# Presentation: 033294

## Update on Drug Substance and Drug Product Draft Guidances

- Steve Miller, Ph.D.
- Office of New Drug Chemistry (ONDC)CDER / FDA

**DIA Annual Meeting**
**June, 2004 – Washington DC**

## Update on Drug Substance and Drug Product Draft Guidances

- Steve Miller, Ph.D.
- Office of New Drug Chemistry (ONDC)CDER / FDA

**DIA Annual Meeting**
**June, 2004 – Washington DC**

**Hot Topics**

## Overview

- Draft Drug Product Guidance
- P2 as opportunity for sharing your understanding of process and formulation
- Other issues with “issues”
- Draft Drug Substance Guidance
- Critical versus Non-Critical Process Controls
- Reprocessing & Reworking
- Starting Materials
- Interim Specification / Sunset / Skip (PQIT)

## Why Revise DS & DP Guidances?

- ICH CTD-Q was major influence in decision to revise the 1987 DS and DP Guidelines
- Primary purpose of revised DS and DP Guidances to provide recommendations for submitting applications formatted according to CTD-Q
- NDAs, ANDAs, Animal Drug Applications
- Revision also provided opportunity to update 1987 guidances

## Drug Product Topics

- Pharmaceutical Development Report
- _FDA Perspective_: will help FDA to focus on aspects of manuf / control with greatest impact on quality/safety/efficacy
- Move along the direction from “One size fits all” towards “What is critical for this product?”
- Challenge: keep review appropriate (balance between applications)
- _Industry Perspective_: Mixed

## Drug Product Topics

- Other areas with many comments
- Manufacturing process description
- “All process controls”
- Critical versus non-critical process controls
- In-Process Controls (“Process Tests”)
- Where to locate justification?
- Periodic Quality Indicator Tests (PQIT)

## Drug Substance Topics

- Issues/Questions brought into focus by  CTD-Q
- One Issue: Critical versus Non-Critical Process Controls
- Revision also provided opportunity to assess FDA’s approaches to DS issues; E.g.,
- Reprocessing and reworking
- Starting materials
- Sunset / Interim Specifications / PQIT

## Critical / Non-Critical Process Controls

- Critical vs. non-critical process controls
- All Process Controls (Critical and Non-Critical)
- S.2.2 Description of Manufacturing Process and Process Controls
- Critical Process Controls
- S.2.4 Controls of Critical Steps and Intermediates
- Definition of “critical”
- Q7A definition: a process step or process control that must be controlled within predetermined criteria to ensure that the drug substance meets its specification

## Drug Substance

**Drug Substance**
_**Quality Controls**_

## Critical / Non-Critical Process Controls

- Partitioning of information on process controls into two sections...
- Opportunity to share knowledge of process with reviewer
- May support customized regulatory approaches (e.g., comparability protocols)
- Future deregulation of non-critical parameters?
- Worth doing?
- How to make it work?

## Critical / Non-Critical Process Controls

_**Challenge:**_ How to convey meaningful set of information to reviewer without restricting future optimization

- Expect change control with involvement of FDA reviewer (e.g., BP-1, BP-2) on appropriate operating parameters

- Allow reasonable variation and optimization for non-critical parameters (record on-site under GMP)

**Balance !**

**Within an application and between appls**

## Reprocessing & Reworking 

_**FDA Perspective:**_** approach in draft DS guidance is generally consistent with past practices and with ICH Q7A recommendations.**

_**Industry Perspectives:**_** ??**

- Generally no filing for occasional reprocessing
- Occasional versus “Established”  Reword/Reprocessing

## Selecting Starting Materials

- Inputs to revision of Starting Material Definition
- 1987 DS Guidance
- ICH Q7A API Guidance
- “Negotiated Starting Materials”
- Today’s Hot Items
- More background in presentation from APIC-CEFIC meeting (Nov 2003) _[http://www.gmp-navigator.com/slides](http://www.gmp-navigator.com/slides)_

## Which Compound Should be the Starting Material?

- General criteria/approach would be valuable
- uniform approach across appls, NDA/ANDA
- currently: much interest and effort; case-by-case
- Three main considerations:
- how much of the synthesis to “report?”
- how complex can the SM be?
- what specification is appropriate for the SM?

## Definition of SMBeginning with the 1987 DS Guideline

- “What constitutes the "starting material" may not always be obvious.”

- “Generally the decision about what is the starting material has been reached by agreement between the applicant and the FDA chemist before submission of the NDA (e.g., during an IND
- End-of Phase 2 meeting, or pre-NDA meeting).”

## Definition of SMin ICH Q7A

- A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be _an article of commerce_, _a material purchased from one or more suppliers under contract or commercial agreement_, or _produced in-house_. API Starting Materials are normally of defined chemical properties and structure.

## Definition of SMin ICH Q7A (cont’d)

- More an inclusive statement
- Defines what *may* be a SM
- Not how to select the SM(s) for a synthesis from the raw materials, intermediates, etc.
- Main purpose may be to clarify that GMPs start with the use of the SM _whether purchased or made in-house_
- Supports determination of SM as part of application review process

## Recommended Approach to Starting Materials in Draft DS Guidance

- Exception for chemicals with significant non-pharmaceutical markets

- Selection Criteria
- Carryover of impurities into DS
- Propinquity (# of steps)
- Isolated and purified substances
- Complexity of Structure

- Robust SM Specification for Minimally Insulating Syntheses

## Hypothetical Synthesis

-  Each reaction arrow represents a change in structure   (not just salt change)
- J can be a starting material, too!

## Slide 20

## WHY?

**Are they sufficient to ensure safety of DS?**

- 	What solvents/reagents are used? Controls needed?
- 		Process Controls as well as DS Specification

- What related substances are carried into DS?
- 	Now; and for new sources of SM in future

## Balancing:

**Balancing:**

**FDA**

**Firm**

**Purification Processes in Reported Synthesis****=  “Insulator” for  DS**

- Future sources of SM (new routes) may bring new related substances

- Multiple (different) purification steps more likely to purge them out

- Synthesis Reported in Application is under BACPAC-1 Control

## Assessing the Reported Portion of the SynthesisWill it be a good “Insulator?”

**Assessing the Reported Portion of the Synthesis****Will it be a good “Insulator?”**

**Are there a reasonable number of purification steps?**

- “Propinquity” (proximity; nearness)
- A starting material should be separated from the final intermediate by several reaction steps that result in isolated and purified intermediates.

- - What is a reasonable number? Counting from SM or FI?

- -	Count all purifications equally? Crystallization vs extractive work-up vs solvent evaporation

- -	Keep a _reasonable_ amount of final synthetic steps under BP-1 change control (solvents, reagents, process controls)

## Propinquity Selection Principle

- Propinquity in Jan 04 draft:
**several** reaction steps with purifications

## How to Handle Commercially Available Chemicals?

## A Commercial Chemical Could be Used Late in the Synthesis

**Pros and Cons of Defining J as a Starting Material:**
- (-) Little synthetic “insulation” between J and DS
- (**+**) Probably not overly complex
- (-) Synthesis of J generally cannot be controlled by applicant
- (**+**) Applicant can purify J if needed

- Overly burdensome to require synthesis of J under GMPs(J fits with the spirit of commercially avail 1987 DS Guide)

## What To Do with Commercial Chemicals Such as J?

**J unlikely to fit all selection principles**
-      Carry over of impurities to DS
-      Propinquity
-      Isolated and purified substance
-      Complexity of structure

- Draft DS Guidance recommends exempting J from the selection principles because it is commercially available

**?**

- “has a Significant Non-Pharmaceutical Market”

## A significant non-pharmaceutical market can be considered to exist...
if the quantity of the chemical needed for the production of the drug substance represents only a small fraction of the chemical’s total market
regardless of whether the chemical is made by the drug substance manufacturer for its own use or is obtained from another firm

- if the quantity of the chemical needed for the production of the drug substance represents only a small fraction of the chemical’s total market
- regardless of whether the chemical is made by the drug substance manufacturer for its own use or is obtained from another firm

- Chemicals with Non-Pharmaceutical Market

- Commercially Available Chemicals

## In general, the starting material and API starting material should be the same for a synthetic drug substance
However for a drug substance derived from a biological source, the starting material (e.g., plant) and API starting material (e.g., extract) can be different

- However for a drug substance derived from a biological source, the starting material (e.g., plant) and API starting material (e.g., extract) can be different

- Starting MaterialsandAPI Starting Materials

## Synthetic Starting Materials

## Starting Materials from Plants or Animals

## Sunset / Interim SpecificationsPeriodic Quality Indicator Tests (PQIT) 

_**FDA Perspective**_**:** These provide flexibility for situations where:
- It is not clear whether routine testing of an attribute is needed to maintain quality/safety/efficacy – agree on limited testing of commercial batches, then decide
- Routine testing for batch release is appropriate, but acceptance criteria difficult to agree on without more data

_**Industry Perspectives**_**:** Seemed strongly
- favorable at AAPS/FDA Workshop on DS/DP
- Specs – how about now?

## AcknowledgementMembers of the Drug Product Technical Committee

**CDER**
- 	Upinder S. Atwal
- 	Norman R. Schmuff
- 	Vispi P. Bhavnagri
- 	Ruth M. Ganunis				Nallaperum Chidambaram
- 	Lawrence Yu
- 	Marie Kowblansky
- 	Rashmi Patel
**CBER Associate**		Chris Joneckis
**Compliance Associate** 	Albinus M. D’Sa

## AcknowledgementMembers of the Drug Substance Technical Committee

**CDER**
- 	John Smith		Scott Furness
- 	Bing Cai		Jon Clark
- 	Eric Duffy		Yung-Ao Hsieh 		Charles Hoiberg	Robbe Lyon			Ramsharan Mittal	Stephen Moore
- 	Tom Oliver		Larry Ouderkirk
- 	Anil Pendse		Edwin Ramos			Suong Tran		Naiqi Ya
**CVM**
- 	 Dennis Bensley 	Raafat Fahmy
**CBER Associate**		Chris Joneckis
**Compliance Associate** 	Edwin Rivera

## Thank You

- MillerS@cder.fda.gov

## Slide 36

## Other Talks of Interest

- Talks on reasoning behind the revision of the DS Guidance from previous chair of DSTC (John Smith) _[h](http://www.fda.gov/cder/ondc/Presentations/Presentations.htm)__[ttp://www.fda.gov/cder/ondc/Presentations/Presentations.htm](http://www.fda.gov/cder/ondc/Presentations/Presentations.htm)_
- Presentation by Wendy Mavroudakis and Betsy Fritschel including thoughts on starting material selection (prior to release of CDER draft DS guide)
- _[http://www.gmp-navigator.com/slides](http://www.gmp-navigator.com/slides)_