cpv/opv process and decision making for · pdf filefor large molecule drug substance: case...

ISPE Process Validation Conference12 – 14 September 2017

Bethesda, MD

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CPV/OPV PROCESS AND DECISION MAKING FOR LARGE MOLECULE DRUG SUBSTANCE: CASE STUDY

Bethany [email protected] Lilly and Company

PRESENTATION OUTLINE1. LILLY’S VALIDATION LIFECYCLE MODEL2. CASE STUDY: LIFE CYCLE APPROACH FOR LARGE MOLECULE

DRUG SUBSTANCE (LEGACY PRODUCT)

• Purpose of Validation Stages

• Documentation Requirements

• Sampling/Testing

• Batch Disposition

• Transitions between Stages

• Routine Monitoring

• Changes

3. CONCLUSIONS4. ACKNOWLEDGEMENTS5. QUESTIONS


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Validation Lifecycle – Lilly’s Model

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Process Validation Lifecycle

Stage 1 Stage 2 Stage 3

DevelopmentQualification andProcess Validation

Ongoing Process Verification

Stage 2a Stage 2b Stage 3a Stage 3b

Commercial Manufacturing

Equipment Qualification(IQ,OQ,PQ)

Process Validation

Heightened Monitoring

Routine Monitoring

Company Confidential © 2017 Eli Lilly and Company


Validation Evolution for Legacy Product (Large Molecule Drug Substance)

1990s - 2000

Product LifecycleProduct Lifecycle

CPPs, PARs Defined mid 2000

Stage 1

Increasing Process Understanding/Control Strategy Evolution

1980s‐Early 1990s

Stage 2

Lifecycle (Stage 2 and 3)

Min. 3 batchesbut often more

Stage 2 -Executed 1 time every 5 years;

Always 3 batches

Routine process monitoring with documented capability analysis

2011‐ now

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Overall Lifecycle Approach - Overview

Stage 2b Process

Validation(Process Related

Impurities and other Monitored

Parameters included as

well)

Stage 3a Heightened Monitoring

(Process Related Impurities and some PV Monitored Parameters if

impact CQA and not controlled)

Stage 3b Routine Monitoring

Every Batch Parameters (i.e., CPPs, In-process Specifications, Final Specifications)

Additional Stage 3b monitoring Process Related Impurities--currently testing minimum of 3 batches per quarter

Typically 20-30 batches minimum

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Stage 3 (On-going Process Verification)

Goal: Maintain state of control

• Are there any trends of concern within my control strategy as more variability is introduced? If yes, how do I adapt my control strategy.

• Potentially establish control limits were applicable.

~40-80 parameters evaluated

Stage 2b (Process Validation)

Goal: Begin to demonstrate control strategy adequacy in commercial manufacturing

• Does data pass acceptance criteriaAcceptance Criteria:• Specifications

• With Internal Release Limits where applicable• Chromatogram Reviews• CPPs

Other Monitored Parameters:• Registered OPPs (Operating Temperature,

Stoichiometry)• Characterization of Process Related Impurities• IMHT Studies (if applicable)• Homogeneity (if applicable)• Stability (if applicable)

Overall Lifecycle Approach - Overview

~225 – 375 parameters evaluated

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Stage 2b (Process Validation)1.Process Flow Documents (PFD) also

include details2.Batch Production Record3.Stage 2b PV Protocol including

Readiness Assessment4.Stage 2b PV Report

Stage 3a (Heightened Monitoring)1.Stage 3a PV Protocol*2.Stage 3a PV Report

Overall Lifecycle Approach – Document Requirements

Stage 3b (Routine Monitoring)1.No protocol; Stage 3a Report concludes

what will be additionally trended through Stage 3b. Note, CPPs and Specifications are always monitored every batch.

2.Annual Product Report (APR) and periodic reports (i.e., QPPA) are used to summarize state of validation which includes capability analysis of quality batch parameters, and the additional Stage 3b monitoring

*Due to complex geneology, 3a protocol is approved with Stage 2b protocol; however pending Stage 2b results may be modified.

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Overall Lifecycle Approach – Sampling/TestingExample – Full Process Stage 2b Validation

Step 1

Step 2

Step 3

Step 4

Step 5

Step 6

Step 7

Step 8

Stage 2b

Stage 3a

Stage 3b

1 Train

2 Final Drug Substance Batches

25

15

15

10

10

5

25

10

Each colored box represents a batch. Numbers in last set of boxes, show how many total

batches for a step exist in 5 Trains.

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Amount of Analytical Testing

Routine Testing

Total #

of

Assays Total # of Results Additional Validation Testing

Total of

Assays/Results

Step 1 g/L (yield) 1 1

Process Related Impurity 1, Process Related Impurity 2,

Process Related Impurity 3, Process Related Impurity 4 4

Step 2 g/L (yield) 1 1 none 0

Step 3

g/L (yield);

Purity 1 2 Process Related Impurity 1, Process Related Impurity 2 2

Step 4 g/L (yield) 1 1


Process Related Impurity 3, Process Related Impurity 5 4

Step 5

g/L (yield);Purity;

Impurity 1;Impurity 2 1 4 none 0

Step 6

g/L (yield); Purity;

Impurity 1; Impurity 2;

Impurity 3 1 5




Process Related Impurity 8 7

Step 7 g/L (yield); Purity; Impurity 4 1 3 Process Related Impurity 2, Process Related Impurity 9 2

Step 8

g/L (yield); Purity; Process Related Impurity 1;

Process Related Impurity 2; Process Related

Impurity 3; Bioburden;

Bioassay....... 7 8





Process Related Impurity 11 9

Plan to Test 20 batches per process step

• 280 Routine assays (500 results)

• 560 additional Validation assays/results

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Overall Lifecycle Approach – Sampling/TestingExample – Full Process Stage 2b Validation

Stage 2b

Stage 3a

Stage 3b

Step 1 100

Step 2 60

Step 3 60

Step 4 40

Step 5 40

Step 6 20

Step 7 100

Step 8 31 32 33 34 35 36 37 38 39 40

If test everything associated with Geneology that includes Stage 3a phase = 40 Final Drug Substance Batches = 1380 additional validation assays on top of routine testing

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BBR17

BBR17 need to clearly say min of 20 is due to statistical analysisBethany Bustard Rexing, 8/10/2017


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Overall Lifecycle Approach – Sampling/TestingExample – Full Process Stage 2b Validation into Stage 3a

Step 1 50

Step 2 24

Step 3 24

Step 4 12

Step 5 12

Step 6 6

Step 7 30

Step 8 1 2 3 4 5 6 7 8 9 10 11 12

Stage 2b

Stage 3a

Stage 3b

Sample and Test 4 additional Process Related Impurities

• Pull sample; • Hold in appropriate storage conditions. • Analysis of first 20 batches determines if

additional testing of samples is required

Reach Batch 20 for Step 1 intermediate, and haven’t started processing Batch 3 at Final Drug Substance

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Stage 2b (Process Validation)

Stage 2b Report must be approved to disposition any Stage 2b and post Stage 2b manufactured batches.

Overall Lifecycle Approach - Batch Disposition

Stage 3b (Routine Monitoring)

Only batches that contain the additional Stage 3b analytical testing must be held until an interim summary (or QPPA/APR) is approved to show the acceptance criteria was met.

All other batches can be disposition under the routine process.

Stage 3a (Heightened Monitoring)

During Stage 3a, interim summaries may be used to disposition batches as long as acceptance criteria met.

Last Stage 3a batch and post Stage 3a batches held until Stage 3a Report approved.

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Frequent Communication between Functions

> Prioritization of Testing to enable batch release

– Following approval of PV report AND Stage 3a testing verified acceptable

> Resolution of issues (logistical, data excursions)

Defined/Developed Data Mining Tools

Standing Data Review Meetings

Templated Reports

Key Factors to Quick Transition 3a to 3b

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HistorianHistorian

ManualData EntryManualData Entry

Analysis / ResultsAnalysis / Results

Read Only

LIMSSAP

Source Systems

MDIRead Only

LIMSSAP

Source Systems

MDI

PI SADPI SADPI SADHierarchyProcess DrivenHierarchyProcess Driven

Defined/Developed Data Mining Tools High Effort Upfront

BUT

Beneficial during Initial

PV

AND

Lifecycle of Process for

Routine Monitoring

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How does Routine Monitoring Occur after Execution?• Who – Scientists,

Engineers, Quality Control• What – Parameters tied to

CQA (Specifications), Parameters with Business Impact (Cycle Time), Leading Indicators (Valve Position)

• When – Daily, Weekly, Monthly

• How – Profile Overlays, Control Charts, Data Historian, Capability Analysis

• Where – Functional Staff Meetings, Cross Functional Process Teams, Management Teams

• What – Key Quality and Business Impact Parameters

• When – Weekly, Monthly• How – Control Charts,

Capability Analysis

• What – Key Quality Impact Parameters• When – Approximately 3-4 times a year

(~ quarterly)• How – Control Charts, Capability

Analysis, Required CAPA• Who – QA Leader, Site Head, QC

Leader and TSMS Leader approval

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Documented Review of

Data

Review of Data via Meetings

Individual Process Owner Monitoring of Data


Examples of How Monitoring is Performed

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Step Profile 1 Parameter trended for last 20 batches


BBR26

BBR26 see if can make the lines bolder so it it easier to seeBethany Bustard Rexing, 8/10/2017


Bethesda, MD

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Parameter Profiles (Continuous Data):

Volume Time

mm

hos

Opt

ical

Den

sity




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Control Charts (Discrete Data):

In Chronological Order By Equipment Set - In Chronological Order



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Stage 2b Process



Parameters included as well)

Stage 3a Heightened Monitoring(Process Related

Impurities and some PV Monitored Parameters if






Overall Lifecycle Approach – Routine Monitoring Signal

Process SignalConcerns with meeting CQAs, Need

to change control strategy which results in Full Process Validation Ensure CQAs met,

understand signal; stay in Stage 3b

CQAs met, but need to understand signal/variability

more

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Stage 2b Process



Parameters included as

well)

Stage 3a Heightened Monitoring

(Process Related Impurities and some PV Monitored Parameters if






Overall Lifecycle Approach – Post Validation ChangesProcess Change

EvaluationFull Process

Validation Required

No validation required, stay in Stage 3b

X

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• Full validation required due to registration of duplicate equipment (i.e., tank)

• Heightened monitoring previously performed.

• No changes to control strategy• Batches included in Full

validation would be compared to previous data, as long as consistent, no ‘Heightened Monitoring’ phase, immediately move to ‘Routine’.

Post Validation Change Examples

Chromatography Column Changes

• Full validation required due to increased column bed height (although still within acceptable range) and change to gradient control.

• Higher potential to impact CQAs due to gradient control changes and final purification step in Drug Substance manufacturing

• Heightened Monitoring (Stage 3a) to be performed following Stage 2b validation

PV Plan with rationale was documented and attached to the approved Change Control prior to Implementation

Duplicate Equipment Installed

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Step

Process Step 1

Process Step 2 X

Process Step 3

Process Step 4 X

Process Step 5

Process Step 6 X

Process Step 7

Process Step 8 X

Process Step 9

Final Drug Substance Spec

Process

Related

Impurity 1

Evaluating Changes to the Routine Monitoring Program

Test 3 batches every quarter

Tested Every Batch – Release Assay

With Limits now in-place, should we reduce testing to only the first 2 process steps quarterly??

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Specification

QL

Step 2 Step 4 Step 6 Step 8 Final DS


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• Complex geneology for Large Molecule Manufacturing presents additional challenges for an OPV program

• Routine Monitoring identifies opportunities for continuous improvements

• Lifecycle concepts and management were initially difficult to incorporate however now the benefits are obvious.

• Matured thinking over time on science and risk based decisions with focus on product quality

• Greater understanding of Process Validation at site

• Greater understanding of process and product

Conclusions

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Gerald Leister

Joanne Barrick

Jerrad Runkle

Kim Emerson

Warren MacKellar

Acknowledgements

Wayne Ball

Tracey Kriauciunas

Jeff Poole

Gregg Gordon

Matt Janeczek

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