DRUG DISCOVERY FINAL EXAM
QUESTIONS WITH COMPLETE
ANSWERS
What is the Chemical Manufacturing and Control group (CMC) - ANSWER-The group
that typically deals with how and where the compound will be prepared. Their first task
is to optimize the synthesis of the drug, with an eye toward performing the reaction on
very large scale...many reactions that we take for granted in a normal organic chemistry
lab are not amenable to "very large scale"
In large scale synthesis, it is best to avoid: - ANSWER-Reactions that need very low
temperatures
Slow, controlled additions
Chromatographic purifications
For purposes of filing an IND, the synthesis must be conducted in a certified Current
GMP (cGMP) facility and include: - ANSWER-Record of thorough documentation and
compliance
All reaction components (reagents, solvents) are of documented quality
All components can be reliably supplied
*reactions run in a cGMP facility is VERY EXPENSIVE!
How can you limit cGMP facility and synthesis expenses? - ANSWER-Developing a
convergent synthesis
Finding multiple commercial suppliers for the advanced intermediates
Conducting only the final step in a cGMP laboratory
IND must include: - ANSWER-Source, purity, and grade in painstaking detail for every
component (reagent, solvent, excipient) in the drug synthesis
With the limits of detection for analytical instrumentation...specialized methods can lead
to greater sensitivity: - ANSWER-Triple quadrupole mass spectrometry
NMR using other nuclei
Elemental analysis
Chemical derivatization
,•What does the FDA require from a purity perspective? - ANSWER-less than or equal to
2g/day | reporting threshold of 0.05% | identification threshold of 0.01% or 1 mg per day
intake (whichever is lower)
greater than 2g/day | reporting threshold of 0.03% | identification threshold of 0.05%
****************IMPORTANT****************
The new drug doesn't have to be >99.95% pure...
However, every impurity that exists above 0.05%, or every impurity that a human will be
exposed to above 1.0 mg/day, must be accounted for and tested for safety (more on
that coming up)
An IND application requires the disclosure of considerable data, including: - ANSWER-
•All of the protocols you've used to analyze the compound to date and your detailed
plans and protocols to use during the clinical trial
•All of the details about the drug candidate (physical, chemical and biological
characteristics)
•Full details about how and where the compound will be prepared and the purity
•Full details about the pharmacology and toxicology of the compound
IND requires full ADME details and for metabolism... - ANSWER-It is studied
extensively, and every metabolite that is expected to be formed above 1.0 mg/day must
be fully characterized
The ADME of each metabolite must be explored
•MBI (mechanism-based inhibition I think?)
Often, radio labelled analogs are prepared to track them
Toxicology is a MAJOR focus for an IND - ANSWER-All preclinical toxicology (e.g.
hERG) is reported
Investigators must determine how much of the drug is toxic
•Maximally tolerated dose (MTD)
•Also called "dose range finding study"
•What is observed
Typically requires > 100 g of product
•Non-GLP toxicology batch (single batch)
What can be used to determine mutagenicity? - ANSWER-Ames test - used to assess
the potential carcinogenic effect of chemicals by using the bacterial strain Salmonella. If
you find that there are many colonies growing on the agar. Your interpretation of this
result is: the chemical being tested is mutagenic.
, That impurity profile is a significant factor when we consider [ ]? - ANSWER-Generic
drugs
•Once this data has been obtained for the active components and impurities, the drug
must be [ ]? - ANSWER-For IV, what type of stabilizing component will be
administered?
How will the integrity of the aqueous solution be ensured?
For oral drugs, will it be a pill? What will be the excipients? If a syrup, how will those
components be secured and monitored?
It is up to the investigator to identify the study plan as well as the intended patient
population in the [ ]? - ANSWER-IND application
Also... IND application is where the drug's name (including the generic name) is decided
and approved
Besides an IND, the FDA requires the submission of the Investigator's Brochure (IB) -
ANSWER-The IB is the information that will be provided to the clinicians who will be
studying the compound
Includes all pertinent safety data as well as the drug characterization
An IB is required for EVERY trial
Phase I is... - ANSWER-a safety study
First in humans, Goal is to determine safety and PK profile, The certified GCP clinics
where the testing will be conducted must be identified in the IND, phase I studies are
often done at a single clinic
Each phase is considered a different clinical trial, with their own protocols and their own
IBs
Phase II and III are... - ANSWER-efficacy studies
Each phase is considered a different clinical trial, with their own protocols and their own
IBs
Phase IV is... - ANSWER-undertaken after approval
Each phase is considered a different clinical trial, with their own protocols and their own
IBs
QUESTIONS WITH COMPLETE
ANSWERS
What is the Chemical Manufacturing and Control group (CMC) - ANSWER-The group
that typically deals with how and where the compound will be prepared. Their first task
is to optimize the synthesis of the drug, with an eye toward performing the reaction on
very large scale...many reactions that we take for granted in a normal organic chemistry
lab are not amenable to "very large scale"
In large scale synthesis, it is best to avoid: - ANSWER-Reactions that need very low
temperatures
Slow, controlled additions
Chromatographic purifications
For purposes of filing an IND, the synthesis must be conducted in a certified Current
GMP (cGMP) facility and include: - ANSWER-Record of thorough documentation and
compliance
All reaction components (reagents, solvents) are of documented quality
All components can be reliably supplied
*reactions run in a cGMP facility is VERY EXPENSIVE!
How can you limit cGMP facility and synthesis expenses? - ANSWER-Developing a
convergent synthesis
Finding multiple commercial suppliers for the advanced intermediates
Conducting only the final step in a cGMP laboratory
IND must include: - ANSWER-Source, purity, and grade in painstaking detail for every
component (reagent, solvent, excipient) in the drug synthesis
With the limits of detection for analytical instrumentation...specialized methods can lead
to greater sensitivity: - ANSWER-Triple quadrupole mass spectrometry
NMR using other nuclei
Elemental analysis
Chemical derivatization
,•What does the FDA require from a purity perspective? - ANSWER-less than or equal to
2g/day | reporting threshold of 0.05% | identification threshold of 0.01% or 1 mg per day
intake (whichever is lower)
greater than 2g/day | reporting threshold of 0.03% | identification threshold of 0.05%
****************IMPORTANT****************
The new drug doesn't have to be >99.95% pure...
However, every impurity that exists above 0.05%, or every impurity that a human will be
exposed to above 1.0 mg/day, must be accounted for and tested for safety (more on
that coming up)
An IND application requires the disclosure of considerable data, including: - ANSWER-
•All of the protocols you've used to analyze the compound to date and your detailed
plans and protocols to use during the clinical trial
•All of the details about the drug candidate (physical, chemical and biological
characteristics)
•Full details about how and where the compound will be prepared and the purity
•Full details about the pharmacology and toxicology of the compound
IND requires full ADME details and for metabolism... - ANSWER-It is studied
extensively, and every metabolite that is expected to be formed above 1.0 mg/day must
be fully characterized
The ADME of each metabolite must be explored
•MBI (mechanism-based inhibition I think?)
Often, radio labelled analogs are prepared to track them
Toxicology is a MAJOR focus for an IND - ANSWER-All preclinical toxicology (e.g.
hERG) is reported
Investigators must determine how much of the drug is toxic
•Maximally tolerated dose (MTD)
•Also called "dose range finding study"
•What is observed
Typically requires > 100 g of product
•Non-GLP toxicology batch (single batch)
What can be used to determine mutagenicity? - ANSWER-Ames test - used to assess
the potential carcinogenic effect of chemicals by using the bacterial strain Salmonella. If
you find that there are many colonies growing on the agar. Your interpretation of this
result is: the chemical being tested is mutagenic.
, That impurity profile is a significant factor when we consider [ ]? - ANSWER-Generic
drugs
•Once this data has been obtained for the active components and impurities, the drug
must be [ ]? - ANSWER-For IV, what type of stabilizing component will be
administered?
How will the integrity of the aqueous solution be ensured?
For oral drugs, will it be a pill? What will be the excipients? If a syrup, how will those
components be secured and monitored?
It is up to the investigator to identify the study plan as well as the intended patient
population in the [ ]? - ANSWER-IND application
Also... IND application is where the drug's name (including the generic name) is decided
and approved
Besides an IND, the FDA requires the submission of the Investigator's Brochure (IB) -
ANSWER-The IB is the information that will be provided to the clinicians who will be
studying the compound
Includes all pertinent safety data as well as the drug characterization
An IB is required for EVERY trial
Phase I is... - ANSWER-a safety study
First in humans, Goal is to determine safety and PK profile, The certified GCP clinics
where the testing will be conducted must be identified in the IND, phase I studies are
often done at a single clinic
Each phase is considered a different clinical trial, with their own protocols and their own
IBs
Phase II and III are... - ANSWER-efficacy studies
Each phase is considered a different clinical trial, with their own protocols and their own
IBs
Phase IV is... - ANSWER-undertaken after approval
Each phase is considered a different clinical trial, with their own protocols and their own
IBs
