Lecture 9: Generic R and D and CMC

Watchman-Hatch Act (1984)

An act recognizing need for better medical care options and affordability; it allows a generic drug firm to submit an ANDA for any drug approved by the FDA so long as the ANDA doesn’t infringe on the patent or market exclusivity of the first drug’s owner

ANDA

Abbreviated new drug application

What is the abbreviated aspect of the NDA

It allows the company to rely on already existing data from the first FDA-approved drug while proving that their generic product has bioequivalence and quality comparable to the first drug (smaller timeframe and less resources)

What does the NDA have to show

safety and efficacy

What does the ANDA have to show

bioequivalance and quality

What does the ANDA NOT have to show:

safety and efficacy

What does an ANDA provide to the generic company

5 years exclusivity plus potential extensions for time spent in review; all patents from part II listed in the Orange book

Orange book

A publication by the FDA that provides information on approved drug products, including patent and exclusivity information for brand name and generic drugs.

Paragraph I

no patent existing; ANDA can be approved immediately

Paragraph II

Patent of owner has expired; FDA approve ANDA immediately

Paragraph III

Patent of the owner has not yet expired but will do so on a particular date: FDA approves the ANDA on the first patent expiry date

Paragraph IV

Patent owner has not provided permission; ANDA can be approved after litigation. This paragraph refers to situations where the patent holder has not granted authorization for the generic product, necessitating legal action before the FDA can approve the ANDA. The owner has 45 days to sue to the generics company; this leads to a 30 month hold on the ANDA while litigation occurs. 180-days First to File exclusivity must also be intact.

180 days First to File

exclusivity granted to the first generic applicant to file an ANDA after a patent holder has litigated or allowed the patent to expire. This exclusivity prevents other generic manufacturers from entering the market for 180 days.

RLD

Reference Listed Drug, the branded drug that serves as the standard for comparison in an ANDA submission.

Which files do ANDAs need

technical and clinical

reverse engineering

the process of analyzing a drug's formulation to recreate it without a patent. This method is often utilized in the development of generic medications.

de-formulization

the process of breaking down a drug formulation into its individual components to understand its formulation and create a generic version.

Raman Imaging

is a technique that uses Raman spectroscopy to visualize chemical composition and molecular structure in materials. It provides detailed images that help analyze the properties of drug formulations.

importance of particle size analysis

If we want to create a bioequivalent drug with similar pk/pd, the size of the particles when dissolved in water plus their subsequent qualities must be assessed to understand how the generic will interact with the body, and compare to the RLD.

PS reduction leads to increases in

homogeneity, reactivity, solubility

PS reduction decreases

crystallinity, bulk density, flow

polymorphs

are chemical compounds that have the same active ingredient (composition) but different physical forms (internal structures)

amorphous solid

is a solid without a defined crystalline structure, leading to unique properties such as increased solubility and enhanced stability in certain applications. it is not considered a polymorph

What are the differences between crystalline and amorphous solids?

Amorphous solids have less defined structure, so increased soluability and dissolution rate