Good Manufacturing Practices (GMP)

Overview

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 What is GMP?

• GMP stands for ‘Good Manufacturing Practice’

• GMP applies to pharmaceutical drug substances/ products
(sterile/non-sterile), API’s, biologicals and medical device
• Covers a manufacturing facility’s practices and standard operation
procedures (SOP), which when followed assure product is
manufactured to the highest quality standards
• Diminishes risks that cannot be controlled via testing of finished
product.
• Regulated by codes of GMP issued by Government Regulatory
bodies

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 Regulations, Codes and Guides

Differences between:

• Regulations have Legal Force

• Codes of GMP are not legally binding (except in
USA) but represent minimum standards of GMP
• “Manufacturing Principles” link the Codes of GMPs
to Regulations and Act
• Guidelines have no regulatory status but are
published to assist interpretation of cGMPs
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 What is the importance of GMP?

• Ensures quality product which is fit for use.

• To protect the consumer.
• To protect the manufacturer.
• To provide a consistent quality product.
• GMP builds Quality into the product at every stage of
supply chain.
• “Product Quality” can be defined as a PURE product which
is correctly IDENTIFIED, is EFFECTIVE, and is SAFE to
use.

You cannot test quality into a products !

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 GMP Compliance Focus

Product Safety Strength/Efficacy

• Manufacture per M of M • Verify formulation

• Practice Change Control • Validate processes
• Verify Raw Materials • QC test programs
• Avoid Contamination

GMP
Purity Identity

• Clean Equipment • Printed Matter Control

• No cross contamination • Identity Tests
• Control microbial growth • Reconciliations/Yields
• Line clearances
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Current International GMP Regulations

MHRA EU

KFDA
HPB
PMDA

FDA

TGA

PIC/S WHO
Major International Codes of GMP

• World Health Organisation (WHO) – 2005; GDP For Pharmaceutical

Products QAS/04.068/Rev2
• Annex 9 WHO Technical Report Series
• EMEA guide to manufacturing medicinal products
• PIC/s Guide to Good Manufacturing Practices (Medicinal) 2006
• United States - FDA CFRs
– 210/211 for Drugs and Biologics - current GMPs
– 820 Quality Systems for Medical Devices - current GMPs
• ICH – API (Q7A)

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 Regulatory Agency and Industry Web Sites

• TGA - http://www.tga.gov.au/
• PIC/s www.picscheme.org
• FDA - www.fda.gov/
• EU Code of GMP - www. pharmacos.eudra.org/
• European Medicines Agency www.emea.eu.int/
• HPB Canada - www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate
• International Conference for Harmonisation (ICH) -
www.ich.org
• Medicines & Healthcare products Regulatory Agency -
www.mhra.gov.uk/

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 Key GMP Requirements

• (1) Quality Assurance (QA)/ Quality Control (QC)

& GMP
• (2) Premises
• (3) Equipment
• (4) GMP Documentation
• (5) Validation

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 Quality Assurance/Quality Control

• If an activity is carried out to appraise manufacturing outcome or

DETECT defects it is usually a QUALITY CONTROL.
CONTROL
• If an activity is carried out to PREVENT the possibility of
occurrence of defects it is usually a QUALITY ASSURANCE
function.
• “There must be a comprehensively designed and correctly
implemented system of Quality Assurance incorporating Good
Manufacturing Practice and thus Quality Control”.

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 Relationship Between QA, GMP and QC

QA is a planned system ensures that

products are of the quality required for
their intended use. Quality Assurance
incorporates GMP.

Good Manufacturing Practice is that

part of QA which ensure that products
are consistently produced and quality
controlled to written standards …. as
required by the marketing authorization or
product specification.

Quality Control is that part of GMP which

is concerned with sampling, specifications
and testing, and with release procedures.

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

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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

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 Premises

Finish of Floors, Walls and Ceilings

• Smooth, impervious, hard-wearing, easy to clean; but not bricks,
tiles or wood
• Vinyl and epoxy/polyurethanes are most common finishes
• Resistant to operations and materials in use
• Angled frames around windows
• Coving on all joints - walls/ceiling, floor/walls, wall/wall
• Windows not opening to the outside
• Avoid sliding doors

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Premises

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 Premises - Containment

CONTAINMENT The action of confining a biological agent or

other entity within a defined space.
– Primary containment: A system of containment which
prevents the escape of a biological agent into the
immediate working environment. It involves the use of
closed containers or safety biological cabinets along with
secure operating procedures.
– Secondary containment: A system of containment which
prevents the escape of a biological agent into the external
environment or into other working areas. It involves the use
of rooms with specially designed air handling, the
existence of airlocks and/or sterilisers for the exit of
materials and secure operating procedures. In many cases
it may add to the effectiveness of primary containment.

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Containment as part of Facility Design

• Material/ Personal flow

• Airlock (AR), Pass-throughs (PT) design
• Room segregation
• Room air classification
• Negative pressure in processing area relative to adjacent rooms
• Directional air flow to sweep away any entrained product
• Dust control at point of dust generation
• Enclosed processing
• Gowning controls to prevent cross contamination of other
products (outer garments, footwear and head wear)
• Dirty equipment control
• Sticky mats

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 Premises

Example of Materials and People Flow

• Arrival of goods Entrance for visitors Entrance for Workers Shipment of goods
• QC Offices Canteen
Gowning
Incoming
• goods Shipping Material Flow
Corridor
• Corridor People Flow
Corridor
• Zone: GMP Clean
Raw
• Materials Packaging Finished
Zone: Packaging
• & Filling Products Zone: Controlled
Packaging Weighing Processing
• Storage
Storage

Washing Machine
Shop

Corridor
Utilities and Services Waste Treatment

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 Equipment

Principle
• Equipment must be
– located
– designed
– Constructed
– Installed
– Validated
– maintained
to suit their intended use

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 Equipment

Principle
• 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
• Equipment must be installed to:
– minimize risks of error
– minimize risks of contamination

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 Equipment

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
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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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 Documentation & Records

What is
being made?
Most of us when
attempting a task
need some sort of
documentation

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 Documentation & Records

And if the drawing is wrong!

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 Documentation & Records

• Good documentation is an essential part of

QA and relates to all aspects of GMP
• Clearly written documentation prevents
errors from spoken communication and
permits tracing of batch history
• Purpose of documentation
– to ensure that there are specifications
for all materials and methods of
manufacture and control
– ensure all personnel know what to do
and when to do it
– ensure that authorized persons have
all information necessary for release
– provide audit trail
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 Documentation
General Requirements
• Documents should be approved, signed and dated by
appropriate and authorised persons
• Documents should be regularly reviewed and kept up-to-date.
When a document has been revised, systems should be
operated to prevent inadvertent use of superseded documents
• The records should be made or completed at the time each
action is taken and in such a way that all significant activities
concerning the manufacture of medicinal products are traceable
• Any alteration made to the entry on a document should be
signed and dated; the alteration should permit the reading of the
original information. Where appropriate, the reason for the
alteration should be recorded

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 Types of GMP Documents/ Records

• Policies and Guidelines Facilities & Equipment Drawings/

Specification
– Plant (Site) Master File
- Equipment P&ID
– Quality Manuals
- HVAC drawings
– Quality Plans
- Facility layout drawings
– VMPs
Records
• Specifications
– Piping hydrostatic testing records
– Starting materials – Piping destructive testing records
– Finished products – Material certifications
– Quality Control Records
• Directions (Procedures and
– Batch Records (process & pack)
Instructions)
– NCFs/CAPA/Audits/OOS/CARs
– SOPs
Protocols & Reports
– Operator (Work) Instruction
Support Documents
– Master Processing/Packaging – Goods Received Register
Instructions
– Standard Names List
– Lab Test Methods
– Status Labels
– Batch Registers
– Complaints Files
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 Validation

• It is a requirement of GMP that manufacturers identify what

validation work is needed to prove control of the critical aspects
of their particular operations.
• Significant changes to the facilities, the equipment and the
processes, which may affect the quality of the product, should
be validated.
• Establishing documented evidence which provides a high
degree of assurance that a specific process will consistently
produce a product meeting its pre-determined specifications
and quality attributes.
FDA Guideline General Principles of Process Validation, 1987

• A risk assessment approach should be used to determine

the scope and extent of validation.
PIC/S Code of GMP- Annex 15 Clause 1

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 Validation

• Validation should Demonstrate that a System / Process is:

– Fit for its Intended Purpose
– Works Repeatably and Consistently
– Safe (with respect to the product)
– Complies with Regulatory Requirements
– Reflects Original Design Intent
– Incorporated into PPM and Calibration Programme
– Design, Installation & Operation supported by Formal
Documentation and Witness Testing
– A ‘Living’ record of installation and operation for future
reference

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 … there are real benefits from
Validating:
• Regulatory compliance
• Minimise corporate product liability risk
• Maximise yields
• Maximise capacity
• Minimise rejects
• Minimise rework
• Minimise complaints
• Reduce unit cost
• Reduce testing requirements
• Reduce new facility/process start-up time

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 Key Validation Terms Defined

Design Qualification (DQ)

• The documented verification that the proposed design of the facilities, systems and
equipment is suitable for the intended purpose.
Installation Qualification (IQ)
• The documented verification that the facilities, systems and equipment, as installed or
modified, comply with the approved design and manufacturer’s recommendations.
Operational Qualification (OQ)
• The documented verification that the facilities, systems and equipment, as installed or
modified, perform as intended throughout the anticipated operating ranges.
Performance Qualification (PQ)
• The documented verification that the facilities, systems and equipment, as connected
together, can perform effectively and reproducibly, based on the approved process method
and product specification.
Process Validation (PV)
• The documented evidence that the process, operated within established parameters, can
perform effectively and reproducibly to produce a medicinal product meeting its
predetermined specifications and quality attributes.
Risk Analysis/ System Impact Assessment
• Method to assess and characterize the critical parameters in the functionality of an
equipment or process.

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 Sequence of Validation

Production
Periodic
Registration
Product
Start-up
Design Process
Facility/Equipment Product Scale Reviews
Phase Qualification Phase up & Transfer
Time

Definition of Installation Operational Prospective Concurrent &

System and Qualification Qualification Performance Retrospective
Sub-systems Qualification Performance
/ Process Qualification /
Validation Process
Validation
(DQ) (IQ) (OQ) (PQ)
Calibration

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 “V Model” for Validation - Relationship
(Specifications and Protocols)

User Is based on
PQ
Design Qualification

Specification

Functional Is based on
OQ
Specification

Is based on
Design
IQ
Specification

Commissioning

Implementation

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 Validation & Project Life Cycle

Engineering Change Management

Impact Client QA CC Client QA Change

Assessment Control Interest

Const’n and Installation

Design Development

Enhanced Design
Commissioning Process
Review DQ PQ Validation

IQ & OQ

Design for Impact

Of Interest to the Regulator

GEP Contribution

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