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A Qualitative Decision Making Tool to Aid in Defining the Number of Lots for a Process
Validation CampaignLeslie Sidor — Amgen Inc.
2012 Midwest Biopharmaceutical Statistics Workshop
May 22, 2012
2Operational Excellence
Outline
Where is Amgen today
Why a qualitative tool
Tool development
Conclusions
3Operational Excellence
Commercial Production
Post-approval Development
PAI & Launch Prep
Val. & File Prep
Process Char.
Comm. Process Development
FIH Process Development
Amgen Commercialization Process
ValidationCampaign
P3 Campaign
Phase 1 & 2 Campaigns Amgen Production Activity
Lifecycle Approach to Process Commercialization Began 10 years Ago
Magnitude of post approval changes can take process back into Commercialization
Amgen’s old paradigm: Validation is a single event in
time using 3 lots
4Operational Excellence
Post-approval Development
PAI & Launch Prep
Conf. & File prep
Process Char.
Comm. Process Development
FIH Process Development
Amgen Commercialization Process
Process Validation Scope Stage 1
Process DesignStage 2
PPQStage 3
Continued Process Verification (CPV)As defined in the FDA Process Validation Guidance (Jan 2011)
Conf. Camp.
P3 Campaign
Phase 1 & 2 Campaigns Amgen Production Activity
Commercial Production
Lifecycle Approach to Process Validation Began 10 years Ago
Magnitude of post approval changes can take process back into Commercialization
Stage 2 will flex in size to assure “process is capable of reproducible commercial manufacturing”
5Operational Excellence
Traditional Statistical Tools to assess process capability Require N > 30 lots
Control charts– Lot release– In process controls– Analytical method performance– Stability data
Process capability indexes– Lot release– In process controls
Need to leverage qualitative information in Stage 1 to avoid statistical issues
Inadequate sample size creates under or over reaction to signals
6Operational Excellence
Goal: Leverage information from Stage 1 using a decision making tool to define size of PPQ
Stage 1Process Design
Stage 2PPQ
Stage 3CPV
Stage 1•Design of Experiments•Multiple Risk Assessments•Critical Quality Attribute Matrix •Comparability•Etc.
Amgen Activities
Stage 2•PV protocols•Validation report•Product comparability•Process comparability•NC trending•Etc.
Stage 3•Control charting for numerous quantitative parameters•Stability trending•Process capability assessment•Analytical method performance•NC trending•Quality System performance•Etc.
Integrate Stage 1 information + indirect performance of the facility using a Decision Making Tool
7Operational Excellence
Attributes of the Decision Making Tool using an index
8Operational Excellence
Relative Ranking for Decision Making
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
For Internal Use Only. Amgen Confidential.
MATRIX
Indicator Characteristics Performance Characteristics Owner Targeted Owner (5 Points) ______ Flag Targeted Flag (7 Points) ______ Class Top 25% (0 Points) ______ Middle 50% (1 Point) ______ Bottom 25% (3 Points) ______ Unknown Class (5 Points) ______ Vessel Type Oil or Chemical Tanker (1 Point) ______ Freighter 10+ Years (2 Points) ______ Passenger Ship (1 Point) ______ Low Commodity Carrier (2 Points)______
Detentions (Past 12 Months) 0 (-5 Points) _______ 1+ ( __ Detentions × 10 Points) _______
Priority 1 Deficiencies (Past 18 Months) 0 (-5 Points) _______ 1-2 (0 Points) _______ 3+ ( __ Deficiencies × 5 Points) _______
Casualties (Past 3 Years) 0 (0 Points) _______ 1+ ( ___ Casualties × 3 Points) _______
PSC Exam – No Priority 1 Deficiency Less than 3 Months (-5 Points) _______ Between 3 and 6 Months (-2 Points) _______ Greater than 6 Months (0 Points) _______
Total Indicator Score ______
Total Performance Score _______
Total Matrix Score: ___________ Ballast Water Exam Required: Yes _____ No ______ U.S. Coast Guard Boarding Required: ______
Score Vessel Priority 17+ I 7-16 II 4-6 III 3 IV
9Operational Excellence
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.
– Consequence of the index: description of the process by understanding sources of variability
List of possible sources of variation that can impact process understanding
Factors affecting the process understanding
Scoring Factors
Items of interest for
scoring
Scoring of the most impactful sources of variability for a molecule
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
-Process-Product
-Raw Materials-Facility
-Risk-Regulatory
-Analytical Methods-Documentation
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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 place?
No Do not proceed to PPQ
These questions are asked before the tool is used and overrides any decision from the tool
12Operational Excellence
Steps 4 & 5: Select a basic scoring or indexing & develop scoring scales for each factor
Performance Characteristic
Factor No: Less process understanding
Product Product comparability has been demonstrated at commercial scale
No =1
DP only: Experience with multiple DS ages
Yes=0
Process Process tracking active in Clinical manufacturing
No=1
Raw Materials All raw materials have been used for the same application at commercial scale
No=1
Average SCORE 75%
Use a binary response and compute % in the “No’s”
13Operational Excellence
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 %
14Operational Excellence
Step 6: Set action threshold for the index
Score (% “No’s) # of Lots for PPQ
+ Transition plan into CPV
> 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
•Option 1: Define # of lots•Option 2: Define # of lots + a transition plan
No Decision has been made at Amgen to define the action threshold
15Operational Excellence
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?
16Operational Excellence
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
17Operational Excellence
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.