# Presentation: 198604

## Quality by Design: A Perspective From the Office of Biotechnology Products

- 	**ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE**** **		      October 26, 2005
- 		   Barry Cherney, Ph.D.
- 		      Deputy Director
- 		     DTP/OBP/CDER

## Overview

- Introduction of Biotech Products – defining the issues
- OBP Practice
- Designing a Quality Product
- Designing a Quality Process
- Implementation

## Office of Biotechnology Products

- Therapeutic Proteins
-  Growth Factors
- Enzymes
- Cytokines
- Chemokines
- Angiogenic factors
- Toxins
- Soluble Receptors/Receptor antagonists
- mAbs (related products)
- These proteins are produced from recombinant or non recombinant cell culture expression systems and from transgenic and non transgenic systems
- Products transferred from CBER to CDER in October 2003
- Excludes ONDCQA regulated protein products

## Biotechnology Products 

- Biotechnology products tend to be:
- Large, complex molecules
- Mixtures of many active ingredients
- Subject to extensive heterogeneity in quality attributes of the API
- Dependent on higher ordered structures and many times, flexibility (e.g. changes in conformation)
- Are sensitive to small changes in manufacturing and impurity profiles, conformation stability limited

## Product Variability

- Carbamylation
- Carboxylation
- Formylation
- Gamma Carboxyglutamic acid
- O-linked Glycosylation
- N-linked Glycosylation
- Methylation
- Oxidation
- Phosphorylation
- Sulphation

-  Amino Acid Substitution
-  Truncation
-  Mismatched S-S bonds
-  N- and C-terminal difference
-  Aggregation
-  Multimer Dissociation
-  Denaturation
-  Acetylation
-  Acylation
-  Addition of lipid
-  Amidation/Deamidation

## Biotechnology Products

- Generally, have poorly understood structure/function relationships
- These properties of the API are hard to fully characterize resulting in uncertainty
- Formulations: majority liquid presentations,
- 	less complexity then other formulations (stability a main issue, sampling size needs improvement )
- Control of the API is a major source of concern for Biotech products.

## Current OBP Practice

## Paradigms

- Quality is ensured by testing and rejecting lots that fail to meet its stated quality (insufficient)
- A guiding principle for the Biotech industry has been that the process is the product (can be too restrictive)
- Quality by design concept:
- Quality cannot be tested into a product; it has to be built by design.  This design incorporates knowledge of the **product** and the **process** to ensure all critical quality parameters are adequately controlled

## Quality Control Strategy

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

## How Much of the Iceberg (desired product) Can We See?

- Characterization

## Comprehensive Quality Control Strategy

- 		       Process
- Facilities and Equipment
- Control of Raw Materials
- In-Process Testing (PAT)
- In-Process Controls
- Process Validation (FED)
- cGMPs	(QC/QA)

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

## Designing a Quality Product

- Design a high quality product that maximizes efficacy while minimizing adverse affects
- Design a robust quality process to efficiently deliver a consistant product with the expected Q, S, and E profile

## Q by D General Requirements for Biotech Products

- Full Characterization of the product’s attributes (establish product variability – the earlier the better)
- Understanding the relationship between the product’s quality attributes and safety and efficacy
-  Understanding the mechanism of action both in terms of efficacy and safety (Biological characterization)
- Understand how process affects critical quality attributes
-    This knowledge is limited for many Biotech products

## The Desired Product

- Dosage form is usually a given, liquid (some vialed as lyophilized power)
- Excipients vary from product to product but mostly affect product stability
- Desired attributes of the API  (Focus for Biotech)
- Opportunity for protein engineering - understanding protein structure/function relationship
- Limit variability for attributes that negatively impact on product quality (via process or product)

## Protein Engineering (rational design)

- Increase manufacturability
- Improving function/new properties
-  Increase specificity/affinity
- Increasing Bioavailability
-  Pegylation
- Glycoslation
- Adding protein domains with increased half life (Fc)
- Adding domains that bind to endogenous long lived proteins

## Protein Engineering

- Reduce tendency for aggregation
- Increase conformational stability
- 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

## Protein Engineering

- OBP has encouraged development of innovative products (not a regulatory requirement)
- Less enthusiastic concerning the use of products whose design increases uncertainly and has no expected value clinically (premise: limit product variability)
- Histidine tag proteins (Quality versus Manufacturability)
- Protein domains that potentially adversely impact safety

## Designing A Quality Process 

## Examples of Problematic Process Designs

- Manufacturing capacity to clear viruses is limited
- Following elimination of aggregates by SEC, the manufacturer performs a heat treatment step for viral inactivation thus reintroduces aggregates back into the process
- Process performed at room temperature with negative impact on quality
- Roller bottle processes (open, multiple fermentations difficult to control)
- Recloning is used to establish new cell banks introducing variability
- Manufacturer recognized the limitations but regulatory hurdles are difficult to overcome particularly after approval

## Process Control

- Current OBP expectations are that critical sources of variation should be identified and controlled (raw materials/ unit operations)
- Controlled through in-process testing (PAT or other tests), monitoring operating parameters and process validation
- Based on long standing paradigm that process consistency = product consistency

- Biotechnology Process Control

**Harvest**

**Fermentor**

**Chromatography Columns**

**Some steps controlled by volume or time few measure product attributes directly**

***D0******2***
***pH***

***Turbidity***
***Conductivity***

***280nm ABS***
***Conductivity***

- The Essence of PAT

- Process decisions (in real time) are based on assessments of critical material attributes
- Forward-feed of incoming material
- Feedback by in-process monitoring
- Product quality is monitored _and controlled_ during the manufacturing process
- End points = achievement of the desired material attribute
- Currently, limited use of PAT in Biotech products but applicability is promising

## Process Control of Unit Operations

- Identify intended functions of unit operations and the critical product attributes potentially affected
- Establish desired limits of attribute (typically established by estimates of process capability)
- Identify critical variables for the process step
- Establish the range of the variables that provides assurance that you can meet your quality expectations
- First principles ??
- Empirical approach using multi variant analysis FED, but can you extrapolate to larger scales?

## Design Space (Fermentation)

- Agitation

- Time

- Critical process parameters

- Media composition

## Expanding the Design Space

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

## Examples from Biotech

- For a highly glycoslyated protein various isoforms were isolated and monitored for relevant bioactivity in a animal model suitable for Pk measurements.  Outcome: widen specs for isoform profile
- Monitored product isoforms from human serum samples over time, showed rates of decay were similar concluded isoforms did not impact bioavailability  Outcome: broaden  acceptance criteria
- Use of multiple lots of drug product in clinical trials to establish a link between variability of product attributes and clinical performance

- Validated bioassay

- Multiple binding/cellular assays

- Biological Activity Matrix

- Purified/induced variants

- Clinical lots

- Stressed lots

- Small Animal/Complex Bioassay

- Clinical/Clin Pharm

- Clinical lot  extremes

- Developmental lots

## Implementation

## Regulatory Relief (based on process understanding)

- Validate the process is capable of impurity removal to appropriate levels (non toxic impurities)
- Relief:  Impurity is not routinely measured when operating under the validated state (removed from specifications)
- Different approaches depending on the nature of the impurity
- Validate capacity to remove those impurities that are added at fixed concentrations (fixed input)
- Validate excess capacity for removal of impurities that variable (alternatively control of input levels of impurities)
- 			Examples: Host Cell Proteins/DNA

## Regulatory Relief (based on product understanding)

- Understanding of the relationship between the quality attribute and its impact on safety and efficacy can reduce regulatory requirements
- 	Relief: 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
- Transitioning to this new paradigm of action versus rejection limits
- Need to discuss more extensively in-house and provide reviewer training

## Implementation of Q by D

- Q by D “a major fear by industry is that reviewers will not understand or be receptive to the submission” paraphrased from Dr. Ken Morris, Q by D presentation October 17, 2005
- OBP review is based on scientific merits of the proposal and not simply reliance on existing practice.  Guidance helps frame the issue but science and knowledge dictates the outcome.
- For example, we try to stay away from proscriptive rules i.e. “rejection limits can be established +/- 3 SD”.   Instead, we evaluate the proposal using our best scientific judgment and are open to other statistical analysis but links between the attribute and what is known regarding its impact on S and E are important.  Lack of knowledge increases uncertainty and may result in tighten controlled.

## Implementation of Q by D

- Structure of OBP
-  Product reviewers a mixture of research/reviewers and full time reviewers
- Research conducted in molecular and cellular biology and pharmaceutical science
- Expertise in biological characterization of protein products is critical for meaningful risk assessment
- Provides hands on experience with latest techniques familiarity with fermentation/purification processes
- Expertise in biological characterization relevant to other CDER products
- Consultations across CDER

- PAT Future Directions

**Many steps controlled by measuring product**
** ****attributes (or by monitoring all DP samples) **

## Continued and Future Directions

- Training of OBP product reviewers in PAT (4 OBP product reviewers will undergo extensive training for Biotech products), Q by D,  and new analytical techniques (Biosensors SPR) for biotech products
- Q by D discussions within and outside Agency
- Encourage biological characterization of products
- Encourage industry to incorporate new or under utilized analytical methods for control of in-process materials and purified proteins