# Presentation: 270510

## Implementation of Quality by Design: 

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

- ACPS 10/5/06

*An Office of Biotechnology Products Perspective*

## Overview

- OBP Products & Quality by Design
- Relevant Product Attributes
- Manufacturing Process
- Implementation Plans

## Office of Biotechnology Products

- Therapeutic Proteins
-  Growth Factors
-  Enzymes
-  Cytokines
-  Chemokines
-  Angiogenic factors
-  Toxins
-  Soluble Receptors/Receptor antagonists
- Monoclonal antibodies
- Related Products

## Office of Biotechnology Products

- These proteins are usually produced from:
- Cell culture
- Recombinant & non-recombinant
- Mammalian, bacterial, yeast, etc.
- Transgenic plants & animals
- Products transferred from CBER to CDER in October 2003
- ONDQA regulates some protein products

**Notes:**
Bioreactor (or source material)
Desired product
Contaminant/impurity load
Downstream processing
Desired product
Viral clearance/inactivation
Removal of in-process reagents
Linkers/chelators
inactivating chemicals
other reagents used in synthesis
Removal of host cell proteins and DNA
need for sensitive assays

In-process controls
Process & hold times
Process parameters & in-process tests
Reprocessing
Comparability studies
Scale-up
bioreactor
downstream processing
Significant manufacturing changes
New facility

## 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.

## Relationships

- Safety
- Efficacy
- (SE)

- Quality
- Attributes
- (A)

- Manufact.
- Process
- (P)

## Comprehensive QbC Strategy

-        Product
- Method Validation
- Release Testing
- Characterization
- Stability Testing

- Process

**Notes:**
Equipment validations, cleaning and maintance are important
Appropriate facility design and oversight is important
Some Raw materials are critical to the quality of the final product non conformances are often associated with inappropriate raw materials.
What are the critical attributes of these materials?

After putting this all together it was apparent to me that this approach is not QBD by rather quality by control So although we have had this mantra of QBD I don’t think it has really been approach in the best way
That’s not to say this approach is bad it works products to ensure that products have the expected performance characteristics as described in the label.  But would you rather drive an e cono car or a high performance luxury sedan.

## What is “Quality by Design”?

- Quality
- “Good pharmaceutical quality represents an acceptably low risk of failing to achieve the desired clinical attributes.”
- Quality by Design (QbD)
- “Means that product and process performance characteristics are scientifically designed to meet specific objectives, not merely empirically derived from performance of test batches.”

- Janet Woodcock (2004)

## Quality

**Quality**
**by**
**Design**

**Moheb Nasr**

## Overview

- OBP Products & Quality by Design
**Relevant Product Attributes**
- Manufacturing Process
- Implementation Plans

## How Much of the Iceberg (Quality Attributes) Can We See?

- How Much of the Iceberg (Quality Attributes) Can We See?

- Characterization

**Notes:**
Release tests only look at a small subset of structural attributes. 
As we have stated biological activity provides some surrogate structural information.

Characterization, often done for comparability, can evaluated much more...although it has its limitations and we need to know what to look for.
For many complex molecules characterization does not capture all product attributes

Therefore we have depended on process to assure each lot of a product is safe and effective
Process knowledge and defined changes are key factors in successful “within manufacturer” changes

As we have advanced and will continue to advance in characterization technology, the question is whether in some cases characterization can provide some or all of the same assurance of “clinically relevant sameness” provided by process knowledge.

We should define some terms regarding sameness for purposes of this discussion-- 

## How Much of the Iceberg (Quality Attributes) Can We See?

- How Much of the Iceberg (Quality Attributes) Can We See?

- Characterization

- MS, NMR
- Orthogonal methods

**Notes:**
Release tests only look at a small subset of structural attributes. 
As we have stated biological activity provides some surrogate structural information.

Characterization, often done for comparability, can evaluated much more...although it has its limitations and we need to know what to look for.
For many complex molecules characterization does not capture all product attributes

Therefore we have depended on process to assure each lot of a product is safe and effective
Process knowledge and defined changes are key factors in successful “within manufacturer” changes

As we have advanced and will continue to advance in characterization technology, the question is whether in some cases characterization can provide some or all of the same assurance of “clinically relevant sameness” provided by process knowledge.

We should define some terms regarding sameness for purposes of this discussion-- 

## 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.

Setting an unachievable bar?
Nat Biotechnol, 2005. 23(9): p. 1054-8
No!
Advances in characterization are opportunities
Timing
Upfront costs
Early characterization benefits 
How to deal with greater information
flexibility not regulatory roadblocks

## Relevant Attributes

- ... those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product (Q6B)
- Can these attributes be defined?
- Often difficult
- Default is to look at many attributes

- Biological Characterization
- Structure/function

**Notes:**
by appropriate techniques (which includes the determination of physicochemical properties, biological activity, immunochemical properties, purity and impurities)

## 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. 

## CQA Multivariate Range

**Notes:**
Characterize a quality attribute with regard to relevant, clinically important parameters, i.e. it’s affect on:
Potency
Bioavailability
Biodistribution
Immunogenicity/ toxicity
This information can be used to set specifications to ensure product quality as it relates to S and E and potentially expand the design space

## The Desired Product

- Desired attributes of the API  (Focus for Biotech)
-  Opportunity for rational protein engineering
- Customize quality
- Increase attributes that are desirable
- Limit attributes that negatively impact product quality (via process or product)
- Understanding structure/function relationships is critical for this approach

## Protein Engineering

- Reduce tendency for aggregation
-   Block free sulfhydryl groups
-   Alter amino acid sequence based on 	computational predictions
-   Glycine repeats or proline insertions
-   Maintenance of net charge
-   Alternate polar and non polar residues
-   Clusters of hydrophobic residues
- Human Calcitonin (Zurdo et al PNAS 2005)
- Immunogenicity considerations

**Notes:**
Immunogenicity

## QSE...by Design

- Safety & Efficacy by Design
- Improving function/new properties
- Increasing Bioavailability
- Reducing immunogenicity
- Selective technologies in development such as phage, ribosome and yeast display
- Quality by design
- These strategies can also be used to select for product quality and manufacturability

**Notes:**
Expression systems E coli versus mammalian versus human.
Ecoli system inclusion versus soluble product
Fc portion useful for extending half life/ may have biological activity but useful for purification by protein A chromatography.  Powerful purification step.

Rational design knowledged based
Empirical 

Increase conformational stability
 Disulfide bridges/ Hydrogen bonding
Reducing immunogenicity
 Eliminate sequences that promote 	aggregation
 Humanizing foreign proteins (mAb)
 Pegylation
 Incorporate structures that are less 	immunogenic (disulfide bond scaffolds)
 T cell epitope engineering

## Overview

- OBP Products & Quality by Design
- Relevant Product Attributes
**Manufacturing Process**
- Implementation Plans

## What is the Relationship Between Attributes & Process?

- What is the Relationship Between Attributes & Process?

- Characterization

- MS, NMR
- Orthogonal methods

**Notes:**
Release tests only look at a small subset of structural attributes. 
As we have stated biological activity provides some surrogate structural information.

Characterization, often done for comparability, can evaluated much more...although it has its limitations and we need to know what to look for.
For many complex molecules characterization does not capture all product attributes

Therefore we have depended on process to assure each lot of a product is safe and effective
Process knowledge and defined changes are key factors in successful “within manufacturer” changes

As we have advanced and will continue to advance in characterization technology, the question is whether in some cases characterization can provide some or all of the same assurance of “clinically relevant sameness” provided by process knowledge.

We should define some terms regarding sameness for purposes of this discussion-- 

## What is the Relationship Between Attributes & Process?

- What is the Relationship Between Attributes & Process?

- Characterization

- MS, NMR
- Orthogonal methods

- Characterization

**?**

-   Process

- MS, NMR
- Orthogonal methods

**Notes:**
Release tests only look at a small subset of structural attributes. 
As we have stated biological activity provides some surrogate structural information.

Characterization, often done for comparability, can evaluated much more...although it has its limitations and we need to know what to look for.
For many complex molecules characterization does not capture all product attributes

Therefore we have depended on process to assure each lot of a product is safe and effective
Process knowledge and defined changes are key factors in successful “within manufacturer” changes

As we have advanced and will continue to advance in characterization technology, the question is whether in some cases characterization can provide some or all of the same assurance of “clinically relevant sameness” provided by process knowledge.

We should define some terms regarding sameness for purposes of this discussion-- 

## Translating CQA to a Manufacturing Design Space

**Notes:**
Characterize a quality attribute with regard to relevant, clinically important parameters, i.e. it’s affect on:
Potency
Bioavailability
Biodistribution
Immunogenicity/ toxicity
This information can be used to set specifications to ensure product quality as it relates to S and E and potentially expand the design space

## The Desired Process

- Desired attributes of the API or drug product
- Opportunity for rational process design
- Choose unit operations that select for
- select for desired product attributes
- minimize impurities/contaminants
- are robust
- Order unit operations to maximize efficiency
- minimize buffer changes
- consider impurities introduced by each step
- Process control
- consider impact of variable inputs
- parameters set based on maximizing multiple variables
- for critical steps- ideally real time & based on a knowledge base (PAT)

## Examples of Problematic Process Designs

- Processes that promote product variability
- Heat treatment step added after aggregate clearance step
- Process performed at room temperature with negative impact on quality
- Recloning is used to establish new WCB
- Processes that are difficult to control
- Roller bottle processes (open, multiple fermentations difficult to control)
- Poor formulation (stability & interactions)

**Notes:**
For Biotech products heterogeneity of the API is a major factor and less complex liquid formulations are common

Stability a big issue  
Proteins tend to be unstable
May change protein conformation
Compatibility problems with some excipients 
(pH, buffers, preservatives )
 Silcone in syringes/ Tungsten
Alternative dosage forms

Formulation is critical in controlling product variability

## Overview

- OBP Products & Quality by Design
- Relevant Product Attributes
- Manufacturing Process
**Implementation Plans**

## Implementation of QbD

- Benefit from other OPS knowledge on implementation
- e.g. ONDQA pilot
- OBP participation in agency CRADAs to facilitate QbD
- OBP Structure
- Mixture of research/reviewers and full time reviewers
- Experience with new technologies, fermentation/purification
- Expertise in biological characterization
- Encourage industry to engineer proteins for quality as well as safety and efficacy
- “desired product”
- Encourage industry to consider “desired process”

**Notes:**
We have no enforcement capability for 
Add forgein protein moieties to increase half life of threputics that have a endogenous counter part is an issue.

## Small Steps

**Product Testing**
- If no likely impact on S and E don’t include as a specification (no rejection limit)
- use as a process consistency measure, where exceeding a limit initiates an investigation
- if not a consistency measure, drop the test entirely
- Need to discuss more extensive in-house reviewer training
**Process Changes**
- Strategy to assess risk
- Select classes of change based on
- supplement load
- variable risk to product
- FDA/industry forums targeted to create risk map for a single class of change
- Publication as white papers

## Small Steps (cont.)

**Complex API pilot**
- Encourage manufacturers to generate and submit data on characterization of structural attributes
- the use of multiple biological assays for characterization
- the generation of a product attribute space
- consideration of associated relief (e.g. greater flexibility for comparability protocols)
- Need to consider & discuss further
**Platform Strategies**
- monoclonal antibodies may share a great deal of structure
- efficient use of prior knowledge
- long history of a regulatory path for modular/generic validation (Mab PTC)
- underutilized
- currently of interest to many biotech companies
- conference to put interested parties together

## Question to ACPS

- Should FDA develop a pilot program and/or initiative to explore specific QbD issues that are important for biotechnology products?
- Such a program could focus on issues such as:
- (1) general approaches to CQA for complex API
- (2) platform approaches/extrapolation for highly related complex APIs.

## Quality Life Cycle Definitions?

***Studies (DOE*****)**

***Conformance Lots***
***“******Validation Studies”***

***Post-Approval***

**    ****Propose**
- (Desired Attributes/Process)

_**Quality Life Cycle Definitions?**_

***Design -Evaluation***

**Identify**
- (Critical/ Key
- Parameters/ &
- Ranges)

**   ****Confirm**
- (Control/ Predict)

**Monitor**

**Commercial **
**Production**

**Optimize**
- (Continuous
- Improvement
- Innovation)

**Notes:**
First provided for P2 in MA, knowledge can be updated throughout the lifecycle of the product 
Illustrate some of the Q8 concepts as part of a product lifecycle

Understanding the product and process remain integral to the development and manufacture of biotechnology and biological products “Know thy process and product”

A comprehensive lifecycle approach to process validation relies on scientific & engineering principles, and progressively builds assurance (confidence) in consistent manufacture of quality product.

## Credits

**Barry Cherney**
- Patrick Swann
- Moheb Nasr
- Keith Webber
- Ajaz Hussain