# Presentation: 167103

## Update onRisk-Based CMC Review 

- Advisory Committee for Pharmaceutical Science
- October 21-22, 2002
- Vilayat A. Sayeed , Ph.D.
- Deputy Director, Division of Chemistry II
- OGD, FDA

## General Principle Followed forDeveloping Decision Trees 

**Probability of**
**Detection**

**Complexity***

***Low***

***High***

***Low***

- ****DS/DP characterization***
***  ******Mechanism of product performance***
***  ******Manufacturing technology***

***Medium***

***High***

***Medium***

***Low Risk***

## Decision Tree - Drug Substance  

- Is the drug substance a synthetic single component or simple inorganic salt?

- No

- Yes

- Drug substance not
- suitable for low
- risk consideration

## Decision Tree - Drug Substance  

- Is the drug substance a
- radiophamaceutical, peptide
-  or oligonucleotide?

- Yes

- No

- Drug substance not
- suitable for low
- risk consideration

## Decision Tree - Drug Substance  

- Is the drug substance well characterized, controlled by contemporary specification, and stable under ambient operating conditions (humidity, air, light and heat)?

- No

- Yes

- Drug substance not
- suitable for low
- risk consideration

## Decision Tree - Drug Substance  

- Drug Substance qualifies as
- candidate for low risk assignment*

- * Any reported drug substance physical characterization issues
- (e.g. polymorphs, hydrates etc)
- Refer to drug product decision tree.

## Decision Tree - Drug Product  

- Is drug substance assigned low risk status?

- yes

- no

- Drug product is not
-  a suitable candidate
- for low risk
- consideration

## Decision Tree - Drug Product  

- Is drug product an IR oral solid, an oral/topical liquid or a sterile solution of simple salts?

- yes

- no

- Drug product is not
-  a suitable candidate
- for low risk
- consideration

## Decision Tree - Drug Product  

- IR Solids: Is the strength per unit at least
-  1 mg or 1% w/w?
- Oral/topical solutions and simple sterile solutions:
- Is the intrinsic solubility ratio NLT 1:30?

- yes

- no

- Drug product is not
-  a suitable candidate
- for low risk
- consideration

## Decision Tree - Drug Product  

- Are there drug-excipient compatibility issues?

- no

- yes

- Drug product is not
-  a suitable candidate
- for low risk
- consideration

## Decision Tree - Drug Product  

- Are differences in physical states of drug substance reported to impact product performance?

- no

- yes

- Drug product is not
-  a suitable candidate
- for low risk
- consideration

## Decision Tree - Drug Product  

- Does the drug product specification conform to contemporary standards?

- yes

- no

- Drug product is not
-  a suitable candidate
- for low risk
- consideration

## Decision Tree - Drug Product  

- Is the drug product degradation profile predictable and are degradants controlled?

- yes

- no

- Drug product is not
-  a suitable candidate
- for low risk
- consideration

## Decision Tree - Drug Product  

- Is the drug product stored at CRT and required no special packaging?

- yes

- no

- Drug product is not
-  a suitable candidate
- for low risk
- consideration

## Decision Tree - Drug Product  

- Are there at least two years real time stability data available on a minimum of three commercial batches?

- yes

- no

- Drug product is not
-  a suitable candidate
- for low risk
- consideration

## Decision Tree - Drug Product  

- Drug product qualifies as candidate for low risk assignment

## Acknowledgement  

- Drug Substance Working Group
- Eric Duffy
- Paul Schwartz
- Marie Kowblansky
- Scott Furness
- Mayra Pineiro-Sanchez
- Rao Puttagunta
- Haripada Sarker

- Drug Product Working Group
- Devinder Gill
- Dan Boring
- Liang Zhou
- Sheldon Markofsky