# Presentation: 530807

## A FRAMEWORK FOR FOLLOW-ON PROTEIN PHARMACEUTICALS

**CHARLES L. COONEY**
**MIT, Department of Chemical Engineering**
**Cambridge, MA 02139**

**FDA/DIA Scientific Workshop**
**Follow-on Protein Pharmaceuticals**
**Arlington, VA Feb. 14, 2005**

**Notes:**
At this meeting three is deep knowledge and diverse opinions on the issues surrounding the concept of follow-on biologicals
As a consequence there is an opportunity to add scientific substance to the debate as an important step in the journey that will lead to clarification of the principles which we evaluate the merits of this class of pharmaceuticals
I agreed to contribute some opening remarks for this meeting because I believe that this dialogue is important in the delivery of quality health care to people worldwide	
My goal is to help provide a framework for the work to be done in the breakout session where there is an opportunity to contribute to the scientific dialog needed to understand the uncertainty related to FoB
Over the past 35 years I have worked with many of you on various aspects of biologicals manufacturing and I appreciate the opportunity to speak here to this important issue.

In spite of the diverse agendas and opinions here I hope we can work towards defining a scientific dialogue absent of profit and political drivers in order to set the principles on which we move forward

## Passion for the High  MountainsEnjoying Risk

**Ama Dablam, 7,000 m, Khumbu Region, Nepal**

## In practice, I manage risk

**In practice, I manage risk**

## FOLLOW-ON PROTEIN PHARMACEUTICALS

- This workshop is about the scientific foundation for developing, evaluating, producing & delivering follow-on therapeutic proteins
- The goal is to assess  the uncertainty and risks and manage the relevant risks associated with follow-on biological products
- The challenge is to reach a consensus for the path to follow in assuring safe and efficacious follow-on products in an environment with multiple agendas.

## YOUR GOAL

**YOUR GOAL**

**Vasco De Gama’s Journey 1497**

**Your Journey Feb 14, 2005**

## Key Concepts

**Analytical technology** **and tools** – define where we are
**Knowledge** – what we have learned
**Uncertainty **– a measure of how well we know something
**Risk** – the result of uncertainty, a hazard
**Desired outcome **– the place we want to go

## What is a Follow-on Biologic?

## A Perspective on the State of Follow-on Biologics Today

- Multiple processes and manufacturers for
- Insulin, Human Growth Hormone, Erythropoietin
- Multiple locations for manufacturing
- Processes for follow-on products may be different because:
- Issues of IP and freedom to operate
- Use of differing analytical methods
- Introduction of new process technology
- Incorporation of prior knowledge into new processes

**Notes:**
Nomenclature for same therapeutic product?
ICH Q5E limits discussion to within manufacturer changes

## PROCESS DESIGN CAN BE 

**A LONG LONELY PATH**

**Kahiltna Glacier, Mt. McKinley at 7,000 ft**

**You need to know where you are and where you want to go**

**Notes:**
We continue to come back to the same theme

## Drivers for Follow-on Biologicals

**Reduced cost of patient care** – Political agenda
**Business opportunity**
- US revenues for biotech drugs in 2003 = $40 billion from sales on >100 approved products
- Average gross margins > 75%
**Expanding patient care**
- New products – 370 biotech drugs in clinical trials
- New markets – global expansion

**Notes:**
Add data on size of business opportunity 

## THE PROBLEM

- Inadequate definition of the molecular complexity associated with the structure and function of protein pharmaceuticals
- Barriers to understanding the complexity
- Analytical methods
- Definition of process space
- Understanding the relationship between structure & function

**Notes:**
The problem may be seen as having two parts, knowing where you want to go and having the metrics to measure where you are relative to that goal.

## EMEA

- Because of molecular complexity, the generic approach is scientifically not appropriate and a biosimilar approach based on comparability needs to be followed to establish acceptable S&E

**CHMP Guideline on Similar Biological Medicinal Products 16 Nov. 2004**

## UNCERTAINTY

- Uncertainty is the foundation of risk
- We need the methods and knowledge to assess and reduce uncertainty to an acceptable level
- We need methods and principles to manage risk
- Need to know where we want to go and have a measure of where we are

## MOLECULAR COMPLEXITY

- Rotating antibody  Jose Saldanha,  Humanization by Design  © 2000

**Penicillin**

**IgG**

******1-Antitrypsin**

## Relationship of Characterization to Purity and Complexity

**Ability to Characterize**

**High**

**Low**

**Purity**

**Molecular **
**Complexity **

**Purity**
**Complexity**

## Probing Molecular Complexity to Reduce the Uncertainty 

**What are the relevant structural features?**
- Primary
- Secondary
- Tertiary
- Quaternary
**What are the purity requirements?**
- Active components
- Impurities
**What are the relevant biological attributes?**
- Primary activity
- Pleotropic activities
- Immunogenicity
- Pharmacokinetics
- Toxicology
**How do the requirements relate to the risks and benefits?**

## PROCESS COMPLEXITY

- Biological vs. Chemical
- Process steps
- Number and type
- Residence time
- Process reagents
- Number and type
- Sourcing
- Process conditions

**When we introduce a process to make a biotherapeutic product do we know the “optimum” conditions for quality and quantity?**

**During routine manufacture, do we improve the quality and quantity of product?**

## Process Flow for Penicillin Production 

## Process Flow for a MAB

## Manufacturing Complexity

- It is not biological manufacturing per se that adds uncertainty
- It is our understanding of how manufacturing operations affect the product
- Limited analytical capability
- Limited process understanding
- This has implications to both improving old and developing new process

**Notes:**
Getting it right in terms of understanding the relationship between the process and the product is a win for both the innovator and the follower and most important the patient
Example of Eprex in which an unexpected interaction of uncoated rubber stoppers and a process additive led to an increase in Pure Red Cell Aplasia

## Probing Process Complexity to Reduce the Uncertainty

- Operating under “validated conditions”
- Learning from variance
- Expanding our knowledge of operating space
- Employing Process Analytical Technology (PAT) across the value chain
- Relating product quality to process quality

## O2 Gradients in Large-Scale Fermentors

**How do O****2**** gradients affect cells***** *****?**
**How do cells respond?**
**Effects on recombinant protein production?**

**Heterogeneous**

## Model System: 1-Antitrypsin

**Elastase inhibitor (44 kDa) ****10 met and 1 unpaired cys**
**Activity lost with oxidation of active site MET358 ****Oxidation of met358 -->  partial loss of neutrophil elastase activity & **_**complete loss of porcine pancreatic elastase**_
**Use in protein replacement therapy**
**Cytoplasmic expression in *****E. coli BL21***

**M358**

**M351**

## O2-Enhanced Degradation is Eliminated in ClpP- Strain

**Wild Type**

**SG1146A (ClpP-)**

**Some background degradation (~18%) remains**
**  ****Other protease responsible**

**O****2****-Enhanced Degradation is Eliminated**** in ClpP****-**** Strain**

## Do we have the analytical techniques to probe a cell’s global response to its physical environment?

## DNA Microarray Experiments

**3,812 Genes representing 89% of *****E. coli***** genome**
**Multi-Gene Groups**
**167 protein complexes**
**190 pathways**
**333 transcription units**

## Hyperoxic Stress Responses

**Increasing                N****2**** ****→ ****Air ****→**** O****2**
**Sustained Response from SoxRS Regulon**

**Increasing                Air ****→**** O****2**
**Short-Term Response from OxyR Regulon**

## Systems Framework for Manufacturing

**Process Materials**

**Package**

**Process Configuration**
**& Operation**

**PRODUCT**

## MANUFACTURING SCIENCE

## PROCESS UNDERSTANDING

***Intensity of Process***
***Understanding***

***Time***

**LEVEL **
**1**

**LEVEL **
**2**

**LEVEL **
**4**

**LEVEL **
**5**

**LEVEL **
**3**

***FDA Minimum Requirement***

***Launch***

***Are we here?***

***Or are we there?***

## CONTINUUM OF PROCESS CHANGE

| Change |  | Improved process | New
Location
 | New
process | New
Process,
Location, &
Company  |
| --- | --- | --- | --- | --- | --- |
| Product | A | A | A | A’ | A’ |
| Process | B | B1 | B1 | B2 | B2 |
| Location | C | C | C1 | C | C2 |
| Company | D | D | D | D | E |

## What is the next step?

## Where do we need agreement?

- Acknowledgment that FoB are a reality
- Nomenclature to share a common dialogue
- Analytical methods to measure where we are
- Reference standards for
- Purity
- Structure
- Efficacy or bioequivalence
- Understanding of acceptable uncertainty
- Purity – impurities and contaminants
- Structure
- Efficacy or bioequivalence
- Strategy for managing a continuum of risk

**Notes:**
Nomenclature – on and off belay makes a big difference, therefore the commands are on-belay and belay-off
Standards, e.g. for purity, structure, efficacy . At one time coomasi stained gels wee the standard of purity, then came silver staining 	
Acceptable uncertainty is in part defined by what we can measure and our knowledge of how this measurement connects to S&E

## GOING FORWARD

- Seek clarity of nomenclature
- Articulation of the scientific principles that help resolve the uncertainty of product similarity
- Relate the principles to the continuum of complexity of biologicals

## IN CLOSING

- Follow-on protein pharmaceuticals are a reality today
- There are significant incentives to expand their availability
- It is important to get it right
- Failure by either innovators or followers will hurt all the players, not the least of whom are the patients