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

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

Qualifications 1998 - 2002: B.A., B.A.I. - Mechanical & Manufacturing Engineering, TCD 2002 - 2003: M.Sc. - Bioengineering, TCD

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

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

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)

Ireland’s Pharmaceutical Industry… Then and Now Exports less that €100 million Employment less than 2000 1973

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 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 2008 Exports less that €100 million Employment less than 2,000 1973

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.

Once a muddy field in Clondalkin…

Now… A Centre of Biotechnology Excellence

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

Aerial View of Grange Castle Drug Substance Central Utilities Building Product Development Centre (PDC) Warehouse Manufacturing Suites Vaccine Conjugation Vial Fill/Finish Syringe Fill/Finish Quality & Administration Building (QA/QC)

Grange Castle Products The first advance in 20 years for the treatment of moderately to severely active rheumatoid arthritis (RA) in adult and juvenile patients Pneumococcal-Meningicoccal Vaccine Relistor is a new product, which will be used for the treatment of opioid-induced side effects, including constipation and post-operative bowel dysfunction. Antibiotic – for the treatment of complicated intra-abdominal infections

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

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

Facility Design & Operation 1) Introduction 2) Aseptic Processing 3) Process Stages 4) Utilities Introduction (inc HVAC)

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

Sterile Processing Parenteral Drugs: Terminal Sterilisation: 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.

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.

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.

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

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

Design concept to minimise challenge to Aseptic Processing Area Fig 2.1 Nested Manufacturing Zone (ISPE Guideline Vol 3)

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

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

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

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