Drug Development Chemistry+ Manufacturing Controls (CMC)

• in vitro and in vivo testing

• standard practices and developmental setting

• Investigational New Drug (IND)

which phase of the drug discovery process is this?

preclinical trials

Which phase of the clinical trials involves testing for

• safety

• pharmacology and distribution/ accumulation

in healthy volunteers

phase 1

which phase of the clinical trials involves

• Single Ascending Doses (SAD) and Multiple Ascending Doses (MAD)

• Exploratory

• Few dozen patients in the disease population

clinical trial 2

which phase of the clinical trials involves

• determine safety and efficacy

• randomized clinical trials with control or placebo

Phase 3 clinical trials

• NDA (New Drug Administration) or BLA (Biological License Application)

• labeling negotiation

• advisory panels recommend to FDA

• Cardiovascular and Renal Advisory Committee (CRDAC)

• Vaccines and Related Biological Products Advisory Committee (VRBAC)

Which components of regulatory review do the above cover?

FDA review

• adverse event reporting (AER)

• risk evaluation and mitigation strategies (REMS)

are apart of which phase of the drug delivery process?

marketing

what is the role of the CMS (Chemistry and Manufacturing Controls) in drug discovery?

turning

Drug Substance (API) —> Drug Product (dosage form)

—> Packaged and Marketed

• active pharmaceutical ingredient (API)

• formulation development

• Quality Assurance and analytical method development

• Clinical Supply

the following are tasks carried out by

CMC

chemistry and manufacturing controls

the CMC assures the _______ and ________ of the robust finished product during ALL phases of development

quality and supply

regulatory authorities need to see detailed standards to ensure consistency of

1. __________

2. __________

3. __________

4. __________

5. ___________

between the PRODUCT used for clinical trials and PRODUCT BATCHES produced for commercial purposes on an ongoing basis

1. identity

2. safety

3. quality

4. stability (purity)

5. strength

the aim of CMC is to turn _______ output into ________ _________ product

research

commercial pharma

*DEFINETLY ON EXAM*:

What are the CORE functions of Pharmaceutical Science (CMC)?

1. process chemistry

2. formulation

3. analytical development

FUNCTIONS OF CMC IN DEVELOPMENT PROCESS:

• ______ chemistry

• formulation

• analytical development

• clinical ___________

• manufacturing (_________)

• ________ management

• quality _______ and ___________

• _________ biochemistry

• safety _______________

• regulatory affairs

• process

• supply

• collaboration

• project

• assurance and control

• pharmacology

• toxicology

list drug dosage forms from SLOWEST to FASTEST

1. tablets (slowest)

2. capsules

3. powders

4. suspensions (in liquid dissolved)

5. emulsions

6. solutions (already dissolved)

tablets are FIRST ______________ into __________ which ___________ into _______________

DISINTEGRATED

granules

DISAGGREGATE

fine particles

SEQ what happens once tablets are DISENTEGRATED into granules then DEAGGREGATED into fine particles

1. dissolution

2. drug in solution

3. absorbed into blood

which dosage form takes the longest to be absorbed? which dosage form is the fastest?

longest = oral

fastest = solutions (particles already fully dissolved in liquid)

which step does each dosage form start from?

• capsules

• powders

• suspensions

• emulsions

• solutions

• capsules —> fine particles (dissolve out of shell)

• powders —> fine particles

• suspensions—> fine particles

• emulsions —> dissolution

• solution —> drug in solution

ORAL administration SEQ:

1. drug is first ________________ in the GI tract

2. they are then ____________ before they are absorbed into the blood

3. once in the blood the drug can be free or bound to __________ _________

4. drugs are then DISTRIBUTED to ________ and ________

5. leading to ________ _____________!

• disintegrated (broken down)

• dissolved (within the liquid)

• plasma proteins

• tissues and fluids

• pharmacological effect

once an oral drug makes it to the blood and is bound to a plasma protein is it attached permanently?

NO drug can be interchanged from free to bound to plasma protein

non- scalable processes should be AVOIDED in formulation development

what is an example of a nonscalable process?

electrospinning may be possible when you are making small portions of a drug, but not LARGE SCALE in an industrial setting

what is the end to end (E2E) development process of Active Pharmaceutical Ingredient ?

1. discovery

2. _____ ______ process

3. process ______ _____

4. __________ transfer

5. _____ _____ manufacture

2. small scale

3. up scale

4. technology

5. full scale

what is the end to end (E2E) development process of formulation ?

1. small _____ ______

2. process ____ ______

3. ______ transfer

4. full scale ___________

1. scale process

2. up scale

3. technology

4. manufacture

what is the end-to-end (E2E) development process of analytics?

1. assay __________

2. assay __________

3. method _________

4. _______ control

development

validation

transfer

quality

________ studies are used to demonstrate to the health authority that drug substance and formulations maintain their psychological, chemical, biological, and microbial properties under different conditions

stability

stability studies are performed to demonstrate whether or not a drug can maintain its properties under certain conditions such as …

• temperature

• humidity

• light

Small Molecules:

• small molecules are natural/synthetic in origin

• animal toxicology studies of small molecules are carried out in which two species?

• small molecules have a very ______ identity down to the ______ level

• synthetic

• one rodent + one nonrodent

• precise atomic

Large Molecules:

• ______ ______ technology is utilized in cell _____- based systems to produce large molecules

• which animals are used in toxicology studies for large molecules?

• is it easy to characterize large molecules down to the atomic level?

• normal levels of variation may exist within a pool of ________ for example, without affecting activity OR _______

• multiple _____ are sometimes used during early development, of which ONE may later be selected for commercial development

• recombinant DNA culture

• primates since large molecules elicit an immune response in nonprimates

• NO

• clones

small molecule drugs are often less than ______ daltons

900

how are small molecular drugs usually administered?

are they able to penetrate cell membranes?

small molecules are more effective for diseases ______ cells

pills + capsules (orally)

YES makes them more effective for diseases WITHIN cells

WITHIN

big molecular drugs (biologics) often weigh more than ___________ daltons

what dosage from are they usually administered in? why?

1000

injections. they are susceptible to digestive enzymes so they must bypass first-pass metabolism

big molecule drugs (biologics) are usually comprised of _______ and ________ ______ which are injected to bypass first-past metabolism due to their susceptibility to digestive enzymes

proteins and nucleic acids

oligonucleotides are LARGE hydrophilic / hydrophobic polyanions

single stranded ASOs are ___-10 kDA

double stranded ______ are about 14kDa

phillic

4

siRNA

Steps in the manufacture of a monoclonal antibody drug product (large molecule drug)

1. development

2. cell culture (expression level)

3. purification (purification yield)

4. stability + storage + transfer

does the development of small or large molecule manufacturing include

• dry granulation

• wet granulation

• direct compaction

• processing

small

does the development of small or large molecule manufacturing include

• development

• cell culture

• purification

• storage

large

following intravenous administration, a ______________ is injected directly into systemic circulation

biotherapeutic

following subcutaneous administration, the biotherapeutic is injected into the ___________ _______ of the subcutaneous tissue

From there it is transported to ______ or _________ capillaries for absorption prior to reaching systemic circulation

extracellular space

blood lymph

are biotherapeutics (large molecules) like antibodies injected intravenously or subcutaneously?

BOTH (IV has higher bioavailability)

what is the rate limiting step of IgGs injected subcutaneously?

long residence in the intersitial space

the fraction of an administered dose of a molecule that reaches the systemic circulation

bioavailability (BA or F)

the bioavailability of drugs administered intravenously is 100% or 1

the bioavailability of drugs administered extravascularly (including subcutaneous) is measured relative to this value as calculated as the ratio of ____- normalized AREA UNDER THE _______ ___________ CURVE

dose

plasma concentration

subcutaneous bioavailability of less than 100% is attributed to incomplete absorption due to

• metabolism

• degradation

• precipitation

• elimination by phagocyte

which therapeutic area has the highest market size based on estimated worldwide 2028 sales

oncology