Marino Nebuloni Quality by Design - Federchimica

Quality by Design nella cristallizzazione

degli API(QbD in API crystallization process)

Marino Nebuloni(REDOX srl – Monza)

Content

• Recent ICH and FDA Guidelines

• ICH Q8, Q9 and Q10

• Quality by Design (QbD)– Example Approach to QbD

– QbD for API crystallization

• Examples of Implementing QbD

• Concluding and Remarks

M. Nebuloni - April 23, 2015

ICH & FDA Guidances

Product

DesignProcess

Design

Manufactu

ring

Process

Monitoring/

Continuous

Verification

ICH Q8/Q8(R)- Pharmaceutical Development

FDA PAT Guidance

ICH Q9 - Quality Risk Management

ICH Q10 - Pharmaceutical Quality Systems


ICH Q8 Guidance

• Provide guidance on Pharmaceutical Development

• Describe good practice for pharmaceutical product development

• Introduce the concepts of:– Designe Space

– Flexible regulatory approaches

– Quality Risk Management (Q9)


QbD Definition (ICH Q8(R))

A systematic approach to development, that begins with

predefined objectives and emphasizes product and process

understanding and process control, based on sound science and quality

risk management


Why QbD ?

• High level of assurance of product quality

• Cost saving and efficiency for industry– Increase efficiency of manufacturing process– Minimize/eliminate potential compliance actions– Provide opportunities for continual improvement– Facilitate innovation

• More efficient regulatory oversight– Enhance opportunities for first cycle approval– More focused PAI and post approval cGMP

inspections


Quality Risk Management Process


Role of Quality Risk Management in

Development & Manufacturing


Quality by Design Approach

Target Design Implementation


6 Steps - QbD Process for

Crystallization Product Development


Crystallization Strategy

Exploration Exploitation

Crystallization Development

Strategy

Exploration: Existing Knowledge not sufficient to solve the problem identified.

New knowledge needs to be created and acquired to

contribute to the existing body of knowledge

Exploitation: Utilization of existing knowledge for innovative problem solving


CQAs & CPPs in Crystallization

• Critical Quality Attribute (CQAs)

– A CQA is a physical, chemical, property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.

– API Particle Size, Purity, dissolution, polymorphism, stability, ……

• Critical Process Parameter (CPPs)

– A process parameter, e.g. temp, time, speed, when variable it can affect the CQA of a product or process

– Critical Process Parameters (CPP) identified using a risk analysis investigated extensively using a DOE.

• Non-Critical Process Parameters

A process parameter identified as low risk which leads to low probability of product failure


CQAs for a Solid API properties(Example)

CQAs Target

Polymorphism Form I

Particle Size Distribution d10, d50, d90

Morphology plates

Flowability specification

Density (apparent / packed) specification

Specific Surface Area specification

Melting Point specification


CQAs for Solid API Stability

(Example)

CQAs Target

Drying Temperature Range values

Packaging behaviour Compression value

Coalescience Storage temperature

Humidity Range of % RH

Light Exposure Lux value

Milling / Micronization Polymorphism/amorphous

Etc.


CPPs(Example Mixing Unit Operation)

1. Mixing Time

2. Mixing Speed

3. Process temperature in crystallization

4. Drying Temperature

5. Grinding Process


Risk Assessment (General Approach)


Simple Risk assessment in

crystallization (example)

Quality

Attribute of

DS, or Unit

Operation

CPP

Potential

Risk

Probability of

Occurrence

(Lo, Med, Hi)

Potential

Impact to

the Quality

Risk

Reduction

/Mitigation

DS Solid State

Form

New

polymorph of

DS formed

Med More complex

formulation

Develop a

back-up

formulation

DS solvates New Impurities Hi Instability on

storage

Perform

process

optimization

Reduction PS

distribution

Change in

Dissolution

Hi Reduction

product shelf-

life

Change in

grinding

process

Temperature New

polymorph

Lo OOS Define process

TemperatureM. Nebuloni - April 23, 2015

CQAs – Unit Operation Relationship in

crystallization (Example)


Variability is the Problem

A process CANNOT have a constant output from

a fixed process and variable input M. Nebuloni - April 23, 2015

Conceptual Representation of Knowledge,

Design and Control Spaces

1. Specifications

2. Continuous Improvement without Regulatory Approval

Design Space: crystallization and

Drying Unit Operation (Example)

Physical Properties (or )

Unit Operation CPP Design Space

Polymorphism Form I or Form II

Crystallization Temperature Range (> 5°C - < 60°C)

Rate of coprecipitate Range 2 – 4 L/min

Drying time & Temperature Time 4- 6 hours - 50- 60°C

Drying Time & vacuum value &

Temperature

Range of time vs Temperature vs

vacuum


Example I– QbD application to prevent

API crystallization in injectable DP

1. Solubilization of the API at defined pH

2. pH correction 3. Storage the solution before the

dispensing in vials (time temperature influence)

4. Filtration of the solution5. Final Control of particle presence


Investigation approach


FBRM on line

Critical Quality Paramiters

Concentration

Filtrability

pHSolid state

Induction

Time


FBRM application for monitoring the API crystallization particles


Induction Time

0 time

Time

GrowingNucleation


Information collected on the time during the crystallization


Scale-upLaboratory

Definition of CQAs

F.B.R

.M.

Production

Quality Control

P.A.T.

F.B.R

.M.

OptimizationM. Nebuloni - April 23, 2015

Experimental Data

0

1000

2000

3000

4000

5000

6000

7000

8000

0.00.00 2.24.00 4.48.00 7.12.00 9.36.00 12.00.00 14.24.00 16.48.00 19.12.00

Tempo (h)

N°

part

icel

le

0

5000

10000

15000

20000

25000

30000

Particelle 1-3 um

Particelle 3-5 um

Particelle 5-10 um

Particelle 10-21 um

Particelle 23-50 um

Particelle 54-100 um

N° totale di particelle

Inizio 2h


• pH= 6.7

• concentration : A mg/mL

• Poor filtrability

Filtrazione

pH

ConcentrazioneNO F

6.7

A

F

6.7

A

NO F

7

A

NO F

7

B

NO F

6.7

B

F

6.7

B

F

7

B

F

7

A

Design Of Experiment


0

1000

2000

3000

4000

5000

6000

0.00.00 2.24.00 4.48.00 7.12.00 9.36.00 12.00.00 14.24.00 16.48.00 19.12.00

tempo (h)

N°

part

icel

le

0

5000

10000

15000

20000

25000

N°

part

icel

le to

tali

1-2 um

3-5 um

5-10 um

10-21 um

21-50 um

54-100 um

N° totale particelle

Inizio 3h


Filtrability

pH

ConcentrationNO F

6.7

A

F

6.7

A

NO F

7

A

NO F

7

B

NO F

6.7

B

F

6.7

B

F

7

B

F

7

A

Final Result

3 h

0.5 h

2 h

0 h

TimeM. Nebuloni - April 23, 2015

Results of Investigation

Critical Parameters (CQAs) and Process Parameters (CPPs)

to be strectly controlled in the Storage solution before and after filtration:

1. Reduce the solution evaporation (fix the concentration limits-range)

2. Define the filtration temperature

3. Control the filtration time and the presence of crystals traces (< 3 microns) by on line method

4. Control the final pH before the dispensing.

5. Avoid any cooling conditions yhay induces nucleation -definition of Temperature limits


Example II – QbD application to prevent

API crystallization into undesired

polymorphic form.

1. Two polyomorphic Forms (Form A & Form B)

2. Form A dissolution in specification3. Influence of temperatura in the

Crystallization process4. Morphology and Filtration 5. Final Control of Particle Size

DistributionM. Nebuloni - April 23, 2015

Control Crystalliazion of a active polymorphic Form by on-line Raman spectroscopy

Polymorphic Form A high melting temperature

(active form)

Polymorphic Form B low melting temperature

(OOS form)


1890 1501800 1700 1600 1500 1400 1300 1200 1100 1000 900 800 700 600 500 400 300 200

105

4,1

-0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

4,0

Raman Shift / cm-1

%T

1698,7

1667,2

1642

1621,5

1580,6

1517,6

1473,5

1391,6

1342,8

1220

1193,2

1116

1004,3

949,14849,94

834,2 582,24

Form A

XRPD

pattern

Raman

spectrum

Form A - Crystal Morphology


1920 4391800 1700 1600 1500 1400 1300 1200 1100 1000 900 800 700 600 500

105

3,5

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

1,8

2,0

2,2

2,4

2,6

2,8

3,0

3,2

3,4

Raman Shift / cm-1

%T

1709

1694,5

1651

1614,8

1582,2

1531,5

1495,3

1437,4

1379,5

1348,7

1209,3

1165,9

1115,2

1095,3

1003

829,19642,74

592,05

Form B

XRPD

pattern

Raman

spectrum

Form B - Crystal Morphology

(aggregates)


1796 9091600 1500 1400 1300 1200 1100 1000Raman Shift / cm-1

%T

1697,3

1666,5

1707,61693,6

1649,8

1003,3

1496,9

Forma Bpura

Forma A pura

1774 15581750 1725 1700 1675 1650 1625 1600 1575Raman Shift / cm-1

%T

1707,61693,6

1649,8

1697,3

1666,5

Reference band

1574 13011550 1525 1500 1475 1450 1425 1400 1375 1350 1325

105

1,6

-0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

Raman Shift / cm-1

%T

1497

Banda di quantificazione Form B

quantification by

Raman spectrum


Quantification of Form B in production batches

Nome Descrizione

1574 13011550 1525 1500 1475 1450 1425 1400 1375 1350 1325Raman Shift / cm-1

%T

1497Lotto

From aria ratio, Form B present about 12%

Specification from DMF: < 10 %

Form B


Lab Scale Experiments

Raman & FBRM (Lasentec) into RC1 calorimeter

Immagine RC1

RC1

FBRM

Probe


Crystalliztion control by on-line spectroscopy

Fo

rma

B 1

666

cm

-1

Ra

ma

n s

hif

t

Fo

rma

A 1

497

cm-1

R

am

an

sh

ift


Forma B 1666 Raman shift

Forma A 1497 Raman shift

N° totale di particelle (Lasentec)

Polymorphyc concentration of Form A and Form B during the

crystallization process & Particle Counting


Is QbD really a new concept in

crystallization?

• QbD is not a new concept from the technology perspective

• QbD is new relative to regulatory review and submission

• QbD is optional and should not become a regulatory requirement as agreed to in ICH Q8

• QbD will not necessarily be included in all submissions

• Generation of QbD information during the process phases should be at industry benefict

FDA: What is the advantage of QbD?

Emphasizes product and process understanding and process control

Conclusion

Full implementation of Quality by Design is a

benefit for:

�Manufacturers – less regulatory examination and lower manufacturing costs

�Regulators – less regulatory severity without sacrificing quality

�Patients – increase in availability of high quality pharmaceuticals


QbD in API crystallization process

Thanks for the

Attention

M. Nebuloni


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Marino Nebuloni Quality by Design - Federchimica