Technobis Crystallization workshop · 2018-10-15 · Solution crystallization controlled via...

© 2018 Alkermes. All rights reserved.


Particle size control during

recrystallization and scale-up Naomi Briggs, Jacklyn O’Neil, Anthony Moffa,

Technobis Crystallization workshop

October 3rd 2018


Background:

Me, particle size control, crystallization

Problem Statement

Solution: Crystallization development

Scale-up considerations

Drug product: consideration & performance

Summary

2

Outline


Focused on developing innovative

medicines for the treatment of

central nervous system (CNS)

diseases

Diversified commercial product

portfolio and a substantial clinical

pipeline of product candidates

Research and development

center located in Waltham,

Massachusetts

− Headquarters in Dublin, Ireland

− Research and manufacturing

facility in Athlone, Ireland

− Manufacturing facility

in Wilmington, Ohio

Approximately 2,100 employees

Nasdaq: ALKS

Alkermes: A Global Biopharmaceutical Company 3

Wilmington, OH

Waltham, MA

Dublin, Ireland

Athlone, Ireland


4

Background - Me

Undergraduate: M.Sci Forensic and Analytical Chemistry

Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow.

Sept. 2006 - June 2010

- Industrial Placement, Reading Science Services, July 2008-2009

- Masters thesis: A structural database for salt selection studies.

Postgraduate: Pharmaceutical Science PhD

Strathclyde Institute of Pharmacy and Biomedical Sciences,

University of Strathclyde, Sept. 2010 – Sept. 2014

Polymorph Control of Pharmaceuticals within a Continuous Oscillatory Baffled Crystalliser

Postdoctoral: Massachusetts Institute of Technology

DARPA Pharmacy on demand (POD) June 2015 – November 2017

Lead Engineer II: Alkermes, Waltham, Massachusetts,

Process development drug substance, November 2017 – Present


5

Background – Particle size control

Why is it important?

Bioavailability, stability, processability

Typical routes of control:


6

Background – Crystallization

𝜎 = 𝐶 − 𝐶∗

𝐶∗ C = solution conc. C∗ = equilibrium solution conc. @ constant T & P

𝐽 = 𝑘𝑏𝑆𝑏 𝐺 = 𝑘𝑔𝑆𝑔

Step 1: Nucleation (1y) Step 2: Growth

Approach A

𝐽 = 𝑘𝑏𝑆𝑏 𝐺 = 𝑘𝑔𝑆𝑔


Approach B (simplified)

Nucleation controlled through seed addition

Solution crystallization controlled via supersaturation (𝜎) most commonly by temperature and/or antisolvent addition.

𝑱 & 𝑮 are both complex processes

Considerations; Seed generation; Size dependent growth; Breakage (collision breeding/micro attrition); 𝐽 2y (surface breading); Agglomeration

𝑮 is a complex processes


The Challenge 7

Reactive Crystallization: Base + Acid = Salt (Compound A)

PSD overlay of Compound A manufactured at 2 sites

No PSD control = processability challenges for drug product


100 μm

The Challenge… Continued.... 8

Jet Mill Sieve fraction

Uni-modal distribution Uni-modal distribution dv50 ~100μm suitable DP processing characteristics

10 μm

10 μm

How to: • Produce uni-modal dv50 ~100μm • Scale the process

Accelerated degradation during stability

Approach: • Controlled recrystallization

Sieving = ~80% material unused per batch


Crystallization Development 9

1) Identify solvent system (Crystal 16)

Solu

bili

ty (

mg/

ml)

3) Detailed 3D solubility (Crystalline)

2) Kinetic information (Crystalline)

Large MSZW ~25 ˚C (𝜎 1.2)

R2 of 0.987

Solvents

Co-solvent system identified


Crystallization Development… Continued.... 10


Approach A

Large MSZW ~25 ˚C (𝜎 1.2) Investigated: • Various process volumes and operating conditions Result: • Agglomerated product - not individual particles




Approach B (simplified)

Nucleation controlled through seed addition

𝑮 is a complex processes

Investigated: • Various process volumes and operating conditions Result: • Not individual particles 𝑚𝑖𝑐𝑟𝑜𝑛𝑖𝑧𝑒𝑑

𝑺𝒆𝒆𝒅 𝒎𝒂𝒕𝒆𝒓𝒊𝒂𝒍

𝑛𝑜𝑛 − 𝑚𝑖𝑐𝑟𝑜𝑛𝑖𝑧𝑒𝑑


𝐽 = 𝑘𝑏𝑆𝑏



x10

x4

x4

After seeding x4 Seed slurry x4

x4

Seed Aggregation

Growth of

agglomerates

Thermal de-

agglomeration

Primary particle

growth

Approach C

+ Step 4: Growth Step 3: Heat +

De- agglomeration? Individual particles?


Background:


Problem Statement




Summary

13

Outline


Scale-up Considerations: Mixing 14

Other important considerations: • Plant and equipment tolerances • Sensitivity of the process – critical steps? NOR/PAR • Complexity of the process – can it be simplified?


Scale-up Considerations: Tolerances 15

0:00:00 0:28:48 0:57:36 1:26:24 1:55:12 2:24:00

Tem

pe

ratu

re (

C)

Time (hours)

“holding” at seed temp °C

6°C

1°C

Low σ High σ

Antisolvent - +

Solvent + -

API (Compound A) - +

Seed temperature + -

Normal charge 0.05 0.68

Critical charge 0.17 0.51

Temperature:

Charges:

- Under charge/ low T, + Over charge/ high T

• Seed T was dropped based on risk

of dissolving seed

• Critical charges narrow σ

• Co-solvent system a challenge, but

possible


16

Scale-up Considerations: Operation

• GMP requirement for Polish filtration: - Operation driven by solubility & kinetic’s

- max ΔT with solvent composition change

%Antisolvent T Sol. °C ΔT °C

0 >40 50 51 14

67 42 23 75 60 5

Vo

l (%

)

Size (µm)

Dry seeding product

• Ruled out dry seeding • Simplified seed solvent preparation

• Seeding method: - Historically seed with saturated solution - Dry v wet (& wet solvent choice) assessed


17

Scale-up Considerations: Equipment and mixing

Desire: Mixing insensitive process and/or well understood effect on CQA’s Reality: Mixing effects are complex and not always easy to understand Other considerations:

• CMO Vessel availability • Equipment variation across manufacturing sites

EasyMax 2 L 20 L 115 L

General rule of thumb for efficient mixing: • D/T = ~ 1/2 • C/D = ~ 1/2 • H/D > 1.5 Second impeller should be used D = Impeller diameter T = Tank diameter H= Liquid height C = off bottom clearance.

Handbook of industrial mixing, Science and Practice, E.L. Paul, V. A. Atiemo-Obeng, S. M. Kresta, Wiley, 2004

380 L

H

C

T

D


18

Scale-up: 2 L mixing study

EasyMax 2 L

20 x scale-up

Size (µm)

Vo

l (%

)

Min Mid Max

Just suspended Mid point Before

cavitation 240 rpm 360 rpm 540 rpm

Transitional Transitional Turbulent

Initial scale-up mixing study suggested mixing insensitivity for the recrystallization process


19

Scale-up: 20 L mixing study

rpm baffled D50 Yield (%) 120 no - - 250 no 103.9 82.8 250 no 106.4 80.8 210 yes 115.1 72.2 120 yes 129.4 83.0

2 L 20 L

Size (µm)

Vo

l (%

)

10 x scale-up

Build up in 20 L vessel, 120 rpm, baffled, prior to antisolvent addition


20

Scale-up: Pilot plant production

20 L 115 L

5 x scale-up

Target 100µm Target 100µm


21

Scale-up: Mixing study 2L

• 3 best trending mixing descriptors • How to inform further scale-up?

HYD RCI PBT

HYD RCI PBT

HYD

RCI

PBT

HYD

RCI

PBT


22

Scale-up: 30 kg batch

115 L 380 L

4 x scale-up

Target 100µm


23

Scale-up: 30 kg batch PSD Illustrate some data on improved processability here e.g flow function comparison

Batch 1

Batch 2

Batch 3

Batch 4

Batch 5

Batch 6


Background:


Problem Statement




Summary

24

Outline


Various options for isolation and drying during production:

− e.g. clam shell, agitated filter driers, tray drying

− Comilling identified as and addition step prior to packaging

Brief investigation on tip speed and screen size

25

Drug product considerations: De-lumping

Size (µm)

Vo

l (%

)

Size (µm)

Vo

l (%

)


Drug product: Production improvements 26

Material characterization directing drug product processability include:

PSD, Surface Area, Bulk and Tapped Density, Flow Function, Wall Friction, Permeability

Applied Normal Stress kPa

Perm

eab

ility

x 1

0^9

cm

2

Lot Se

gre

gati

on

an

d

flu

idiz

atio

n r

isk

fact

or


An addition recrystallization step added for PSD control

Utilized heat cycled for de-agglomeration to insure

production of single particles

Simplified some process steps to reduce manufacturing

risk

Mixing studies to inform best scale-up descriptor

Improved particle properties for drug product

processability

27

Summary


28

Thank-you!

Technobis Crystallization workshop · 2018-10-15 · Solution crystallization controlled via...

Documents

Transcript of Technobis Crystallization workshop · 2018-10-15 · Solution crystallization controlled via...