control strategy implementation considerations for...

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Control Strategy Implementation

Considerations for a Continuous Drug Product

Manufacturing Process

Hayden Thomas 5th October, 2015

©2015 Vertex Pharmaceuticals Incorporated1

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© 2 0 1 4 V e r t e x P h a r m a c e u t i c a l s

I n c o r p o r a t e d

Regulatory/Quality Considerations

Deep Process Understanding

Traceability & Segregation

Process Monitoring - IPCs and Sampling

Process variability

RTRT Batch Release

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Deep Process Understanding - Quality by Design

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Determine high risk areas of the design space and continually monitor process performance

Design a manufacturing process to consistently deliver the intended performance of the product; Establish design space, product specifications and critical control points

Define desired product performance upfront; Identify potential Critical Quality Attributes (CQAs) early in development

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Deep Process Understanding - Quality by Design

• Early investment in process

development

– CM consumes more material at

initiation

– Need for “discontinuous”

operations or science of scale

tools to bridge the gap to fully

continuous operations

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Linking Upstream and Downstream Experiments

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Traceability: Understanding Residence Time Distribution

Mass

Unit

Material FlowMass Unit + RTD’s

RTD

Forward & Back Mixing

Unit Op #1 Unit Op #2 Unit Op #3 Unit Op #4 Unit Op #5

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PAT/IPC - Detection & Removal of Non-conforming

Material

Unit Op #1

IPC #1

Mass

Unit

Material Flow Mass Unit + RTD’s

Issue

Unit Op #2 Unit Op #3 Unit Op #4 Unit Op #5

IPC #2 IPC #3IPC #4

IPC #5

Where to Segregate?

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Segregation of Non-Conforming Materials

• Two segregation points:

– Post Milling

– Post Compression

• Strategy:

– Segregate at earliest

possible point in the

process

– Automation and RTD

knowledge is used to

segregate non-conforming

material

– OOS procedures are

followed

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Processing Monitoring Capability Considerations

• Ability to detect responses to planned changes or unplanned

disturbances

• Sampling should be representative

• Measurement frequency time determined by system dynamics

– Flow rate, RTDs, short & long term variation and unit dose

• Consider characterization of potential failure modes of the

sampling device

– What to do when device is down, cleaning or referencing

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1. At-line NIR incoming material attributes

2. NIR blend potency

3. Granule properties

a. NIR granule uniformity, moisture

b. Laser diffraction particle size

4. NIR final blend, potency and moisture

5. Tablet properties

a. Raman API form and ID

b. Weight, thickness, hardness

6. Raman film coat thickness

1

2

3

4

566

PAT Capability

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Improved Product Quality Assurance Through

Comprehensive Process and Product Monitoring

• Control software displays all active unit operations and alarms on HMI

• IPCs, CPPs, and PPs with design space limits are monitored in real time

• Process control charts available for operator review

• Batch summary reports: material tracking, alarms, IPCs, CPPs and PPs with design

spaces, etc. available for batch review

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Process Control - PAT for IPCs and RTRT

• Both IPCs and RTRT are based on PAT measurements of in-process materials

• In-Process Control Measurements

– Analysis of in-process materials to assess material against in-process action and

warning limits for conformance /non-conformance

• RTRT

– Analysis of up-stream in-process materials to assess the batch as a whole against the

release specifications for end product

– Only material passing all IPCs are included in the batch and the batch analysis for

release

• Not all IPC measurements need to be inputs to the RTRT methods

• Not all inputs into the RTRT methods need to be in-process controls

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In-Process Control Real Time

Release Testing

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Examples of How PAT Can Be Used for IPC and

RTRT Measurements

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Step PAT Measurement Use

IG Blending LIW Feeders

mass flow

Gravimetric IPC

Drying Temperature Granule discharge temperature IPC

PAT 3 (NIR) Water content in granules IPC

PAT 3 (Laser

Diffraction)

Granule particle size distribution RTRT

EG Blending LIW Feeders

mass flow

Gravimetric IPC

LIW Feeders

mass flow + PAT 3

(NIR; granules)

Final Blend Potency IPC

PAT 4 (NIR) Final Blend Potency IPC / RTRT

Water Content in Final Blend RTRT

Compression PAT 5 (Raman) Physical Form RTRT

PAT 5 (WTH) Core tablet weight thickness, hardness IPC /RTRT

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Examples of PAT Used For IPC Measurements for

Continuous Manufacturing

In-Process Control Method(s) Step

LIW Feeder mass flow Gravimetric IG Blending

Granule water content Granule discharge temperature Drying

NIR (milled granules)

LIW Feeder mass flow Gravimetric EG Blending

Final Blend Potency NIR (final blend)

NIR (milled granules) + EG LIW feeders

Core tablet weight thickness, hardness PAT 5 (Kraemer) Compression

Redundant IPC measurements

• Method redundancy is built into the IPC strategy for the CM Rig

− However, only one method is required to produce results per IPC for manufacture

• Ensures continuous monitoring of the process [coverage when NIR systems are undergoing on-

going performance verification)]

• Intention is to operate with both methods active

− If discrepancies between results arise, the non-conforming result will be acted on

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IPC Test Result Decision Tree

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Example of RTRT for Continuous Manufacturing

• A composite sample will be taken after tablet printing for retains, stability, and

any release testing not amenable to RTRT (e.g. appearance)

• Traditional end product testing performed for appearance

Critical Quality Attribute

PAT Technology RTRT Method Material

Identification Raman Confirm presence of API Core Tablet

AssayNIR

Weight

API Content

Tablet Weight

Final Blend

Core Tablet

Dissolution

Laser Diffraction

NIR

WTH

Granule Particle Size

API Content, Water Content

Tablet Weight, Hardness, Thickness

Milled Granules

Final Blend

Core Tablet

Water Content NIR Water Content Final Blend

Content Uniformity

NIR

Weight

Variance in API Content

Variance in Tablet weight

Final Blend

Core Tablet

Physical Form Raman API physical form Core Tablet

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Process Control

• CM is always processing and does not permit reprocessing

• Quality decisions need to be made in real time– Non-conformance to IPC acceptance criteria results in removal of the material

– Control actions should be taken within the IPC range to ensure that IPC acceptance

criteria are met

– Action limits to adjust the process should be set within the IPC acceptance criteria and

monitored in real time

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Process Control

• Sampling plan should be defined for each measured attribute

– Account for short/long term process variation and process drift

– Minimum sampling frequency to be defined, met, and justified for each IPC

– Methodology to address batch uniformity – produced across a timescale

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Process Release - Target Sampling Rate

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• A target sampling rate is defined for each PAT measurement used as

an IPC measurement or in the RTRT calculation for an end product

CQA

• Target sampling rate > IPC statistically, justified sampling plan

PAT Technology Material Measured Attribute Target Rate

NIR (PAT 3) Milled granules Water content in granules

DS content in granules

Once per minute

Laser Diffraction (PAT 3) Milled granules Particle size distribution Once per minute

NIR (PAT 4) Final blendDS content

Water ContentOnce per minute

Raman (PAT 5) Core tabletDS identification

DS physical formOnce per 2 minutes

WTH (PAT 5) Core tablet

Weight

Thickness

Hardness

Once per 2 minutes

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Process Release - PAT Methods Sample a Large

Percentage of the Batch

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Analysis of a hand full of tablets by Regulatory QC Methods

vs

PAT data collected repeatedly during manufacture

PAT methods sample a significantly larger percentage of the batch providing an

appropriate assessment of in-process materials and batch quality

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Process Release – Example Target Sampling Rate

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• A target sampling rate is defined for each PAT measurement used as

an IPC measurement or in the RTRT calculation for an end product

CQA

PAT Technology Material Measured Attribute Target Rate

NIR (PAT 3) Milled granules Water content in granules

DS content in granules

Once per minute

Laser Diffraction (PAT 3) Milled granules Particle size distribution Once per minute

NIR (PAT 4) Final blendDS content

Water ContentOnce per minute

Raman (PAT 5) Core tabletDS identification

DS physical formOnce per 2 minutes

WTH (PAT 5) Core tablet

Weight

Thickness

Hardness

Once per 2 minutes

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Process Release - Example RTRT Minimal

Sample Size Criteria

• A minimum sample size is defined for each PAT point used to assess

an end product CQACritical Quality

AttributePAT Technology In-Process Material Attribute Minimum Sample Size

Identification Raman API identification in core tablets NLT 10 Tablets

AssayNIR Final blend API content NLT 50%*

Weight Core tablet weight NLT 50%*

Dissolution

Laser Diffraction Milled granule particle size distribution NLT 50%*

NIR Final blend API and water content NLT 50% *

WTH Core tablet weight, thickness, hardness NLT 50%*

Water Content NIR Final blend water content NLT 50%*

Content Uniformity

NIR Final blend API content NLT 50%*

Weight Core tablet weight NLT 50%*

Physical Form Raman API physical form in core tablets NLT 10 Tablets

NValid Results = Number of valid results obtained

NTarget Results = Theoretical number of results at the target measurement rate

��

�� 100

Actual Sample Size for Assay, Dissolution, Water Content, and Content Uniformity

* NLT 50% target sample size achieved + NMT 15% in a contiguous segment not sampled

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Conclusions

• There are many Regulatory and Quality aspects to consider when

defining your CM control strategy

• Taking a QbD approach provides deep process understanding that

serves as the foundation for the control strategy

• Control strategy implementation requires a sophisticated process control

system that also can control and manage the PAT systems and data

• Real time in-process controls require PAT measurements

(spectroscopic and/or non-spectroscopic) that can be acted on in real

time

• In-process material PAT analysis can be leveraged for RTRT to

appropriately characterize the end product CQA’s of the batch for

release

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Acknowledgements

• Team at Vertex

– Pharmaceutical Development

– Technical Operations

– Supply Chain Management

– Quality

– CMC Regulatory

– GIS

– Facilities

• Equipment manufacturers

• Our CMOs, suppliers, and research collaborators

• FDA, EMA, MHRA

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