cbravery@advbiols.com

Process Characterisation:What’s expected for approval?

Christopher A Bravery

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• Why is process characterisation important

• What do we mean by it?

• When should we do what?

• What is expected for approval?

Overview

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The Importance of Characterisation

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Common Deficiencies: Characterisation

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• Critical assays (potency, identity, other) are not…

• … validated, reproducible, quantitative, sensitive, specific, biologically relevant

• Stability program inadequate, unsuitable, or absent

• Characterization data insufficient to establish lot release specifications

• Comparability not adequately demonstrated

• Safety issues

• High levels of bioburden resulting from contamination

FDA Common Causes of Hold Actions:Post-Phase 1

From: Wonnacott et al. (2008). Cytotherapy 10(3): 312-316.

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• Significant change(s) made late in development, without adequate product comparability data

• Viral clearance evaluation studies may be needed

• Process validation data incomplete, inadequate, or absent

• Inadequate stability studies

• Characterization data inadequate to support establishing specifications

• Consistent manufacturing inadequately demonstrated

• Compliance issues - contract manufacturers, finish and fill facilities

BLA Issues

From: Wonnacott et al. (2008). Cytotherapy 10(3): 312-316.

• Quality• The Applicant has made considerable progress towards the

improvement of critical quality aspects in the manufacture and control .......

• The outstanding major concerns raised during the procedure could be resolved and are now considered adequately addressed with data and/or follow-up commitments.

• A number of control measures as well as adequate tools to monitor functionality of the cells and to perform a robust process validation have been successfully implemented. Some activities related to the specification limits are still under development and await their final implementation. The Applicant has committed to address these minor outstanding issues through follow-up measures.

ChondroCelect (from EPAR, 2009)

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CTD Sections covering manufacturing process and controls

S.2.2 Description of Manufacturing Process and Process ControlsS.2.3 Control of MaterialsS.2.4 Controls of Critical Steps and IntermediatesP.3.3 Description of Manufacturing Process and Process ControlsP.3.4 Controls of Critical Steps and IntermediatesP.5 Control of Drug ProductS.2.6 Manufacturing Process DevelopmentP.2.3 Manufacturing Process DevelopmentS.2.2 Description of Manufacturing Process and Process ControlsP.3.3 Description of Manufacturing Process and Process Controls

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• For the purpose of this talk, process characterisation includes (or overlaps) with;

• Process development

• Process optimisation

• (DS/DP/intermediates, starting and raw materials characterisation)

• (analytical method development and qualification/ validation)

Process Characterisation?

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• Design and development of a manufacturing process that can consistently and reliably (ideally robust) manufacture batches of product.

• Identify all sources of variability and control these sources through appropriate control strategies

Taking into consideration your

• Target product profile (TPP)

Recommend developing a

• Quality target product profile (QTPP)

What are you trying to achieve?

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• ICH Q10 defines a ‘Control Strategy’ as “a planned set of controls derived from current product and process understanding that assures process performance and product quality”.

• Elements of a Control Strategy may include:• Risk Assessment

• CQAs

• CPPs and non-CPPs

• In-Process Controls (IPC)

• Process monitoring

• Procedural Controls (batch records, SOPs, material inventory)

• Specifications (release testing, stability testing (DS & DP))

Manufacturing Control Strategy

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Process Development Strategy

3 4 5 6

3 IV 5 6

Old Process

New Process

What impact does the changed step have on the next step? e.g.

Δ yield, Δ concentration, Δ purity, Δ impurities, etc.

Stages of Product Development

GMP

Post Market Approval

Market Approval

Drug Discovery

Basic Research

Disease Pathophysiology

In-Process Controls/Process Parameters

Product /Process Characterisation

Approved ProductInvestigational ProductPoC

© 2010, Consulting on Advanced Biologicals Ltd

Scale Up/OutCommercial ProcessPilot Process Development Process

Research Process

Non-Clinical Development Phase IIIPhase IIPhase I

Clinical Development

PR

OD

UC

T/P

RO

CE

SS

QU

AL

ITY

Lead Candidate/s

Product Development: What should I be doing by when?

Release Specifications/Stability Specifications

Potency Assay (release)

Biological characterisation assaysBiological characterisation (disease/product)

In vivo/ in vitro Models

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Stages of Product DevelopmentPost Market Approval

Market Approval

Product/Process Characterisation

Approved ProductInvestigational Product

© 2010, 2015 Consulting on Advanced Biologicals Ltd

Scale Up/OutCommercial ProcessPilot Process Development Process

Non-Clinical Development Phase IIIPhase IIPhase I

Clinical Development

QU

AL

ITY

A Lot to do in P2

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Identification of cQA Confirm cQA

Identification of likely PP Confirm cPP

Process Validation

Method Validation

Identify likely cQA

Characterisation

Risk analysis/experience

Experimental evidence

Method Qualification

Process Qualification

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• Early stage (e.g. FIM) not much process understanding is expected from regulators

• Commercially it’s a balance between investment in process development and de-risking

• Need to confirm the product is safe in man first

• In depth process characterisation takes time/resources

• based on existing experience and risk analysis to identify likely important process parameters (and QA).

• Analytical methods should at least be qualified

Early Development?

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• Mid-stage (i.e. after FIM) work should have started on identifying (by experiment) the CPP and CQA of process intermediates

• in addition to DS/DP/starting and raw materials – not discussed here

• In most cases the process used in P3 will be used for early commercial

• So CPP/CQA should (where possible) all be identified before initiating of P3

Mid Development?

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• Late stage (i.e. P3) should be focussed on confirming CPP and any CQA of intermediates etc to allow:

• process validation

• analytical method validation

• Justification of specifications (JOS)

• Any process characterisation still on-going adds risk (unexpected findings)

• Process changes (including significant changes in specifications) during P3 are strongly discouraged

• Process changes after P3/pre-submission are only possible if sufficient product/process characterisation is available to demonstrate comparability.

Late Development?

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Process Characterisation

Process DesignQTPP• Manufacturing scale

• Batch size DS/DP/Cell Bank

• 1 batch size or >1?• Considering (TPP):

• Business model• Logistics• Shelf-life• Projected sales• etc

Normal OR (NOR)

[Acceptance Criteria]

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Characterisation Range[Characterised/knowledge

space]

Operating Range (OR)[Proven acceptable range (PAR)]

Cri

tica

l qu

alit

y at

trib

ute

(cQ

A)

Process Parameter (PP)

cQA

Ran

ge

Act

ion

Lim

its

Batch data

Characterisation data

Defining Specifictions

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Hypothetical Case Study

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• Break down process into unit operations

• Process flow step numbers are useful, e.g.

• 1, 2, 3 (unit operations)

• 1.1, 1.2 1.3 (sub-steps within unit operation)

• Or similar.

• Each step should have a defined purpose; e.g.

• Wash step (case study 1)

• Enzyme digest step (case study 2)

Unit Operations

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Curzall Case Study 1: Wash Step

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Example Unit Operation:wash step following enzyme #1

Isolated Cells

Quench(dilute ± inhibitor)

temp ( )

CentrifugeForce (× g), time (min),

temp ( )

ResuspendCulture medium

Un

it O

per

atio

n

• Wash away process-related impurities

• What outcome is required?

• Which impurities

• Impact on following step

• Impact on final DP (e.g. are there later washes)

• What is an acceptable residue in final DP?

• What is the purpose of the unit operation?

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Isolated Cells

Quench(dilute ± inhibitor)

temp ( )

CentrifugeForce (× g), time (min),

temp ( )

ResuspendCulture medium

Un

it O

per

atio

n

• How many washes are needed?

• Volume/wash

• Type of diluent

• Centrifuge time and force

• Overall duration of the unit operation (stability)

• Commercial considerations, e.g. CoGs

• PBS cheaper than media

• ↑ washes = ↑ cost

• ↑ time = ↑ cost

Example Unit Operation:wash step following enzyme #2

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Isolated Cells

Quench(dilute ± inhibitor)

temp ( )

CentrifugeForce (× g), time (min),

temp ( )

ResuspendCulture medium

Un

it O

per

atio

n

• Explore effectiveness of wash

• Assay to measure impurity, e.g. ELISA (qualified)

• Experiments test concentration before and after each wash to confirm effectiveness of the step.

• If level of impurity is cQA of the next step then you might include an IPC (test for impurity); this might be a limit test or quantitation depending on need.

Example Unit Operation:wash step following enzyme #3

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Curzall Case Study 2:Collagenase Digest

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Optimising each step

Need to characterise each step for the following reasons:

• Understand what the step does/how it works

• Intended function – e.g. digest the tissue to release the cells

• Secondary effects – e.g. cell damage/death, release of other cell types

• To be able to set process parameters and in-process controls.

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Optimisation of enzyme digest

Factors to consider might include:

• Source of collagenase (raw materials characterisation)

• Concentration of enzyme

• Duration of digest

• Size of tissue biopsy/diced tissue biopsy pieces

• Culture media (e.g. buffer system, pH, osmalality trace minerals/metal ions, protein/serum)

• Temperature

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Identifying likely PP/QA

Assuming you want to retain the in situ characteristics of the cells but release them from the tissue.

Characteristics Parameters

phenotype/genotype- cellular active- cellular impurity

viability proliferative capacity cell yield biological activity indicators of early cell damage

Time/duration enzyme type enzyme supplierpH temperature size of tissue piecesreaction media compositionco-enzymesStability of enzyme in solution

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Optimisation example: Curzall

Assumptions: Since collagenase works between pH: 6 – 8, this is outside the range that the cells are happy in and controlled by the buffer system of the culture medium, so not a ‘critical’ parameter here, and little value in measuring it in-process.CO2 is a critical parameter because the culture media chosen is dependent on CO2

to maintain pH. This is easily controlled continuously by the incubator.

Step characterisation conclusionsNo cells are released during the first 5 minutesYield of curicytes doesn’t increase after 10 minutesAfter 15 minutes the proportion of fibroblasts in the curicyte starts to increase significantly.After 20 minutes viability starts to decrease significantlyOptimum time therefore determined to be 10 minutes, with an operating range of ± 2 minutes where quality is not significantly altered.

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Optimised process parameters

Collagenase Solution:Collagenase: 900 – 1,100 CDU/mLin optimised reaction buffer solution

Collagenase raw material specification:CDU: 1,000 – 3,000 /mgFALGPA : 4-10 U/mgOther enzymes: <1 U/mLetc.

Collagenase step parameters:Collagenase solution: 1.8 – 2.2 mL/mg tissueDigest time: 12 ± 2 minutesTemperature 37 ± 0.5 CCO2: 5 ± 0.5 %

Reaction buffer specification:HBSSbuffered pH: 7.4 ± 0.2indicator dyesupplements etc.Stability >6 hours at 4±2 C

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• In-process controls can help to ensure a process step has achieved its intended effect.

• IPC may be necessary for next unit operation, e.g. cell count, purity/impurity level etc (possibly critical IPC).

• Allows early batch failure (e.g. catastrophic failure)

• May allow process adjustments (e.g. adjustment of concentration) prior to next step.

• General information for process problem solving (useful but not critical)

In-Process Controls

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Set In-Process Controls

Collagenase step IPC:Cell yield: >106 (viable) nucleated cellsViability: >70%

Viability might be included because it:

• indicates a problem with the digest (based on optimisation experiments)

• influences the next step (adherence to flask),

Late-stage Manufacturing Process Flow

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2.1

2.2

Normal OR (NOR)

[Acceptance Criteria]

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Characterisation Range[Characterised/knowledge

space]

Operating Range (OR)[Proven acceptable range (PAR)]

Cri

tica

l qu

alit

y at

trib

ute

(cQ

A)

Process Parameter (PP)

cQA

Ran

ge

Act

ion

Lim

its

Batch data

Characterisation data

Defining Specifications

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• If you haven’t characterised the process then even apparently straightforward comparability such as for tech transfer (no significant changes in unit operations) can be difficult

• While you may use a single site for clinical development, you may want regional manufacturing sites

• Consider MACI EPAR (EMA website).

Additional Thoughts

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• Characterisation of the process serves the following purposes:

• Provides process knowledge

• Allows process optimisation

• Allows process control

• Contributes to product consistency and quality

• Importantly it enables process changes (comparability) without which major process changes such as introduction of automation may be difficult/impossible without clinical bridging data.

Conclusions

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ADDITIONAL SLIDESFOR FURTHER INFORMATION

DEFINITIONS

‘Control Strategy is a

Planned set of controls,

Derived from current product and process understanding that assures process performance and product quality

The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.’ (ICH Q10)

Critical Quality Attribute (CQA):

A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality (Q8(R2))

Critical Process Parameter (CPP):

A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality (Q8(R2))

DEFINITIONS

In-Process Control (or Process Control):

Checks performed during production in order to monitor and, if appropriate, to adjust the process and/or to ensure that the intermediate or API conforms to its specifications (Q7)

Applies similarly to the drug product

In-Process Tests:

Tests which may be performed during the manufacture of either the drug substance or drug product, rather than as part of the formal battery of tests which are conducted prior to release (Q6A)

DEFINITIONS

‘Real time release testing (RTRT)

is the ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls’ (Q8(R2))

Process Analytical Technology (PAT):

A system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality (Q8(R2))

DEFINITIONS