GMP

1. Basics of Good Mfg Practice (GMP)
What is Quality Management?
 The aspect of management function that determines
and implements the “quality policy”
 The overall intention and direction regarding quality,
as formally expressed and authorized by top
management
 The basic elements are:
 An appropriate infrastructure or “quality system”
encompassing the organization structure,
procedures, processes and resources
 The systematic actions necessary to ensure
adequate confidence that a product (or service) will
satisfy given requirements for "Quality”
12/22/20181

2. Principles of Quality Assurance (QA)
 Quality assurance is a management tool
 Wide-ranging concept
covers all matters that individually or collectively
influence the quality of a product
 Totality of the arrangements
to ensure that the drug is of the right quality for the
intended use
 Quality Assurance incorporates GMP
12/22/20182

3. QA System should ensure:
 Products are designed and developed correctly
 Complying with, e.g. CGMP, GCP, GLP
 Production and control operations are defined
 Managerial responsibilities are defined
 In job descriptions
 The manufacture, supply and use of correct starting
and packaging materials
 Controls are performed, including intermediates,
bulk, calibration and validation
 Correct processing and checking of the finished
product 12/22/20183

4.  Products are sold/supplied only after review by the
authorized person
Complying with marketing authorization,
production and QC requirements
 Proper storage, distribution and handling
 Procedures for self-inspection and/or quality audits
 Reporting, investigation and recording of
deviations
 System for change control/approval
 Regular evaluation of product quality to verify12/22/20184

5.  Manufacturer is responsible for the quality of the
product
 Fit for intended use
 Comply with marketing authorization
 Safety, efficacy and quality
 Requires a comprehensively designed and well
implemented QA system
 Fully documented, and effectiveness monitored
 Competent personnel, sufficient premises,
equipment and facilities
12/22/20185

6. Good Manufacturing Practices (GMP)
 That part of QA that ensures the products are
consistently produced and controlled
Quality standards
Marketing authorization
 Aim: Diminishing risks that cannot be controlled by
testing of product
 Contamination and cross-contamination
 Mix-ups (confusion)
12/22/20186

7. Basic Requirements for GMP
 Clearly defined and systematically reviewed
processes
 Qualification and validation is performed
 Appropriate resources are provided:
Qualified and trained personnel
 Premises, space, equipment and services
Materials, containers, labels
 Procedures, storage, transport
Laboratories and in-process control
 Clear, written instructions and procedures
 Records of actions, deviations and investigations
 Records for manufacture and distribution
 Proper storage and distribution
 Systems for complaints and recalls
12/22/20187

8. Components of GMP
1. Premises
 Principle
 Important aspects to be kept in mind to ensure the
suitability of the operations to be carried out for
different dosage forms and product range:
 Location
 Design
 Construction
 Adaptation
 Maintenance
12/22/20188

9. Location
 Geography, climate, noise and economic factors
 Neighbors
What do they do?
What impact can they have on the business?
 Pollution/effluent control
 Minimum risk for contamination of products and
materials
 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 12/22/20189

10.  General
 The layout and design should aim to:
 Minimize risks of errors
 Permit effective cleaning
 Permit effective maintenance
 Avoid cross-contamination, build-up of dirt
and dust
 Avoid any adverse effect on the quality of
products
 Design Principles
 Keep in mind:
 Material flow
 People flow
 Process flow 12/22/201810

11. Design
 Suitable design and construction to facilitate good
sanitation
 Cleaning and disinfecting according to detailed written
procedures records maintained
 Maximum protection against entry of insects, birds and
animals
 Procedure for rodent and pest control
Construction
Suitable materials
Electrical supply
Suitable lighting (especially for visual on-line
checks)
Temperature and relative humidity control
Appropriate and effective ventilation 12/22/201811

12.  The temperature and relative humidity should be
controlled, monitored in accordance with an SOP, and
the results recorded.
 The limits should be appropriate according to the
materials stored and product processed
 Dust generating operations
e.g. during sampling, weighing, mixing, packing of
powders, etc.)
 Measures should be taken to prevent cross-
contamination
 Measures to facilitate cleaning
 Design of areas for weighing of materials
 Proper air supply
 Dust control measures (including extraction of dust
and air)
 Easily cleanable surfaces
12/22/201812

13. Maintenance
 Careful maintenance done
 Repairs and maintenance should not present any
hazard to the quality of the products
 Specific areas
 Ancillary areas
 Storage areas
 Weighing areas
 Production areas
 Quality control areas 12/22/201813

14. Ancillary Areas
 Rest and refreshment rooms separate from
manufacturing and quality control areas
 Changing, washing and toilet areas accessible and
appropriate numbers
 Maintenance workshops separated from production
 Animal houses well isolated – separate air handling and
entrance
Storage areas
 Separate receiving and dispatch bays
Materials and products protected from weather
 Area to clean incoming materials provided
 Cleaning of incoming containers
 Cleaning with a cloth, or duster
12/22/201814

15.  Storage areas of sufficient capacity
 Orderly storage of categories of materials and products
 Separate and segregated areas: starting materials,
packaging materials, intermediates, bulk, finished
products, quarantined, released, rejected, returned and
recalled products and materials
 Appropriate temperature and relative humidity conditions
within defined limits
 Provided, controlled, monitored and recorded
 Good storage conditions: clean, dry and appropriate
lights
 Quarantine area: clearly marked and access restricted
 A separate sampling area is the norm: no risk for
contamination or cross-contamination
 Safe and secure areas for highly active, radioactive12/22/201815

16. Printed packaging materials
 Critical to ensure compliance with correct labelling
of products
 Special attention to sampling
 Special attention to safe and secure storage
 Ensure compliance with specifications, prevent
mix-ups
Weighing areas
Weighing operations – in separated areas
Appropriate design
Provision for dust control
Smooth, impervious, durable, easy-to-clean
finishes
Cleaning procedures and records
12/22/201816

17. Production areas
 Minimize risk of cross-contamination:
 Dedicated and self-contained facilities for some
products such as
 highly sensitizing materials (e.g. penicillins)
 biological preparations (e.g. live microorganisms)
 Separate facilities for other products such as some
antibiotics, hormones, cytotoxic substances
 Non-pharmaceuticals normally not in the same facility,
e.g. pesticides, herbicides
 Layout in accordance with sequence of production
 Appropriate cleanliness level
 Adequate work and in-process storage space
 Orderly and logical positioning of equipment
minimizes risk of contamination, mix-ups and missing12/22/201817

18.  Specially designed areas for packaging
 Layout to avoid mix-ups and cross-contamination
 Starting and packaging materials, intermediates and
bulk exposed to environment:
 Interior surfaces (walls, floors, ceilings) – smooth,
free from cracks and open joints
 No shedding of particles
 Easy and effective cleaning permitted
 Disinfection if needed
 Design of pipe work, light fittings, and ventilation points
– no recesses that are difficult to clean
 Access for maintenance from outside production areas
 Drains of adequate size, and equipped to prevent
back-flow 12/22/201818

19.  Effective ventilation with air control facilities
 Including filtration of air to a sufficient level to
prevent contamination and cross-contamination –
also external environment
 Control of temperature and relative humidity where
necessary
 Regular monitoring of conditions during production
and nonproduction periods
 Windows should not open to the outside
 Finishing of floors, walls and ceilings
 Should be smooth, impervious, hard-wearing, easy
to clean.
 No bricks, tiles, wood or sliding doors where residue12/22/201819

20. Quality Control areas
QC laboratories should be separate from
production areas
Separate areas for biological, microbiological and
radioisotope methods
Suitable design with sufficient space to avoid mix-
ups and cross contamination
Suitable space for storage of samples, reference
standards, solvents, reagents and records
Suitable construction materials
Prevention of fumes
Ventilation
Separate air supply (production and QC)
Separate rooms for some instruments to protect
them from interference (e.g. electrical, vibration,
12/22/201820

21. 2. Personnel
 Principle
Establishment and maintenance of satisfactory
system of QA, manufacture and control of products
and actives rely on people
Must be sufficient qualified personnel to carry out
tasks
Individual responsibilities must be clearly defined
and understood by individuals concerned
Written job descriptions
All personnel should be aware of the principles of
12/22/201821

22.  Personnel requirements:
Adequate number of persons
With necessary qualifications
With practical experience
 An individual’s responsibilities should not be so
extensive as to present a risk to quality
 All personnel should be aware of GMP
 Must receive training in GMP:
Initial training
Continuing training
Including hygiene standards 12/22/201822

23.  Motivated to
support the establishment and maintain high-
quality standards
 Prevent unauthorized access
To production areas
Storage areas
Quality control
 Stop personnel who do not work in these areas
using them as passage ways 12/22/201823

24. 3. Sanitation and Hygiene
 Scope
 High level of sanitation and hygiene practised – in
every aspect of manufacturing. It covers:
 Personnel
 Premises
 Equipment and apparatus
 Production materials and containers
 Products for cleaning and disinfection
 All potential sources of cross-contamination
 Personal Hygiene
 Health examinations:
Before and during employment
Periodic eye examinations for those who do visual
inspections
12/22/201824

25.  Training:
 Practices in personal hygiene
 Written procedures and instructions
 Written procedures and instructions - to wash hands
before entering production area
 Some also use disinfectants
 Signs in areas (e.g. changing rooms)
 Illness or open lesions:
May affect the quality of products
Should not handle starting materials, intermediates or
finished products, etc.
Instruction and encouragement to report to supervisors
 Direct contact between product and operator:
Should be avoided
Starting materials, primary packaging materials, 12/22/201825

26.  Protection of product from contamination:
Clean clothes appropriate to personnel activities
Including hair covering (e.g. caps)
 Check change rooms/changing facilities
Hand washing, signs, drying of hands
Used clothing stored in separate closed containers
while awaiting cleaning
Laundering of clean area clothing according to an
SOP and in an appropriate facility
Procedure for disinfecting and sterilizing when
12/22/201826

27.  Smoking, eating and drinking not allowed in production
areas, laboratories and storage areas
 No chewing (e.g. gum), or keeping food or drinks
allowed
 No plants kept inside these areas
 Toilets should not open directly into production or
storage areas
 Personal hygiene procedures including wearing
protective clothing apply to all persons entering into
production areas:
Full-time employees
Temporary workers
Contractor's employees
Visitors 12/22/201827

28.  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
 Appropriately designed airlocks
 Appropriately designed ventilation system with air
12/22/201828

29.  Avoidance of Cross-Contamination
 Special precautions should be taken to prevent
generation and dissemination of dust
 Proper air control – supply and extraction, suitable
quality
 Due to uncontrolled release of:
 dust, gas, particles, vapours, sprays, organisms,
residue, insects
 Measures that can be taken to prevent cross-
contamination also include:
Segregated areas
Ventilation systems
Airlocks -Appropriately designed airlocks
Clothing
 Closed processing systems 12/22/201829

30.  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
 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 12/22/201830

31. 12/22/201831
 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)
4. Equipment
Objectives
 To review the requirements for equipment
 Selection, design, use and maintenance
 To discuss problems related to issues around selected
items of equipment
Principle
 Equipment must be

32.  Equipment
 Principles
 Equipment layout and design must aim:
to minimize risks of error
to permit effective cleaning and
maintenance
 To avoid:
cross-contamination, dust and dirt build-up
any adverse effect on the quality of
products
 Equipment must be installed to:
minimize risks of error 12/22/201832

33. Pipes
 Fixed pipe work
 clearly labelled
 indicate contents and direction of flow
 Service pipings and devices
 adequately marked
 non-interchangeable connections or adaptors for
dangerous gases and liquids
 E.g water lines, equipment components, air-handling
systems 12/22/201833

34. 5. Documentation
General Principles
 Good documentation is an essential part of the QA
system
 Should exist for all aspects of GMP
 Purpose of documentation
Defines specifications and procedures for all
materials and methods of manufacture and control
Ensures all personnel know what to do and when to
do it
Ensure that authorized persons have all information
necessary for release of product
Ensures documented evidence, traceability, provide
records and audit trail for investigation 12/22/201834

35.  Design and use
 Depends upon manufacturer
 Some documents combined into one, sometimes
separate
 Why are documents so important?
 Communication, Cost, Audit trail
 Documents should be
 Designed, prepared, reviewed, distributed with care
 Comply with marketing authorization
 Design of documentation important
 Look at the “Style” of the document
 Instructions in the imperative
 Short sentences preferred to long sentences
 Approval of documentation
 Approved, signed and dated by appropriate responsible
persons 12/22/201835

36. a. Master Formulae
 Master formula for each product and batch size
 Manufacturing instructions include:
 Name of product with product reference code
 Dosage form, strength and batch size
 List of starting materials including quantities and
unique reference code
 Expected final yield with acceptable limits (and
intermediate yields)
 Processing location and principal equipment
 Equipment preparation (e.g. cleaning, assembling,
calibrating, etc.)
 Detailed stepwise processing instructions and
checks, pretreatments, sequence of additions, times,
temperatures, etc. 12/22/201836

37.  Authorized packing instructions for each product, pack
size and type, and to include:
Name of the product
Dosage form, strength and method of application
Pack size (number, weight or volume of product in
final container)
List of all packaging materials (quantities, size, types
and code number)
Examples of printed packaging materials, with
location of batching information
Special precautions, including area clearance checks
(before and after operations)
Description of the packaging operation including
equipment to be used 12/22/201837

38. b. Batch Processing Record
 Record kept for each batch processed
 Based on the master or specifications (e.g. copied to
avoid errors)
 Check suitability of area and equipment
 clear of previous products, documents, materials
 Checks recorded
 Information recorded during processing include:
 Name of the product, batch number
 Dates and times (e.g. start, major steps, completion)
 Name of person responsible for each stage of
production
 Name of operators carrying out each step (check
signatures) 12/22/201838

39. 12/22/201839
 Reference number and quantity of materials used in
the batch
 Main processing steps and key equipment
 In-process controls carried out, person's initials, and
results obtained
 Yield at each stage with comments on deviations
 Expected final yield with acceptable limits
 Comments on any deviations from process
 Area clearance check, instructions to operators
 Record of activities

40.  Standard Operating
Procedures
 Which activities require
SOPs?
 Equipment and analytical
apparatus:
Assembly, validation
Calibration
Internal labelling,
quarantine and
storage of materials
Operation
Maintenance and
cleaning
Personnel matters:
Qualification
Training
Clothing
Hygien
 Environmental monitoring
 Pest control
 Complaints
 Recalls
 Returned goods
12/22/201840

41.  SOP and records for
receiving materials
 Name of material as on
delivery note
 Name and in-house code
 Date of receipt
 Supplier's and
manufacturer's name
 Batch number
 Quantity and number of
containers received
 State of container and
other information
 Other SOPs include:
 Internal labelling,
quarantine and storage of
materials
 Operation, maintenance,
calibration and cleaning of
all instruments and
equipment
 production and QC
 Sampling of materials
 Batch numbering systems
 Material testing at all
stages of production
12/22/201841

42. 6. Validation
Validation is an essential part of GMP, and an
element of QA
 Basic principles include:
Safety, quality and efficacy of products
Built into the product – as it cannot be "inspected
or tested into a product“
Critical steps in the process need to be validated
Need for confidence that the product will
12/22/201842

43. Qualification and Validation
 Qualification and validation are essentially
components of the same concept
 The term qualification is normally used for
equipment, utilities and systems
 The term validation is normally used for processes
 In this sense, qualification is part of validation
Validation: Approaches to validation
 Two basic approaches:
1. Evidence obtained through testing (prospective
and concurrent validation), and
2. Analysis of accumulated (historical) data
(retrospective validation)
12/22/201843

44.  Whenever possible, prospective validation is preferred.
 Retrospective validation is no longer encouraged
 Retrospective validation is not applicable to sterile
products
 Both prospective and concurrent validation, may
include:
1. extensive product testing, which may involve
extensive sample testing (with the estimation of
confidence limits for individual results) and the
demonstration of intra and inter-batch homogeneity;
2. simulation process trials;
3. challenge/worst case tests, which determine the
robustness of the process;
4. control of process parameters being monitored
12/22/201844

45.  Validation should be performed:
1. For new premises, equipment, utilities and
systems, and processes and procedures;
2. At periodic intervals; and
3. When major changes have been made.
 Validation in accordance with written protocols.
 A written report on the outcome to be produced.
 Validation over a period of time, e.g.
 At least three consecutive batches (full production
scale) to demonstrate consistency. (Worst case
situations should be considered.)
12/22/201845

46.  Distinction between in-process controls and
validation
 In-process tests (performed during the
manufacture of each batch; their objective is to
monitor the process continuously)
 Demonstrate suitability for new manufacturing
formula or method
 Process, materials and equipment to prove
consistent yield of a product of the required quality
 Manufacturers to identify what validation work is
needed
 Significant changes (facilities, equipment,
processes) - should be validated
 Risk assessment approach used to determine the
12/22/201846

47.  Qualification
 Qualification should be completed before process validation is
performed
 A logical, systematic process followed
 Start from the design phase of the premises, equipment,
utilities and equipment
 Major equipment and critical utilities and systems normally
require IQ, OQ and PQ
 Calibration and verification
 Traceability to standards used
(e.g. national, regional or international standards)
 Calibrated equipment, instruments and other devices to be
labelled, coded or otherwise identified
indicate status of calibration and recalibration due date
 If not used for a certain period of time
 function and calibration status to be verified
shown to be satisfactory before use
12/22/201847

48. Qualification stages
 There are four stages of qualification:
 Design qualification (DQ);
Installation qualification (IQ);
 Operational qualification (OQ); and
Performance qualification (PQ).
 All SOPs for operation, maintenance and calibration
should be prepared during qualification
12/22/201848

49.  Training provided and records maintained
Design qualification: Provides documented
evidence that the design specifications were met
Installation qualification: Provides documented
evidence that the installation was complete and
satisfactory
 During IQ:
Purchase specifications, drawings, manuals,
spare parts lists and vendor details should be
verified
Control and measuring devices should be
calibrated 12/22/201849

50. Operational qualification: Provides documented
evidence that utilities, systems or equipment and all its
components operate in accordance with operational
specifications
 Demonstrate satisfactory operation over the normal
operating range as well as at the limits of its operating
conditions (including worst case conditions)
 Operation controls, alarms, switches, displays and other
operational components should be tested
Performance qualification: Provides documented
evidence that utilities, systems or equipment and all its
components can consistently perform in accordance
with the specifications under routine use
 Test results collected over a suitable period of time to
prove consistency 12/22/201850