CASE STUDY

RISING TO THE CHALLENGE

OF BIOPHORUM’S SMALL
FLEXIBLE FILLER (SFF) URS

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COLLABORATE
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©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 1
Contents
Contents............................................................................................................................................................................................................. 2

Groninger develops next-generation filling using SFF URS................................................................................................................... 3

Introduction...................................................................................................................................................................................................... 5

The future of small flexible fillers...........................................................................................................................................................5

How the URS benefits the biopharmaceutical industry...................................................................................................................5

Key requirements of BioPhorum’s SFF URS........................................................................................................................................5

Groninger takes up the SFF URS challenge ............................................................................................................................................... 8

Groninger’s approach – overview ............................................................................................................................................................... 9

Groninger’s approach – meeting the priority elements of the SFF URS ..........................................................................................10

Groninger’s approach – seeking acceptance ..........................................................................................................................................11

Modular and mobile filling in a broader context ...................................................................................................................................12

Modular and mobile ................................................................................................................................................................................ 12

Benefits of implementing the modular and mobile vision............................................................................................................ 12

Next steps .......................................................................................................................................................................................................13

Summary ..........................................................................................................................................................................................................14

References.......................................................................................................................................................................................................15

List of tables
Table 1: Summary of approaches taken by Groninger to address the SFF URS’ requirements......................................................................................................................................................... 11

Table 2: The vision and benefits of modular and mobile technologies for filling operations.............................................................................................................................................................. 12

©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 2
Groninger develops next-generation
filling using SFF URS
This article details a seminal example of how BioPhorum
can partner with biopharmaceutical suppliers to address
the needs of the industry and facilitate positive and lasting
change. BioPhorum’s Small Flexible Filler (SFF) URS allowed
Groninger to build a line that would otherwise not exist,
defining a strategic direction for the future of liquid fill and
finish for the biopharmaceutical industry.
Within two and a half years of BioPhorum publishing the SFF URS,
Groninger, a German supplier to the industry, has developed a gloveless,
robot-based, automated filling line that aligns with the URS and relevant
current regulatory expectations.

©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 3
Authors
Thorsten Häfner Dawood Dassu
Groninger & Co. GMBH BioPhorum Fill Finish Lead
Deborah Hill Clare Simpson
Facilitator, Isolator of the Future BioPhorum Technology Roadmapping Lead

Acknowledgements
Bayer Pfizer
Joshua Durrin* Rich Urban*
Eli Lilly Roche
Justin Svec* Jason Vorhees*
Mingh Luong**
Merck & Co Inc., USA
Brian Hanlion BioPhorum
Carmen Torres Rodrquez* Scott Ewan**
Malcolm Gilmore*

*SFF URS authors ** Technical author

©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 4
Introduction

The future of small flexible fillers How the URS benefits the
In May 2018, BioPhorum’s Small Flexible biopharmaceutical industry
Fillers workstream published a user
The URS lays the foundations of the industry’s
requirement specification (URS)1, outlining the
expectations of equipment suppliers. It allows industry
biopharmaceutical industry’s needs for future
suppliers to develop appropriate technology and to focus
development of small flexible fillers.
on the areas that are important to its future direction.
The URS was developed to give direction to machine and The URS should also help vendors understand where
isolator manufacturers and vendors, and to facilitate future technology innovations are most needed.
biopharmaceutical industry transition into the world of
personalized and specialized medicines developed for
smaller patient populations. This change of direction
Key requirements of
necessitates a move away from the more traditional large- BioPhorum’s SFF URS
batch manufacturing paradigm which employs high-speed The URS outlines many requirements for small flexible
filling lines to deliver low per-unit costs, towards a more fillers across the main aspects of filling operations. Some
agile model, leveraging filling lines that can be switched elements are considered more important to industry, or
rapidly between a number of lower volume products to more urgent and these elements are listed here:
maximize utilization and capacity.
• Modular plug-and-play capability
With a view to the future of pharmaceutical
• A gloveless isolator, improving sterility
manufacturing, which is trending towards use of single-use
assurance level
technologies and components, the URS includes elements
that open the door to these more flexible approaches, • A low reject rate of <0.05 percent
while recognizing the current limitations of sensor and • 30-minute changeover time between
filling capabilities. the last acceptable filled unit to the first
Additionally, ever stricter sterility requirements drive acceptable filled unit
the need to move operators further away from the filling • Standardized, ready-to-use components
process, and to reduce the number of human interventions
• No human intervention needed inside sterile
during processing, ideally to none. The URS reflects an
areas after decontamination.
expectation that most filling operations will ultimately be
performed robotically, removing operators even further.
To meet the combined need for flexibility and reduced
operator involvement, modularity is highly likely to play
a major role in future filling operations. It’s envisaged
that today’s highly customized, single-product systems
will be replaced with simpler, modular systems that will
provide the flexibility to accommodate a given plant’s
various products and ease changeover from
one product to another.

©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 5
About BioPhorum
BioPhorum’s mission is to create
environments where the global
biopharmaceutical industry can
collaborate and accelerate its rate of
progress, for the benefit of all.
Since its inception in 2004, BioPhorum has become the open and trusted
environment where senior leaders of the biopharmaceutical industry come
together to openly share and discuss the emerging trends and challenges
facing their industry.

Growing from an end-user group in 2008, BioPhorum now comprises over

110 manufacturers and suppliers deploying their top 5,000 leaders and subject
matter experts to work in eight focused Phorums, articulating the industry’s
technology roadmap, defining the supply partner practices of the future, and
developing and adopting best practices in drug substance, fill finish, process
development and manufacturing IT. In each of these Phorums, BioPhorum
facilitators bring leaders together to create future visions, mobilize teams of
experts on the opportunities, create partnerships that enable change and
provide the quickest route to implementation, so that the industry shares, learns
and builds the best solutions together.

©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 6
About Groninger
Groninger & co. gmbh2, is a technology
leader in building aseptic filling machines
and processes for the pharmaceutical,
cosmetics and consumer healthcare
industries. Groninger pride themselves
on high levels of quality and service in
designing customized machines, backed
by over 40 years of positive customer
experiences.
Groninger seeks to go further than simply meeting the requirements of its customers
by addressing the challenges of the future through research and development to offer
innovative solutions.

Groninger consistently looks to research and development to ensure continuous

innovation in their equipment, with a range of advanced patents demonstrating their
worldwide reputation as a leader in innovation.

©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 7
Groninger takes up the SFF URS challenge
Following on rapidly from publication of
the BioPhorum SFF URS, Germany-based
technology and equipment supplier
Groninger began their own process of
delivering on the SFF URS requirements.
Groninger extracted insight from three key sources to
inform their development approach:
• BioPhorum’s SFF URS
• General market feedback

Groninger had already generated a number of ideas • Groninger’s own experience in this arena.
independently but needed industry input to answer Taking these three inputs, Groninger began to develop
questions such as What defines a small batch? and their gloveless filling concept, intended to address the
What constitutes low speed? The SFF URS provided requirements of the SFF URS, apply robotics intelligently,
clear guidance to Groninger on these vital knowledge and to meet all relevant GMP requirements.
gaps and allowed them to move forward with their
filler developments. Groninger were keen to meet
the requirements of the URS, not only because it
meets industry needs, but also because it helps filler
developers. Most filler design is fulfilled through
bespoke orders. This approach does not lend itself to
short lead times or standardization of components,
etc. Aligning with industry needs – as detailed in the
URS – not only gives industry what it needs, but also
provides technology vendors with confidence that
a more standardized (and less bespoke) approach
would continue to add value through, for example,
faster implementation, reduced inventory, and faster
response times.

©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 8
Groninger’s approach – overview
The initial development focused on the
aspects of the URS where Groninger felt
they could make an immediate impact.
Groninger’s initial development focus
broadly matches the areas that BioPhorum’s
SFF subject matter experts highlighted as
important or urgent elements:
1. Integrated and automated 100% in process control
(IPC) for fill weight required, with feedback control
2. Minimal product loss during filling operation – the
target reject rate is 0.05%
3. Capability to fill multiple formats
(e.g. vials 2–50R, syringes 0.5–10ml, cartridges and
capsules up to 10ml) with quick or no changeover
time
4. Users must be able to operate the isolator/filler
without gloves, i.e. the filler/isolator should be
gloveless
5. Technology must be capable of handling toxic and
non-toxic materials
6. Automated environmental control and monitoring
(both viable and non-viable).
©BioPhorum Operations Group Ltd | September 2021
Essentially, as Groninger sees it, industry wants a filler
that, without human intervention, will automatically:
• Load materials and components
• Fill product into primary containers
• Monitor 100% of the fill including a complete
track and trace system for each container
• Close the filled container
• Allow rapid change over from one product to the
next, irrespective of format.
Groninger created the robotic filler project to take their
isolator line beyond gloveless robotic fill and finish. This
approach allowed Groninger to incorporate 90% of SFF
URS elements into a commercially-available filling line
within two and a half years.
Robotics has long been a trend in the biopharmaceutical
industry, although often without a clear direction or
specific purpose. Leveraging robotics as a general industry
trend, and in addition to the focus provided by the URS,
Groninger have been able to apply robotics to the need for
a gloveless (and ideally, operator-free) filling operation.
Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 9
Groninger’s approach – meeting the
priority elements of the SFF URS
Groninger tackled each of the priority areas
they identified (see Table 1) with a highly
modular approach. Solutions to challenges
were developed in a rational and connected
manner which allowed each to be developed
individually, but with the capacity to be
brought together as a collated series of
unit operations, ultimately forming an
interconnected automated filling line.
1. Integrated and automated 100% in process
control (IPC) for fill weight required, with
feedback control
2. Minimal product loss during filling operation –
the target reject rate is 0.05%
Groninger addressed these elements of the URS
through the development of their SmartFill system.
This system fills the product into its primary
container, managing priming, re-dosing and with a
continuous feedback to the pump to ensure even
and accurate filling. The intelligent and smart use of
robotics avoids air turbulence above open containers
with a best-in-class first air approach. A ‘run empty’
mode allows for the last few containers of product to
be filled efficiently, minimising product loss.
©BioPhorum Operations Group Ltd | September 2021
3. Capability to fill multiple formats (e.g.
vials 2–50R, syringes 0.5–10ml, cartridges
and capsules up to 10ml) with quick or no
changeover time
This requirement is managed, among other things, by
application of format-part-free sorting and automated
setup of indirect product-contact parts. Traditional
changeover requires many parts. Groninger’s next-
generation line uses robotic-based sorting for all
movements. Again, all movement is below the open
container to avoid contamination. Robotic sorting
represents a great improvement in eliminating airborne
contamination and addresses many concerns around the
cleaning, sterilizing and installation of sorting systems. The
robotic line is not limited with respect to batch sizes as
the entire process is designed for a continuous infeed and
outfeed of packaging material, product and waste material.
4. Users must be able to operate the
isolator/filler without gloves, i.e. the
filler/isolator should be gloveless
Groninger have moved from the current ‘state-of the
art’ filling setup, to remove gloves (and humans) from the
process in their next-generation paradigm. Robots manage
the processes traditionally executed by humans in line
setup and operation, e.g. settle plate handling and line
setup for different products and containers.
Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 10
5. Technology must be capable of handling toxic
and non-toxic materials
Groninger meet this specific need via the modular
nature of their filler. Through use of different isolator
modules which create distinct zones within the filler
and adding vacuum-free handling and automated
cleaning technologies, the line can rapidly switch
between different product types (this also meets the
requirements of the Annex 13 revision draft).
6. Automated environmental control and
monitoring (both viable and non-viable)
Groninger addressed this specific requirement by looking
at where operator activity could be removed. Infeed
and handling of settle plates is managed by robots, with
all moving parts below the plate to minimise the risk
of contamination, eliminating human intervention. In
addition to facilitating human-free traditional monitoring
methods, this approach allows for easy integration of rapid
micro-method tools via the filling line’s modular set up.
This flexibility ties in with the recent draft of the revision
to the EMA’s Annex 1. The regulatory position on settle
plates remains unchanged and these remain even in next-
generation isolators. Introduction of settle plates via an
RTP port is managed by code/camera to allow tracking.

Table 1: Summary of approaches taken by Groninger to address the SFF URS’ requirements

# Design/development element How addressed

1 Integrated and automated 100% in process control (IPC) for fill weight required, with Addressed with SmartFill
feedback control

2 Minimal product loss during filling operation – the reject rate target is 0.05%

3 Capability to fill multiple formats (e.g. vials 2–50R, syringes 0.5–10ml, cartridges and Format-part-free sorting
capsules up to 10ml) with quick or no changeover time Automated set up
Indirect product-contact parts

4 Users must be able to operate the isolator/filler without gloves, i.e. the filler/isolator Automated settle plate handling
should be gloveless. Automated install of contact parts
Automated setup of filling equipment
Move to next generation, robotic filling path

5 Technology must be capable of handling toxic and non-toxic materials Different isolator modules
Vacuum-free handling
Automated cleaning

6 Automated environmental control and monitoring (both viable and non-viable) Infeed and handling

©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 11
Groninger’s approach – seeking acceptance
A frequent question is Who has one of Groninger have been able to secure a first order for
these? and there is a common lack of desire the new filling line from a regional CDMO customer in
to be first. The pharmaceutical industry is Germany. By partnering with this relatively small customer
conversative in nature and often slow to early in the process to develop the new line, Groninger
change. Part of this comes from regulatory has been able to work with the customer with more open
requirements and filings. It can be difficult communication than is common with larger, multinational
to demonstrate that new technology is customers, enabling rapid feedback and exchange of ideas.
equivalent to, or better than, existing
technology, especially if your company is the
first to adopt a new practice or technology.

Modular and mobile filling

in a broader context
Modular and mobile
The concept of modular and mobile filling The TRM Phorum’s 2017 publication of Part 5 of
was first introduced to BioPhorum’s Small and their overarching Biomanufacturing Technology
Flexible Filler community through BioPhorum’s Roadmap – Biomanufacturing technology roadmap:
highly strategic Technology Roadmapping 5. Modular and mobile4 highlights how modular
(TRM) Phorum. and mobile technologies fit in to the vision of the
biopharmaceutical industry. See Table 2.

Table 2: The vision and benefits of modular and mobile technologies for filling operations

Enabling technologies and capabilities Vision Benefit

Modular and mobile Manufacturing systems that are quick to configure, assemble, • Rapid tailoring of capacity to meet demand
scale and relocate, using plug-and-play standard designs and • Manufacturing process available in weeks
standard validation approaches • Mobility of facilities throughout lifecycle
• Reduction in capital expenditure

©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 12
Benefits of implementing the
modular and mobile vision
As discussed by the TRM Phorum, mobile and
modular filling includes several benefits that
could be realised through adoption of such an
approach. These benefits were first discussed
by a new workstream within BioPhorum’s Fill
Finish community, focussed on small flexible
fillers, and ultimately led to the development
of the SFF URS.
The benefits are summarised below:
Flexibility aligned with emerging product
classes and smaller patient populations
As an unprecedented number of biologics make it past
Phase I, and target small patient scales, to manufacture
such a wide portfolio of drugs, the only viable solution
would be a small-scale, rapidly deployable, modular and
mobile approach.
Payer pressure to reduce cost
Application of mobile and modular concepts in
streamlining and managing costs is going to be crucial, as
traditional ways of manufacturing and economies of scale
in the cost of goods per product do not apply in supplying
small dosages.
Next steps
In development of their robotic filler,
Groninger has understandably made
assumptions to allow them to move forward
with such pace. Industry customers will
always have specific requirements or
preferences to meet the specific needs of
the company or its products. company and
product factors will necessitate further
development and refinement to continually
work towards creating the ‘perfect’ filler.
©BioPhorum Operations Group Ltd | September 2021
Regional manufacturing
Modular and mobile concepts may assist
with regional access by enabling rapid,
cost-effective delivery of standard, modular
facilities to local regions (in-country/for
country).
Speed to clinic and fast to market
Moving from bespoke to standardized, off-
the-shelf solutions will reduce both the cost
and completion time of ready-to-use biologics
facilities.
‘Repurposability’
Modular and mobile cleanroom systems are not
designed and constructed as product-dedicated
systems but can be utilized for multiple product
lifecycles or processes.
Scalability
Independent modular and mobile cleanroom units
would be scaled without interruption of existing
processing space.
This opens the door to industry and technology
developers and vendors maintaining open,
transparent dialogue to ensure that the most
important and relevant elements of filler
design and function are being developed.
Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 13
Summary
Groninger started work on their next-generation, automated
filling line within months of BioPhorum publishing its URS
for small flexible filler technology5. Within two and a half
years they had successfully developed a commercially viable
automated filling line, utilizing robot handling to minimize
human interventions and with a modular design to maximize
flexibility and allow filling of multiple product formats and
toxicities. In addition to meeting the requirements laid out
in the URS, Groninger have ensured their new filler also
complies with relevant current regulatory expectations.
This rapid development in response to an industry-aligned URS
exemplifies how BioPhorum’s teams of subject matter experts can
spark the industry’s supplier community into direct and specific action
to address industry needs of and facilitate positive and lasting change.
Groninger’s new automated filling line would not exist (certainly in its
current form) without the BioPhorum SFF URS.
As BioPhorum continues to generate industry-aligned URS documents
across a range of topics within the fill finish space, and more broadly
across the biopharmaceutical industry, this article highlights just a
fraction of the potential that exists for future technology developments
and holds great promise for the future direction of biopharmaceutical
medicine manufacture and supply.

©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 14
References
1 URS for small flexible filler technology https://www.biophorum.com/download/user-specific-
requirements-for-small-flexible-fillers/
2 Groninger & co. gmbh https://www.groninger.de/en/
3 EU GMP Annex 1: Manufacture of Sterile Medicinal Products
4 Biomanufacturing technology roadmap: 5. Modular and mobile https://www.biophorum.com/download/
modular-mobile/
5 URS for small flexible filler technology https://www.biophorum.com/download/user-specific-
requirements-for-small-flexible-fillers/

©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 15
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The contents of this report may be used unaltered as
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with correct source citation, as follows ‘Entity,
Author(s), Editor, Title, Location: Year’

https://doi.org/10.46220/2021FF005

Disclaimer
This document represents a consensus view, and as
such it does not represent fully the internal policies of
the contributing companies.

Neither BioPhorum nor any of the contributing

companies accept any liability to any person arising
from their use of this document.

The views and opinions contained herein are that of

the individual authors and should not be attributed to
the authors’ employers.

©BioPhorum Operations Group Ltd | September 2021 Rising to the challenge of BioPhorum’s small flexible filler (SFF) URS 16