Stainless steel or plastic? The Rentschler decision …download.knect365lifesciences.com/Slides/2017/B17155/Frank... · Jeff Johnson, Merck & Co, Bioprocessing Summit 2015 NPC recognizes

Stainless steel or plastic?

The Rentschler

decision process

BPI West, March 1, 2017

Content

February/March 2017BPI West, San Francisco 2

1 Introduction

3 Scale

4 Safety

2 Cost

5 Outlook

● Laupheim in the South of Germany

● Frankfurt Airport – 2.5 h

● Munich Airport – 2 h

● Stuttgart Airport – 1 h

Location of the Company Rentschler


Laupheim

Full-Service Concept of Rentschler


Biomanufacturing

● Upstream

● Downstream

● Fill & Finish

● Quality Control

Bioprocess

Development

● Cell Lines

● Processes

● Analytical

Methods

● Formulations

Consulting

Services

● Consulting and

Planning

● Project

Management

● Regulatory

Support

● Pioneer in mid scale single-use manufacturing

● More than 100 batches in fed-batch and perfusion mode

● Majority of the products in phase I/II and some in phase III in single-use bioreactors

Outstanding Single-use Experience


Planned expansion

2010 2011 2013 2014 2015 2016

1 000 L XcellerexTM

bioreactor

2 000 L XcellerexTM

bioreactor2nd 2 000 L XcellerexTM

bioreactor

2012

1st ÄKTATM ready system Single-use tangential flow filtration Single-use virus filtration

2017

1 000 L HyCloneTM

bioreactor

OPUS® 45 cm pre-packed columns

2nd ÄKTATM

ready system

ReadyToProcess 20 cm columns

Upstream

Downstream

Utilization of Single-use equipment


0 % Hybrid 100 % [DSP]

[USP]100 %

Hybrid

0 %

Single-use

Technology

Stainless

Steel

R&D, clinical

production

Small scale

Production

< 2,000 L

Large scale

production,

Dedicated facility

Is this really true?

Shire 4× 2000 L

Single-use bioreactor

facility for

Gaucher’s disease

drug VIPRV

Fully Disposable Process


USP

DSP

Filtration

Chromato-

graphy

Shukla, TIBT, 2013

Bags

Parameter SU SS Comments

Energy ++ -- Less steam, less heating, ventilation, and air conditioning

Labour +/- +/- No clean in place (CIP), no sterilize in place (SIP) but a lot of

manual activities for preparation of manifolds (less automation)

Material + - Less CIP media, fewer spare parts

Consumables - + Higher cost for single-use material

Maintenance ++ - Less complex equipment, lower effort for preventive maintenance

Turnover time + - Much faster, no CIP/SIP of unit operation systems

Supply chain -- + Some items with long lead time, higher dependency on certain

suppliers

Quality + + Extractables and leachables to be addressed, lower risk of cross

contamination

Success rate + + Applicability of SU 98 %, 1-2 % failure rate (mostly due to leaks)

Risk of microbial

contamination

+ - Closed systems are much easier to generate (e.g. weldings of

tubings)

Comparison: Single Use vs. Stainless Steel


Benefits and Limits of Disposables (CDMO Perspective)


QualitySupplier qualification

Flexibility

Transportation risk

Standardization

Scale limitation

Customization

Supplier dependency

SafetyLeachables & extractables

Lower cross contamination

Fully closed process

Particulates

Sterilization

Leakage

Waste management

Cost

Lower investment

Smaller footprint

Reduced complexity

Lower maintenance

Storage space

Repetitive consumables

Supplier monopolyInventory

Time

Faster installation

Faster changeoverDelivery lead times

Shelf liveLogistics

Faster time to market

Schmidt, Am Pharm Rev, 2016

Content


1 Introduction

3 Scale

4 Safety

2 Cost

5 Outlook

Cost of Goods (COGs)


Capital

● Process equipment

● Buildings

● Utilities

Labour

● Process

● Indirect

● Quality (QC/QA/RA)

Other

● Waste management

● Utilities

● Insurance

● Maintenance

Materials/consumables

● CIP/SIP media

● Buffers, Water

● Raw materials

● Resins

● Filters

● Tubing/manifolds/connectors

● Bags

COGS Comparison – 2,000 L SU vs. 3,000 L SS for 100 kg/yr


● 2,000-L SU: 36 batches; 3,000 L SS: 24 batches

● Assumptions: titer 2 g/L, yield 70 %, fed batch

● Overall COGS difference (+20 % for 2,000 L variant)

Process Economics – Single-use Virus Filtration (15 b/yr)


Details:

● 98 % less water usage (m3/batch)

● 85 % more plastic waste (kg/batch) appr. 15 kg

● Quattroflow pump

(disposable pump head)

● Up to 4 m² filters

Comparison of Facility Types Based on Net Present Cost (NPC)


Jeff Johnson, Merck & Co, Bioprocessing Summit 2015

NPC recognizes total

cost associated with

facility (construction,

capital, operating costs)

Additional

facility

Content


1 Introduction

3 Scale

4 Safety

2 Cost

5 Outlook

Step Max. Limit Cause

USP

Reactor volume 2,000 L

(3500 L ABEC

Nov 2015)

Pressure stability of polymer material

Low power input through stirrers

Low O2 / heat transfer rates

Cell retention 1,000 L Size of hollow fiber (ATF10)

Centrifuge 1,000 L Comparatively high investment costs

Low flow rates / g-forces

DSP

Chromatography

column

60 cm (56 L)

diameter

(2,000 L)

Stability of material

Ease of packing

Chromatography

systems

510 L/h

(1,000 L)

Tubing and pump

Scale Limits of Single-use Equipment


● Dynamic Body Feed Filtration

● Single-use centrifuges

o Unifuge – Pneumatic Scale Angelus (up to 4000 g / 240 L/h)

o kSep-Systems (up to 2000 g / 720 L/h)

o Comparatively high investment costs

o Low flow rates/g-forces

Cell Removal/Retention with Single-use Systems

February/March 2017BPI West, San Francisco 17Pictures are courtesy of PSA and kSep Systems

Single-use Chromatography


Classical packed column

● Scale limitation (60 cm dia)

● Resin selection

Monolithic column

● Ideal for large molecules

● High flowrate

● High resolution

● Fixed bedheight

● Scale limitation 128 L CV

3D macroporous hydrogel

● High capacity

● High flowrate

● High salt tolerance

● Scale limitation (0.5 L)

● Only AIEX (and CIEX)

Charged membrane

● High flowrate

● IEX and HIC

● Ideal for FT mode

● Scale limitation 5 L

Single-use Pumps and Chromatography Systems


ÄKTA Ready HF

510 L/h

Mobius FlexReady

480 L/h

QuattroFlow qf5050su

5000 L/h

Content


1 Introduction

3 Scale

4 Safety

2 Cost

5 Outlook

Safety/Risk Assessments


Single-useTechnologies

Extractables:

● Compounds that originate from a

component (or a system) in solution

after exposure of the material at

conditions that are more extreme

than typical operation conditions

o Temperature

o pH

o Polarity

o Time

o Contact surface

Leachables:

● Compounds that originate from a

component (or a system) in solution

under typical operation (or storage)

conditions

● Expected to be a subset of

extractables


Issues with Disposables: L&E

Extractables

Leachables

Summary on Overall Risk Assessment


Leachables & Extractables - Modules of Process Specific RA


Module 1

Overall risk assessment,

identification of relevant materials

Module 2 *

Module 1 + Manufacturer documentation

Module 3A *

Module 2 + Material-specific risk assessment

Qualitative evaluation of extractables data

(data representative/worst case)

Module 3B *

Material-specific risk assessment, Module 3 A +

Quantitative evaluation of extractables data

Module 4

Support of extractables / leachables studies (e.g. supply materials, support study design)

Incre

asin

g c

osts

and e

ffort

* May require a 3-way Confidentiality Agreement

0

1

2

3

4

5

6

Jan 15 Feb 15 March15

Apr 15 Mai 15 Jun 15 July 15 Aug 15 Sep 15 Okt 15 Nov 15 Dec 15 Jan 16 Feb 16 Mar 16 Apr 16 May 16

Reje

cte

d q

ty

Timeline

Timeline Complaints Bioreactor Bags in total

Quality Issues with Disposables – Bioreactor Bags


● Separation of film layers

● Incomplete welding seams

● Punctures, holes

● From September 15 until May 16, 14 % of reactor bags were faulty!

● Current failure rate <1 %

Quality Issues with Disposables – Bioreactor Bags


● Current polypropylene used in gas

filters housings is somewhat prone to

cracking during handling (<1.0 %).

● An alternative polypropylene

formulation is now available from

Meissner that mitigates this issue.

Change will be implemented through

CCN.

● Question whether this spacing is

within specification

● No failures related to the sparge line

check valve have been reported to

date (supplier information)


Quality Issues with Disposables

Experienced and mindful operators combined

with a comprehensive documentation.

Check Valve Specification

Quality Issues with Disposables


● Packaging changes● Chemical

compatibility

● Mechanical stability

Content


1 Introduction

3 Scale

4 Safety

2 Cost

5 Outlook

● Verification of feasibility (Technical, economical)

● Assessment of risks (Product, process)

● Future strategies (Implementation, process and logistics continuity)

Decision Tree


● To date, the decision-making on whether and when to use single-use (SU)

devices or stainless steel (SS) equipment for biopharmaceutical manufacturing is

ambiguous.

● None of the arguments in terms of safety, cost-effectiveness, or operational

efficiency is fully convincing to choose one technology platform or the other.

● The service provider business model particularly forces CDMOs to look for more

flexible production capacity, fast campaign change-overs and rapid

production at varying scales.

● These demands are nicely fulfilled by single-use equipment which made CDMOs

the early adopter of that technology.

Conclusion


● Rogge, Pharma Bio World, 2012

● Shukla, TIBT, 2013

● van der Meer, BioProcess Int, 2014

● Martin, BioProcess Int, 2014

● Rios, BioProcess Int, 2014

● Ding, Pharm Eng, 2014

● Rogge, BioProcess Int, 2015

● Schmidt, Am Pharm Rev, 2016

References


Tel.:

Fax:

www.rentschler.de

Rentschler Biotechnologie GmbH

Erwin-Rentschler-Str. 21

88471 Laupheim

Germany

Rentschler Inc.

400 Oser Ave., Suite 1850

Hauppauge, NY 11788

USA

Contact

Dr. Frank Gießelmann, Director USP

Production

0049739270179400497392701300

[email protected]


Documents

Stainless steel or plastic? The Rentschler decision …download.knect365lifesciences.com/Slides/2017/B17155/Frank... · Jeff Johnson, Merck & Co, Bioprocessing Summit 2015 NPC recognizes