Sie sind auf Seite 1von 18

Advisory Committee for Pharmaceutical Sciences

Manufacturing Subcommittee
July 20, 2004

Life Cycle Management for Process and


System Control
An Industry Proposal
Tobias Massa, Ph.D.
Executive Director
Global Regulatory Affairs
Life Cycle Management
An Industry Proposal for ICH Q10

Utilization of science and risk-based quality management systems to


enable post-approval change and improvement.

Represents collective recommendation of the following organizations:


EFPIA
JPMA
PhRMA

20 July 2004 Company Confidential 2


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Life Cycle Management
An Industry Proposal for ICH Q10

Define the type of activities which a manufacturer may take, using risk
management processes (Q9) when appropriate, to
– monitor and evaluate quality of products, processes and systems appropriately
– make and manage improvements/changes appropriately

in order to demonstrate that Industry understands the manufacturing


process, controls the process appropriately and can manage post-approval
changes effectively based on product and process knowledge (Q8).

To create a guideline against which these aspects of a manufacturer’s


quality systems can be inspected.

20 July 2004 Company Confidential 3


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Life Cycle Management
An Industry Proposal for ICH Q10

Monitor and evaluate processes with feedback loops, to measure,


analyze, plan, act and review which:
• Identify trends
• Demonstrate control or the need for action

Manage and rectify undesirable occurrences (e.g deviations, complaints,


audit and inspection findings, root cause analysis.)
• Implementation and monitoring of corrective and preventive actions

Handle desired occurrences (improvements)


Manage/implement change and monitor the effect of change.

20 July 2004 Company Confidential 4


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Life Cycle Management
An Industry Proposal for ICH Q10

The outcome:

Gives Industry the opportunity via a harmonized standard to realize the


full potential of Q8 and to utilize Q9.
Encourages and motivates Industry to improve and optimize processes,
equipment, facilities, systems and procedures.

Gives Regulators the confidence that Industry can be responsible for


greater self-management of improvements and changes.
• Companies with good quality management systems
• Well controlled processes and products.

Quicker and more secure availability of products in the marketplace.

20 July 2004 Company Confidential 5


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
FDA Quality Concerns (C. 2001)
• Dealing w/ multi-factorial systems; weak causal links established
– DOE’s used very little by pharma manufacturing
– Don’t understand impact of raw material variability, so same suppliers and
processes are used
• Variability → increased risk → more compliance
• Testing to document quality
• Quality assurance based on documentation; not quality by design
• Manufacturers produce 2 products today; 1 for the patient and 1 for the FDA (paperwork)

• Quality can not be tested into products, it needs to be “built-in” (QUALITY BY


DESIGN)

Ajaz Hussain, Deputy Director, OPS, CDER (2001)

20 July 2004 Company Confidential 6


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Typical GMP Process

Any variability here Shows up here


Raw Material
Process Product

•Optimized & set during


development
•Controlled as closely as Process Variables
possible during production

20 July 2004 Company Confidential 7


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Deming on Variability and Inspections
Depending on inspection is like treating a symptom while the
disease is killing you. The need for inspection results from
excessive variability in the process. The disease is variability.
Ceasing dependence on inspection means you must
understand your processes so well that you can predict the
quality of their output from upstream activities and
measurements. To accomplish this you must have a thorough
understanding of the sources of variation in your processes
and then work toward reducing the variation. Ceasing
dependence on inspection forces you to reduce variability.

Deming, 1950

20 July 2004 Company Confidential 8


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Key Observations In Deming’s Comments
“…must understand your processes…”

“…predict the quality …from upstream activities and


measurements...”

“…work toward reducing the variation…”

Isn’t this Quality by Design?

20 July 2004 Company Confidential 9


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
FDA
The Desired State
Product quality and performance are ensured through the design of effective
and efficient manufacturing processes

Product and process specifications are based on a mechanistic understanding


of how formulation and process factors affect product quality and
performance

Continuous product and process improvement

Relevant regulatory policies and procedures are tailored to reflect current


level of scientific knowledge and associated risk

Risk-based regulatory approaches recognize:


• the level of scientific understanding of how formulation and manufacturing
process factors affect product quality and performance
• the capability of process control strategies to prevent or mitigate the risk of
producing a poor quality product

Moheb Nasr (DIA, June 2004)


20 July 2004 Company Confidential 10
T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Relationship between science, risk
management and the regulatory process
More
More
Reduction of risk

Manufacturing Science
by good design
III and control
strategies
RISK

Low complexity,
II
robust process,
high capability
effective Q systems

Less Less
High Regulatory Process Category Low
III- High; II-Medium; I-Low 21

20 July 2004 Company Confidential 11


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Life Cycle Management
How does it work?
• Design quality into development of process and controls
• Use data rich experiments to identify critical to quality attributes of process

• Development data (including failures and validation protocol/data) in


application: Pharmaceutical Development and Manufacturing Science Report
• We have to figure out how to share these data with regulators!!!

• Validation (consistency run ??) protocol

• Validation summary

• Interim specifications

• Comparability protocol

• CONTINUOUS IMPROVEMENT--Supplements without Prior Approvals

20 July 2004 Company Confidential 12


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Process Control and Capability Cycle
Development History

Integrated Validation Master Plan


process • product • systems

Process Flow Document

Technology Transfer

Qualification

Validation

Execute & Monitor

Technical Evaluations Quality (GMP) Evaluations


process • product quality systems

Countermeasures Countermeasures
process • product quality systems

Site Quality Plan

20 July 2004 Company Confidential 13


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Integrated Quality / Sustainable Quality

Influence the design of new solutions

Continuously improve products

Quality by Quality in Quality through


Products

Design Execution Monitoring

Process & Product Patient Safety


Manufacturing
Development Surveillance

Integrated Quality. Continuous Improvement.


Quality Systems

Systems Control Auditing

Quality by Quality in Quality through


Design Execution Monitoring

Continuously improve processes

Influence the design of new systems

20 July 2004 Company Confidential 14


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
21st Century Quality Approach
•Add PAT •Add PAT
•Measure raw material •Measure critical quality
attributes attributes

Raw Material PAT PAT


Process Product

Adjust CPP’s Adjust CPP’s


in response to in response to
RMA’s CQA’s

Process Variables

Combination of feed forward and feedback control of CPP’s provides even


greater control of critical quality attributes

20 July 2004 Company Confidential 15


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Q10 is only part of the solution!!
Regulators regulate regionally, Manufacturers commercialize
globally.
Multiple regional regulations governing manufacturing changes
are not harmonized--each region (US, EU, Japan, others) has
unique regulations.
Differences include regulatory filing mechanism for same change,
review cycles, data requirements and interpretation of same data.
Result is resistance to change and logistical hurdles that could be
avoided.

20 July 2004 Company Confidential 16


T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Why harmonized standards for Quality Systems?

Product A One CMC dossier


Submitted and reviewed
Differences in specs,
A1 A2 A3 A4 in-process controls,
shelf life = 4
Process Improvement proposed & submitted “products”

A5
Time

2 processes running 3-5


Change
submitted A6 “products”
A7 Logistical nightmare
Change requested by authority

A9 A8 A6
20 July 2004 Company Confidential 17
T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company
Why harmonized standards for Quality Systems?

Change in API which affects 3 formulations

Product A One CMC dossier


Product A One CMC dossier
Product A One CMC dossier
Submitted and reviewed
Submitted and reviewed
Submitted and reviewed
Differences in
Differences in
Differences in A1 A2 A3 A4
specs, in-process
A1 A2 A3 A4 specs, in-process
A1 A2 A3 A4 specs, in-process controls, shelf life =
controls, shelf life =
controls, shelf life =
Process Improvement proposed & submitted 4 “products”
Process Improvement proposed & submitted 4 “products”
Process Improvement proposed & submitted 4 “products”
A5
A5
A5 2 processes running

Time
2 processes running
Time
Time

2 processes running Change


Change
3-5 “products”
Change 3-5 “products” submitted
3-5 “products” submitted A6
submitted A6 A7 Logistical nightmare
A6 A7 Logistical nightmare
A7 Logistical nightmare Change requested by authority
Change requested by authority
Change requested by authority
A9
A9 A8 A6
A9 A8 A6
A8 A6

A logistical impossibility !!!


20 July 2004 Company Confidential 18
T.Massa ACPS MSC Copyright © 2004 Eli Lilly and Company