Presentation on theme: "So, What is Biomanufacturing?"— Presentation transcript:
1So, What is Biomanufacturing? *Bench Top to Bottle*Facilities in Biopharmaceutical ManufacturingCompetencies/Job and Career Opportunities
2Basis of the Bioeconomy Central Dogma: DNA RNA ProteinDiscovery Research (DNA Centric)Process Development and Biomanufacturing (Protein Centric)
3The Drug Discovery, Development and Approval Process for Biopharmaceuticals (Biologics)DISCOVERY DEVELOPMENT LAUNCHTesting PhaseDiscovery / Preclinical TestingTest PopulationLaboratory and animals studiesPurposeAssess safety biological activity and formulationsSuccess Rate5,000 compounds evaluatedManufacturinActivitiesCell line construction, Cell bankingYears6.5Approximate Cost$350MClinical TrialsPhase IPhase IIPhase III20 to 100 healthy volunteers100 to 500 patient volunteers1,000 to 5,000 patient volunteersDetermine safety and dosageEvaluate effectiveness, look for side effectsConfirm effectiveness, monitor adverse reactions from long-term use5 enter trialsProcess development, assay development,process optimization, scale-up, cGMP manufacture1.523.5$70M$100M$200MFile applicationReview process / approval1 approvedCommercial manufacture1.5$80MPhase IVAdditional post-marketing testing required by FDA=15= $1BFile NDA at FDAFile IND at FDA
4Career Opportunities in Biotechnology/Biomanufacturing Research & Development(Pre-Clinical):Discovery Research,Bioinformatics,Lab SafetyOperations:Process/Product,Development,Manufacturing& ProductionQuality:Quality Control& AssuranceClinical Research:Clinical Research,Regulatory AffairsFinance &Administration:Finance,Business Development,Administration,Information Systems,Legal, Facilities ManagementVP of Research/DevelopmentVP of OperationsDirection of QualityMedical DirectorVP of Finance & AdministrationDiscovery ResearchScientific DirectorAssociate Scientific DirectorPrincipal ScientistSenior ScientistScientist IIScientist ISenior Research AssociateResearch AssociateProcess/ProductDevelopmentDirector of Process/ProductProcess Development SupervisorProcess Development AssociateProcess Development TechnicianQuality Control(QC)Clinical ResearchManagerFinanceChief Financial AdvisorAccounting ManagerAccounting ClerkChemistryQC AnalystQC TechnicianBusiness DevelopmentDirector of Business DevelopmentRegulatory AffairsManager of Regulatory AffairsRegulatory Affairs AssociateClinical Data Manager/AssociateAdministrationDirector of Human ResourcesHuman Resources RepresentativeSafety ManagerPurchasing Agent/BuyerReceptionistAdministrative AssistantMicrobiologyQC AnalystQC TechnicianManufacturing& ProductionManufacturing SupervisorManufacturing AssociateManufacturing Technician(Operator)Manufacturing Instrumentation/Calibration TechnicianBioinformaticsScientist/EngineerAnalyst/ProgrammerMolecular ModelerQuality Assurance(QA)QA Manager/SupervisorQA Documentation SpecialistQA Documentation CoordinatorInformation SystemsManager of Information SystemsSystems AnalystAnalyst/ProgrammerLab FacilitiesFacility Manager/Supervisor(Animal Sciences)VeterinarianLab Assistant/GlasswasherLegalPatent / IP AttorneyFacilities ManagementFacilities ManagerFacilities TechnicianShipper/Receiver
5Business of Biotechnology Discovery Research (identifying, cutting out and pasting in various genes to create an “expression vector”; expression vector via the central dogma creates RNA from the genetically engineered DNA of the expression vector and the protein(s) of interest from RNA; the proteins are the biopharmaceuticals.Process Development (during which animal trial and clinical trial materials are made) identifies and maximizes the efficiency of the equipment and processes used to culture the cells that make the protein (upstream processing) and to purify it by centrifugation, filtration, and chromatography (downstream processing). Parallel to identifying equipment and processes for production, quality control microbiology and quality control biochemistry tests are developed for raw materials and the equipment and processes utilized to make the biopharmaceutical and the biopharmaceutical itself using current Good Manufacturing Practices as spelled out by the Code of Federal Regulations 21 CFR 210 and 211 that includes following equipment and process SOPs and recording everything in a Batch Record (quality assurance).m
6Business of Biotechnology BiomanufacturingCommercial scale biomanufacturing involves the building of a facility to produce the biopharmaceutical following upstream processing and downstream processing equipment and process SOPs. Samples are tested in quality control microbiology and quality control biochemistry laboratories to make sure the molecule has been produced correctly. cGMPs guide the process of manufacturing a biopharmaceutical and everything is documented (‘If you didn’t document it you didn’t do it.’) A new protein requires a facility to be prepared for its production and 400 to 600 individuals are hired, usually at least 50% are technicians. The largest bioreactor in such a facility is 25,000 liters.Once constructed and commissioned, the facility’s equipment and process SOPs must undergo validation.All instruments must be calibrated (instrumentation/calibration or metrology often part of facilities) and the set up, maintenance and use of each piece of equipment is logged.Environmental Health and Safety (EH&S) requirements are of central importance.21 CFR Part 210 and 211 is highly enforced during the making of an FDA approved protein for commercial production and widespread use (quality assurance).
7Ten Technician Jobs Anchor Ten Biomanufacturing Departments Facilities/MetrologyValidationEnvironmental Health and Safety (EH&S)QAUpstream ProcessingDownstream ProcessingQC MicrobiologyQC BiochemistryProcess Development
10Production Clean Rooms Cleanrooms are Maintained by Facilities/Metrology Technicians to the Following Specifications
11Facilities: General Cleanroom Design HEPA filters in ceilingExhaust vents on floorSeamless and rounded floor to wall junctionsReadily accessible cornersFloors, walls, and ceilings constructed of smooth hard surfaces that can be easily cleanedLimited equipment, fixtures and personnelLayout of equipment to optimize comfort and movement of operatorsPressure Differentials between roomsAirlocks to control air balance
12Facilities: HEPA Filters High Efficiency Particulate AirMinimum particle collection efficiency:99.97% for 0.3µm diameter particles.DisposableFilter made of pleated borosilicate glass microfiber
14Facilities: Pressure Differentials Used to maintain airflow in the direction of higher cleanliness to adjacent less clean areasA minimum of Pascals should be maintained between the aseptic area and an adjacent room with a different clean room classifications (doors open)
15Facilities: AirlocksPermit the passage of objects and people into a clean room.Consists of two airtight doors in series which do not open simultaneously.Spray down materials with 70% IPA before placing in the airlock
16ISOPROPYL ALCOHOL Powerful disinfectant and antiseptic Mode of action: denatures proteins, dissolves lipids and can lead to cell membrane disintegrationEffectively kills bacteria and fungiWhat is not killed by IPA?Why are aqueous solutions are preferred?
19Biopharmaceutical Manufacturing QC MicrobiologyA significant portion of the cGMP regulations pertain to the quality control laboratories including the QC Microbiology Unit which carries out microbiological testing of the product and the microbiological control of site utilities and environment. The principal functions of this unit are: Environmental Monitoring, Microbiological Testing and ID, and the Cell Culture Collection.Environmental Monitoring = Monitor non-viable and viable contamination (bioburden) throughout the facility using laser particle counter and microbial air sampler.Microbiological Testing and ID = Gowning certification, air sample processing, production (raw materials, upstream and downstream processing, aseptic fill and finish and storage) and other samples for microbiological contamination (bioburden); ID using Microbial ID System (Biolog, API Strips, PCR, other tests). Use LAL test for endotoxin in WFI water, raw materials and product. Test for mycoplasma in cell cultures (PCR, other tests).Cell Culture Collection = Testing and release of cell banks.
23ENVIRONMENTAL MONITORING “In aseptic processing, one of the most important laboratory controls is the environmental monitoring program”Guidance for Industry: Sterile Drug Products Produced by Aseptic ProcessingCurrent Good Manufacturing Practice, FDA, September 2004
27Production Clean Rooms Cleanrooms are Maintained by Facilities/Metrology Technicians to the Following Specifications
28Utilities Managed by Facilities/Metrology Technicians Water*: 200,000 to 300,000 liters of water are used per day in a commercial biopharmaceutical manufacturing facility.WFI: sand, diatomaceous earth, charcoal filter, water softener, RO, uv treatment, distillation, and constant circulate in a loop at 80 C degrees. WFI piped to production equipment for CIP and SIP processes and for making media and buffers for production.DI and USP water used in QC labs (less pure); chilled potable water used for cooling.Gasses:Air, oxygen, and carbon dioxide to keep cells happy, nitrogen, and helium (to check for leaks in equipment).HVAC: Heating, ventilation, and air conditioning in clean rooms and gray spaces.Waste*:Cells (sludge) - heat to very high temperatures and to sewer; liquids (media and buffers) treat with base and acid in a series of (three) tanks until neutral pH and to sewer.*Piped with 316L stainless dairy piping, triclover clamps, and valves.
30“If you didn’t document it, you didn’t do it.” Quality Assurance“If you didn’t document it, you didn’t do it.”
31Quality Assurance21 CFR Parts contain the minimum current good manufacturing practice for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements of the act as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess.
32Assures the product reproducibly meets predetermined specifications BIOMANUFACTURINGDOCUMENTATIONAssures the product reproducibly meetspredetermined specificationsQUALITYASSURANCEAPPROVES ALLDOCUMENTSandMAINTAINSTHE FILES“If you didn’t document it, you didn’t do it.”
33TYPES of DOCUMENTS RAW MATERIAL SPECIFICATIONS SOPs MASTER BATCH PRODUCTION RECORDSPRODUCTION BATCH RECORDSDEVIATION FORMSNUMBERING SYSTEMVALIDATION RECORDSEQUIPMENT USE and CLEANING LOG BOOKSCOMPONENT, CONTAINER and CLOSURE RECORDSDISTRIBUTION RECORDSCOMPLAINT FILES
35SOP: Standard Operating Procedure PurposeScopeResponsibilitiesReferencesDefinitionsPrecautionsMaterials/EquipmentProcedureAttachmentsHistory
36Scope Purpose References Definitions Responsibilities Describes why the SOP exists.ScopeDefines to whom and to what the procedureapplies.The person or people responsible for performing and updating the SOP.May also include the person responsible for overseeing the activities of the SOPResponsibilitiesDocuments such as manufacturer manualsand other SOPs that were consulted to write the SOP and those that should be consulted toperform the SOP.ReferencesDescribes any words, phrases or abbreviations specific to the SOPEx:Do not include pH, it is common terminologyDefinitions
37Precautions Procedure Attachments History Describes any hazards associated withthe procedure or with materials used in performing the procedurePrecautionsMaterials andEquipmentAny and all materials and/or equipment that are needed to execute the SOP.ProcedureA step by step description of theprocedure organized into subgroupsAttachmentsLists attachments by name and number. Attachments are all documents that are necessary to perform the SOP. Typically includes diagrams and drawingsHistoryOrigin of document and revisions