Risk Control:

The Evolution of Multi-use Controls

A Case Study

July 2009 CMC Strategy Forum:

Practical Applications of Quality Risk
Management
Julia Edwards
Regulatory CMC

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Objective

Slide 2

Document the evolution of risk assessment and Quality Risk Management.

Demonstrate how Quality Risk Management can be used to assess the risk of
cross-contamination due to multi-use operations in a Drug Substance
manufacturing facility.
Provide a practical example of how Quality Risk Management (QRM) can be
leveraged to make risk control decisions.
Propose an approach to regulatory submissions that utilize Quality Risk
Management principles as described in ICH Q9.

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Benefits and challenges of Quality Risk

Management (QRM)

Slide 3

ICH Q9 offers a systematic approach to quality risk management.

The principles and systematic approach described by ICH Q9 enable more
effective, informed, and consistent risk-based decisions that benefits both
industry and regulators.
Although both industry and regulators benefit from QRM, it is not without
challenges

Time consuming
Involves many people of differing opinion and background
Rigor of applying quantitative values to often intuitive situations can be tedious
Integration of QRM within the Quality System instead of being an additional activity
Ongoing maintenance as a living process
Risk Management plans, protocols, assessments and Risk Control Strategies
require significant resources to execute appropriately

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Multi-use Operations Definition

Slide 4

Multi-use refers to the types of products that can be produced within the
same Drug Substance manufacturing facility
Multiple commercial products
Clinical and commercial products
Products derived from different host cells

Multiple
commercial
products

Multiple clinical
and commercial
products

July 2009 CMC Strategy Forum

Multiple clinical
and commercial
products and
multiple host
cells

Julia Edwards, Genentech Inc.

2208, Genenteh

The Evolution of Quality Risk Management

and Multi-use Operations
Several incremental changes were
made to the approach for multi-use
controls to bring us to current state

July 2009 CMC Strategy Forum

Slide 5

QRM

Julia Edwards, Genentech Inc.

2208, Genenteh

The Evolution of Quality Risk Management

and Multi-use Operations
Several incremental changes were
made to the approach for multi-use
controls to bring us to current state

Slide 6

QRM

Operated multihost/multiproduct
clinical/commercial
facility

Risk Assessment
July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

The Evolution of Quality Risk Management

and Multi-use Operations
Several incremental changes were
made to the approach for multi-use
controls to bring us to current state

Slide 7

QRM

Asked to perform multihost risk assessment by

regulators
Operated multihost/multiproduct
clinical/commercial
facility
Use of systematic Risk
Assessment to assess
multi-use risk
Risk Assessment
July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

The Evolution of Quality Risk Management

and Multi-use Operations
Several incremental changes were
made to the approach for multi-use
controls to bring us to current state

Slide 8

QRM

Asked by regulators to
include additional
granularity and detail in
risk assessment
Asked to perform multihost risk assessment by
regulators
Operated multihost/multiproduct
clinical/commercial
facility

Formalized approach to risk

management and cross
contamination concepts
Use of systematic Risk
Assessment to assess
multi-use risk

Risk Assessment
July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

The Evolution of Quality Risk Management

and Multi-use Operations
Several incremental changes were
made to the approach for multi-use
controls to bring us to current state

Growing network of
facilities with multi-use
considerations

Asked by regulators to
include additional
granularity and detail in
risk assessment
Asked by regulators to
perform risk assessment
for multi-host facility
Operated multihost/multiproduct
clinical/commercial
facility

Formalized approach to risk

management and cross
contamination concepts

Slide 9

QRM

Extension of concepts to
regulatory submission
strategies that can be
executed across multiple
products, facilities, and
types of multi-use
operations

Use of systematic Risk

Assessment to assess
multi-use risk
Risk Assessment
July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Practical Application of Quality Risk

Management

Slide 10

QRM

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Tiered approach to multi-use controls

Slide 11

Baseline controls for each multi-use

operation defined commensurate
with the overall
cross-contamination risk.

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Slide 12

ICH Q9 QRM

Initiate
Quality Risk Management Process
Risk Assessment
Hazard Identification

Risk Communication

Risk Analysis
Risk Evaluation
Risk Control
Risk Reduction
Risk Acceptance

u
n
a
c
c
e
p
t
a
b
l
e

Risk Management tools

QRM process provides

systematic approach to ensure
the appropriateness of baseline
controls given differences in
facility design, systems, and
products.

Output / Report and Implementation

Risk Review
Risk Event

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Risk Identification

Slide 13

Failure Mode and Effect Analysis (FMEA) chosen as risk assessment tool.

Team of subject matter experts from relevant disciplines were convened to

assess risks.

Risk Identification was performed in several steps, recognizing the

complexity of multi-use operations, while allowing for categorization where
possible to minimize repetitive risk analysis.
1.
2.
3.
4.
5.
6.

Develop a process map grouping together similar unit operations, where possible
Assess risks that apply to more than one unit operation only once as a general risk
For each step of the process map identify relevant risk categories
Classify risks as either a cross-contamination or non-routine event
If the risk is a cross-contamination risk, determine the touch point
Identify all potential failure modes for the unit operation, risk category, and touch
point (as applicable)

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Process Map and Risk Category

July 2009 CMC Strategy Forum

Slide 14

Julia Edwards, Genentech Inc.

2208, Genenteh

Cross-contamination concepts focus Risk

Identification

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

Slide 15

2208, Genenteh

Results of Systematic Risk Identification

Slide 16

Utilization of this risk identification

process for a large multi-product
drug substance manufacturing
facility resulted in the identification
of ~300 risks

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Risk Analysis

Slide 17

Following risk identification, risk analysis was performed

Used defined scoring criteria to evaluate severity, probability of occurrence, and the
ability to detect each failure mode
Drive consistency of risk assessment across sites and products by pre-defining severity
scores
Type of cross-contamination (e.g., product, host cells, adventitious agents)
Type of multi-use operation

ICH Q9 requires the assessment of risk to patient safety, based on subject matter
expertise this may not be possible
The impact to product quality serves as a more conservative surrogate for patient safety

The severity scores for a contamination event remain the same regardless of where in
the process the event occurs.
The severity reflects the effect of the failure mode. Therefore, if the effect is unchanged, the
severity score must remain consistent regardless of process location.

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Scoring Criteria

Slide 18

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Pre-defined Severity Scoring

Slide 19

Multiple
commercial
products

Clinical and
Commercial
Products

Clinical and
Commercial
products;
Multiple hosts

Cross-contamination with adventitious

agents

10

Cross-contamination of one product

with another

10

10

Cross-contamination of cells between

products

10

10

Non-routine event during processing

Cross-contamination of one denatured

product with another

Cross-contamination of raw materials

from one product to another (animal
derived)

Cross-contamination of raw materials

from one product to another (non-animal
derived)

Failure Effect

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Example of Risk Analysis

Multiple Commercial Products

July 2009 CMC Strategy Forum

Slide 20

Julia Edwards, Genentech Inc.

2208, Genenteh

Example of Risk Analysis

Multiple Commercial Products

Slide 21

Multiple commercial
products

Clinical and
Commercial
Products

Clinical and
Commercial
products; Multiple
hosts

Cross-contamination with adventitious

agents

10

Cross-contamination of one product with

another

10

10

Cross-contamination of cells between

products

10

10

Non-routine event during processing

Cross-contamination of one denatured

product with another

Cross-contamination of raw materials from

one product to another (animal derived)

Cross-contamination of raw materials from

one product to another (non-animal derived)

Failure Effect

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Example of Risk Analysis of Crosscontamination Risk

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

Slide 22

2208, Genenteh

Example of Risk Analysis of Crosscontamination Risk

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

Slide 23

2208, Genenteh

Risk Evaluation, Acceptability, and Control

Slide 24

The resultant scores for severity, occurrence, and detection are multiplied to
obtain an overall score and represents the Risk Priority Number (RPN)
SEV x OCC x DET = RPN
The RPN score determines risk acceptability and directs discussion around
potential risk mitigation for unacceptable risks
Risk zones determine the extent of risk mitigation activities required

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Risk Prioritization Matrix

July 2009 CMC Strategy Forum

Slide 25

Julia Edwards, Genentech Inc.

2208, Genenteh

Risk Control

Slide 26

Risk control is the process through which decisions are reached and protective
measures are implemented for reducing risks to, or maintaining risks within
acceptable levels
The totality of the circumstances shall be taken into account when considering control
measures.
Risk acceptance is decided by the appropriate system/process owner or management team

Risk reduction
Processes for mitigation or avoidance of risk when it exceeds a specified level
May include mitigation of severity and probability of harm or improve the
detectability of hazards
New risks may be introduced by risk reduction measures and risk assessment may
need to be revisited

Risk acceptance

A decision to accept risk

Formal or passive decision
Either requires a decision to reduce risk to an alternate level, or
Acknowledges that risk can not be entirely eliminated

If an unacceptable risk cannot be further reduced, formal acceptability of risk must be

documented and approved by appropriate management and Quality.
Slide courtesy of Emabelle Ramnarine, Genentech
July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Risk Control Example

July 2009 CMC Strategy Forum

Slide 27

Julia Edwards, Genentech Inc.

2208, Genenteh

Systematic Risk Assessment can be

Leveraged in Regulatory Submissions

Slide 28

Systematic approach to decision making as described in ICH Q9 supports the

development of regulatory submission strategies such as expanded
Comparability Protocols

Effective use of expanded comparability protocols across products, facilities, and

changes
Reduces the number of regulatory submissions of the same type
Minimizes lot release restrictions associated with post-approval change submissions

Definition of baseline controls in conjunction with QRM risk control procedures

allows the setting of appropriate acceptance criteria across multiple products,
facilities, and types of changes

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Risk Assessment and Comparability protocols

Slide 29

Site
Inspection

Risk
Assessment

Baseline Controls and

requirements

Scope and Limitations

Expanded Comparability
Protocol
July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Conclusions

Slide 30

Quality Risk Management, although challenging, offers many benefits for

regulators and industry.
QRM has evolved significantly over past years and will continue to evolve as
regulators and industry become more familiar with the practical benefits and
applications.
The ability to make consistent, transparent, and science-based decisions in
risk control allow for the extension of utilizing QRM in regulatory submissions.
QRM can be leveraged in regulatory submissions such as expanded
Comparability Protocols that can be broadly applied across products,
facilities, and types of changes.

July 2009 CMC Strategy Forum

Julia Edwards, Genentech Inc.

2208, Genenteh

Acknowledgements
Emma Ramnarine
Krista Terry
Jennifer Sexton
Andrea Goddard
Mark Skoog
Eric Fallon
JP Gabriel
Christa Hartmann
Kathleen Bigelow-Houck
Euan Cunningham
Consuela Stewart
Wassim Nashabeh
Hoang Phan
Robert Caren
Jerry Cacia

July 2009 CMC Strategy Forum

Slide 31

Ron Williams
Vijay Palsania
Jenna Carlson
Lara Collier
Mary Beth Grace

Julia Edwards, Genentech Inc.

2208, Genenteh