CPPT 9010: Facility Design & Operation

D.I.T. DT275
Masters in Chemical and
Pharmaceutical Process Technology
24th November 2009

Clement Farrar
BA BAI MSc MIEI
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 Lecture Overview

 1) Introduction
 2) Aseptic Processing
 3) Process Stages
 4) Utilities Introduction
 5) Assignment Introduction/ Workshop

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 Qualifications

 1998 - 2002: B.A., B.A.I. - Mechanical &

Manufacturing Engineering, TCD

 2002 - 2003: M.Sc. - Bioengineering, TCD

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 Work Experience

 2003 - Present: Wyeth BioTech (now Pfizer), Grange

Castle, Clondalkin

 2003 - 2008: Process Engineer - Drug Substance

Start Up to Commercial Production
 2009: Process Engineer - Syringe Fill Finish Start Up

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Wyeth At A Glance
 Founded in 1860 by two Wyeth brothers in Philadelphia
 Became American Home Products Corporation in 1926
 Changed to Wyeth in 2002

 Corporate headquarters – Madison, New Jersey

 2008 Sales – $22.8 billion
 Approximately 47,400 employees worldwide: 22,600 U.S. and 24,600
international
 2009 – Became part of the Pfizer

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Wyeth Pharmaceuticals’ Leadership Positions

#1 Antidepressant

#1 RA & Psoriasis Biologic

#1 Vaccine

#1 HRT

#1 I.V. Antibiotic

#1 Hemophilia B

#1 Infant Formula (In Aggregate Market Where We Compete)

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 Ireland’s Pharmaceutical Industry…
Then and Now

Exports less that €100 million

1973Employment less than 2000
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 Ireland’s Pharmaceutical Industry…
Then and Now
Exports €16.7 billion – Largest net exporter of
pharmaceuticals in the world

Employment 24,500 - 2 out of every 5 pharmaceutical

jobs created in Europe in 2008 were in Ireland - 50%
hold a third level qualification

2008 120 companies including 13 of the top 15 worldwide

Replacement value of the investment by the pharma

sector in the Irish economy exceeds €40 billion – €3
billion in Corporation Tax

€7 billion invested in last nine years

Exports less that €100 million

1973 Employment less than 2,000

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Why Ireland?
 Availability of fully serviced 90 acre site
 Quality and availability of workforce
 Support from Government, IDA Ireland and South
Dublin County Council
 Corporation Tax regime in Ireland
 Focus on Research in Ireland
 35 years of manufacturing experience in Ireland.

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 Once a muddy field in Clondalkin…

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Now… A Centre of Biotechnology
Excellence

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Grange Castle At-A-Glance

 Largest capital investment ever undertaken by Wyeth

 1,224 full time employees and 220 contractors
 Producing some of the world’s top medicines
 The anchor for the establishment of a biotechnology cluster in
Ireland
 One of the largest biotech campuses in the world
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Aerial View of Grange Castle
Drug
Central Utilities Substance
Building

Warehouse Product
Development
Centre (PDC)

n u f ac t uring
Ma
Suites

Vaccine
Vial Conjugation
Syringe Fill/Finish
Fill/Finish

Quality & Administration

Building (QA/QC)

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 Grange Castle Products

The first advance in 20 years

for the treatment of Pneumococcal-
moderately to severely active Meningicoccal Vaccine
rheumatoid arthritis (RA) in
adult and juvenile patients

Relistor is a new product,

Antibiotic – for the which will be used for the
treatment of treatment of opioid-
complicated intra- induced side effects,
abdominal infections including constipation and
post-operative bowel
dysfunction.
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Recruitment
 80,000 job applications to date
 25,000 Interviews conducted to date
 1,224 full time employees in place today
 220 full time contractors
 11% of employees relocated from international locations
 Half of this group are Irish people returning home
 95% with third level qualifications
 55% male; 45% female
 Average age 37

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Aim of Module
 Experienced Process Engineer working in the
industry
 Invite any Questions I may be able to answer
from my experience
 Assignment - aim is to try to get you thinking in a
real life ‘facility design’ frame of mind
 Give you as much knowledge/ experience to
allow you use your skills & knowledge
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 Facility Design & Operation

 1) Introduction
 2) Aseptic Processing
 3) Process Stages
 4) Utilities Introduction (inc HVAC)

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 Learning Outcomes
At the end of this Lecture you should be able to …..

 Describe what is meant by Aseptic Processing

 Define what is meant by a Critical Process step
 Define types and sources of Contamination in Aseptic operations
 Describe how contamination risk is minimised
 Describe key factors influencing facility design
 Describe the process steps in a typical Aseptic process
 Define the area Classification Requirements for typical process steps
 Describe what is meant by ‘Direct’ and ‘Indirect’ impact utility systems

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Sterile Processing
 Parenteral Drugs:
 Injectable drugs bypass the body’s natural defences so must be sterile
 Terminal Sterilisation:
 Sterilise drug in final container (after manufacture and packaging)
 Preferred method of sterilisation
 Moist Heat Sterilisation
 Gamma Radiation
 E-Beam
 Microwave
 Many drugs not suitable for this method of sterilisation
 Aseptic Processing:
 Individual components are sterilised separately and brought together in the final
form in a sterile environment.

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 Aseptic vs. Sterile

 Definition of Aseptic
“Free of or using methods to keep free of Pathological
Micro-organisms” synonym : sterile

 Sterile processing area is also know as the Aseptic

Processing Area, Critical Processing Area or Sterile
Core.

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 Aseptic Facility Design
Aseptic Processing Area
Area where critical process steps carried out
Critical Process Steps
Activities during which the sterilised product and container / closure
are exposed to atmosphere

Design must minimise challenge to Aseptic Processing Area – HOW?

Flow of raw materials, components, drug product containers, closures, in-
process materials, drug products and people through the facility shall be
designed to prevent contamination.

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 Contamination – Types & Sources
 Non-Viable (Particulates) including Endotoxins
 Sources: Equipment, Clothing, Water, Air

 Viable (Micro-Organisms)
 Sources: Equipment, People, Water, Air, Tools,
Excipients, Active Ingredients

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 Contamination – Preventative Measures
 Non Viable:
 Contact Parts are cleaned and sterilised
 Water is purified
 Air is HEPA Filtered

 Viable:
 Interventions in sterile core are minimised
 Solutions are sterile filtered through a 0.2m filter
 Air is HEPA Filtered

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 Design concept to minimise challenge to
Aseptic Processing Area
Fig 2.1 Nested Manufacturing Zone (ISPE Guideline Vol 3)
Nested Manufacturing Zones (Diagrammatic Product: Out-Flow Not Shown

External Areas
Street, Offices, Restaurant

Transition Zone
Brings People, Materials etc., from External Areas to the
Manufacturing Areas in a ‘Controlled’ Manner

Clean Area
Provides a Protective Envelope to Minimise the
Challenge to the Critical Areas

Critical Processing
Remove Raw
People Change Change Area Compounding
Outers Materials
e.g. Point of Fill

Sterilise

Remove
Outers

Container Closures

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 Aseptic Facility Design
Fig 2.2 Sterile Manufacturing Flowchart (ISPE Guideline Vol 3)
 Highlights interdependence of operations in support of the core sterile activity
 Highlights importance of support area design to GMP Compliance of Aseptic Processing Area
Sterile Manufacturing Flowchart

People Materials Services

Actives
Container / Equipment Air / Water /
Gowning +
Closure Components Gases Liquids
Excipients

Control of Flows Into Aseptic Area

Cleaning / ASEPTIC PROCESSING AREA Cleaning /

Sterilisation Sterilisation
Terminal Sterilisation?

Control of Flows Out of Aseptic Area

Waste
Dirty Equipment
Components for
Clothing Materials Effluents Re-Use

PRODUCT

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 Exercise 1
You are members of a project team designing a new
sterile product (s) facility –

Discuss what product / process information you would

need to ensure the facility can handle this new
product

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 Exercise Answer
Key Factors Influencing Facility
Design
 Product
 Form - liquid/ powder
(lyopholised)
 Product Characteristics-
light sensitive/ Excipients-
number, quality, form,
hazards etc.
 Presentation- vials/
syringes
 Market- market need,
regulatory requirements-
IMB/ FDA

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 Exercise Answer
Key Factors Influencing Facility Design
 Process
 Degradation with thermal sterilisation?
 Process duration - will impact production capacity
 Cross Contamination Issues - e.g. strong antibiotics
 Current Facility Capacity - spare capacity or shortfall

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