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Good Manufacturing Practices in the manufacture of medicines


Good Manufacturing Practices in the manufacture of medicines The World Health Organization (WHO) GMP rules are the subject of the course * Requirements for QA Systems ... – PowerPoint PPT presentation

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Title: Good Manufacturing Practices in the manufacture of medicines

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

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!

Basic Principles of GMP
Introduction to the Training Course
Programme Overview I
  • Basic Principles of GMP
  • 1. Quality Management
  • 2. Sanitation and hygiene
  • 3. Validation
  • 4. Complaints and recalls

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

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

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

Basic principles of GMPin more detail
1. Quality Management
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

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)

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

Quality Management
  • Determines and implements the quality policy
  • The basic elements are
  • an appropriate infrastructure or quality system
    encompassing the Procedures, Processes, and
  • 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

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

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

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
  • 5. Define controls for all stages of manufacture
    and packaging

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

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!
Quality Management
  • Basic Requirements for GMP I
  • 1. Clearly defined and systematically reviewed
  • 2. Critical steps validated
  • 3. Appropriate resources personnel, buildings,
    equipment, materials
  • 4. Clearly written procedures
  • 5. Trained operators

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

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

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

Manufacture is based on clearly written
  • Procedures
  • batch manufacturing instructions
  • testing instructions
  • SOPs needed for all departmants
  • Preparing these documents is very important task
    (see Documentation)

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

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

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

Proper storage and distribution
  • When a new drug is developed, stability studies
    determine the storage conditions and its
  • However, the storage conditions should be met!
  • Also during distribution!

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
  • 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

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

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

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.

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

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

Basic Requirement for Quality Control - I
  • Objects
  • Starting materials
  • Packaging materials
  • Intermediates
  • Bulk products
  • Finished products
  • Environmental conditions

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

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

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

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

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

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

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

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
  • Describe the action to be taken in each case

Quality Management
  • Issues 1
  • Quality Management manual not established in
  • 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

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

Before starting definitions
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

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

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

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!

2. Sanitation and Hygiene
Sanitation and Hygiene
  • Objectives
  • Review measures to ensure good sanitation in
  • premises
  • equipment
  • processes
  • To review measures to ensure good personnel

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

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

Design of Premises - II
  • Effective cleaning and disinfection
  • choice of materials and chemicals, validation
  • Drains no back-flow, in sterile areas at a
  • Protection from insects, vermin and weather
  • from receipt of raw materials to despatch of
    released product

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

Avoidance of Cross-contamination - I
  • Segregated areas
  • Ventilation systems and airlocks
  • Clothing
  • Closed processing systems
  • Cleaning and decontamination

Avoidance of Cross-contamination - II
  • Segregated areas and separate facilities for
  • live vaccines and other biological materials
  • penicillin products
  • campaign processing

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

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

personnel in different coloured garments
Avoidance of Cross-contamination - V
  • Closed processing systems, i.e.
  • totally enclosed water purification systems
  • tanks fitted with appropriate filtration -
  • removable lids
  • present special cleaning difficulties, sometimes
  • clean-in-place (CIP)

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

Product Operations Sanitation 1
  • Work-flow
  • designed to avoid potential contamination
  • access restricted to authorised persons
  • operators
  • QC staff
  • warehouse staff
  • maintenance personnel
  • cleaners
  • the more critical the more restriction!

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

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

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

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

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

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
  • Validation and removal of disinfectant before

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

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

Personnel Hygiene 2
  • Illness
  • staff with illness or open lesions should not
    handle starting materials, intermediates or
    finished products

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!

Personnel Hygiene 4
  • Contact between product and operator
  • avoid direct contact
  • if direct handling unavoidable, gloves should be
  • check glove disinfection (for sterile production)
    and disposal

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

(No Transcript)
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

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

Personnel Hygiene 8
  • There should be no plants kept inside any factory
  • Rest and refreshment areas should be separate
    from manufacturing areas.
  • Toilets should not open directly into production
    or storage areas.

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

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

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

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

Exam topic
Sanitation and hygiene in GMP
  • Design of premises (walls, ceilings, floors,
    drains, cleaning programme, protection from
    external factors)
  • Avoidance of cross-contamination (mention
  • Campaign working versus dedicated manufacture
    areas for certain drugs (examples!).
  • Clothing
  • Health measures
  • Cleaning
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