Drug Product Formulation: Exam 2

List of the chemical instabilities found in proteins

Hydrolysis, deamination, disulfide exchange, oxidation, pyroglutamate in mabs, racemization

The causes of protein oxidation are:

metal ions, light, sonication, oxygen

Name three conditions that could favor protein deamidation

sequency considerations, conformational effects, exposure to alkaline pH, extreme pH, ionic strength

Name three applications of MS in biopharmaceutical analysis

1. identifying a protein’s primary amino acid sequence

2. post-translational modifications

3. detect, identify and quantify molecules separated by their mass-to-charge ratio

Name three strategies that could be used to prevent protein oxidation

1. reducing agents

2. environmental controls (temp and light)

3. chelating agents

What is MS/MS? How does MS/MS work?

Name three types of analyzers used in mass spectrometry

quadrupole, traps, and time of flight

When comparing CD (circular dichroism) with FTIR spectroscopy, which is the main advantage of the latter in drug product development?

FTIR can accommodate any sample (solution, suspension, solid) because it is more versatile and not affected by light scattering

Which pH conditions would likely favor the isomerization of Asp to iso-Asp?

mildly basic pH conditions (pH 7-9)

In developing a formulation for phase I clinical trials, which is the main advantage in using a formulation platform vs. a complete pre-formulation approach?

Allows for a faster to clinic evaluation because it uses previously tested components and familiar regulatory path while cutting costs

What is the primary concern in using Arrhenius kinetics in formulation development?

It assumes a consistent degradation mechanism for all temperatures; failure of extrapolation happens due to behavior changes when temps fall below the Tm for complex molecules

Which is the most convenient parenteral route of administration for protein therapeutics from the patient’s perspective?

subcutaneous injection

What are the break force and the gliding force?

break force is force required to dislodge the plunger from its resting position in the syringe. Gliding force is force needed to maintain plunger movement once static friction has been overcome

Name two ways of producing solid dosage forms for therapeutic proteins.

lyophilization and spray drying

The most common parenteral routes of administration are:

1. continuous intravenous infusion

2. intravenous injection

3. intramuscular injection

4. subcutaneous injection

Viscosity is a manifestation of

protein-protein interactions and may be due to self-association

What is a non-Newtonian fluid?

A substance that’s viscosity changes depending on the shear force applied to it (ketchup)

Name the three most typical devices for self-administration of drug products.

1. pre-filled syringe

2. autoinjector

3. large volumes device

The most common sugars used in formulation development are:

sucrose, trehalose, sorbitol

In developing a DP, why is a flat dose preferred over a variable dose (adjusted by weight)?

to simplify administration, reduce medication errors, and minimize drug wastage

What chemical instabilities could be identified by CE-SDS?

aggregation, fragmentation, and mild non-denaturing conditions

What are the advantages of a subcutaneous route of administration vs. intravenous administration?

1. drug is delivered directly into systemic circulation in IV

2. SC relies on tissue absorption

3. SC formulations can tolerate suspensions, emulsions, or depot systems that allow slower drug release

4. SC limited to 0.5-50mL affecting drug concentration and formulation strategy

5. must minimize tissue irritation, pain and inflammation

Which is the most common excipient employed to decrease the viscosity of a protein solution?

Arginine