Personnel

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Basic Principles of GMP
Personnel
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Personnel

• Principle
• Establishment and maintenance of satisfactory
  system of QA and manufacturing of products and
  actives rely on people
• Must be sufficient qualified personnel to carry
  out tasks
• Individual responsibilities must be clearly
  understood by individuals concerned
• All personnel should be aware of the principles
  of GMP that affect them

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Entering into a production area 1

• Question who is the supervisor now?
• Wrong answers
• he just left us
• he is supervising us from the office
• we know what to do, do not need any
• Right answer
• according to the SOP No now I am!

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Entering into a production area 2

• Question what are you doing now?
• Wrong answers
• do not ask me!
• we are making granules
• the boss said that we should
• Right answer
• we are working according to the SOP No, the
  batch identification data are written on the door
  of this cabinet as well as on the equipment!

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Personnel

• General - I
• Adequate number of qualified people with
  practical experience Is it easy?
• An individuals responsibilities should not be so
  extensive as to present a risk to quality Is it
  easy?

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Personnel

• General - II
• Individual written job description
• Organization Chart
• No gaps or unexplained overlaps
• Adequate authority to carry out responsibilities

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Personnel

• General - III
• Individuals must receive training in GMP
• initial training
• continuing training
• including hygiene standards
• Motivated to
• support the establishment
• maintain high-quality standards

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Personnel

• General - IV
• Prevent unauthorized access to production,
  storage, quality control
• Stop personnel who do not work in these areas
  using them as passageways

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Personnel

• Key Personnel - I
• Key personnel (which normally should be
  full-time) positions include
• Head of Production
• Head of Quality Control
• (Head of Sales and Distribution)
• Heads of Production and Quality Control should be
  independent of each other

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Question

• Theoretically, how many people must work in the
  smallest possible manufacturing site?
• 3!
• The Head of Production and the Head of QC are
  independent of each other there should be a
  General Manager they are dependent of!

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Personnel

• Key Personnel - II
• Key personnel should posses the qualifications
  of
• Scientific education. For example
• chemistry, biochemistry, chemical engineering,
  microbiology, pharmaceutical sciences and
  technology, pharmacology and toxicology,
  physiology or
• other related science subjects relevant to the
  responsibilities to be undertaken

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Personnel

• Key Personnel - III
• (Key personnel should posses the qualifications
  of, contd)
• Practical experience.
• under professional guidance
• able to take difficult decisions in a
  professional and scientific way,
• resolve the problems encountered in manufacturing
  and QC

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Personnel

• Shared Responsibilities I
• Heads of Production and Quality Control may share
  some responsibilities depending on national
  regulations
• authorization of written procedures (SOPs) and
  other documents, including amendments
• environmental monitoring and control, and plant
  hygiene
• process validation and calibration
• training, incl. application and principles of QA
• approval and monitoring suppliers

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Personnel

• Shared Responsibilities II
• designation and monitoring of storage conditions
• retention of records
• monitoring compliance with GMP
• inspection, investigation, and taking of samples
  to monitor factors which may affect quality

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Personnel

• Head of Production Responsibilities - I
• Product production and storage according to
  appropriate documentation
• Approval and implementation of production
  instructions, in-process QC and ensure strict
  implementation
• Evaluate production records signed by
  designated person before passing to QC

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Personnel

• Head of Production Responsibilities - II
• Maintenance of production department, premises
  and equipment
• Process validation and calibration performed,
  recorded and reports made available
• Training of production personnel initial and
  continuing

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Personnel

• Head of Quality Control Responsibilities - I
• Approval or rejection of materials, packing
  materials, intermediates, bulk and finished
  products
• Evaluation of batch records
• Carrying out of necessary testing
• Approval of quality control procedures sampling
  instructions, specifications, test methods, and
  other QC procedures

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Personnel

• Head of Quality Control Responsibilities - II
• Approval and monitoring of all contract analysis
• Maintenance of quality department, premises and
  equipment
• Validation, including analytical procedure
  validation, and calibration of control equipment
• Initial and continuous training of QC personnel

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Personnel

• Useful reference documents for inspectors
• Organization Chart
• Job descriptions

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Personnel

• Training - I
• Training, in accordance with a written programme
  for
• all personnel whose duties take them into
  production or
• into control laboratories and
• for others whose activities could affect the
  quality of the product
• On induction and continuing
• on theory and practice of GMP
• approved by either the head of Production or QC
  as appropriate
• training records should be kept
• training before undertaking any new task

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Personnel

• Training - II
• Staff in special areas
• clean areas or
• working with highly active, toxic, infectious,
  sensitizing materials
• should be given specific training methanol
  and unexperienced workers
• The concept of QA and its understanding and
  implementation should be fully discussed during
  training

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Personnel

• Visitors or Untrained Personnel
• Preferable not to take them in. If this is
  unavoidable, for example GMP inspectors
• Must be given information in advance
  particularly about
• personal hygiene and
• protective clothing requirements
• Must be accompanied and closely supervised at all
  times

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End of Personnel Section
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Basic Principles of GMP
Premises
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Premises

• Principle
• Premises must be located, designed, constructed,
  adapted and maintained for the operations
• Minimize risks of errors and cross-contamination
  
• Permit effective cleaning
• Permit effective maintenance
• Minimize build-up of dirt and dust
• Eliminate any adverse effects on quality

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Premises

• Principle
• Premises must be located to minimize risks of
  cross-contamination e.g. not located next to a
  malting factory with high airborne levels of yeast

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Premises

• Location
• Geography, climate,
• noise and economic
• factors
• Neighbours
• What do they do?
• What impact can they have on the business?
• Pollution/effluent control
  

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Premises

• Premises should be
• built to
• Facilitate sanitation
• Be maintained and cleaned
  easily
• Services availability
• Protection against entry of insects or other
  animals

Your opinion?
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Premises

• Lighting important, particularly when
  organoleptic control
• Moisture, heat, change of air they should not
  disturb the equipment

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Premises

• Allergenes, live microorganisms dedicated areas
• Hormones, citostatics, non-medicines not on the
  same area/line as other medicines (segregated
  areas) or campaign working and thorough cleaning
  or dedicated manufacturing lines

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Manufacture with pathogenic viruses
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Premises

• Manufacturing area
• Pipework no dead ends, far anogh from the wall
  to permit cleaning

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Premises

• Pipes and pipings
• Fixed pipework
• clearly labelled
• indicate contents
• direction of flow
• Service pipings
• adequately marked
• non-interchangeable connections or adaptors
• Dangerous gases and liquids

water
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Premises

• Ancillary Areas
• Rest and refreshment rooms
• Changing, washing and toilet areas
• Maintenance workshops
• Animal houses

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Premises

• Other Areas
• Personnel rest areas /cafeterias/changing rooms
• away from operating areas
• prevention of cross-contamination
• prevention of operators going outside in work
  clothes
• provision of access control
• prevention of visitors access to operating areas
• Maintenance service areas
• separated from production areas whenever possible

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Premises

• Design Principles
• Process flow
• Material flow
• People flow

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Premises

• Example of Materials and People Flow
• Arrival of goods Entrance for visitors Entrance
  for Workers Shipment of goods
• 
  
  
• 
  
  Material Flow
• 
  
  People Flow
• 
  
  Zone Clean
• 
  
  Zone Packaging
• 
  
  Zone Controlled
• 
  
  
• 
  

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Premises

• Weighing areas
• Control systems
• Environmental controls, dust control
• Segregation
• Smooth, impervious, durable, easy to clean
  finishes
• Cleaning
• Documentation

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Premises

• Production and Packaging
• Logical flows of materials and people
• Adequacy of working space and orderly and logical
  positioning of equipment
• Interior surfaces smooth/crack-free/easy to clean

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Premises

• Windows should not open to the outside!

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Premises

• Finish of Floors, Walls and Ceilings
• Difficult but not impossible to get right
• Smooth, impervious, hard-wearing, easy to clean
• Resistant to operations and materials in use
• Windows not opening to the outside
• Avoid sliding doors

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Premises
Not these!

• Finish of Floors, Walls and Ceilings
• Difficult but not impossible to get right,
  smooth, impervious, hard-wearing, easy to clean
  but not bricks, tiles, wood or sliding doors!

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Not this!
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Not this!
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Not this!
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Premises

• Finish of Floors, Walls and Ceilings
• Much better

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Muchbetterceiling!
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Much better!(corridor)
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Much better!(see thecorners,floor, walls)
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Premises

• Cross-contamination
• 1. Segregated areas
• 2. Airlocks and pressure differentials
• 3. Treatment of recirculated air
• 4. Protective clothing
• 5. Effective cleaning procedures
• 6. Closed production systems
• 7. Residue testing
• 8. Status labelling

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Premises

• Manufacturing and Packaging I
• Pipework and other fittings sited to avoid
  recesses
• Drain design
• equipped to prevent backflow
• open channels avoided

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Premises

• Manufacturing and Packaging II
• Effective air handling to suit product
• temperature
• humidity
• filtration
• monitoring

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Premises

• Manufacturing and Packaging III
• Specifically designed and laid out to avoid
  mix-ups and cross-contamination
• Changing facilities to provide segregated access
• Prevention of cross-contamination
• Suitable lighting levels

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Premises

• In-Process and QC laboratories
• Located separate from but near manufacturing
• prevention of cross-contamination
• separate biological , microbiological,
  radioisotopic areas
• Designed for the operations being carried out
• suitable storage space

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Premises

• Warehouse I
• Storage areas of sufficient capacity
  for
• Clean, dry and maintained within acceptable
  temperature limits records of thermometer in
  log-books, maximum-minimum thermometer, automatic
  recording apparatus
• Receiving-dispatching packs area under cover,
  protection from heat, dirt, and rain tablets in
  cellophane blisters and rain

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Premises

• Warehouse II
• Areas clearly marked and access limited for
  quarantine status good.
• QC sampling area with GMP standards
• Segregated areas for rejected, recalled and
  returned materials
• Separate areas for highly active, hazardous,
  narcotic materials
• Printed materials storage

Closed area! Enter with permission!
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Premises

• Warehouses
• adequte space to store different products in
  separate spaces
• Quaratine types segregated areas or computerised
  stores with built-in quarantine, but always
  labelling

Rejected
Quarantine
Released
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End of Premises Section
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Basic Principles of GMP

• Equipment

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Equipment

• Principle, 1
• Equipment must be
• located
• designed
• constructed
• adapted
• maintained
• to suit their intended use

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Equipment

• Principle, 2
• Equipment layout and design must aim
• to minimize risks of error
• to permit effective cleaning
• to permit effective maintenance
• And to avoid
• cross-contamination
• dust and dirt build-up
• any adverse effect on the quality of products

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Equipment

• Principle, 3
• Equipment must be installed to
• minimize risks of error
• minimize risks of contamination

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Equipment

• Balances and Measuring Equipment
• Appropriate range
• Precision
• Available to
• production
• quality control
• Calibrated
• scheduled basis
• checks
• records maintained

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Equipment

• Production equipment
• Design
• easily and thoroughly cleaned
• scheduled basis
• Location
• Maintenance
• No hazard to the products
• suitable non-reactive materials
• non additive
• not absorptive
• Defective equipment
• removed
• labelled

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Equipment

• Control laboratory equipment
• Equipment and instruments
• suitable for the tests to be performed CHN
  analysator for routine purposes?
• Defective equipment
• removed
• labelled

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Equipment

• Washing and Cleaning
• Design promotes easy cleaning
• On scheduled basis
• Washing and cleaning equipment
• Manual
• Automated (Clean in place (CIP), Steam in place
  (SIP))
• Not the source of contamination

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End of Equipment Section
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Basic Principles of GMP

• Materials

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Materials

• Objectives 1
• To review specific requirements for each type of
  material
• Starting materials
• Packaging materials
• Intermediate and bulk products
• Finished products
• Rejected and recovered materials
• Recalled products
• Returned goods
• Reagents and culture media
• Reference standards
• Waste materials
• Miscellaneous materials.

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Materials

• Objectives 2
• To examine the problems associated with
  materials, and how to overcome them

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Materials

• Principle
• Objective of the pharmaceutical manufacturer
• produce finished products
• combination of materials
• Materials combined
• active pharmaceutical ingredients
• auxiliary materials(excipients)
• packaging materials
• Special attention

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Materials

• General requirements for materials
• All incoming materials and finished products
• quarantined after receipt,
• until released for use
• distribution
• stored
• under appropriate conditions
• orderly fashion (batch segregation)
• materials management
• stock rotation (FIFO or FEFO)

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FIFO and FEFO

• FIFO First In, First Out if the material has no
  shelf-life (only re-analysis date, e.g. the
  majority of substances)
• FEFO First Expire, First Out if the material
  (mostly dosage-forms and some degradable
  substances) has shelf-life

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Materials

• Starting Materials I
• Purchasing
• Suppliers
• Consignment
• integrity
• seal
• order
• delivery note
• suppliers labels
• Cleaned and labelled

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Materials

• Starting Materials II
• Damaged containers
• Different batches in one consignment
• Starting material label
• name and internal code
• batch number(s), (supplier and manufacturer on
  receipt)
• status
• expiry date or re-test date
• Sampled containers identified

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Materials

• Examples of Labelling of Starting Materials

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Materials

• Starting Materials III
• Use only released material
• Dispensing
• designated persons
• written procedure
• accurately weighed
• clean, labelled containers
• Independent checks
• material and weight
• Dispensed material
• kept together and labelled

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Materials

• Packaging materials I
• Primary and printed materials
• as for starting materials
• purchasing, handling and control
• No unauthorized access
• Storage and transport
• avoid mix-ups
• issue and return SOP

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Materials

• Packaging materials II
• Specific reference number for batch or
  consignment
• Packaging department checks
• quantity, identity and conformity
• Outdated or obsolete material

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Materials

• Intermediate and bulk products
• Appropriate conditions
• Purchased
• as starting materials

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Materials

• Finished products
• Quarantine until released
• Storage conditions
• Evaluation and documentation
• product release

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Materials

• Rejected and recovered materials
• Rejected materials
• Clearly marked
• Stored separately in restricted areas
• Action
• Reprocessing
• exceptional
• procedure and records
• batch number
• additional testing

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Materials

• Rejected and recovered materials
• Recovery
• prior authorization
• additional testing

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Materials

• Recalled products and returned goods
• Recalled products
• identified
• stored separately
• access controlled
• fate
• Returned goods
• SOP decision regarding the fate
• nature of product, storage conditions
• history, time lapse
• records

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Materials

• Reagents and culture media
• Recorded upon receipt or preparation
• Reagents
• preparation in accordance with SOP
• label
• concentration, standardisation factor,
  shelf-life, date that re-standardisation is due,
  storage conditions
• signed and dated
• Culture media
• positive and negative controls

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Materials

• Reference standards
• Official reference standards
• use only as per monograph
• storage
• Reference standards prepared by the producer
• tested, released
• stored in same way as official reference
  standards
• Secondary or working standards
• appropriate checks and tests
• regular intervals
• based on official reference standards

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Materials

• Waste materials and miscellaneous materials
• Waste materials
• proper and safe storage
• toxic and flammable materials
• separate, enclosed, as per legislation
• not allowed to accumulate
• collected for safe disposal
• regular intervals
• Miscellaneous
• rodenticides, insecticides, sanitizing material
• contamination risks

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Exam topics
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Personnel in GMP

• In general (which personnel dou you needfor drug
  manufacture?)
• Organisational charts, job descriptions
• How to regulate access to drug manufacturing
  areas
• Who are Key personnel, their relationship and
  main responsibilities
• Training and its topics

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Premises in GMP

• Principles (location, design, space, etc.)
• Design principles of manufacturing premises
• Design and operation principles of Warehouses
  (incl. storage of printed materials. Weighnig
  areas, windows)
• How to prevent cross-contamination

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Equipment in GMP

• Principles (location, design, installation,
  maintenance)
• Handling of pipework
• Use of balances
• Production equipment positioning
• Labelling status

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Materials in GMP

• What is quarantine?
• Proper labelling (colour, and content)
• What to do with containers arrived damaged
• What are the primary and secondary packaging
  materials
• Special measures for printed materials
• How to store rejected materials, when may
  recovery or reprocessing be done
• Speak about reference standards