Process Quality Risk Assessment at Novartis

Barry O Donovan, ChemOps PTL

11-Nov-2010

Process QRA: Purpose

The QRA identifies and quantifies the operational
parameters and associated ranges of the process with
respect to the quality of the product.
The QRA document and the underlying experimental
results are auditable documents particularly during PAIs
Chemical production uses the QRA (Quality Risk Analysis)
document as a basis for the validation of a production
process.
General principle:
For steps prior to API Starting Material the parameters listed in the
table considered critical to the quality of the intermediate produced in
the step and have no direct effect on the quality of the API.
2 | Quality Risk Assessment | Barry O Donovan | 11-Nov-2010 | Business Use Only

Principle of QRA generation and handover

Draft QRA presented to Chemical production after prototype campaign
ie after the final synthetic route is defined.
Review and agreement of gaps in the cross functional development /
production team -> Joint input
Finalised QRA must be available ahead of launch / validation campaign
Parameters and associated ranges transcribed to chemical production
QRA version
Incorporated into master batch record and form the basis for validation
QRA is a living document that can be updated periodically based on
production experience

3 | Quality Risk Assessment | Barry O Donovan | 11-Nov-2010 | Business Use Only

QbD Development Road Map Chemical Development DS Activities

Road map/milestones/documentation

Legend

Risk Assessmts,
Protocols &
reports

Peer Reviews

DS synthesis
CHAD/Chem
CHAD/
Chem Ops

D3

CSP

sPOC

ISA

POC

CSP

PCM1

PCM2
Prot. adequate

P2

P1

Synthesis
Strategy I

Synthesis
Strategy II
Quality
Review I

PCM3
Prototype

Exp.Report

Exp.Report

Process Challenge

Quality
Review III

Quality
Review II

Experiments/Batches Confirmation
Exp.Report
Process Challenge

QRA protocol
Peer review assessment

Peer review assessment

Launch

Synthesis
Strategy III

Experiments
Exp.Report

Scientific peer review

Sub

Process Challenge Meetings

Process
Evaluation
Meeting
PEM

Ph. III readout

Ph IIb readout

Ph IIa readout

Exp.Report
Process Challenge

QRA report

Peer review assessment

Management / Scientific peer review

Reports

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Process Eval/Challenge

Exp.Report

QRA update

Launch

Process for generation of QRAs

QbD approach recently introduced, currently in the piloting
phase.
Enhanced scientific basis for parameter setting by FMEA
Clear action plan for preparation of the QRA rather than dependance
on chemists knowledge or experience.
Methodology involves walk-through / analysis for each step of the
chemical process
Output is construction of a design space i.e. area of parameter setting
where the process can deliver to the required specification

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Risk Management
tools

New QRA Template

Fishbone

Critical parameters list / Parameters

interaction / Design Space

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FMEA table (RPN numbers)

QRA Experiments & DoE

Example parameters
Parameter

Set
Variation
point
+/&
, P, M
accept
DoE
able Informatio
range
n
1.2.2
1.38e
q.
Quant. B2
2.0

1.5.2 / 4.4 1.38e

q.
CDI
quantitiy

Rating of Effect
crit = c
uncrit=u

1.5

1.25

1.0

1.0

1.25

1.5

2.0

Effects on product quality and process

under critical conditions

Reference to
literature or
experiment

Comments

NVA237 B3 is water soluble; when

distributed between toluene and water or
NVA237-allmeth1brine it is completely in the aq. phase as can
001
be seen by the colour already but also by
GC-analyses.
DS (B6) batches
E-46312
were never
Bix09021a (B5),
contaminated with
B3 (spiked with 17mol% B2) gave good
E-46312
542-07 (the product
drug substance B6
Bix09023a (B6)
derived from B2 in
the next step).
Analysis for 542although excess B2
07 underway!
is used.
1.25 was the former set point for several
campaigns and experiments.
Incomplete conversion to B3 PAK fails
conversion does not increase with higher
reaction time.
See DoE
Low conversion to B3 (>12% B1); cannot be
improved by longer reaction time. 10mol% E-46312
B1 in B3 1% B1 in B5 <0.1% B1 after Bix09021a (B5),
E-46312
first recrystallization already.
See DoE B3
Bix09023a (B6)
Former set point running well
Upper limit in DoE
experiments
Earlier experiments
E15876Bix 07005

7 | Quality Risk Assessment | Barry O Donovan | 11-Nov-2010 | Business Use Only

Example parameters
5.7

T=60C 110C 48h

20% and 50% solution of NVA237 B3 in toluene were

E-47312Bix09024 a &
refluxed for 48h without a sign of changing its composition. b

Slow formation of the propylester (2.4% after 56h at 6090C); during crystallization afterwards the byproduct is
eliminated completely into the mother liquor.

Time and t = ?h
Temp.
during
evap. of B3
6.5 / 7.1

60C

90C

Maximal
Temp. of
B5- and B6solutions
8.1

Of course such a prolonged heating to this unusually high

temperature would result in lower yield.
46-50C 5C

Seed
temperatur
e
8.2.
B10
Type of
seeds
8.3
Amount of
seeds for
B5

0.3%

12.8% during 18h stirring at 5C)

NVA237-bixeldo2-001 That s the advantage of

propanol; heating in
methanol causes a much
faster decompostion to the
corresponding methyl
ester.
E-46213Bix09011 A

C/U

16.7% 522-05 (

60C

Dissolution of seeds

E-47312Bix09026 a&b Lasentec-experiment and

visual inspection

B10 + 522-05
(50%)

522-05-content of B5: 3.2% compared to 2.9% in

experiment using B10 alone

E-47312Bix09028 K1a
(comp. to K1b)

0%

No crystallization may occur (clear solution even at 5C)

E-46213Bix09011 A

0.05%

0.15%

0.1%

U/C

0.3%

1%

10%

The amount of seeds

seams to be a major factor
Content 522-05: 10.7% (vs. 5.4% when seeded with 0.3%) E-47312Bix09026for the robustness of
K1a/b
522-05: 3.2% (although half of seed was 522-05)
crystallization of B5 in
E-47312Bix09028 K1a view of the 522-05Results are not robust
content. Several
PCII, Eexperiments with only
15876Bix07018
0.05% came out with a
E-47312Bix09026-K1b content of 522-05 of
>10%.
E-15876Bix07012/15

8 | Quality Risk Assessment | Barry O Donovan | 11-Nov-2010 | Business Use Only

Risk Management
tools

Old process for QRA generation: Limitations

Quality
- No risk assessment of process parameter/variable
- Absence of critical quality attribute
- Not well documented, relatively low traceability

Methodological
OVAT
- Principally One variable at the time strategy (Although DoE is not excluded)
- No or few information on parameters interaction

Critical parameter denomination

- Not clear-cut
- No methodology to assess/rank/prioritize risks
- Still: Criticality of some parameters or critical conditions show up not until scale-up or
even launch

Need for a stand alone document

9 | Quality Risk Assessment | Barry O Donovan | 11-Nov-2010 | Business Use Only

Risk Management
tools

Current QRA vs. new QRA template-GAP Analysis

Descriptor
Table of contents

Current QRA

New QRA

New data available from :

Automatically generated

History of Process

CER

Synthesis Scheme

LV/BV

Raw Materials data

LV/BV

Process Description and

Manufacturing equipment scheme

LV/BV

Manufacturing Flow Chart

Chemical production

Control strategy

CER

Fishbone diagram / FMEA Table

Elaborated during Proc.

Challenge / Chemist

Allows DoE presentation

QRA

Summary
Design space

Elaborated during QRA

Follow-up action
10 | Quality Risk Assessment | Barry O Donovan | 11-Nov-2010 | Business Use Only

Elaborated during QRA

Elaborated after QRA

Risk Management
tools

QRA summary
New QRA is a tool:
Systematic approach based on:
- Science (ICH Q8)
- Risk assessment (ICH Q9)

New QRA is a document:

Based on ICH-Q9 tools (Fishbone, FMEA table,

Living stand-alone document which gather key information/data and avoid later on
difficult data mining

Methodological (allows continuous improvement):

Encourage chemists (Development, Chemical production) to think about process overall
risk
Encourage chemists to seek for parameters interaction (DoE)

11 | Quality Risk Assessment | Barry O Donovan | 11-Nov-2010 | Business Use Only

Back-up

12 | Quality Risk Assessment | Barry O Donovan | 11-Nov-2010 | Business Use Only

Peer Review
concept

Tools for the Scientific Peer Review

Risk Collection / Assessment table
No
.

Risk description and

categorization

Probability of
Occurrence

Severity [Description
of Impact in case of
Occurrence]

Status /Risk Minimization Plan

1.1
2.1

Risk Categorization
Regulatory
Quality
Non-Technical Risks

Risk Minimization plan (eg)

mitigate
investigate cause
monitor
accept

Format of table aligned with table of TDP to reduce redundancies

13 | Quality Risk Assessment | Barry O Donovan | 11-Nov-2010 | Business Use Only

Timelines /
Who