18-20: Biologics Flashcards
Biologics
-derived from living systems
-recombinants, blood factors, mRNA, vax, cell and gene therapies
Common features of biologic drugs
-biological origin (animal or cellular)
-high molecular weight
-higher order structure
Early biologics
-insulin from pig pancrease in 1920s
-making vax in eggs 1957 (we still do this)
-recombinants in the 1980s: rinsulin from bacterial cells
mAbs
-leading rprotein drug
-first mAB, OKT3 for transplant rejection
-high molecular weight
-2 light chains, 2 heavy chains, disulfide bonds
-produced in mammalian cells bc posttranslational glycosylation is important to function
CAR-T
-2017
-Kymriah
-living drug
-T cells removed from blood, transfected w antigen receptor that recognizes cancer antigen
-grown in culture
-returned to patient and infused
mRNA vax
-contain mRNA in lipid nanoparticles
-mRNA cosed for spike protein
-four lipids that condense mRNA and enable delivery to cytoplasm
-PEG-lipid, cationic lipid, helper lipid, cholesterol
Biologics today
-protein factory (CAR-T)
-transfection reagent (mRNA)
-theraputic agent (mAB)
-instructions for transfected cells (DNA vax)
-flu vax in eggs
Dosage forms for biologics
-usually parenteral bc cant survive tummy
-exceptions: oral vax, some oral peptides
Common dosage forms for biologics
-solution for injection
-pen or autoinjector
-pre-filled syringe
-lyophillized powder for reconstitution
Biologics Part 1 summary
-important repidly growing lcass
-mAbs, mRNA, therapies, vax
-nucleotide and peptides will also be discussed
-injection, pens/autoinjectors, syringes, lyophilized solids
Why solution formulation for biologics
-easy and cheap
-convenient bc no reconstitution
-can be inspected visually before admin
clinical concerns for biologics in solution
-efficacy
-steriliry
-side effects (dose-limiting immune response)
-pain on injection
Formulation concerns for biologics in solution
-stability (aggreagation, shelf-life, storage)
-viscosity and ease of injection (affected by API concentration)
-manufacturing (cost and time)
Formulation variable for biologics in solution
-solution properties (pH, ionic strength/tonicity, drug conc, volume, excipients
-container
-storage conditions
pH formulation variable
-max stability at 3-4
-but not a good pH for injection
-additives can make this worse
Concentration formulation variable
-aggregate content inc w inc protein concentration
-high conc in aggreagation risk
How do proteins aggregate
-chemical reaction
-unfolding esp partial
-colloid interactions
Excipeint formulation variable
-help stabilize protein
-preferentially excluded from protein surface promote interactions w water and stabilize native structure
Clinical effects of formulation EPO and PRCA example
-erythroportein used to treat anemia in renal disease
-anti-EPO antibodies reduces drug effect and natural EPO
-PRCA can result
-inc PRCA associate w inc change in container closure
-formation of EPO aggregates has been suggested
What if solution formulation doesn’t work
-store at fridge temp
-freeze
-freeze0dry for resonstitiution
-re-engineer protein molecule
-abandon drug candidate
Prefilled syringes, pens, and autoinjector reminder
-not formulations
-medical device
-solution inside is formulation
-together they are combination products
Practical considerations of solution formulations of biologics
-store at rec temp
-protect from light
-avoid agitation
-examine vial for particulates prior to admin
-be aware of potential adverse immune responses
-DONT SHAKE
Covid mRNA vax
-suspenions of LNP in solution
-mRNA in LNPs
-not active w/o LNP
-suspension
Biologics part 2 summary
-solutions for injections are common for biologics
-solution properties desirable for slinical use may not be optimal for stability
-aggregation is a serious instability influenced by formulation, storage, and handling
-be aware of potential for adverse immune response
shaking might make aggregation
worse
Pros of syringes, pens, autoinjectors
-convenience
-ease of transport
-discrete
-inc compliance
-reduce risk of dosage error or contamination
Disadvantages of pre-filled syringes, pens, autoinjectors
-higher cost than vial plus syringe
-cannot mix 2 drugs
-drug waste due to priming
-greater surface to volume ratio, lubricants, can induce aggregation
Common features of pre-filled, pens, syringes
-drug solution
-needle
-piston/plunger
-housing
Special concerns for pre-filled, pens, autoinjections
-higher surface-volume ratio
-lower total volume
-lube, oils could cause droplets in solution
Proteins are surfactants
-can unfold when exposed to surfaces or interfaces
Part 3 summary
-prefilled, pens, autos used to deliver solution formulations of biologics
-formulation concerns for biologics in solution apply
-higher surface to volume ratio than in vials and the use of lubricants may promote aggregation
Advantages of lypophilized powders
-reduce rates of degradation
-improve stability and shelf-life
-fridge usually not needed
-can use in pre-filled, pens, and autos (dual chamber)
disadvantages of lypophilized powders
-must be reconstituted prior to injection; less convenient than solutions
-more expensive and time consuming to manufacture
What is lypophilization
-freeze-drying
-removes water by sublimation
-occur at low temp and low pressure
-gentler than other methods of removing water
-better for fragile drugs
-same process for instant coffee
How does lyophilization work
-freezing
-vacuum
-sublimation
-dry powder
Lypophilization can cause instability
-promote aggregation
-disulfide scrambling can be accelarated
-protein structure can be preturbed (inhibited by lyo and cryo protectancts
-aggregated protein can be observed on reconstitution
Clinical considerations of lyophilization
-use caution when:
-reconstituting
-storing and handling
-when admin (look at it)
Lyophilized summary
-used for biologics that are unstable in solution
-must be reconstituted prior to injection
-use care when reconstituting solutions
