1. Facilities Design & Environmental Flows in Biomanufacturing Processing

2. Introduction to Facilities
Physical buildings or set of buildings
Building referred to as FACILITY or SITE
Features of a bio-manufacturing facility:
Sections/units based on process req’mt
Warehouse/storage
Control rooms/areas
Maintenance shop
HVAC system
Utilities( Air, Gases, Water, Electricity
Security
Offices/Locker rooms/Break rooms etc……

3. Facility Design Features unique to processes
Features unique to products
Designed to control the environment
That in turn protect these processes and products from
contamination/adulteration due to
Microorganisms, molds
Airborne contaminants

4. Design and Regulatory Framework
How do companies decide upon design?
Understand & examine primary element
to have a clean environment
To protect the product and the process

5. FDA’s Role in Facility Design

6. cGMP Requirements for Facility Design
21 CFR 211 subpart C--Buildings and Facilities
Design and construction features
Lighting
Ventilation, air filtration, air heating and cooling
Plumbing
Sewage and refuse
Washing and toilet facilities
Sanitation
Maintenance
Drug Manufacturing Inspections can be found at

7. Facilities and Equipment Systems
Cleaning and maintenance
Facility layout and air handling systems for prevention of cross-contamination (e.g. Penicillin, beta-lactams, steroids, hormones, cytotoxics, etc.)
Specifically designed areas for the manufacturing operations performed by the firm to prevent contamination or mix-ups

8. Facilities and Equipment Systems cont.
General air handling systems
Control system for implementing changes in the building
Lighting, potable water, washing and toilet facilities, sewage and refuse disposal
Sanitation of the building, use of rodenticides, fungicides, insecticides, cleaning and Sanitizing agents

9. CP 7346.832, Pre-approval Inspections/Investigations

10. CP 7346.832, Pre-Approval Inspection/Investigations Facility Design
5. Building and Facilities:
The addition of any new drug to a production environment must be carefully evaluated as to its impact on other products already under production and changes that will be necessary to the building and facility.
Construction of new walls, installation of new equipment, and other significant changes must be evaluated for their impact on the overall compliance with GMP requirements.

11. Compliance Program 7346.832, Pre-Approval Inspection/Investigations
5. Building and Facilities
For example:
New products, such as cephalosporins, would require that:
- the firm demonstrate through appropriate separation and controls that cross-contamination can not occur with regard to other products being made in the same facility.
- Also, facilities that may already be operating at full capacity may not have adequate space for additional products.

12. Biosafety Levels BSL-1 to BSL-4 BSL-1: basic lab
BSL-2: basic lab + aerosol confinement
biosafety cabinet
BSL-3: containment laboratory
2 door separation from building occupants
BSL-4 maximum containment laboratory
separate building from general research population

13. Biosafety Level 1 Area Door Sink Easily cleaned work surfaces
Impervious bench tops
Sturdy furniture
Windows fitted with fly screens

14. Biosafety Level-1 Concepts of Biosafety
Well characterized agents
Agents not known to cause disease (in healthy human adults)
Prophylactic treatment available
Open bench procedures
Animals in open cage system or open environment
(outdoors)
Good laboratory practices, GLPs

15. Biosafety Level -1 Lab
Work can be performed on an open lab bench or table
Personal protective equipment , (lab coats, gloves, eye protection) are worn as needed
An example of microbe that is typically worked wiith at a BSL-1 is a non-pathogenic strain of E. coli.

16. Biosafety Level -1 Practices
Bench-top work allowed
Daily Decontamination
Manual pipetting
Required Hand washing
Red bag waste
Bio cabinet not required (unless creating aerosols)
2˚ containment

17. Biosafety Level-2 Laboratory
BSL-1 Lab plus:
lockable doors
chairs covered with non-fabric material
Biosafety cabinets installed as needed
eyewash available
negative airflow, non-recirculation recommended
door closed when work is in progress
Autoclave within facility

18. Biosafety 2 - Laboratory
BSL-1 Lab plus:
lockable doors
chairs covered with non-fabric material
Biosafety cabinets installed as needed
eyewash available
negative airflow, non-recirculation recommended
door closed when work is in progress
Autoclave within facility

19. Biosafety Level-2 Laboratory cont.
Access to the laboratory is restricted when work is being conducted.
Appropriate personal protective equipment (PPE) is worn, including lab coats and gloves.
Eye protection and face shields can also be worn, as needed.
All procedures that can cause infection from aerosols or splashes are performed within a biological safety cabinet (BSC)
Working with microbes that are typically indigenous and associated with diseases of varying severity.
An example of a microbe that is typically worked with at a BSL-2 laboratory is Staphylococcus aureus.

20. Biosafety Level-2 Practices
Concepts of Biosafety
Agents associated w/ human disease
Treatment for disease available
Agent poses moderate hazard to personnel and environment
Direct contact or exposure
Percutaneous exposure
Scratch, Puncture, Needle stick
Mucus membrane exposure
Eyes, Mouth, open cut

21. Biosafety Level-2 Practices
Limited access to lab when work in progress
Daily decontamination
Mechanical pipetting
Lab coat, safety glasses and gloves required
Red bag & sharps containers required

22. Biosafety Level-2 Practices, contd.
Biohazard Sign posted at entrance to lab
Label all equipment (incubators, freezers, etc.)
Documented training
Baseline serology or pre-vaccination may be required

23. Signs and Labels

24. Biosafety Level 3 Laboratory
BSL-3: used if working with
Microbes that can cause serious or potentially lethal disease through respiratory transmission.
Respiratory transmission is the inhalation route of exposure.
Typical example of a microbe that is typically worked with in a BSL-3 laboratory is
Mycobacterium tuberculosis, the bacteria that causes tuberculosis.
Appropriate PPE must be worn, and respirators might be required
All work with microbes must be performed within an appropriate BSC

25. Biosafety Level 3 Working in High Containment
Indigenous or exotic agents
Aerosol transmission
Serious health effects
Treatment may or may not exist

26. Biosafety Level 3 Practices
Public access NOT permitted
Daily decontamination after spill and upon completion of experiment
Autoclave required and waste is disposed at the end of day
Required foot activated handwashing sink and controls
No sharps unless absolutely necessary

27. Biosafety Level 3 Practices, contd.
Aerosol minimization procedures required
Wrap around disposable clothing is required. Specialized equipment may be required depending upon procedures
Biohazard: Signs and labels posted

28. Biosafety Level 3 Practices, continued
Bench top work not permitted
Documented training and personnel competency certification (for BSL-3 procedures)
Baseline serology
Spills – report immediately and treat accordingly
Vaccinations/post exposure protocols and SOP’s, Biosafety Manual, Biosafety Officer

29. BSL 3 Design Elements Negative airflow (into lab)
Most negative at rear of lab
> 12 air changes per hour
Dedicated exhaust fan
Exhaust velocity >3000 fpm, away from intakes, people
Direct exhaust, no recirculation

30. BSL 3 Design Elements cont.
Airflow monitor, gauges
Keycard, locked access
Doors open inward, self-closing
Door sign at entry
Class II BSC
Means of communication to areas outside lab

31. Biosafety Level 4
For work with extremely dangerous agents that cause life-threatening diseases
When there is no available vaccine or therapy
Work is performed in complete isolation using:
BSC
Full body, air supplied, positive-pressure personnel suits
Facility is generally a separate building or isolated zone
Special ventilation requirements
Special waste management system
Preventing release of these agents into the environment
Positive Pressure Personnel Suits (PPPS)
Space suits, Blue suits, Moon suits

32. Class I Biological safety cabinets
Open fronted
Negative-pressure ventilated cabinet
Provides only worker protection NOT
product protection

33. Class II Biological safety cabinets
- Negative-pressure ventilated cabinet
Provides HEPA-filtered, recirculated
airflow within the cabinet
Exhaust air is HEPA-filtered
Provides personnel and product protection
Types of Class II BSCs
Class II A: HEPA filtered air is discharged into the room
Class II B: HEPA filtered air is discharged out of the room
Class II A/B: Can be used either way.

34. Class III BSC Ventilated cabinet - totally enclosed
Gas tight construction
Operations are conducted through attached rubber gloves.
Both supply and exhaust air are HEPA-filtered
Provides both personnel and product protection

35. Essentials of Ideal Facility Layout
Principle of minimum movement
Principle of flow
Principle of space
Principle of safety
Principle of flexibility
Principle of interdependence
Principle of overall integration
Principle of minimum investment
Principle of Environment control