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biopharm > module 1 > Flashcards

module 1 Flashcards

1
Q

name and explain the 2 types of drugs

A

Biologics
- vaccines, proteins, nucleic acids
- high molecular weight
- manufactured through living organisms

Small molecules
- low molecular weight
- manufactured using living organisms + chemical synthesis
- where most money is spent

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2
Q

describe pharmaceutical companies

A
  • invest heavily in research
  • discover + develop new molecular entities
  • large companies
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3
Q

describe generic pharmaceutical companies

A
  • limited investment in research
  • do not discover new entities
  • adapt or circumvent patents
  • specialize in methods + formulation
  • large to medium sized
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4
Q

describe biotech companies

A
  • exploit academic discoveries
  • invest heavily in research (not on market)
  • smaller companies
  • exist shortly, taken over by larger companies
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5
Q

describe contract research organizations (CRO’s)

A
  • specialized services: testing, synthesis, manufacturing, research
  • contact clinical trials
  • small companies
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6
Q

how many new molecular entities are approved each year?

A

around 40

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7
Q

explain the difference between molecular entity and product

A

molecular entity: pure active ingredient

product: formulation that contains molecular entity
formulation includes API (active Pharma ingredient + excipients)

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8
Q

how much time does it take to create a new molecular entity?

A

12 years average

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9
Q

list and describe the 5 stages for the formulation of a new molecular entity

A

discovery
1-3 years
start with an idea, drug candidate identified

development 1-2 years
drug candidate into sellable investigational new drug

clinical trials
1-5 years, 3 rounds
drug tested in humans for safety and efficacy
new drug application filed

FDA approval
6 months to 1.5 years

Market

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10
Q

describe drug candidate

A
  • identified 1-3 years after research
  • driven by chem + biochem
  • data is confidential
  • animal testing needs ethical review
  • no approval needed for most testing, enters development
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11
Q

describe IND

A
  • investigational new drug
  • application to FDA to start clinical trials
  • Includes pharmacology and toxicity data from animal to ensure safety
  • manufacturing information to ensure consistency: method + purity profile
  • Plan for clinical trials and investigator info
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12
Q

describe NDA

A
  • new drug application
  • application to FDA to enter market
  • safety
  • efficacy: do benefits outweigh the risks
  • labelling
  • info from human and animal trials
  • manufacturing: reproducibility, maintain quality
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13
Q

describe ANDA

A

-abbreviated new drug application
- application to FDA to enter market as generic version of drug
- Data showing that the drug identity, dose, formulation, route of administration, and performance are included

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14
Q

what are the 2 most common methods used to identify leads

A
  • High Throughput Screening HTS
  • Rational drug design
  • Natural products
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15
Q

Describe HTS testing

A
  • quickly tests a large number of compounds for biological activity
  • compound tested at same dose
  • assay provides yes/no response
  • use variety of compounds (structures + chem types)
  • hit: positive response
  • most hits false: impure, decomposition, reactivity
  • retest using purified samples at multiple concentration
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16
Q

what are PAINS and their role in HTS

A
  • pan assay interference compounds
  • major source of false positive in HTS
  • show activity in virtually any biological test
  • interfere with tests by reacting with biological targets
  • mechanisms include: detergents, strong acid/base, nucleophile/electrophile
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17
Q

describe re-testing hits and concentration dependent manner

A
  • based on the principle that compounds interact with biological targets in a concentration-dependent manner
  • dose-response curve typically shows an increase in effect as the concentration increases, often following a sigmoidal shape
  • fail to show a dose-dependent response may be eliminated as false positives
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18
Q

describe the hit to lead process and how much time it takes

A
  • requires 3-6 months
  • HTS, yes or no response
  • counter screen to reject non specific
  • database search to reject pains
  • routine assay/dose response to reject compounds that do not show dose response
  • purification, resynthesis, retest, reject compounds that mis behave
  • synthesize + test analogs, reject compounds that don’t show SAR (Structure-Activity Relationships)
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19
Q

features of drugs developed by HTS

A
  • aromatic rings, easy to change
  • no defined stereochemistry (stereogenic centres)
20
Q

describe natural products

A
  • chemicals isolated from plants, animals, microbes
  • chemicals are secondary metabolites, not required for life, used for secondary purpose such as: poison, colour, fragrance
21
Q

Describe SAR

A

Structure activity relationships
- involves making small changes in a drug structure and observing the resulting changes in biological activity

to:
- to optimize drug properties
- identify parts of drug that interact with target

22
Q

describe the difficulties in using natural products

A
  • require large amount of source
  • difficult to perform SAR (Structure-Activity Relationships) as they have complex structures
  • limited to only chemical modification
23
Q

features of natural product structures + example

A
  • aliphatic
  • sterocenters
  • lots of functional groups

example: penecillin

24
Q

describe rational drug design

A
  • design lead using known chemical structure
    ex: enzyme substrate, inhibitor, existing drug
  • knowledge of mechanism
25
Q

features of rational drug design molecules + examples

A
  • active part ace inhibitor in catopril which regulates BP, starting point is venom
  • acyclovir used to treat herpes resembles guanine, transforms in the body to become active
  • aromatic + aliphatic
  • limited stereochemistry + functional groups
26
Q

what processes are used for lead optimization? describe each

A
  • SAR and SPR
27
Q

Describe the difference between SPR and SAR

A

SAR:
- tests molecule activity
- determine relationship between structural modifications and activity
- how to optimize or come up with new

SPR:
- variety of tests, multiple variables to consider
- optimize several properties:

  • potency: lowest dose possible

-selectivity: ratio between dose that gives desired biological activity vs undesired, high selectivity is rare (BENEFITS OUTWEIGH THE RISKS),

  • solubility in h2o, chemical stability, toxicity, synthesis ease, acid base behaviour
28
Q

What is the end result of the discovery phase?

A
  • turn lead to drug candidate
  • requires 1-3 years
  • chemical properties known
  • basic biological profile is known
  • backup compounds are identified
29
Q

What is the end result of the development phase?

A
  • turn drug candidate into sellable product (investigational new drug)
  • FDA approval to start clinical trials
  • determine safety for humans
  • confirm activity
  • large scale manufacture process
  • formulation
30
Q

what are the 3 requirements for a patent

A

novelty
- new invention/discovery

utility
- be used for a purpose

non-obviousness
- not an obvious solution or idea

31
Q

describe process chemistry + company goals for this

A
  • establish methods for large scale synthesis (reactions don’t work the same on large scale as small scale)
  • limited purification methods: crystallization and distillation
  • regulated by good laboratory practice
  • optimize synthesis for lowest cost
32
Q

what are the FDA requirements for large scale synthesis?

A

RELIABILITY;
constant yield
constant purity
constant purity profile (same impurities in same proportions)

33
Q

describe how drug companies perform safety testing during drug development phase?

A

safety testing I in vitro
- no living organism, in test tube or petri dish
- as many biochemical assays as possible (usually tested by CRO’s)
- minimize positive results
- drop lead for deal breakers: carcinogenicity, interference with organ function

safety testing II (in-vivo)
- smallest sized animals (less drug)
- fewest animals (less money)
- 2 species (AT LEAST ONE PRIMATE FOR HUMAN SIMILARITY)
- rats + dogs

34
Q

describe excipients and list some examples

A
  • non medicinal ingredients, usually from food industry
  • stabilizers: acid/base protect from degradation due to oxygen
  • preservatives : prevent bacteria or mold
  • disintegrates: help deliver drug, starch
  • flavours: sweetness for kids, safety in adult medication
  • colours: safety and identification
  • fillers: ensure correct dosing, cellulose, MgSO4
35
Q

give examples of types of formulations

A

-pills, capsules, liquids
- digested orally

topical cream, patch, nasal spray, eyedrops
- bypass liver, if ingested may not reach bloodstream fast enough

36
Q

Nuremberg code for research on humans

A
  • voluntary participation
  • informed consent
  • prior animal studies
  • benefits must outweigh the risks
  • done by qualified scientists
  • no unnecessary suffering
  • must stop if become dangerous
37
Q

Describe phase I of clinical trials

A
  • less than a year
  • small #, healthy volunteers
  • focus on safety only
  • main purpose to find MAX safe dose
  • 30% fail
38
Q

Describe phase II of clinical trials

A
  • less than a year
  • small number of patients
  • effective dose
  • focus on safety and efficacy
  • 70% fail
39
Q

Describe phase III of clinical trials

A
  • large number of patients
  • safety and efficacy
  • look for rare side effects
  • 70% fail, 6% pass
40
Q

What happens after phase 3 of clinical trials?

A
  • IND - NDA
  • new drug application filed for market approval
  • FDA review takes 6 months to 1.5 years
41
Q

Describe early government regulations surrounding drugs

A

before 1907: completely unregulated

1907: board of food and drug inspection
- focused on labelling (list of ingredients)

1938: food and drug administration
- establish to ensure safety
- FDA established
- animal testing (except species type) + clinical trials now required
- directions for proper use now required

42
Q

Describe orphan drugs

A
  • for rare conditions (less than 200,000 ppl affected)

FDA encourages this through:
- faster + smaller clinical trials
- 7 year market exclusivity
- tax credits of up to 50% of research costs

43
Q

Describe modern safety standards in animal testing for humans

A
  • 2 species
  • 1 must be primate
  • show that drug is bioavailable (gets in body)
  • must use relevant dose
44
Q

Describe the theory of teratogenicity for thalidomide + its mechanism

A
  • drug was sold as racemate (2 stereoisomers possible)
  • s enantiomer was teratogenic

SEE MECHANISM

45
Q

How does the FDA function?

A
  • all testing is done by companies, provide full data to FDA
  • inspect to make sure it meets guidelines –> approval
  • FDA requires companies to monitor products + report any problem
  • FDA provides inspections for manufacturing
46
Q

5 major phases of discovering new drug

A
  • discovery
  • development
  • phase I
  • phase 2
  • phase 3
47
Q
A

biopharm (4 decks)

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