Download - Quality Aspects in Continuous Manufacturing
Quality Aspects in Continuous ManufacturingDr. Eric J.M. MeierNovartis Pharma AGHead QA Continuous Manufacturing
ISPE Conference: Future Pharmaceutical ManufacturingContinuous Manufacturing – Qualification and Validation in Practice18. May 2017
Global Technical Research & Development QA
Global TRD Quality2 ISPE Nordic Affiliate Conference | 18. May 2017
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The views and opinions expressed in this presentation are those of the author and do not necessarily reflect the official policy or position of Novartis or any of its officers.
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Agenda
CM Implementation ScenariosStandards & Guidelines
Control StrategyDefinition of a Batch
State of Control OperationBatch release
Validation approach
Quality Considerations
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CM could dramatically change the way we understand drug manufacturing.
A unique opportunity to redefine the industry paradigm of how drugs are produced & pave the way to an even faster, more precise & reliablemanufacturing approach.
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...the journey is long.
Research & Development
of Continuous Manufacturing
technologies.
2007-2012
Initiate
From Research & Development
to in-house implementation.
2013- 2016
Operationalize
2017 & beyond
Continuous Manufacturing
development leadingto approvable product &commercial manufacturing.
Embed
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Implementation Scenarios from Batch to CM
Complexity/Development effort
Pot
entia
l ben
efit
for q
ualit
y &
cos
t
Batch
Chemical or Pharmaceutical CM
End-to-End integration
Partial CMintegrationIntroduction of CM steps or sequencesin batch process
Entire chemical line and / or entire pharmaceutical line in CM mode
Entire line in CM mode
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Novartis Continuous Manufacturing Strategy
Ultimate Goal: Complete end-to-end Process
Reaction Work-up Crystali-sation Drying Granulation Drying Tabletting Coating
raw materials drug product
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Continuous manufacturing train: the sum of multiple unit operations.
End-to-End Approach
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Standards & guidelines relevant to CM• Pharmaceuticals produced by CM need to comply with
current applicable compendial monograph and GMP standards.
• Examples were Ph.Eur. likely is relevant and applicable:• Near-infrared spectroscopy (2.2.40);
• Raman spectroscopy (2.2.48);
• Demonstration of uniformity of dosage units using large sample sizes (2.9.47); etc.
• Other examples of areas covered by compendialmonograph: physical and physicochemical methods e.g. monographs on spectroscopy, monographs on chromatography, etc.
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Lifecycle Approach: Phases & Standards
GMP
Pharmaceutical Development
CommercialManufacturing Discontinuation
Investigational products
Technical Trial
Material
Clinical Trial
Material
PhaseI II III
DP: EU GMP Guide I, Annex 13DS: EU GMP Guide II, Section 19
DP: EU GMP Guide IDS: EU GMP Guide II
CommercialMaterial
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• ICH guidelines e.g. ICH Q8, Q9, Q10, Q11
• EU guidelines e.g. EU guideline for Good Manufacturing Practice, Annex 15: Qualification and Validation; Annex 17: Real Time Release Testing;
• FDA DRAFT Guidance: Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base
• Standards and white papers e.g. • ASTM International Standard Guide for Application of Continuous Processing in the
Pharmaceutical Industry, E2968-14, 2015; • Regulatory and Quality Considerations for Continuous Manufacturing; May 20–21,
2014 Continuous Manufacturing Symposium, published by Allison et al, Journal of Pharmaceutical Sciences, 104: 803-812, 2015.
• Regulatory Perspectives on Continuous Pharmaceutical Manufacturing:Moving from Theory to Practice; September 26-27, 2016 Continuous Manufacturing Symposium, published at https://iscmp2016.mit.edu/regulatory-white-paper .
Other standards & guidelines relevant to CM
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Conclusion on regulatory situationin continuous manufacturing• Current regulatory framework is adequate to apply
continuous manufacturing.
• Current regulations and guidelines are supportive for the development and manufacture of pharmaceutical continuous manufacturing processes.
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Potential approach to control strategy -process performance and product quality
Determine critical quality attribute and process control points to monitor and control the relevant specification
Determine the process dynamics at these points and derive the necessary measuring frequency
Verify process performance based on the points for the desired runtime
Optionally disturb the process with small spikes to demonstrate effectiveness of the process control system
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Control Strategy and Off-Line IPC
- Traditional IPC samples to monitor process- Support of PAT development- Confirmation and back up of PAT methods
Mixing & Granulation
API Feeder
Excipients
Drying Sieving Tableting
LOD BU CU
Sampling
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PAT Implementation
PAT Equipment
PAT feasibility PAT method development
Reference method
development
PAT method
validation
Validated reference method
Qualified Equipment
Reference method
validation
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Control Strategy and PAT
- Multiple physical principles assess state of process- Primary objective: verification of robust operation, but:
allow feedback and feedforward loops, if required
Mixing & Granulation
API
Feeder
Excipients
Drying Sieving Tableting
LOWAPI
LOD(NIR)
BU(NIR)
Feeder
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Example: Dryer in state of control ?
Perfect agreement with step data
Razor-sharp process appears poor
6 min
Apparent dispersion of CQAs is in reality instable process
Affects observed process capability
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Choice of solution drives apparent performance
Optimal control may give better performance
Equipment improvements may even be better
Performance is what matters in the end
Batch it
Back mix
Optimalcontrol
Example: Dryer in state of control ?
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Add Back mixingCreates apparent homogeneitypotentially bad product is still in
Batch it
Truncate, divertCreates real homogeneity, yield lower
Apply active controlCreates real homogeneity, yield high
betterbest
good
Evaluating overall performance and process performance matters!
Process Control Options
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• Define, how much sooner do we need to know before an unstable process can leave the spec limit (pre-warning time leads to action limits)
• Determine maximum rate of change of the process and align measuring (sampling) frequency with maximum rate of change such that no process change exceeding suitable ranges can be missed
• Link action limits with sampling=measuring period and rate of change• Measure constantly at this sampling rate=system update rate• Effectively 100% controls of product quality, as process can not deviate undetected
Qua
lity
para
met
er
Minimum sampling period
This is what we need to avoid and discard
USL
LSL
UAL
LAL
Usable material
Usable material
Safety buffer
Time axis
Understanding process dynamics (rate of change) and process sensitivity allows to set the frequency of observation/sampling/measurement
Sample rate of the CPPs, CQAs and IPCs
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System Performance Verification (Option)
Usable material, 1 Lot
USL
LSL
UALLAL
USL
LSL
UALLAL
USL
LSL
UALLAL
USL
LSL
UALLAL
+
+
+
+
-
-
-
CP
P 4
CP
P 3
CQ
A 2
CQ
A 1
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What is a batch ?
2) Batch means a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture.
21 CFR 210.3
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What is a batch, lot etc? 21 CFR 210.3
(10) Lot means a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits.
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Glossary of the EU GMP Guideline:
A batch is a defined quantity of starting material, packaging material or product processed in one process or series of processes so that it could be expected to be homogeneous.Note: In the case of continuous manufacture, the batch must correspond to a defined fraction of the production, characterized by its intended homogeneity.
Batch DefinitionEU
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EU GMP Guide, Part II (ICH Q7), Glossary:
A batch is a specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval.
Batch DefinitionEU
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State of Control Operation
Key characteristics:- Material collection in state of control operation- Events are basis for flagging and diversion decision- Divert material at the appropriate point of the CM process
State of ControlOperation
State of ControlOperation
even
t
Lot 1 Lot Lot N
t
t = 0Start up
waste
Lot
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Batch Size
In traditional discrete manufacturing, the lot size is a technical consequence, e.g. limited by the amount of the same initial incoming mass.
In the continuous manufacturing mode batch and lot sizes are decoupled from such constraints.
The batch size (and run times) can now be based on the size of each order, balancing acceptable business risk and effectiveness.
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Continuous MonitoringAutomation and Big Data
Data collection• CPP• Key equipment
operating parameter • CQA• PAT• Events• Room monitoring• Etc.
Process Control System
State of Control Operation
Release
Data evaluation
Data Storage
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Batch Release
- Material collection in state of control operation- Material from events or deviations diverted / segregated- Deviations investigated and closed- Batch records reviewed- Process data, IPC, PAT, room & media data meet
requirements- Missing final product attributes characterized or RTRT (real
time release testing) done
Ramp down
State of ControlOperation
Lot 1 Lot N
tt = 0
Start up
Lot 2
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Continuous verification occurs over the lifecycle of a product:
Validation Approach: Continuous Verification
Product and process
understanding
Continuous quality monitoring
and control
Process performance evaluation
Acceptance and release
Continuous process
improvement
[ASTM E2537]
Based on the large amount of data generated until and including process performance qualification (PPQ), no classical validation batches will be manufactured. The continuous performance verificationshall be used as an alternative validation approach.
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Lifecycle Approach: DoE – CpV – Routine
GMP
Pharmaceutical Development
CommercialManufacturing Discontinuation
Investigational products
DoE & process verification
ContinuousPerformance Verification
Product & process understanding
noTechnology
Transfer
no scaleup
System
EquipmentRoomMedia
PeopleTraining
QualityCulture
ContinuousImprovement
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Acknowledgement
Thanks goes to the support of the cross-
functional Novartis Continuous Manufacturing
Team including:
• Technical R&D, Markus Krumme et. al.
• Regulatory CMC, Diane Zezza et. al.
• Quality
Thank You