Biopharmaceutical Product Design and Development

• A biopharmaceutical product is medicine used to cure diseases
• Biopharmaceutical facilities include infrastructural buildings, structural design considerations, and cleanroom designs
• Utilities for biopharmaceutical facilities include water, steam, compressed air, and gases like nitrogen; water is most important

Design Sequence

• Research phase consists of molecule identification and small-scale development
• Development phase includes cell culture, animal studies for toxicology, and clinical trials:
  • Phase 1 trials involve 20-80 volunteers for safety
  • Phase 2 trials involve 200-500 volunteers for efficacy
  • Phase 3 trials involve 3000-5000 volunteers for population analysis
• Process phase includes manufacturing development from micrograms to kilograms of product

Biopharmaceuticals

• Biopharmaceuticals are GMOs which produce elevated amounts of therapeutic proteins to prevent and treat life-threatening diseases
• High risk of contamination, especially from viruses
• Exhibit high degradation and complexity
• Examples include insulin, etanercept, recombinant proteins like insulin and growth hormones, antibodies (Humira, Herceptin, Enbrel), vaccines, gene therapy, and personalized medicine, such as treatments targeting specific proteins that promote cancer proliferation

Pharmaceuticals

• Pharmaceuticals are chemical small molecules
• Less complex, low denaturing, and exhibit low contamination risks
• Examples include aspirin, ibuprofen, and atorvastatin

Expression Systems

• Bacteria and yeast are used to generate simple proteins without post-translational modifications
• Mammalian cells are used to produce complex proteins
• GMP guidelines are part of good manufacturing practice

Quality Assurance

• Guidelines and quality assurance ensure appropriate standards exist
• This leads to good quality, consistent, and reproducible products
• Product quality involves process control and tight specifications
• Understanding the entire process is important to design parameters and control processes for a secure outcome
• USA follows FDA, Ireland follows EMA (HPRA component authority); to ensure product quality
• EU follows Eudralex guidelines and EU legislation decided upon by the european commission
• Volume 4 contains all the GMP guidelines specifically for medicines
• Annex has the regulations (1-7); guideline is a broad understanding
• European Medicines Agency (EMA) uses EU legislation to determine recommendations for medication approval
• Annex 15 and 16 are important notes for inspections

A Drug can be Adulterated

• If the methods, facilities, or controls used in manufacturing, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice
• FDA's importance of facility and production, as per FD&C Act 501(a)(2)(B)

Upstream Manufacturing

• Upstream- inoculum stage involves transfecting plasmid into cells
• Vials with these transfections are called master batch
• Master batch frozen cells are thaw vials
• Cell Culture involves putting scale up cells 5ml – 500mls → 5L-500L-- 50,000L into seed bioreactors

Primary Recovery

• Primary recovery (harvesting) includes separation of cells and proteins
• Centrifugation causes cells to form into a pellet, which is discarded

Downstream

• Downstream (purifications)
• Protein A affinity chromatography is where Protein A binds the Fc region of antibodies and separates them
• Protein A is produced by bacteria on skin
• Cation and anion chromatography is where Cation-anion exchange allows for pH adjustments

Viral Filtration

• Filter size is at 700Da and antibodies cant’ go through sized 1500 daltons
• Viruses are endogenous
• Harvesting – primary recovery
• Centrifugation, microfiltration, depth filtration
• Purification happens downstream to ensure protein conformation is right
• Remove any contaminents and ensure right protein concentration
• Formulation adjusts protein concentration with added excipient or stabilizers
• Filling is a stand alone operation where sterilised product is aseptically filled into sterilised containers
• Terminally sterilised biologics are sterilized at the end
• Lyophilisation removes all moisture

Bioprocessing

• Critical process parameters of fermentation include oxygen, water, and nutrients

Facility Design

• Facility design prevents adverse consequences
• Ireland is gateway of EU with low corporation tax, english speaking, and has an educated workforce
• Many production facilities re built multi product or general pupose
• This limits exposure to microbiological contamination
• General considerations include flow of materials, defined areas, adequate personnel facilities

Income Materials

• Quarantine before release or rejection of intermediates
• Everything raw materials have to be tested to ensure standards and held
• Failed material needs to be quarantined or holded before discarding
• Production should be very separate from the test lab
• Multiproduct considerations require dedicated manufacturing facilities because of higher regulatory risks
• Facility design must prevent contamination and cross-contamination

Conceptual Design Phase

• Assists in locations, local infrastructure, manufacturing requirement decisions
• Determine production capacity
• Used for process diagrams, floor plans, building layouts, estimates of construction time and construction costs
• Basis of design (BOD) document is the most important as it lists all specifications for design by facilities
• Contains complete descriptions of facilities
• Checklist contains contamination control, HVAC, monitoring, equipment process support services

HVAC

• Heating, Ventilation, and Air Conditioning
• Basis of Operations Document defines how the facility will be used during manufacturing
• Explains manufacturing and is complimentary document for BOD
• Process items will dictate batch size and production frequency

Processes

• Preparation of materials and use of disposable liquid systems
• Open vs. closed systems must be controlled and follow cleaning regimes
• Containment strategy and material distribution must be followed
• Process support areas involve autoclaving and depyrogenation
• What do you want of the phase includes HVAC, costing and manufacturing

Manufacturing Logistics

• Design should reflect the manufacturing logistics
• Design driven by:
  • Market Potential
  • Penetration of a delivery system
  • Patient dose number of packs
  • Downtime

Utilities & HVAC

• Consider process facilities → PW (purified water), WFI (what for injection), Steam and clean gases
• Critical for fill-finish plants to be contiguous and intakes/exhausts segregated
• Process Equipment layout should consider size, costs etc
• Access Corridors should allow covered material movement and personnel access to all facilities

Personnel Access

• Restrict movement of people and require essential people to have secondary/primary clothing
• Design Creep is a result of too many suggestions and inadequately developed control of facilities
• Detail Design Considerations include layouts, sizes, quantities and procurement
• Design Qualification continues through construction

Construction

• Phase continues through construction
• Used for planning application that is complete and submitted
• A new kitchen = wrong sizes, wrong materials, lots of adjustments

Construction Facilities

• Types include a building’s construction from a green field, a brown field, or a fit-out
• Modular approach- building it off site and piecing them together in the end
• Clean Rooms → room where airborne particles are limited for aseptic conditions
• Design should have vents for ventilation
• Seamless/rounded floor to wall junctions prevent vermin, allow easy cleaning and minimise corners

HVAC

• Should consider room grade, temperatures
• HVAC determines environmental controls
• Considerations - Airborne particulates, pressure

Air Flow

• Maintain relative direction of airflow between spaces
• HVAC configurations include less return air
• AHU functions to distribute of dumps air
• Louvers adjust volume
• HEPA filters remove airborne particles and borosilicate glass

Cleanroom Classifications

• Cleanrooms control airborne particles and are built with HEPA filters
• Laminar flow cabinet class A → ISO 5

Explore biopharmaceutical product design, covering facility infrastructure, utilities, and the significance of water systems. Learn about the research, development, and process phases, including clinical trial stages and the role of genetically modified organisms (GMOs).