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

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Outline

Where is Amgen today

Why a qualitative tool

Tool development

Conclusions

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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

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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”

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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

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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

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Attributes of the Decision Making Tool using an index

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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

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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

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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”

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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

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

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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

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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.