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

Disclaimer

This presentation is based on publicly available information.

These slides are intended for educational purposes only and for the personal use of the audience. These slides are not intended for wider distribution outside the intended purpose without presenter approval.

The content of this slide deck is accurate to the best of the presenter’s knowledge at the time of production.

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.


Agenda

CM Implementation ScenariosStandards & Guidelines

Control StrategyDefinition of a Batch

State of Control OperationBatch release

Validation approach

Quality Considerations


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.


...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


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


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


Continuous manufacturing train: the sum of multiple unit operations.

End-to-End Approach


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.


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


• 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


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.


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


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


PAT Implementation

PAT Equipment

PAT feasibility PAT method development

Reference method

development

PAT method

validation

Validated reference method

Qualified Equipment

Reference method

validation


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


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


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 ?


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


• 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


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


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


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.


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


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


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


even

t

Lot 1 Lot Lot N

t

t = 0Start up

waste

Lot


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.


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


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


Lot 1 Lot N

tt = 0

Start up

Lot 2


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.


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


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

quality aspects in continuous manufacturing

Documents