4 real time release testing - industry.siemens.com · outline • what is real time release testing...

Real Time Release Testing

Line Lundsberg-Nielsen, NNE PharmaplanPAT seminar , 6 October 2010

Outline

• What is Real Time Release Testing (RTRT)• How QbD provides the opportunity for real-time release

testing in lieu of end-product testing: QbD, PAT & RTRT• Minimal versus Enhanced Control strategy• How to develop a control strategy facilitating RTRT:

Linking CQAs, CPPs, DS, CS• Implementation of RTRT, practical issues• Examples of cost reduction – benefits by introducing

RTRT• Organisational aspects of changing to RTRT• Conclusion

Real Time Release Testing, NNE Pharmaplan 20102

What is real Time Release testing

What is Real Time Release Testing?

• Real Time Release Testing (RTRT) is defined in ICH Q8(2):– 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

• Real time release testing can replace end product testing, but does not replace the review and quality control steps called for under GMP to release the batch.

• Real time release testing is “moving the QC lab into the process” and “measure the CQAs where they are generated”

• Parametric Release: One type of RTRT. Parametric release is based on process data (e.g. temperature, pressure, time for terminal sterilization) rather than the testing of a sample for a specific attribute (ICH Q8 Q&A).

• Batch release: Approved RTRT may form a basis but more aspects needs to be taken into account in the decision of a Qualified Person to release a batch. These aspects could include batch results of testing for an attribute not subject to RTR T as well as specific GMP requirements.


Controlling CQAs and CPPs

• The QbD approach helps to identify what is critical for the product quality incl what to control, where and how

• Focuses on what matters – and not controlling every thing

• Reduced risk of failure of important controls• Critical Quality Attributes can be measured

in real-time during manufacturing• Quality decisions can be made using

these measurements to– Control and adjust the process

as needed– Make go/no-go decisions– Replace IPC or add more value to IPC– Real time release testing to

replace end product testing


End product testing

FIXEDPROCESS

Disturbance

OUTPUTINPUTS

QC end product

test result

Several days later...

6 Real Time Release Testing, NNE Pharmaplan 2010


ADJUSTABLEPROCESS

Disturbance

OUTPUTINPUTS

Process analyzers used to measure the process parameters and adjust the process

1,41,61,82,02,22,42,62,83,0

Y

Immediately!

SattLineNIR interface

ARMA filterFinding denoised

Gradient

Zero Crossing + -Matched Detector filterSIGN function


Example:API purity – controlling reaction by NIR

• Reaction developed and understood during development – typical tools are IR, NIR and Raman

• At commercial scale NIR is used to control the reaction

• Stop the reaction at Maximal API Concentration• Stopping time differs from Batch to Batch • Real time release measurement of the API assay and

bi-product (impurity)• No sampling for in-process control or end-product

testing for this CQA


Benefits by introducing Real Time Release Testing

• The outcome of a high level of process understanding• Controlling the process• Adjust for variability in raw and in-process materials• Increase yield, reduce waste, scrap• Reduce the risk of losing a batch• Reduced QC test• Increased control activity on the manufacturing shop floor• Reduced cycle time• Real time monitoring of CPPs and CQAs for free (must also be included in

continuous process verification and Annual Product Review)• Quality of the finished product can be measured during manufacturing –

no surprises!• Regulators might be more interested in the beginning but this will fade as

process understanding has been demonstrated – reduced inspection frequency


Challenges by introducing Real Time Release Testing

• New – not familiar to many• PAT tools in place (in-line analysers, PAT data management, multivariate

data analysis, process control) • Require new skills and reorganisation of work• Risk associated with implementing PAT

– Installation of probes, representative sampling, failure of instrument, failure of multivariate models, failure in feed forward & backward controls, etc

• Backup strategy must be in place • Models needs frequent update• If RTRT fails it cannot be replaced by end-product testing• Regulators might be very interested in the beginning...


Quality by Design (QbD), Process Analytical Technology (PAT) &

Real Time Release Testing (RTRT)

What is QbD really about?The patient.....

• Understanding what the patient needs• Designing and developing a product meeting these needs• Designing and developing a manufacturing process

capable of delivering the product that meets these needs

QbD and PAT links the patient,

product and process

ProcessUnderstanding


Quality by Design, QbD

ICH Q8(R2)

Control Strategy (PAT, RTRT)


Definition:

A systematic approach to development that begins with predefined objectives and emphasizes product and process understandingand process control, based on sound science and quality risk management

PAT and Real Time Release Analysis

ICH Q8

Process Analytical Technology is: A system for designing, analyzing, and

controlling manufacturing through timelymeasurements (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

CQAs and CPPs

In-line & on-line analysers

Predictive models



IdCPP

and Materialattributes

IdCPP

and Materialattributes

IdCQAsId

CQAsQuality targetProduct profile (QTPP)

What is critical to the Patient

SOPPAT PAT, RTRT

PAT PAT, RTRT

SOP

Design Space

Critical Quality Attributes

Critical Process Parameters

PAT

QbD in One Page – small molecule

Material Attributes

Control Strategy •-•7•-•6•-•5•-•4•-•3•-•2•-•1•0•1•2•3•4•5

•-•1•0•1•2•3•4•5•6•7•8•9•1•0•1•1•1•2•1•3•1

Control StrategyDesign Space

Quality Target Product Profile

QRM


Upstream Downstream Formulation,Fill & Finish

QualityRisk Assessment

DesignSpace

ImplementedControl

Strategy

R&D

Production

ControlStrategy

QbD in One Page – large molecule

Based on ISPE/PQLI 2009 A-Mab Case Study


Quality Target Product Profile

Control Strategy

Control Strategy

• 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)

Manual Simple Advanced, automated


Control StrategyEvery product MUST have a control strategy

Minimal• Drug product quality controlled

primarily by intermediates (in-process materials) and end product testing

Enhanced• Drug product quality ensured

by risk-based control strategy for well understood product and process

• Quality controls shifted upstream, with the possibility of real-time release testing or reduced end-product testing


ICH Q8

Laying out the control strategy

1. Identify CQAs2. Identify related CPPs and Material Attributes (MAs)3. Develop the design space for the CPPs and MAs4. Develop the control strategy ensuring the CPPs and MAS are

always within the design space5. Based on risk-assessment plan how the control strategy can

be implemented

• This process starts in development• It is a lifecycle activity and• The Control Strategy can be updated as new knowledge has

been gained


Linking it all togetherCQAs, CPPs, Design Space,

Control Strategy

Oral solid dosage, API synthesis and dry granulation roller compaction process

Based on PQLI CS work


Oral solid dosage

• Content Uniformity (CU) has been identified as CQA• API Particle Size Distribution (PSD) has an impact on CU• Design Space has been developed for the API PSD• Unit Operations having an impact on the CU is:

– Drug Substance• Reaction – impact on PSD• Crystallisation – impact on PSD• Drying – impact on PSD

– Drug Product• Dispensing – API PSD• Blending - homogeneity

PSD: 80-160 μm PSD: 6-20 μm


Defining the Control Strategy

11

22

33


Reaction

Crystallisation

Ethanol

InputMaterials

Drying

Based on PQLI CS work

Control Strategy Challenge: API - link between CQAs and Controls


Control Strategy Challenge: Drug Product - link between CQAs and Controls

Blend Mill

Blend

RC/Mill FinalBlend

CompressFilm Coat

Packaging

RawMaterials

Mg Stearate

Based on PQLI CS work26 Real Time Release Testing, NNE Pharmaplan 2010

Summary: Control Strategy for CU – RTRT

Drug Product Control Strategy

CQA Unit Operation CPP or MA Controls

Content Uniformity

Dispensing API PSD Obtained from API CoA

Final blend API Blend uniformity On-line NIR

API Control StrategyCQA Unit

OperationCPP or MA Controls

Content Uniformity

Reaction PSD: Ratio of EtOH/API On-line NIRConcentration (feedback control)

Crystallization PSD Specification FBRM PSD, determination

Drying Cooling RateAutomated processcontrol


Implementation of Real Time Release Testing

Practical issues related to implementing the RTRT• The Pharmaceutical Quality System must support the operation of the control strategy• Make a Risk Assessment focusing on the potential failure mode of operating the Control Strategy and

RTRT– What if the RTRT fails?

• Examples of additional elements to the Pharmaceutical Quality System:– Responsibilities – Q involvement– How to control the process – automation, feedback, feed-forward, manual– Alarms– Sampling – Data trending– OOS definition – Batch release strategy– Equipment mal-function strategy– Updating and validation of multivariate models– Training


Examples

Conventional testing versus Real-time release testing

Dispensing

Reaction

Crystallisation

Drying

Purification

LAB

Dispensing

Blending

Compression

Coating

LAB

Assay (HPLC)Purity, related

impurities, ((HPLC)Residual solvent (GC)Moisture content (KF)

Heavy MetalsEtc…

ID, Assay, CU (HPLC)Purity, ((HPLC)

Dissolution,Appearance

Moisture content (KF)Etc…

NIR, on-line (reaction id)

IR, on-line (purity, assay)

FBRM, on-line (PSD)

NIR, on-line (Moisture, purity

NIR, on-line, blend homogeneity

NIR, on-line (assay, CU, ID)

Vision, on-line (appearance)

NIR, at-line (id raw materials)

NIR, at-line (id raw materials)


CQA: CU, dissolution, ...Crystal size during formation - PSD

• Focuses beam reflectance measurements can be used to measure PSD

• Measure crystal diameter• Probe inserted into reactor

Ref: Figure Pfizer


RTRT of PSD

• FBRM used to define the best cooling ramp

• FBRM used to measure PSD in-line

• RTRT of PSD • No sampling and

QC test

Ref: Figure Pfizer


Design Space for drying

Effect of inlet temperature and air flow on degradation and generation of fines

Air flow

Inle

t tem

pera

ture

Degradation

Air flow

Inle

t tem

pera

ture

Degradation

Air flow

Inle

t tem

pera

ture

Degradation

Air flow

Inle

t tem

pera

ture

Air flow

Inle

t tem

pera

ture

Air flow

Inle

t tem

pera

ture

Air flow

Inle

t tem

pera

ture

Degradation and fines

Air flow

Inle

t tem

pera

ture


Air flow

Inle

t tem

pera

ture


+ =

Fines


Ref: Mock P2

Design Spaceand Control Strategy for drying process

Known edge of failure due to fines

% H2O

2.0%1.5%

18.5%

Drying time

Known edge of failure due to degradation

Regions of uncertainty17.5%

Trajectories describing the boundaries of the design space where product quality is assured

Known edge of failure due to fines

% H2O

2.0%1.5%

18.5%

Drying time

Known edge of failure due to degradation

Regions of uncertainty17.5%

Trajectories describing the boundaries of the design space where product quality is assured

Example, Mock P2, picture: Pfizer35 Real Time Release Testing, NNE Pharmaplan 2010

Fluid bed drying - NIR


Ref S. Hammond, Pfizer

RTRT of moisture content by NIR Fluid bed drying

40 80 120 160 200

-2.0

-1.8

-1.6

-1.4

-1.2

sec

Sep.21.2000/11:51:25AMSECT: RUN5D2.DAT / 1409.2nm [10E-4]

R5D2DP.DAT Pfizer Ltd. / Aspect Plus V1.52

Filter cleaning

Wet

Dry

1 2 3 4 5 6 7 8 9 10

1410 1430 1450 1470

-0.8

-0.4

-0.0

0.4

0.8

nmMay.11.2001/11:46AMSample values [10E-4]

FBD2R2D2.DAT Pfizer Ltd. / Aspect Plus V1.62

Peak Height Decreasing With Drying

Peak Height Increasing With Drying

Water

Product

• RTRT of moisture content• No sampling• No waiting for LoD results• Reduced risk of processing

poor quality material

37 Real Time Release Testing, NNE Pharmaplan 2010Ref S. Hammond, Pfizer

Tablet dissolution, real time release

At-line FBRM Measurement in Acetone

0

1

2

3

4

5

6

10 100 1000Chord Length (µm)

Equ

ival

ent V

ol%

Dry Mix = 62µm 1.5 min = 75µm 3 min = 79µm 4.5 min = 86µm 6 min = 95µm 7.5 min = 105µm 9 min = 120µm 10.5 min= 150µm12 min = 180µm

FBRMPSD

ProcessParameters

ProcessParameters

ProcessParameters

Multivariate calibration

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100

5m in

10m in

15m in

20m in

30m in

45m in

60m in

Dissolution, ref

Materialattributes

Dissolutio

n, predicted

Based on case by Higgins, MSD, 200938 Real Time Release Testing, NNE Pharmaplan 2010

Cost savings, example from AstraZeneca

• First batch released October 18th 2007• 4 days from start of manufacture to release• Batch packed on Friday October 19th 2007• Batch on the market Monday October 22nd 2007• Substantial cost savings on stockholding and QC

Thanks to Rob Hughes – AZ 39 Real Time Release Testing, NNE Pharmaplan 2010

Organisational Aspects

RTRT versus traditional QC lab

RTRT : the end of traditional QC labs ?

OrThe start of A more cost effective business model

facilitating “Right first Time” and continuous improvement


?

• Fewer people in the QC doing traditional end-product testing but more people involved in updating, maintaining and validating PAT applications (multivariate models)

• Fewer people in manufacturing due to less scrap & shorter lead time

• More people in manufacturing to execute the control strategy

• More training and new skills – empowering of people

• More cross-functional team work upfront – Risk Assessments– Establishing the business processes

• Different approach to Quality– Cross functional approach– Quality decisions– Role of QP

Organisational impact


Conclusion

• Real Time Release Testing is a QbD option – not a requirement• RTRT requires the application of PAT and PAT data management• RTRT approved by health authorities • Huge savings reported by Big Pharma

• When the challenge of implementing a new way of working has been addressed, huge benefits

• Can be applied to new and marketed products• The Generic Industry is also very interested in RTRT – help to

reduce cost

• Ties perfectly with continuous manufacturing • Will be a competitive advantage – if not already so!

• Good luck!


Thank you for your attention!

[email protected]


Is RTRT like the beautiful

woman or the old witch?

4 real time release testing - industry.siemens.com · outline • what is real time release testing...

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