26 may 2016 line lundsberg-nielsen, vibeke brun jensen ...€¦ · ifpac jan 2016 | implementing...

Implementing CPV in Smaller Organizations

26 MAY 2016Line Lundsberg-Nielsen, Vibeke Brun Jensen & Monica Hueg

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Outline

CPV/OPV – regulatory expectations, differences and similarities

Challenges for smaller non-US companies

CPV/OPV Roadmap

Case study: OSD product

ISPE Nordic May 2016 | Implementing CPV | Lundsberg, Jensen & Hueg, NNE Pharmaplan

CPV/OPV expectations

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• Are there actually any real differences in expectations?

• Both FDA and EMA refer to a three stage life cycle approach to Process Validation that is science

and risk based and supported by ICH Q8, Q9, Q10 and Q11

• The FDA has, since 2011, required that CPV programmes should be emplaced for both new and

legacy products

• With Annex 15 coming into force Oct 2015, EMA also expect that OPV programmes for new and

legacy products will be emplaced

• So what is the problem in Europe? – If there even is a problem?

• Why is it so complex and difficult to implement CPV/OPV?


Lifecycle Approach to Process Validation - FDA and EMA

The Product Life Cycle

Scie

nce

& R

isk B

ase

d A

pp

roa

ch

Process Design

Stage 1

ICH Q8, Q11

(Inspection)

FD

A

Pharmaceutical

Development

ICH Q8, Q11

Dossier (Submission)

EM

A

Qualification (Equipment)

Annex 15

Process Validation (PV Guide,

Annex 15)

Traditional, Continuous Process

Verification (PAT) or Hybrid

(Submission, assessment,

GMP, Inspection)

During Development Before Sales During Commercial Manufacturing

DevelopmentTechnology

Transfer

Commercial

Manufacturing

Product

Discontinuation

Facility,

Utility &

Equipment

Qualification

Stage 2.1

Process Qualification

Stage 2

(Inspection)

Process

Performance

Qualification

Stage 2.2

Ongoing Process Verification

Annex 15

(GMP, Inspection)

ICH Q10

Link to Product Quality Review

Continued Process

Verification

Stage 3

(GMP, Inspection)

ICH Q10

Link to Annual Product

Review

PA

TIE

NT

& P

rod

uct F

ocu

s

Quality Risk Management (ICH Q9) & Pharmaceutical Quality System (ICH Q10)

4 ISPE Nordic May 2016 | Implementing CPV | Lundsberg, Jensen & Hueg, NNE Pharmaplan

FDA versus EMA expectations to CPV/OPV

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Ref.: Grace McNally, FDA, CDER, OPQ, OPF, FDA PDA Joint Reg Conf; Washington D.C., Sept 2015


The Challenges (maybe not only in Europe….)

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• Lack of lifecycle process validation concept

• Lack of the needed skill sets or in house training e.g.

statistical skills

• Do not know how to start the implementation of

CPV/OPV (particularly difficult for legacy products)

• Products not prioritized in terms of patient, quality and

supply risk.

Concepts and skills

• Minimal process understanding

• No overview of the real product and process risk

• Lack of QTPP, CQAs or CPPs

• Investigate process variation to and understand

sources, to control them

Process Understanding

• Lack of procedures or templates for the three PV

stages

• Lack of procedures for how to apply statistical tools in

PV and how to act on the outcome of the analysis

• Lack of procedures for data collections from manual

processes

• Unclear nomenclature

Procedures

• Lack of QRM procedures in place and if, they are not

operational (typically just copies of the standards and

guidelines)

• Very few useful risk assessments

• If they do risk analysis, it is often very complex with

lack of overview and done as a one off activity

Quality Risk Management (QRM)


More Challenges (… and still not only in Europe….)

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• Limited knowledge of the differences and similarities

between the FDA and EMA expectations on PV

• How to comply with them both?

Regulatory Expectations

• ‘We do PQR (APR) so why OPV (CPV)?’

APR/PQR

• Reluctant to move to the new lifecycle PV paradigm

and change PQS accordingly

• See the new OPV/CPV expectations as additional

elements to their existing Quality System.

• Patchwork – when new PV elements are added.

Becomes very complicated – requires lot of work with

limited value

Pharmaceutical Quality System (PQS)

• They will have to change their mind-set

Attitude


Fixed Mindset vs. Growth Mindset

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Growth MindsetFixed Mindset• Intelligence is static

• Leads to a desire to look

smart

• Avoid challenges

• Get defensive or give up

easily

• See effort as fruitless or

worse

• Ignore constructive

(negative) feedback

• Feel threatened by the

success of others

• Result: they may plateau

early and fail to reach

their full potential

• Intelligence can be

developed

• Leads to a desire to learn

• Embrace challenges

• Persist in the face of

obstacles

• See effort as the path

to mastery

• Learn from criticism

• Find lessons and

inspiration in the

success of others

• Result: they reach

even higher levels of

achievement

Based on ‘The Mindsets’: C. Dweck,

Professor of Psychology,

Stanford University


So what do we use a new Growth Mindset for?

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Process Validation Lifecycle

Is the commercial process capable of producing

reproducible products?

We must demonstrate being

In Control

Capable

Reproducible

Does the process remain in a state of control?

What is the Performance?

We must ensure the process is:

Predictable

Capable

Does the process remain in a state of control?

Predictable, Capable, Performance

Ongoing detection of

Process and Product Variability and Drift

Stage 2: PPQ/PV Stage 3A: CPV/OPV Stage 3B: CPV/OPV


Establishing a CPV/OPV Programme

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• The basis for making a CVP/OPV Programme depends on whether the CVP/OPV is

to be performed for a new product/process or an existing product/process

• For a new product the CVP/OPV is based on knowledge obtained during Process

Design and PPQ/PV

• For legacy products where CVP/OPV will be established for the first time, the

CVP/OPV will be based on prior knowledge from the years of commercial

manufacturing including the initial PV prior to product launch


CVP/OPV for legacy products – where do you start?

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• A good starting point for establishing

a CVP/OPV programme for legacy

products and thereby complying, is

to evaluate the products by

prioritising according to the risk to the

patient, quality and supply

• Based on that priority list, the

CVP/OPV programme for each

product can now start to be built

using a CPV/OPV roadmap


CPV/OPV Roadmap – new and legacy products


Case study – CPV/OPV for Product N

• A legacy wet granulated OSD product in two strengths, 10 and 20 mg tablets

• Around 50 batches manufactured per year with none or limited release problems

• Product assumed to be robust, no risk analysis has been performed

• The QTPP does not exists, CQAs and CPPs have not been identified

• Batch release data available for release attributes, including:

• Assay

• CU

• Dissolution

• Process performance and capabilities have not been calculated

THE GOAL is to establish a CPV/OPV PROGRAMME and demonstrate the product remains in a state of

control by monitoring relevant product and process data and, by evaluating the Cpk and Ppk

IFPAC Jan 2016 | Implementing CPV | Lundsberg & Hueg, NNE Pharmaplan13

Prior knowledge – current control strategy

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The existing control strategy is based on end product testing, IPCs and raw material

testing:


Initial product quality and performance baselineAssay

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Analysis of the Assay• A statistical evaluation of the

performance and capability of

the release attributes and the

IPCs were performed for the

last 50 batches

Assay

• No special cause variation

observed

• The process is shifted by

nearly 1% in assay but is

stable and well within the

specifications

• No additional monitoring

activities are required


Initial product quality and performance baselineDissolution

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Dissolution

• Dissolution is within

specification but the variation

could lead to a dissolution

value below target

• The root cause of this variation

must be explored and action

taken to improve

Analysis of the Dissolution


Initial product quality and performance baselineGranule particle size

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Granule particle size

• The particle size varies

significantly

• The process is not in control

• OOSs are observed

• The impact of this variability on

the product quality must be

understood

• Further investigation to find the

root cause of this variability

must be made

Analysis of IPC granule particle size


Initial baseline for Product N

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Analysis summary

• See table

• A Cpk and Ppk of more than 1.6 is

classified as the process being

robust (green), between 1 and 1.6

being average (yellow) and below 1

weak and non-robust (red)

• The CPV/OPV Programme will

focus on what is critical (red)


The CPV/OPV Programme (I)


The CPV/OPV Programme (II)


CVP/OPV Report

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• The outcome of the CPV/OPV

activities must be documented in an

CPV/OPV report

• The report will cover the data

presentation, plots and analysis

• Conclusions based on the analysis

in terms of:

• Root cause analysis

• Improvement activities

• Change to the control strategy

• Changes to the CPV/OPV

programme

Analysis of IPC granule particle size

Batch 392015


CPV/OPV Report, granule particle size

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• The variability of the granulate particle

size shows an insufficient robustness of

the granulation process

• A correlation between the granulation

fluid spray rate and the granulate particle

size could not be demonstrated

• The root cause for variations in the

granulate particle size needs to be further

evaluated

• It has been proposed that other process

parameters must be monitored during

granulation, such as air flow rate. As well

as additional sampling during granulation

process to increase process

understanding


CVP/OPV Report, assay

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Analysis of Assay

Batch 392015

• Based on the evaluation of the 50 batches

and the acknowledging the process is very

robust, the control limits have been defined

to:

• LCL: 98.9 % label claim and UCL: 103.0 %

label claim

• These control limits will be used for the

ongoing monitoring programme – used as

basis for levels and frequency of routine

sampling and monitoring


Lifecycle CPV/OPV Approach

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• The initial risk assessment can now

be updated

• The CPV/OPV Programme must be

updated if any changes are proposed

in the report in relation to:

• The Control Strategy

• Monitoring programme

• Monitoring Frequency

• Review Frequency

• As with the case of granule particle

size, knowledge about critical steps

and potential CPPs will evolve during

the CPV/OPV

IFPAC Jan 2016 | Implementing CPV | Lundsberg & Hueg, NNE Pharmaplan

Conclusion

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• Establishing a CPV/OPV programme requires a change in mindset and acknowledgment of the

growth potential in process robustness and product quality – the PQR/APQR is a status report

and does not provide the same growth opportunities

• All the elements (data, information, knowledge) needed to set up a CPV/OPV programme are

present (GMP data) – it is just a matter of combining them in the right order to get the puzzle to

fit.


Thank you for your attention and remember

26

Line Lundsberg-Nielsen

[email protected]

Monica Hueg

[email protected]


Vibeke Brun Jensen

[email protected]

26 may 2016 line lundsberg-nielsen, vibeke brun jensen ...€¦ · ifpac jan 2016 | implementing...

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