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Extemp > Biologicals > Flashcards

Biologicals Flashcards

1
Q

What are biologicals?

A

Medicinal products which are produced by, or derived from, a living system.
Can be from a whole organism or isolated cells. Also known as biopharmaceuticals.

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2
Q

What is the highest selling biologic?

A

Humira/adalimumab treatment for RA etc.

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3
Q

Production of therapeutic proteins relies largely on:

A

Recombinant DNA methods.

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4
Q

How does humanisation of antibodies occur?

A

Phage display
Transgenic mice
Immortalised memory B-cells

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5
Q

What are the benefits of using yeast cells to produce therapeutic proteins? [9]

A
  1. doubling time of ~4hrs
  2. High concentration production
  3. High MW proteins possible
  4. S-S bridges possible.
  5. Secretion sometimes possible.
  6. Singular/native aggregation state.
  7. Correct folding
  8. No pyrogens.
  9. Cheaper than mammalian cell use.
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6
Q

Why would we not want to use yeast cells to produce therapeutic proteins? [3]

A
  1. Retrovirus use not possible
  2. Secretion sometimes not possible
  3. More expensive than bacterial cells.
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7
Q

What are the benefits of using bacterial cells to produce therapeutic proteins? [3]

A
  1. 0.5hr doubling time.
  2. High concentration production possible.
  3. Cheaper than yeast and mammalian cell use.
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8
Q

What are the disadvantages to using bacterial cells for production? [6]

A
  1. Limited MW proteins possible.
  2. Limited S-S
  3. No secretion
  4. Misfolding can occur
  5. Retrovirus use not possible
  6. Pyrogens possible.
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9
Q

What are the advantages to using mammalian cells for production of therapeutic proteins? [7]

A
  1. High MW proteins
  2. No limits on S-S bridges
  3. Secretion possible
  4. Singular/native aggregation state.
  5. Correct folding
  6. Retrovirus use possible
  7. No pyrogens.
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10
Q

What are the disadvantages to using mammalian cells? [3]

A
  1. Long generation time: >24hrs.
  2. Expensive.
  3. Low concentrations/yield.
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11
Q

What two ways can protein inactivation occur?

A
  1. Conformational changes: formation of incorrect structures, aggregation.
  2. Chemical oxidation and other chemical changes see flashcards for biopharmaceuticals.
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12
Q

What are the possible consequences of aggregation/denaturation of protein product? [4]

A
  1. Altered formulation stability.
  2. Hyper or hypo-potency
  3. Off target binding, increase in side-effects, clearance.
  4. Patient may generate ATAs: neutralising antibodies: making drug ineffective, break in tolerance, cross-reactivity with endogenous proteins.
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13
Q

What types of aggregates exist?

A

Soluble and insoluble.

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14
Q

How do soluble aggregates differ to insoluble ones?

A
  1. Soluble are normally low in number and visually undetectable.
  2. They cannot be filtered out with 0.2micrometer filters.
  3. Soluble aggregation is reversible by dilution/pH.
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15
Q

How are insoluble aggregates different to soluble aggregates?

A
  1. Insoluble aggregates = more individual proteins, visually present as turbidity.
  2. Can generally be removed by filtration.
  3. Often irreversible, non-covalent can be dissociated by detergents.
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16
Q

How is the formation of soluble aggregates often reversed?

A

Dilution or changing the pH.

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17
Q

How can aggregation be precipitated? [8]

A
  1. Freezing and thawing.
  2. Agitation (interface formation)
  3. Sonication
  4. Contact with silicone oil.
  5. Low or High pH
  6. Low or High Salt
  7. Specific salts
  8. Heat
18
Q

What are lyophilised formulations of drugs? [4]

A
  1. Freeze-dried protein with excipients.
  2. Shipped/stored at ambient temps.
  3. Requires reconstitution to take place and time allowed for full dissolution.
  4. Air entrapment can occur and agitation during and after dissolution.
19
Q

Describe the liquid formulations of protein drugs:

A
  1. Shipped and stored at 2-8*C
  2. Volume required directly withdrawn, no need for reconstitution.
  3. Less manipulation needed.
  4. Agitation and inadvertent freezing can occur.
20
Q

How can aggregate formation occur during the use of liquid formulations of protein drugs?

A
  1. agitation and inadvertent freezing and then thawing.
21
Q

How are lyophilised formulations of drugs shipped/stored?

A

Ambient temps.

22
Q

What IV diluents can be used with protein formulations?

A

Saline: normally ok, some small hydrophobic proteins are less soluble/insoluble at high salt conc.
Dextrose: normally not ok, can react with lysines on protein surface to form Schiff’s bases at ambient temperature.
Ringers solution: sometimes ok, check SPC.

23
Q

Why can contamination occur with the use of lyophilised formulations?

A

They require a reconstitution stage. More stages required in the prep than with liquid alternatives.

24
Q

Which IV diluents are normally not ok to use with protein formulations and why?

A

Dextrose is normally not ok to use as it can react with lysine residues on the protein surface to form schiff’s bases at ambient temperatures.

25
Q

How can aggregate formation occur during the use of lyophilised formulations of protein drugs?

A

Air can become entrapped during the reconstitution stage and also agitation can occur.

26
Q

Which protein residues can react with Dextrose IV diluent to form Schiff’s bases at ambient temperature?

A

Lysines.

27
Q

Can Ringers solution be used as an IV diluent in protein formulations?

A

Sometimes: check individual SPC.

28
Q

Why can Saline sometimes not be used as an IV diluent for a protein formulation?

A

Some small hydrophobic proteins are insoluble at high salt conc.

29
Q

What are the advantages to administering protein formulations via the IV route? [4]

A
  1. 100% BA of large doses.
  2. Easily controlled/discontinued if side effects.
  3. Immediate access to central compartment.
  4. Easy weight-based dosing can occur.
30
Q

Why would we not choose to administer a protein drug via the IV route? [3]

A
  1. Patient inconvenience, painful.
  2. Risk of protein adsorption to sides of IV bag.
  3. Agitation during transport and preparation may be too significant.
31
Q

What advantages are there to SC administration of biologicals? [4]

A
  1. Patient compliance and convenience
    2 Wide acceptability (insulin delivery)
  2. May require no compounding to take place, reduced risk of contamination.
  3. Autoinjector use possible.
32
Q

What downsides are involved with SC delivery of biological therapeutics? [2]

A
  1. Lower maximum dose per time than IV.

2. Cannot stop administration of dose as injection is immediate.

33
Q

What are the advantages and disadvantages to Intravitreal delivery of biologics? What is an example of a therapeutic delivered this way? [4]

A
  1. Direct site of action: 100% BA.
  2. Patients dont like being injected in their eyeballs.
  3. Risk of injection site injections complications are greater than with SC. Local skin infection versus eyeball infection.
  4. Mucagen, aptamer and RNA drug to treat age related wet macular degeneration. Mops up excess VEGF, injections every 6 weeks.
34
Q

What are the advantages to Buccal and sublingual delivery? [6]

A
  1. Saliva: rapid solubilisation of drug.
  2. CNS delivery via neuronal transport via olfactory nerves.
  3. Bypass 1st pass, GI degradation of proteins.
  4. Loose, less-keratinised epithelium.
  5. Low enzyme degradation.
    6 Patient compliance.
35
Q

What are the disadvantages of buccal and sublingual delivery? [5]

A
  1. Less than 100% BA.
  2. Variability.
  3. Mucus barrier.
  4. Excess saliva can cause rapid clearance into GI.
  5. Highly potent drugs must be used as absorption of high MW is low.
36
Q

What are the pro’s of pMDI delivery of biologics?

A
  1. Local delivery,
  2. High SA/bloodflow
  3. Bypass 1st pass effect/GI degradation
37
Q

What are the downsides to pMDI delivery of protein formulations? [6]

A
  1. Devices so far have been large and bulky (and expensive failures)
  2. Proteins are not stable in organic solvents (use supercritical fluids/CO2)
  3. Particle size distribution can vary.
  4. Patient usability issues.
  5. Denaturation of proteins due to shear or air/water interfaces.
  6. Each device requires individual testing.
38
Q

What is Holoclar?

A

Limbal stem cell transplantation approved by the EMA in December 2014. Cures blindness caused by corneal burning.

39
Q

What is the process of tissue engineering?

A
  1. Isolation of cells.
  2. Expand the cell number
  3. Seed on a suitable scaffold.
  4. Culture under suitable conditions to generate a mature tissue.
  5. Implant this tissue in a patient.
40
Q

How can corneal burning caused blindness be treated?

A

Holoclar. Limbal stem cell transplantation.

Extemp (12 decks)

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