# Presentation: 839150

## Ajaz S. Hussain, Ph.D.
Office of Pharmaceutical Sciences, CDER, FDA
July 8, 2003

- Office of Pharmaceutical Sciences, CDER, FDA
- July 8, 2003

*FDA Workshop on Innovative Systems for Delivery of Drugs and Biologics: Scientific, Clinical and Regulatory Challenges*_*Session: Preclinical Challenges*_**An** **Perspective on** **Quality by Design: A Preclinical Opportunity**

## Current Initiatives at FDA

- Promoting, Protecting the Public Health
- The PAT Initiative
*http://www.fda.gov/cder/OPS/PAT.htm*
- cGMP’s for the 21st Century Initiative
*http://www.fda.gov/cder/gmp/index.htm*
_**This workshop**_**: Improving Innovation in Medical Technology: Beyond 2002**
*http://www.fda.gov/bbs/topics/news/2003/beyond2002/report.html*

## Evolutionary Steps: Pharmaceutical Product & Process Development

- “Art”	   Science & Engineering based
- Dosage forms 		Drug Delivery Sys. 	Intelligent Drug Delivery
- Trial-and-Error	    DOE 	     CAD
- Few creative options tested 			Many creative options  tested
- End product testing  		“Real time” QA
- Batch processing		Continuous processing

*The first version of this slide was created in 1991 for a graduate course*
* “**Advanced Drug Delivery Systems” at the University of Cincinnati. Ajaz Hussain*

## Dosage Forms: Performance

## Typical CMC and cGMP Considerations

- Ensuring consistent quality and performance
- [Design] (specifications)
- Manufacturing process and controls
- Test methods and Shelf-life
- Process validation and manufacturing under cGMP
- “Bridging Studies”
- Post-Approval Changes
- [Continuous Improvement]

## Drug + Delivery System

**Anatomy, Physiology, Pathology,..**

**Pharmacology, Pharmacokinetics **

**Biopharmaceutics**

**Physico-Chemical Attributes**

**Delivery**
**System**

## Quality by Design

- Achievement of product and process performance characteristics that are adequate for their intended use through scientific understanding and management of sources of variation and other risk factors during manufacture.

## Design Objectives

## Drug Delivery Systems

- Past/Present
- Route of admn.
- Deployment relatively simple
- Drug delivery rate based on PK(/PD)
- Improve compliance
- Improve S&E
- Present/Future
- Deployment simple to complex (surgical)
- Delivery to target site(s)

- Quality and performance consistency based on traditional chemistry testing
- Gaps in “physical” test methods
- Need to be proactive for future products

## Defining Design Considerations and Specifications: Intended use?

- Intracoronary stents are _deployed_ to form a scaffolding for the coronary artery vessel wall _during coronary angioplasty_, thereby preventing recoil of the atherosclerotic vessel wall or protrusion of plaques or dissected intimal flaps into vascular lumen
- greater luminal dilatation than balloon angioplasty alone (e.g., *N Engl J Med* **331** (1994), pp. 489–495; *Am J Cardiol* **81** (1998), pp. 1286–1291)

## The leading processes of restenosis (solid lines) and correspondent inhibitory (dashed lines) effects of different biological agents. MMP indicates matrix metalloproteinase; VEGF, vascular endothelial growth factor.

**Circulation. 2003;107:2383-2389**

## How should we identify and optimize critical factors?

- Trial-n-error experimentation under all or selected (critical/assumption) anticipated “intended use”
- _Opportunity:_ Computer analysis employing numerical technique of the finite element (FE) method (e.g., Int. J. Cardiol. March 2001, Pages 51-67) coupled with computational fluid dynamics?
- simulate the response of different stents deployed under different conditions and the results verified with targeted experimental measurements
- identify critical variables for considerations in designing a suitable/capable manufacturing process

## Release Rate?

- Design objectives?
- Optimal *in vivo* release profile?
- Mechanism, rate, duration,..?
- Specifications?
- Controls and Tests
- Factors that influence release profile?
*In Vivo*
- Design and manufacturing factors
*In Vitro* Test method?
- Quality assurance
*In Vivo* Relevance?

## A, Concentration profile based on bulk elution model. 

- A, Concentration profile based on bulk elution model.
- B, Image of fluorescein distribution at 200 μm from luminal surface of bovine carotid artery

**Microscopic imaging of arteries reveals zones of high an low concentrations **
**that identically followed stent geometry**

- (Circulation. 2001; 104:600-605)

## Optimal decision making

- Requires diversity of information:
- Sources of information: theoretical models, test data, computer simulations, expertise and expert judgment (from scientists, field personnel, decision-makers...)
- Content of the information: information about system structure and behavior, decision-maker constraints, options, and preferences...
- Multiple communities that are stakeholders in the decision process

*Sallie Keller-McNulty* Los Alamos National Laboratory Statistical Sciences

## A Drug Quality System for the 21st Century

- Pharmaceutical manufacturing is evolving from an _art_ form to one that is now _science_ and engineering based.
-  Effectively using this _knowledge_ in regulatory decisions in establishing specifications and evaluating manufacturing processes can substantially improve the _efficiency_ of both manufacturing and regulatory processes.
- This initiative is designed to do just that through an _integrated systems approach_ to product quality regulation founded on _sound science and engineering principles_ for _assessing and mitigating risks of poor product and process quality_ in the _context of the intended use_ of pharmaceutical products.

- _[http://www.fda.gov/cder/gmp/21stcenturysummary.htm](http://www.fda.gov/cder/gmp/21stcenturysummary.htm)_

## Desired State

- Product quality and performance _achieved and assured by design_ of effective and efficient manufacturing processes
- Product _specifications based on mechanistic_ _understanding_ of how formulation and process factors impact product performance
- Continuous "real time" assurance of quality

- _[http://www.fda.gov/cder/gmp/21stcenturysummary.htm](http://www.fda.gov/cder/gmp/21stcenturysummary.htm)_

## Desired State

- Regulatory policies tailored to recognize the level of scientific _knowledge_ supporting product applications, process validation, and process capability
- Risk based regulatory scrutiny relate to the:
- _level of scientific understanding_ of how formulation and manufacturing process factors affect product quality and performance, and
- the capability of _process control strategies to prevent or mitigate risk_ of producing a poor quality product

- _[http://www.fda.gov/cder/gmp/21stcenturysummary.htm](http://www.fda.gov/cder/gmp/21stcenturysummary.htm)_