biologics Flashcards

Question

Why are Biologics typically so unstable?

Answer 1

Instability of biomacromolecules inherent due to biological origin Conditions must be compatible with biological molecules BUT this means they are good food for microbes – or atleast good environment Also, many reactions of biological molecules are thermodynamically favourable in these conditions Finally, almost all Biologics contain proteins- and proteins are relatively unstable

Answer 2

1) Proteins have three-four layers of vital structure 2) Basic polypeptide chain is susceptible to a range of degrading reactions with water and oxygen 3) Many changes are irreversible physical instability and chemical instability like oxidation , hydrolysis, isomerism, racemisation ALL proteins are unstable

Answer 3

Denatured proteins – won’t work, often irreversible

Answer 4

Chemical’ storage different from ‘food’ storage Salt/cleaning chemicals vs protein rich foods Small molecule drugs vs biomacromolecules Microbial contamination is the major problem for wet foods Another is ‘disintegration’ or ‘degradation’ of fresh foods food solutions Canning: autoclave (steam sterilise) and seal aseptically Drying: air drying (biltong), freeze drying (fruit freezing: peas biologics solution Filter sterilise and seal aseptically Works for some (must certify cold-chain storage) Works for some (expensive; need for reconstitution)

Answer 5

sterilisation - prevent microbial growth preservatives - prevents microbial growth stabilisers - Reduces chemical and physical instabilities of proteins Fridge- Reduces rate of chemical and microbial spoilage freezer - Reduces rate of chemical and microbial spoilage Lyophilisation- Prevents aqueous phase degradation (hydrolysis etc.) and microbial growth

Answer 6

+ Stabilises protein - Proteins are susceptible to hydrolysis and oxidation- and other chemical reactions. Removal of water prevents these reactions. Also prevents microbial spoilage, although + Can increase shelf life significantly - Typically freeze-dried proteins can be stored at room temperature or higher- although for safety, usually kept in fridge - Freezing damage- Freeze-drying is the most common way to remove water from biological materials- but freezing creates ice crystals, which can damage protein -expensive - Slow and complex manufacturing process requires large and highly specialised equipment- pharmaceutical grade freeze-dryer

Answer 7

Freeze protein plus excipients in vial (without lid!) (ideally fast and controlled) Powerful vacuum applied to frozen material Ice is sublimed- i.e. turned into water vapour – very slowly without melting Finally, freeze dried protein (plus excipients) left behind as a “cake”

Answer 8

Freeze protein plus excipients in vial (without lid!) (ideally fast and controlled) Powerful vacuum applied to frozen material Ice is sublimed- i.e. turned into water vapour – very slowly without melting Finally, freeze dried protein (plus excipients) left behind as a “cake”

Answer 9

Excipients can interact with and alter function of protein Solubility-enhancers – not needed for many proteins. Note: protein solubility lowest solubility at i.e.p. Detergents – e.g. polysorbate 20 or 80, albumin. Prevent interface-induced unfolding Buffers – phosphates, citrates Preservatives – e.g. phenol, benylalcohol Antioxidants – e.g. ascorbic acid, sulphites, cysteine Lyprotectants – Non-reducing sugar added during removal of water to protect structure of protein. Osmotic compounds: ensure isotonicity (sugars, NaCl)

Answer 10

Availability often limited by large molecular size 1) Permeability through epithelia 2) Access to tissues from blood vessels 3) Cell membranes (although drug target usually not within cells) Common problem- oral delivery unsuitable Different route for each class/example Route typically used is dictated by the characteristics of each class

Answer 11

Availability often limited by large molecular size 1) Permeability through epithelia 2) Access to tissues from blood vessels 3) Cell membranes (although drug target usually not within cells) Common problem- oral delivery unsuitable Different route for each class/example Route typically used is dictated by the characteristics of each class

Answer 12

gene therapy proteins and peptides - Injected (im, sc, id), inhaled- TYPICALLY potent; low, precise doses needed, Overdose can cause problems Usually short half-life and often high frequency monoclonal antibodies -Injected: IV infused or Subcutaneous TYPICALLY low specific activity; high doses needed Overdose unlikely Long half life often low frequency vaccine : Injected (im, sc), also oral Must be delivered to lymph nodes where immune response is generated

Answer 13

Usually are injected or infused. ROUTE AND DOSE DEPENDS ON TYPE Potency is more difficult to quantify for biologic agents Monitoring is a key component of early therapy. New modes of administration eg transdermal vaccines

Answer 14

Depends on exact therapeutic BUT often: High activity -Control of dose vital Fast clearance following iv injection- serum half life short -Typically im/sc -Better for patient -’Depot’ effect If protein too large - subject to lymphatic drainage Bioavailability less than 100% BUT: many other experimental routes of delivery explored including: Inhaled, transdermal, oral

Answer 15

Depends on exact drug/ condition BUT typically: High dose needed- blocking or killing High injection volume- can be too high for subcutaneous Serum half life very long Typically intravenous or [in some cases, if dose can be achieved] subcutaneous

Answer 16

Peptides (T cells) Structures (B cells)

Answer 17

Similar or different from other ‘bio’ therapeutics? -Great promise, but little actual clinical success -Fundamental risk of mutagenesis by gene insertion Large field of research, major progress in last 20 years Also major advances in last 5 years Still totally unique approach to medicine But yet to find the ‘killer application’ Only two licensed therapies worldwide Gendicine (head and neck cancer, p53 adenovirus) Glybera (rare enzyme deficiency) http://www.uniqure.com/products/glybera/

biologics Flashcards

(42 cards)