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GGood ood MManufacturing anufacturing PPractices (GMP)ractices (GMP)

OverviewOverview

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express written permission of SeerPharma Pty Limited, SeerPharma (Singapore) Pte Ltd or its subsidiaries.

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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 GMPsto 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

GMP

• Printed Matter Control• Identity Tests• Reconciliations/Yields• Line clearances

• Clean Equipment• No cross contamination• Control microbial growth

• Manufacture per M of M• Practice Change Control • Verify Raw Materials• Avoid Contamination

• Verify formulation• Validate processes• QC test programs

Product Safety Strength/Efficacy

IdentityPurity

Current Current International GMP Regulations

TGA

EUMHRA

HPB

FDA

WHO

PMDA

KFDA

PIC/S

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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 DETECTDETECT defects it is usually a QUALITY CONTROLQUALITY CONTROL.

• If an activity is carried out to PREVENTPREVENT the possibility of occurrence of defects it is usually a QUALITY ASSURANCEQUALITY ASSURANCEfunction.

• “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.

Quality Control is that part of GMP which is concerned with sampling, specifications and testing, and with release procedures.

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.

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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

•

• Material Flow

• People Flow

• Zone: GMP Clean

• Zone: Packaging

• Zone: Controlled

•

Q C

Offices Gowning

Canteen

Incominggoods

Corridor

Corridor

Shipping

Corridor

Packaging

Weighing Processing

Filling

Raw Materials

& Packaging

Storage

Washing

Machine Shop

Finished Products Storage

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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DocumentationGeneral 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

– Plant (Site) Master File

– Quality Manuals

– Quality Plans

– VMPs

• Specifications

– Starting materials

– Finished products

• Directions (Procedures and Instructions)

– SOPs

– Operator (Work) Instruction

– Master Processing/Packaging Instructions

– Lab Test Methods

Facilities & Equipment Drawings/ Specification

- Equipment P&ID

- HVAC drawings

- Facility layout drawings

Records– Piping hydrostatic testing records– Piping destructive testing records– Material certifications– Quality Control Records– Batch Records (process & pack)– NCFs/CAPA/Audits/OOS/CARs

Protocols & Reports

Support Documents– Goods Received Register– Standard Names List– 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

Time

Design Phase

Definition of System and

Sub-systems

Facility/Equipment Qualification Phase

Installation Qualification

Operational Qualification

Prospective Performance Qualification

/ Process Validation

Concurrent & Retrospective Performance Qualification /

Process Validation

Periodic Product Process Reviews

Production Registration

Start-upProduct Scale up & Transfer

Calibration

(DQ) (IQ) (OQ) (PQ)

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

PQ

OQ

IQ

Is based on

Is based on

Is based on

User Specification

Functional Specification

Design Specification

Implementation

Design Q

ualification

Commissioning

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Validation & Project Life Cycle

PQ

IQ & OQ

Commissioning Process Validation

Enhanced Design Review DQ

Design Development

Engineering Change Management

Impact Assessment

Client QA Change Control Interest

Design for Impact

Of Interest to the Regulator

GEP Contribution

Const’n and Installation

Client QA CC