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A Qualitative Decision Making Tool to Aid in
Defining the Number of Lots for a Process
Validation Campaign
Leslie Sidor — Amgen Inc.
2012 Midwest Biopharmaceutical Statistics Workshop
May 22, 2012
Outline
Where is Amgen today
Why a qualitative tool
Tool development
Conclusions
Operational Excellence 2
Lifecycle Approach to Process
Commercialization Began 10 years Ago
Magnitude of post approval changes can
take process back into Commercialization
Amgen
FIH Process Comm. Process Process Val. & PAI & Launch Post-approval
Commercialization Development Development Char. File Prep Prep Development
Process
Amgen Production P3 Validation
Phase 1 & 2 Campaigns Commercial Production
Activity Campaign Campaign
Amgen’s old paradigm:
Validation is a single event in
time using 3 lots
Operational Excellence 3
Lifecycle Approach to Process Validation
Began 10 years Ago
Magnitude of post approval changes can
take process back into Commercialization
Amgen Post-
FIH Process Comm. Process Process Conf. & PAI & Launch
Commercialization approval
Development Development Char. File prep Prep
Process Development
Amgen Production P3 Conf.
Phase 1 & 2 Campaigns Commercial Production
Activity Campaign Camp.
Process Validation
Scope Stage 1 Stage 2 Stage 3
Process Design PPQ Continued Process Verification (CPV)
As defined in the FDA Process
Validation Guidance (Jan 2011)
Stage 2 will flex in size to assure “process is capable of
reproducible commercial manufacturing”
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Traditional Statistical Tools to assess
process capability Require N > 30 lots
Control charts
– Lot release
– In process controls
Inadequate sample
– Analytical method performance
size creates under or
– Stability data over reaction to
signals
Process capability indexes
– Lot release
– In process controls
Need to leverage qualitative information in Stage 1 to avoid
statistical issues
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Goal: Leverage information from Stage 1 using
a decision making tool to define size of PPQ
Stage 1 Stage 2 Stage 3
Process Design PPQ CPV
Stage 1 Stage 2 Stage 3
•Design of Experiments •PV protocols •Control charting for numerous
•Multiple Risk Assessments •Validation report quantitative parameters
Amgen •Critical Quality Attribute Matrix •Product comparability •Stability trending
•Comparability •Process comparability •Process capability assessment
Activities
•Etc. •NC trending •Analytical method performance
•Etc. •NC trending
•Quality System performance
•Etc.
Integrate Stage 1 information + indirect performance of
the facility using a Decision Making Tool
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Attributes of the Decision Making Tool using an
index
Tool maps qualitative factors into a numerical index
to describe factors that impact ability to control the
process
Tool uses qualitative characteristics of performance
– Direct measures
– Indirect measures
Tool needs to be…
– Objective
– Simple to use
– Adjustable to allow for continuous improvement
– Appropriately specific
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Relative Ranking for Decision Making
MATRIX
Indicator Characteristics Performance Characteristics
Owner Detentions (Past 12 Months)
Targeted Owner (5 Points) ______ 0 (-5 Points) _______
Flag 1+ ( __ Detentions × 10 Points) _______
Targeted Flag (7 Points) ______ Priority 1 Deficiencies (Past 18 Months)
Class 0 (-5 Points) _______
Top 25% (0 Points) ______ 1-2 (0 Points) _______
Middle 50% (1 Point) ______ 3+ ( __ Deficiencies × 5 Points) _______
Bottom 25% (3 Points) ______ Casualties (Past 3 Years)
Unknown Class (5 Points) ______ 0 (0 Points) _______
Vessel Type 1+ ( ___ Casualties × 3 Points) _______
Oil or Chemical Tanker (1 Point) ______ PSC Exam – No Priority 1 Deficiency
Freighter 10+ Years (2 Points) ______ Less than 3 Months (-5 Points) _______
Passenger Ship (1 Point) ______ Between 3 and 6 Months (-2 Points) _______
Low Commodity Carrier (2 Points)______ Greater than 6 Months (0 Points) _______
Total Indicator Score ______ Total Performance Score _______
Total Matrix Score: ___________ Score Vessel Priority
17+ I
Ballast Water Exam Required: Yes _____ No ______ 7-16 II
4-6 III
U.S. Coast Guard Boarding Required: ______
3 IV
Source: US Coast Guard, Field Demonstration Workshop on Performance-Based Inspection of Vessels
Entering the St. Lawrence Seaway (Prioritizing Vessels for US Coast Guard Inspection), April 2000
Operational Excellence 8
For Internal Use Only.
Amgen Confidential.
Step 1: Define what the index will represent
What does this index represent?
– Is it consequence based: the final number represents the
impact from consequences of interest.
Items of List of possible sources
of variation that can Scoring of the most
interest for impact process impactful sources of
scoring understanding variability for a
Factors affecting molecule
Scoring the process
Factors understanding
– Consequence of the index: description of the process by
understanding sources of variability
Scoring of Performance Characteristics that describe
process understanding. Index will drive the size of the PPQ
campaign
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2. Brainstorm factors that could affect the
index
Team members: 16 staff over 8 functional areas
Over 100 factors were identified
Factors were classified into 8 Performance
Characteristics
-Process -Raw Materials -Risk -Analytical Methods
-Product -Facility -Regulatory -Documentation
Factors were modified to remove ambiguous language
(e.g.: robust, approximate, successful, etc.)
DISADVANTAGE: Miss a key functional area, factor list
will be incomplete
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Step 3: Identify specific situations for
which specific actions are required
Question Answer Action
Is this a new facility? Yes Proceed to PPQ, but Perform the
maximum amount of work based on
the action threshold
Is process locked? No Do not proceed to PPQ
Is a PPQ protocol in No Do not proceed to PPQ
place?
These questions are asked before the tool is used
and overrides any decision from the tool
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Steps 4 & 5: Select a basic scoring or indexing &
develop scoring scales for each factor
Performance Factor No: Less process
Characteristic understanding
Product Product comparability has been No =1
demonstrated at commercial scale
DP only: Experience with multiple DS Yes=0
ages
Process Process tracking active in Clinical No=1
manufacturing
Raw Materials All raw materials have been used for No=1
the same application at commercial
scale
Average SCORE 75%
Use a binary response and compute % in
the “No’s”
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Considerations for scoring
All factors are not created equal
Apply appropriate weighting: Should a “No”
for some factors be worth 2 points?
Possibilities for average score
– Compute straight % for the “NO’s” (assumes each factor = 1
point if NO)
– Weight some factors greater than 1 point, then compute %
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Step 6: Set action threshold for the index
•Option 1: Define # of lots
•Option 2: Define # of lots + a transition plan
Score (% “No’s) # of Lots + Transition plan into CPV
for PPQ
> 80% >6 + monitor PPQ parameters for next 15 lots;
then move to CPV
>60% to < 80 % 5 to 6 + monitor PPQ parameters for next 10 lots;
then move into CPV
>40 % to < 60% 3 to 4 + monitor PPQ parameters for next 5 lots;
then move into CPV
< 40% 1 to 2 Move into CPV
No Decision has been made at Amgen to define
the action threshold
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Final steps are not complete
Step 7: Organize the scoring scale, index calculation
and action thresholds into an SOP
– A white paper will be written describing development and
rationale
– An SOP or training will be needed on how to use the tool
– Documentation of the tool user’s answers and the
justification of the answers will be incorporated into the tool
Step 8: Verify the documentation makes sense and
refine as needed
– Does the score make sense?
– Did we miss some factors?
– Does the weighting need further refinement?
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Conclusions
Statistical tools are not appropriate for low
sample sizes
Implement a qualitative decision making tool
that leverages Stage 1 information
– Follow systematic approach to develop tool
– Test tool to look for gaps before implementation
– Evaluate documentation for ease of use
Overall size of PPQ campaign also needs to
consider comparability and stability
requirements
Operational Excellence 16
References
Guidance for Industry Process Validation: General
Principles and Practices, January 2011
Levy, P.: Determining and Justifying the Number of
Process Validation Batches: Making Initial Batch Release
Decision. Presented at ISPE: Lessons Learned from 483s
Process Validation Track, February 2012
Field Demonstration Workshop on Performance-Based
Inspection of Vessels Entering the St. Lawrence Seaway
(Prioritizing Vessels for US Coast Guard Inspection); April
2000
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ABSTRACT:
The new FDA Process Validation guidance recommends a lifecycle approach for process validation
by allowing the manufacturer to incorporate process and product understanding into the timing and
size of the validation campaign (referred to in the FDA document as Process Performance
Qualification or PPQ). This paper describes a qualitative decision making tool to help determine an
appropriate size of the PPQ. The tool is based on criteria from seven key focus areas that aid in the
understanding of process capability and product consistency. These seven areas are product
understanding, process understanding, facility information, raw materials, status of analytical
methods, regulatory considerations and level of documentation. The tool lists performance
characteristics for each focus area. The user then lists a binary response of “yes” or “no” for each
characteristic. The justification for the number of lots for a process validation campaign is then
determined based on the percentage of “no” responses.
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