1. cGMP Biopharmaceutical Facility Basic Construction

2. Manufacturing FacilitiesDifferent types of facility and factory engineeringPrimary business plan

3. Specification Consultants, Audit, accreditation body Project engineering Contractor(s) Project Engineering Civil Engineering Mechanical engineering Electrical Engineering Chemical Engineering Technology- Product(s) Legalization Contractors Raw Materials Suppliers? Location, road and traffic connection Main Utilities (W,E,G) Instrument suppliers Systems Scheduling and LogisticHuman ResourceMarketing and client net-work NEW PLANT

4. Types of Biopharmaceutical Facilities Conventional Modular Design Engineering Product Based Platform Cell Factory Based Platform Technology / application Dedicated Facility Multi-purpose Facility Process BS1, BS2, BS3 Biosafety Class

6. Modular facility is more than prefabricated building!!!

7. Modular concept in Pharmaceutical and Biopharmaceutical Facilities

10. Life-time of Modular Biopharmaceutical Plant

11. Conventional vs Modular Design ConventionalModular TimeSpeed may governed by many factors (location related) Can cut 6 to 12 months of the project schedule Facility final qualityQuality may effected by the level of skilled worker in the area, available raw materials for major construction Allow design of complex, high-quality project in are where is a shortage of skilled worker Site disruptionHighLow Safety during manufacturingHigh riskLow risk CostUsually less than modular by 30% (material, labor cost) Usually higher than conventional 30% Design changeEasier ifCould be done if consider in the initial Engineering Value (Company assess)Less than ModularHigh value factory (more attractive for investors)

12. Technology Application Product Platform Based Manufacturing facility is designed for one product or certain group of products Rigid platform structure Example: Insulin Production in Novo Nordisk and Elli Lilly Cell Factory Platform Based Flexible platform structure Preferable in mid- and small pharmaceutical company Preferable for Toll- Manufacturing facility

13. Product Based Platform vs Cell factory Based Platform

14. Product Based Platform Less Flexible Dedicated for one product (or branch of product) Limited use as Toll-ManufacturingLess ExpensiveFor well-establish productsLow-Value facility (in case of sale) Cell factory Based Platform More flexible Can produce different types of products from the same biofactory (without or with minimal modification) Easily applied as Toll-ManufacturingMore expensive For well-establish products and new products High-value facility (in case of sale)

18. Biosafety Level BSLAGENTSPRACTISESAFETY EQUIPMENT (Primary Barriers) FACILITIES (Secondary Barriers) 1Not known to consistently cause disease in healthy human adults Standard animal care and management practice, including appropriate medical surveillance programs As required for normal care of each species Standard animal facility no recirculation of exhaust air directional air flow recommended Handwashing sink recommended 2Associated with human disease. Hazard: Precutaneous exposure, ingestion, mucous membrane exposure A BSL-1 practice plus: Limited access Biohazard warning signs Sharps precautions Biosafety manual decontamination of all infections wastes and of animal cages prior to washing A BSL-1 equipment plus primary barriers: containment equipment appropriate for animal species, PPEs, laboratory coats, gloves, face and respiratory protection as needed A BSL-1 facility plus: autoclave available handwashing sink available in the animal room mechanical cage washer used

19. Biosafety Level (cont.) BSLAGENTSPRACTISESAFETY EQUIPMENT (Primary Barriers) FACILITIES (Secondary Barriers) 3Indigenous or exotic agents with potential for aerosol transmission: disease may have serious health effects A BSL-2 practice plus: controlled access decontamination of clothing before laundring cages decontaminated before bedding removed disinfected foot bath as needed A BSL-2 equipment plus Containment equipment for housing animals and cage dumping activities Class I or II BSCs available for manipulative procedures (inoculation, necropsy) that may create infectious aerosols. PPEs appropriate respiratory protection. A BSL-2 facility plus physical separation from access corridors self-closing, double door access sealed windows autoclave available in facility 4Dangerous or exotic agents that pose high risk of life treating disease; aerosol transmission, or isolated agents with unknown risk of transmission A BSL-3 practice plus: entrance through change room where personal clothing is renoved and laboratory clothing is put on; shower on exiting all wastes are decontaminated before removal from the facility A BSL-3 equipment plus Maximum containment equipment (i.e. Class III BSC or xxx containment equipment in combination with full body, air- supplied positive pressure, personnel suit) used for all procedures and activities A BSL-3 facility plus separate building or isolated zone dedicated supply and exhaust vacuum and decontamination systems other requirement outlined in the lab

20. Special Safety Requirement High Sporulating fungal cultivation Air born spore Spore germinating in filter system and surface Pichia pastoris cultivation Using of toxic, flammable substrate (methanol) Vaccine production using pathogens Vaccination planControlled access Special equipment Design Special treatment of biomaterial HVAC (differential pressure)

21. Recommended Facility and Practice for BSL 2 & 3 BSLAgentsPracticeSafety Equipments (Primary Barriers) Facilities (Secondry Barriers) 2Associated with human disease. Hazard comes from autoinoculation, Ingestion, mucous membrane exposure Standard Microbiological Practice plus Biohazard sign sharps precautions Biosafety manual defining any needed waste decontamination or medical surveillance policies Primary barriers involving Class I physical containment devices used for all manipulations of agents that cause splashed or aerosols of infectious materials; personnel protection equipment involving protective lab, clothing, gloves, respiratory protection when required Open bench top sink required plus autoclave available 3Indigenous or exotic agents with potential for aerosol transmission: disease may have serious or lethal consequences Similar to BSL-2 BSL-2 plus physical separation from access corridors self-closing double door access Exhaust air not recirculated Negative airflow into laboratory

22. Primary Business Plant (Cost Estimation) Technology (Process availability) Facility required GMP requirement Reviewing by consultation committee Facility Cost Project Cost (35%) Technical Decision Process Cost

23. Let’s Start Our Facility!

24. Project Concept Change / Revision Technical data, Know-How, Consultant Overall Cost Estimation Complete Concept Review Options Develop Options Basic design Project Basic Idea Project Objective (product, market etc)

26. Project Contractor(s) (Build/ Design/ cGMP/ Validation. Etc…) Plus (Know-How, trainning, SOP, PV) Fully Turn-Key approach (including Technology Transfer ) (Build/ design/ cGMP/ Validation, etc…) Fully Turn-key approach (Building, electrical, equipment, HVAC) Major Contractor Approach all contracts managed by the client (sometimes, more than 30 contracts!) Fully Client Managed

27. What are the cGMP regulation which we should follow in our new facility? Would you like to continue? Go to next lecture No or Yes