# Presentation: 168175

## Risk Management for Complex Pharmaceuticals: 

- Steven Kozlowski, M.D., Director
- Office of Biotechnology Products OPS/CDER

- ACPS 10/6/06

*An Awareness Topic*

## Overview

- Background
- Complex Product Risk Assessment
- Less than the Whole 9 Yards
- Future Considerations

## Risk Management Tools (ICH Q9)

- Basic risk management facilitation methods (flowcharts, check sheets etc.);
- Failure Mode Effects Analysis (FMEA);
- Failure Mode, Effects and Criticality Analysis (FMECA);
- Fault Tree Analysis (FTA);
- Hazard Analysis and Critical Control Points (HACCP);
- Hazard Operability Analysis (HAZOP);
- Preliminary Hazard Analysis (PHA);
- Risk ranking and filtering;
- Supporting statistical tools.

## Risk Management (ICH Q9)

- Principles
- Link to patient protection
- Effort commiserate with *potential* risk

## Risk Assessment (ICH Q9)

- Risk = Probability X Severity
- What might go wrong?
- What is the likelihood (probability) it will go wrong?
- What are the consequences (severity)?

- Use in Quality Management & Regulatory Operations
- Inspections & Audits
- Facilities, Equipment & Utilities
- Materials Management
- Manufacturing & Change Control
*Assessment of Product Quality*
*Complex Products*

**Notes:**
Risk Identification
Risk Analysis Evaluation

## FMEA Bottom Up Semi-Quantitative

## FTA Top Down Quantitative

## Quantitative Risk Assessment

- Minor

- Important

- Major

- Catastrophic

- Severity

- Probability

## Probabilistic Risk Assessment (PRA)

- What it means?
**	****	**** ****	***Michael G. Stamatelatos, NASA*
**	**
- Includes uncertainty of quantitation
- Modeling for unknown information
- Integration many initiating events
- Examples of modeling
**	****	**** ****	***Fayssal M. Safie, Chad Hoffman, Rich Pugh...AIAA Pub*
- Similarity Method
- Probabilistic Structural Analysis
- Distributions of important variables
- Simulations (Monte Carlo, etc.)

## NASA PRA 

- Fayssal M. Safie, Ph.D., CRE

## Overview

- Background
**Complex Product Risk Assessment**
- Less than the Whole 9 Yards
- Future Considerations

## 1 structure
higher order structure
post-translational modifications
heterogeneity

- 1 structure
- higher order structure
- post-translational modifications
- heterogeneity

**Structure of complex molecules**

- Monoclonal Ab MW ~150,000 Da

**Notes:**
Assessment of the biological properties constitutes an equally essential step in
establishing a complete characterization profile. An important property is the
biological activity that describes the specific ability or capacity of a product to achieve
a defined biological effect.
A valid biological assay to measure the biological activity should be provided by the
manufacturer. Examples of procedures used to measure biological activity include:
· Animal-based biological assays, which measure an organism's biological response
to the product;
· Cell culture-based biological assays, which measure biochemical or physiological
response at the cellular level;
· Biochemical assays, which measure biological activities such as enzymatic
reaction rates or biological responses induced by immunological interactions.
Other procedures such as ligand and receptor binding assays, may be acceptable.

Potency (expressed in units) is the quantitative measure of biological activity based
on the attribute of the product which is linked to the relevant biological properties,
whereas, quantity (expressed in mass) is a physicochemical measure of protein
content. Mimicking the biological activity in the clinical situation is not always
necessary. A correlation between the expected clinical response and the activity in
the biological assay should be established in pharmacodynamic or clinical studies.

The results of biological assays should be expressed in units of activity calibrated
against an international or national reference standard, when available and
appropriate for the assay utilized. Where no such reference standard exists, a
characterized in-house reference material should be established and assay results of
production lots reported as in-house units.

Often, for complex molecules, the physicochemical information may be extensive but
unable to confirm the higher-order structure which, however, can be inferred from the
biological activity. In such cases, a biological assay, with wider confidence limits, may
be acceptable when combined with a specific quantitative measure. Importantly, a
biological assay to measure the biological activity of the product may be replaced by
physicochemical tests only in those instances where:

· sufficient physicochemical information about the drug, including higher-order
structure, can be thoroughly established by such physicochemical methods, and
relevant correlation to biologic activity demonstrated; and
· there exists a well-established manufacturing history.

Where physicochemical tests alone are used to quantitate the biological activity
(based on appropriate correlation), results should be expressed in mass.
Test Procedures and Acceptance Criteria for Biotechnological/Biological Products
For the purpose of lot release (section 4), the choice of relevant quantitative assay
(biological and/or physicochemical) should be justified by the manufacturer.

2.1.3 Immunochemical properties

When an antibody is the desired product, its immunological properties should be fully
characterized. Binding assays of the antibody to purified antigens and defined
regions of antigens should be performed, as feasible, to determine affinity, avidity and
immunoreactivity (including cross-reactivity). In addition, the target molecule bearing
the relevant epitope should be biochemically defined and the epitope itself defined,
when feasible.
For some drug substances or drug products, the protein molecule may need to be
examined using immunochemical procedures (e.g., ELISA, Western-blot) utilizing
antibodies which recognize different epitopes of the protein molecule.
Immunochemical properties of a protein may serve to establish its identity,
homogeneity or purity, or serve to quantify it.
If immunochemical properties constitute lot release criteria, all relevant information
pertaining to the antibody should be made available.

## Attributes & Combinatorics

**2 x 6 x 4 x 4 x 5 x 5 x 2 = 9600**

**(9600)****2****≈ 10****8**

**Notes:**
These changes are not necessarily independent

The vast majority of these occur at miniscule levels or not at all

They are generally not characterized in many products

However some of these may matter. There have been difference in products pot change that have not been correlated with a particular structural attribute. Maybe some of these depend on combinations of changes.

Characterization of structure and heterogeneity is not enough-

## Laurence J. Peter, American business humorist

- Some problems are so complex
- that you have to be highly intelligent
-  and well informed

- just to be undecided about them.

## Probabilistic Risk Assessment

- People tend to think that lack of data is a reason not to perform a PRA, but the exact opposite is true
- PRA is generally used for low-probability and high-consequence events for which insufficient statistical data exist.
- If enough statistical data exist to quantify system or sub-system failure probabilities, use of some of the PRA tools may not be necessary
*Michael G. Stamatelatos, NASA*
- May serve as organizing framework
*Bilal Ayyub, U of MD*

## Protein LogicDiagram

- Protein

## Functional Event Sequence Diagram

- Oxidation
- Site 1

## Safety

- Oxidation
- Site 1

**Acceptable**
**Product**

- Batch
- Failure

**Clinical**
**Failure**

- Is Level Low Enough (*or High Enough*) not to
- Generate an Immune Response?

-  Detectability of Oxidation
- with Impact?

*Y*

*Y*

- Is Oxidation
- Without Impact
- On Safety?
- (Immunogenicity)

- Does the Immune Response
-  Lack Clinical Significance?

## Functional Event Sequence Diagram

- Oxidation
- Site 1

- Is Oxidation
- Without Impact
- on Activity?

**Acceptable**
**Product**

- Batch
- Failure

**Clinical**
**Failure**

- Is Level Low Enough
-  not to Matter?

-  Detectability of Oxidation
- with Impact?

*Y*

*Y*

## Event Tree (Quantification)

- Oxidation
- Site 1

- Low
- Level

- No
- Impact

- Detectable

- Scenario
- #

- End
- State

## Assigning Probabilities

- Actual Data
- Similarity Method
- Same Product
- Models (animals, bioassays)
- NASA Ground tests
- Related Product or Component
- Direct Data (clinical)
- Models (animals, bioassays)
- Probabilistic Structure Analysis
- e.g. probability of docking to all known receptors
- Far off

## Biological Activity Matrix

**Notes:**
Figure 3. Biological Activity Matrix. Since no one bioassay, animal model or pharmacodynamic marker is likely to define all the relevant activities of an antibody, a combination of studies is likely to provide the most useful information. This matrix lists a variety of studies that are complementary. If such studies are performed with product variants during product development, the integration of study results may provide important information on product structure function relationships. 

## Assessing Relatedness for Assigning Probabilities

- Same primary sequence
- Alignment in shared framework/domains
- BLAST surrounding sequences
- T-cell-like
- Protein Structure Databases
- B-cell-like
- Molecular Descriptors (Cramer)
- In silico immunogenicity prediction
- Need measures of uncertainty associated with each strategy used

## Evolution of  Monoclonal Antibodies

**Notes:**
The participation in regulatory review allows the researcher reviewer a reality check for the real regulatory impact of the MOA data

## Monoclonal Antibodies as a Risk Management Platform

- 50% of licensed MAbs are IgG1
- It is estimated that greater than 50% of Mabs under development are humanized or human IgG1s
- 50% of products may share 95% of their sequence
-  Valuable human *in vivo* MAb data
- Isoform based PK data
- Large safety database for shared attributes
- All IgG1 products
- Endogenous IgG1 variants
- Radiolabeled antibodies & imaging (generally not humanized)

## Monoclonal Antibodies as a Risk Management Platform

- Isoform bioassays
- Fc binding & Effector Function
- Nature of target interaction
- Soluble, host cell based or on pathogen
- Accessibility of target
- Ability of target to signal
- Role of effector function
- Cross-reactivity

## Overview

- Background
- Complex Product Risk Assessment
**Less than the Whole 9 Yards**
- Future Considerations

## Even Without a PRA

- Nothing is more difficult, and therefore more precious, than to be able to decide.
*Napoleon Bonaparte *
- Even a correct decision is wrong when it was taken too late.
*Lee Iacocca *

## FMEA for Product Quality 

*Patrick Swann*

## Combination Products

- Primary Mode of Action
- Driver of jurisdiction between FDA Centers
- Toxic component overrides targeting
- Administrative Ease vs Risk Assessment
- Risk Assessment more Appropriate for Resource Allocation

## Antibody Conjugate

- P=?
- Probabilistic Risk Assessment

**Notes:**
These changes are not necessarily independent

The vast majority of these occur at miniscule levels or not at all

They are generally not characterized in many products

However some of these may matter. There have been difference in products pot change that have not been correlated with a particular structural attribute. Maybe some of these depend on combinations of changes.

Characterization of structure and heterogeneity is not enough-

## Very Complex Combinations

## Overview

- Background
- Complex Product Risk Assessment
- Less than the Whole 9 Yards
**Future Considerations**

## Considerations

- Follow up on prior programs
- Draft Report on Transdermal Patches
- Plan for Conference on Risk Management & Pharmaceuticals
- Bilal Ayyub, U of MD
- Further OPS education on Risk Management
- Seminar Series
- Consider approached to encourage exploration of of risk management strategies for complex products
- If Antibody Platform approach used in QbD
- Strategize to best utilize Risk Management
- Best initial system for PBR

## Homework

- Fault Tree Analysis for above product
- Assign probabilities to all possibilities
- Due 5PM today
- Also...consider relative importance of investing in risk management for complex products