 7. Proper storage and distribution
• 8. Recall system
• 9. Complaint handling

35
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

36
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!

37
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 letterltby faxltTV
  and press warning if life threatening, etc.
• Involvement of national regulatory authorities
  according to local law

38
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

39
Quality Management Cascade

• Quality relationships
• Quality Management (overall policy)
• Quality Assurance (concept ensuring that the
  policy is achieved)
• GMP (how to do it)
• Quality Control

including
40
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.

41
Quality Management

• Basic Requirements for Quality Control
• Resources
• Adequate facilities
• Trained personnel
• Approved procedures

42
Quality Management

• Basic Requirements for Quality Control
• Tasks
• Sampling
• Inspecting
• Testing
• Monitoring (materials, environmental conditions)
• Releasing/rejecting

43
Basic Requirement for Quality Control - I

• Objects
• Starting materials
• Packaging materials
• Intermediates
• Bulk products
• Finished products
• Environmental conditions

44
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

45
Basic Requirements for QC - III

• 7. Ingredients are of the required purity
• 8. Proper containers compatibility!
• 9. 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

46
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. Correct labelling
• 4. Stability testing
• 5. Complaint investigations
• 6. Environmental monitoring

47
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

48
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

49
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

50
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

51
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 companys quality management
  programme
• Describe the action to be taken in each case

52
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

53
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
• No commitment to training

54
Before starting definitions
55
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

56
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

57
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

58
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!

59
2. Sanitation and Hygiene
60
Sanitation and Hygiene

• Objectives
• Review measures to ensure good sanitation in
• premises
• equipment
• processes
• To review measures to ensure good personnel
  hygiene

61
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

62
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

63
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

64
Design of Premises

• avoidance of cross-contamination
• Definitions
• Contamination by a foreign matter
• Cross-contamination by a material also
  manufactured there

65
Avoidance of Cross-contamination - I

• Segregated areas
• Ventilation systems and airlocks
• Clothing
• Closed processing systems
• Cleaning and decontamination

66
Avoidance of Cross-contamination - II

• Segregated areas and separate facilities for
• live vaccines and other biological materials
• penicillin products
• campaign processing

67
Avoidance of Cross-contamination - 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

68
Avoidance of Cross-contamination - 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

69
personnel in different coloured garments
70
Avoidance of Cross-contamination - 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
• clean-in-place (CIP)

71
Avoidance of Cross-contamination - VI

• Cleaning and decontamination
• procedure for removing soil and dirt
• remove all cleaning chemical residues or
  disinfectant residues
• must remove or reduce micro-organisms

72
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!

73
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

74
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

75
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!

76
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

77
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

78
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

79
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

80
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

!
81
Personnel Hygiene 2

• Illness
• staff with illness or open lesions should not
  handle starting materials, intermediates or
  finished products

82
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!

83
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

84
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

85
(No Transcript)
86
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

87
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

88
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.

89
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?

90
Sanitation and Hygiene

• Possible Issues Sanitation 1
• Mixed production
• Penicillins
• Product versus batch changeovers
• Water systems
• How long should a cleaned status last for?

91
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

92
Sanitation and Hygiene

• Possible Issues Hygiene
• Personal hygiene
• Health checks
• Dealing with health problems
• Personal responsibility
• Training records
• Frequency of handwashing

93
Exam topic
94
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