Single-Use Technologies: Accelerating Bioprocess Design · 2019. 11. 5. · 4 BioProcess International September 2019September 2019 Sponsored W ith worldwide sales of biologics reaching

In association with

Single-Use Technologies:

Accelerating Bioprocess DesignKey Insights from the Experts

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Sponsored

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .3

AUTOMATIONSmart Modular Package Units for Single-Use Processing: Addressing Cost, Speed, and Flexibility Challenges in Biologics Manufacturing . . . . . . . . . . . . . . . . . . . . . . . . . . 4Burkhard Joksch and Stuart Tindal

PARTICLE CONTROL

. 12 Visible Particulate Matter in Single-Use Bags: From Measurement to Prevention . . . . . . . .Klaus Wormuth, Melanie Gauthier, Mathieu Labedan, Veronique Cantin, Fanny Gaston, Manon Thaust, Nelly Montenay, and Magali Barbaroux

INTEGRITY TESTINGIntegrity Redefined: Consistent Robustness and Integrity Testing Lead to Enhanced Process Integrity and Patient Safety . . . . . . . 17 Marc Hogreve, Carole Langlois, Katell Mignot, and Jean-Marc Cappia

2 BioProcess International September 2019

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SUPPLY CHAINGoing Beyond the Simple Customer–Supplier Relationship: Ensuring a High-Quality Supply Chain Through Transparent Partnerships . . . 23 Claudio Catallo

SAFETY ASSURANCEEmbedded Particles in Single-Use Bags: Risk to Bag Integrity and Drug Product Purity, or Only a Cosmetic Defect? . . . . . . . . . . . . . . . . .Klaus Wormuth, Lucie Delaunay, Veronique Gissinger, Nelly Montenay, and Magali Barbaroux

BioProcess International

September 2019 BioProcess International 3Sponsored

T he biopharmaceutical industry is experiencing a sea change. Drug developers are delving deeper into antibody–drug conjugates (ADCs), cell and gene

therapies, and other novel drug classes. But those therapies require complex manufacturing and rigorous quality control, elevating costs for process sponsors and patients alike. Compounding the problem is an unprecedented number of markets for biopharmaceuticals, making time to market and manufacturing capacity increasingly important considerations.

Companies turn more and more to single-use technologies (SUTs) to mitigate production challenges — and with good reason. SUTs clearly decrease conventional costs while increasing process integrity. Yet as the writers in this compilation suggest, SUTs are now making possible new, exciting ways to configure, operate, and evaluate biomanufacturing. In what follows, BioProcess International gathers key insights from biopharmaceutical industry experts at Sartorius Stedim Biotech (SSB) to explore how SUTs can realize high-quality yet cost-effective end-to-end bioprocessing. The studies herein identify not only the advantages of SUTs but also the things companies need to ensure process success when adopting them.

Perhaps the most exciting development driven by SUT innovation is the redesign of the bioprocess workspace. Because time to market is increasingly crucial to commercial success, drug manufacturers are racing to decrease time spent changing over bioprocesses and building new facilities. To open this report, Burkhard Joksch and Stuart Tindal explain how SUTs are offering manufacturers much needed versatility during product changeover and facilities redesign. Joksch et al point out that SUTs now allow companies to experiment with modularized, ballroom-style facilities free of fixed equipment. Smart modular package units for integrated upstream and downstream bioprocesses are particularly promising. Modular package units supported by SUTs facilitate process changeover, and while they once required remote I/O for executing bioprocessing transitions, “smart” versions are highly integrative and enable local, “recipe-driven” executions of process steps. The increased control substantially decreases automation-related project effort, while the simplification of bioprocess executions reduces batch contamination risk.

Given the above benefits, cost-effective, end-to-end biomanufacturing becomes a real possibility. Yet articles by Klaus Wormuth and Melanie Gauthier et al. and Marc Hogreve et al. remind us that the industry needs to investigate those technologies’ impacts on drug product quality. Indeed, critical gaps in process integrity remain because SUTs make it difficult to control interactions between drug substance and raw materials. Wormuth and Gautier et al. call for increased study of visible particulate

matter in single-use bioprocess bags. Although the US Pharmacopeia (USP) compels measurement of subvisible particulates in final drug products, it neglects particulate matter in SUTs. What companies need is a standardized evaluation approach. To emphasize the need, the writers use membrane microscopy to test particle cleanliness in commercial single-use bags. They conclude that the “generation of intrinsic particles could require changes in cleaning and maintenance procedures for single-use system manufacturing process machinery — or in more extreme cases, replacement of existing production systems with cleaner alternatives.”

Hogreve et al. highlight a similar regulatory gap. The use of SUTs at critical bioprocess steps magnifies the importance of integrity assurance. Yet USP updates still emphasize drug product packaging rather than production assemblies. Thus, there is great need for container–closure integrity study of SUTs — not only welds and hose-barb connections but bioprocess bags, which may bear pin-hole defects. To launch future inquiries, Hogreve et al. present the results of a failure mode analysis of SSB’s single-use containers. Based on those findings, the writers unveil a theoretical model that predicts a SUT’s maximum allowable leakage limit (MALL).

Next, Claudio Catallo explains how implementation of SUTs could improve supply chains as much as bioprocessing itself. Catallo reveals SSB’s strategies for global supply chain management, detailing how its larger executive bodies coordinate local suppliers and manufacturers. The system effectively distributes materials, processes, and products across regions with different needs and capabilities. In turn, SSB can anticipate future demand, ensure effective product recall, and ship continuous supplies of drugs to patients who need them.

In this report’s final piece, Wormuth and Lucie Delaunay et al. quantify risks to film integrity and product purity. They applied a unique pressure burst test to single-use films with varying sizes of embedded gel particles. They describe a worst-case scenario regarding leachable chemicals from embedded particles, noting that even under the extreme stresses tested, the risk from embedded particles in SUT films to bag integrity and drug product purity is likely very low.

Despite regulatory challenges and potential gaps in process integrity, the writers in this report remain optimistic about SUTs, particularly as the industry works toward standardizing bioprocesses across regions with different capabilities. Together, these articles yield invaluable perspective on ways that SUTs will help biomanufacturers navigate new scientific and economic terrain. c

INTRODUCTION

Navigating the Era of Single-Use Systems in Biomanufacturing

Brian Gazaille, BPI Associate Editor

4 BioProcess International September 2019 Sponsored

W ith worldwide sales of biologics reaching over $250 billion in 2017 and the market continuing to grow

at a rate of 9.5 % per year (1), biopharmaceutical companies continue to view developing and producing biologics as an attractive proposition. However, the portfolio of biologics is changing. Now many different types of biologics are emerging (e.g., antibody–drug conjugates and cell and gene therapies) with complex manufacturing requirements. And the global market is becoming more competitive as developing countries seek to access and manufacture affordable biologics and biosimilars.

A McKinsey report states that the average costs of drug development (including the cost of product failure in trials) have almost doubled since 2010 from $1.18 billion to $2.18 billion in 2018, whereas forecast sales have fallen from $816 million in 2010 to $407

million in 2018 (2). To remain competitive in this rapidly changing healthcare landscape, biopharmaceutical companies are continually looking at strategies to reduce their costs. One approach is to increase the flexibility of their biologics’ production and improve speed to market, for which facility build times are critical.

The BioPhorum Operations Group (BPOG), a cross-industry organization of biopharmaceutical end users and suppliers, has stated that to respond to these business drivers, the biopharmaceutical industry should aim for a 90% reduction in capital expenditure (CAPEX) and manufacturing costs in the next decade. The industry also should drastically reduce product changeover

times by 90% to improve responses to variability in demand and new biologics classes as well as drive down new facility build times by 70% (3).

Modularization for Flexible ManufacturingPart of the strategy for achieving these ambitious step changes is to improve process productivity and make more efficient use of manufacturing facilities. Traditionally, biologics have been manufactured primarily in stainless-steel based production plants that have a CAPEX of $200 to $500 million to construct (4). These types of facilities have a risk of cross-contamination between batches and require considerable time and resources for steam-in-place (SIP), clean-in-place (CIP), and SIP/CIP

SUPPLIER SIDE

Smart Modular Package Units for Single-Use Processing Addressing Cost, Speed, and Flexibility Challenges in Biologics ManufacturingBurkhard Joksch and Stuart Tindal

PRODUCT FOCUS: All biopharmaceuticals

PROCESS FOCUS: Manufacturing

WHO SHOULD READ: Process development, manufacturing, analytical

KEYWORDS: Disposables, automation, flexibility, modularization

LEVEL: Intermediate/High









SUPPLIER SIDE















SUPPLIER SIDE















SUPPLIER SIDE








validation, resulting in high operating expenditures (OPEX). Additionally, stainless steel facilities are dedicated to production of specific biologics, so automation programs are fixed and inflexible in their applications.

This has led to a move away from stainless-steel to an increased application of single-use (SU) technology. By 2009, SU unit operations began to be adopted in biopharmaceutical facilities, leading to the use of more modularization in manufacturing plants (5). SU unit operations have been developed for complex bioprocess steps including media preparation, cell culture, cell clarification/removal, cross/tangential flow, and virus filtration. The use of closed systems in such operations offers greater flexibility and the basis for building more ballroom-style manufacturing facilities with large areas that have no fixed equipment and minimal room separation due.

The advantages of using this type of modular facility compared with a traditional design for monoclonal antibody (MAb) production at 2,000-L scale were reported to be 42% more batch runs per year (6) as well as a reduction in manufacturing footprint of 45% and CAPEX reduction of 67% (5). This provides a 23% (6) and 32% reduction in the cost of goods (CoGs) (5).

The rise of SU technology has meant that clinical manufacturing as an end-to-end SU process is becoming a possibility (7, 8). Many major biopharmaceutical companies such as Amgen (9, 10) and WuXi (11) are moving toward this concept and have set up plants in Singapore and China using multiple 1,000-L and 2,000-L single-use production bioreactors to run perfusion and fed-batch cell culture in

a scale-out model to produce biologics at scale. According to Amgen, using SU technology has meant that its Singapore plant was constructed and operational in 15 months, and WuXi’s new facility was ready for current good manufacturing practices (CGMP) manufacturing in two years — both a significantly shorter time frame than the four to five years it takes for a predominantly stainless-steel based plant to begin operation. Also, Amgen states that the Singapore plant can deliver the same quantity of biological

products as a traditional facility with a 75% larger footprint (9).

Automation Is Key SU flexible manufacturing is increasingly becoming a popular choice in biopharmaceutical companies because the benefits of modularization and flexibility, as well as (local) automation in the modular package unit, align with this concept. In early days, modular package units were not controlled by any local automation; thus, sensors and actuators had to be

Table 1: Modular package units compared to remote I/O for process integration

Level Advantages Disadvantages

Smart modular package units (entry points 1 and 2 from Figure 2)

Stand-alone capabilitiesPrequalified and pretestedFast implementation and reduced build-up timesFlexibility to change process, move equipment, and use process skidsFewer expensive, skilled bioprocess personne are required to run processesEasy process capacity extension

Requires biopharmaceutical company/CDMO to outsource automation integration to an equipment supplierNeeds equipment and SU supplier with industrial automation integration expertise and capabilities

Remote I/O (entry point 3 from Figure 2)

Standardizes and reduces wiring Increases data availabilityAllows remote configuration and monitoring

No local controllerCannot be used as stand-alone system;Increases engineering effort and testing at the DCS levelRequires continuous in-house industrial automation IT expertise (expensive and highly-sought after personnel) for maintenance and lifecycle improvementsRequires skilled bioprocess personnel to connect and run unit operations

Figure 1: Scope definition of a smart modular package unit in an automation pyramid

Local HMI

Controller Level: PLC

Field Level: Actuators and Sensors

Enterprise Resource Planning: ERP

Plant Management: MES

Process Management: SCADA, DCS

Scopeof smart modular

package unit

The rise of SU technology has meant that clinical manufacturing as an END‑TO‑END SU process is becoming a possibility.


connected to a distributed control system (DCS) by simple hard-wiring.

Automation for biologics manufacturing operates on a number of levels, whereas a modular package unit has a defined scope and has to integrate properly into the process management level and above (Figure 1).

Digital integration of a modular package unit can be performed with different types of interfaces and levels (Figure 2). The Instrument Society of America (ISA) has published ANSI/ISA-88 guidelines for batch control (12). These are industrial engineering standards and recipe definitions, which if implemented by biopharmaceutical companies and equipment suppliers, could ensure seamless integration of automation for SU technology at the

process management level into supervisory control and data acquisition (SCADA) or DCS landscapes.

Flexible Integration: Traditionally, SU technology has been integrated into SCADA or DCS platforms through remote input/output (I/O), thus skipping the control level and the local human machine interface (HMI) (Figure 1, entry point 3). Installation of standardized industrial automation platforms into smart modular package units provides a more flexible method for integration. The first implementation of the Sartorius Stedim Biotech (SSB) automation platform is with the FlexAct® system, which controls specific upstream and downstream unit operations, followed by more SSB units in a series of bioprocessing systems,

where SSB’s bioreactor BIOSTAT® STR, is the second. This allows recipe-driven connectivity to a range of bioprocess unit operation skids and SU components (Figure 2, entry point 1 and 2).

Table 1 details advantages and disadvantages of using a smart modular package unit instead of a remote I/O. Execution of process or control phases from an upper recipe system (by contrast with integration of remote I/O), will reduce the automation-related project effort for installing an upstream/downstream bioprocessing facility by 50–75% (13, 14) because some activities are substantially reduced during the integration. One reason is that a smart modular package unit comes with prequalified and pretested functionalities (Table 2).

A further benefit of this approach is a simple process capacity extension by scaling out. If floor space has been reserved for additional modular package units, they can quickly and easily be connected into an existing automation landscape.

User Guidance Reduces Human Errors: Another benefit of integrating smart modular package units is that they can help overcome manual set-up and running issues. Historically, with the introduction of SU technology, operators were put in charge of process steps for which (e.g.) they had to ensure that a filter did not block or bags and tubing did not leak. The availability of technologies such as SU sensors has enabled creation of control loops to circumvent process deviation and, ultimately, batch losses. However, there remain many manual tasks for operators to perform including setting up SU components as

Figure 2: Overview of entry points for integration of SU smart modular package units into the process management level

Incr

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Ski

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inte

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nce

Entry Point 1“Recipe Level”

Entry Point 2“Sequence Level”

Entry Point 3“Remote I/O”

Specific Recipe for Unit

Functions(Controls and Sequences)

I/Os

Smar

t mod

ular

pac

kage

uni

t

Table 2: A head-to-head comparison of project activities for remote I/O versus modular integration

Activity Remote I/O Modular Integration

Functional Specification • •

Software Design Specification •

Hardware Design Specification •

Module Design and Configuration Specifications (CM/EM/EPH) •

Construction, Coding, and Configuration • •

Module Design and Configuration Specifications (CM/EM/EPH) •

Software Integration Testing • •

Hardware Integration Testing • •

Factory-Acceptance Testing • •

Site-Acceptance Testing • •

Installation of standardized industrial automation platforms into smart modular package units provides a more FLEXIBLE method for integration.


well as calibration and recalibration of sensors before, during, and after a process run. If these tasks are put directly into the smart modular package unit and are guided, a supplier can transfer important process knowledge to an operator through recipe phases that will help to significantly reduce human error during set-up and process runs.

Faster Process Changeover: In multiproduct biopharmaceutical facilities, changeover time between products is an important key performance indicator (KPI). SU technologies enhance performance because they reduce changeover time by eliminating CIP and SIP activities. A flexible automation platform will orchestrate the automation, including activation/deactivation of controls, process sequences, and user guidance and finally adapt the HMI for the operator. This is based on the process setup such as the choice of hardware being used (for example, holders, tanks, and pumps) and wetware (SU consumables). This enables a rapid changeover by permitting use of a flexible, smart modular package unit and ensures process safety. Taking this principle further, a smart modular package unit can host several different process steps that are quick and easy to switch between, shown using the FlexAct modules as an example in this article.

Smart Modular Package UnitsNow in its second generation, SSB’s FlexAct is an example of the first in a series of SSB modular bioprocess package units to incorporate an industrial standard automation platform. The unit can be configured for maximum flexibility to control six different upstream and downstream operations using process skids for buffer and media preparation, cell clarification, crossflow filtration, virus inactivation, and virus filtration at processing volumes ranging from 15 L to 2,000 L (Figure 3).

Because the FlexAct can perform multiple unit operations at a range of scales, it does not require as much cleanroom space as a unit that

performs only a single operation. For example, three FlexAct units running two different unit operations will require approximately half the manufacturing space required by six modular package units running a single unit operation. This scenario not only has the potential to reduce cleanroom footprint, but also cleanroom testing and validation costs. The use of SU technology in a typical MAb manufacturing set-up is reported to require approximately 15% fewer manufacturing staff for drug substance production and 12% fewer QA/QC staff, resulting in an estimated 13% lower total headcount than a stainless-steel facility (15). Therefore, reducing the cleanroom footprint even

further could result in less heating, ventilation, air conditioning (HVAC), and CIP/SIP utilities, as well as lower QA/QC testing and staff costs.

Simplifying the ProcessDigitalization Ready: Incorporating an industrial standard automation platform, as described above, that interfaces with DCSs such as Emerson's Delta-V, Rockwell's Allen Bradley products, and Siemens’ SIMATIC PCS7 into the FlexAct, enables direct automation of and communication with different components, including sensor, actuators, pumps, filters, tubing, and connectors. This allows FlexAct to facilitate use of process analytical

Figure 3: Flexible multipurpose modular package unit for diverse bioprocess unit operations

Virus Removal

Virus Inactivation

Bu er Preparation

Cell Clarification

Media Preparation

Crossflow Filtration

Figure 4: Example process flow diagram showing the application of FlexAct units in an end-to-end CGMP manufacturing process

Upstream Process Harvest Previral Purification

Previral Purification Postviral Purification and Bulk Filtration

Bu�er Prep. Media Prep.

BIOSTAT FlexAct CC Chromo FlexAct VI

Chromo ETO FlexAct PO FlexAct VR FlexAct CF ETO FlexAct MF

FlexAct BP FlexAct MP

Automation

Redefined.

The Foundations for Single-Use Manufacturing.Redefined from A – Z.

Visionary platform technologies lead to high flexibility and prevent human errors.

Benefit from our state-of-the-art automation technologies and configurable standardized solutions to experience the next step in robust production for your biologics.

www.sartorius.com/single-use-redefined

d903BPI019_removecrops.indd 1 2/13/19 10:35 AM


technologies (PAT) and enables a number of data analytics possibilities. The software is prequalified so that operators can connect their skids for SU unit operations and SU components to the FlexAct straight out of the box without having to write additional coding. The software also can be customized, if required.

Easy Set-Up: The FlexAct solution comes out of a configurator to order (CTO) design space, which guides users to identify all the hardware, software, and wetware components they need for their specific unit operation. From that delivered solution, a configurable recipe allows users to perform operations at the desired scale. All steps from wetware installation to postprocess teardown

are guided by recipe operator messages. This reduces set-up time and manual assembly errors because the modular package unit provides clear operational guidance for the correct configuration. Additionally, more than one-unit operation can be installed and overlaid in one system, enabling multifunctional/multiscale capability.

Process Efficiency: FlexAct has the capability for using new types of SU technology such as SSB’s MaxiCaps® MR SU filtration unit. This features 90% less tubing than conventional filters and only two connections, which reduces contamination risks and operational connectivity errors. The module also facilitates control of a number of sensors with a left- and

right-sided interface on the FlexAct COM (central operating module). For ensuring operational performance, a range of sensors can be integrated including BioPAT® Flow sensor, which indicates fluid transfer rate and liquid volume measurement, and BioPAT Pressure, which shows line/filter blockage or permits pressure control. The COM also facilitates process performance control with interfaces for SU sensors such as BioPAT SU conductivity and BioPAT SU pH for in-line monitoring.

Case Study As proof of concept that a modular package unit can maximize efficiency and speed of upstream and downstream unit operations for production of a biologic, FlexAct was used as part of an end-to-end single-use process (Figures 4 and 5) at a cell culture technology company to purify a commercial MAb cultured in a 500-L SU Flexsafe STR bag and BIOSTAT STR bioreactor. Details of operational set-up

Figure 5: Example process layout showing where a FlexAct unit can be used in an end-end CGMP manufacturing process

Washing mbly a Clean TBD TBD Material Entry

19 m2 19 m2 1 9 m2 23 m2 23 m2 23 m2 61 m2 Store StorageW

ashi

ng

Mac

hine

Ster

iliza

tion

Auto

clav

eMAL PAL Column Pack MAL PAL MAL Prep.8 m2 8 m2 22 m2 8 m2 8 m2 9 m2 1 3 m2

Media

LAF

FlexAct CF FlexAct VI, VR

FlexAct MP

FlexAct CC

FlexAct BP

Postviral Purification

25 m2

IPQC20 m2

LAF Bu�er Prep

15 m2

Airlock9 m2

Previral Purification110 m2

Bu�er Prep. and Distribution92 m2

Airlock15 m2

Decontamination25 m2

DeconAutoclave Waste

Staging26 m2

Media Prep. and Distribution

61 m2 Airlock8 m2

Airlock8 m2

DPB

Harvest118 m2

Cell Culture66 m2

DPB BiosafetyCabinet

Inoculation59 m2 DPB

PAL6 m2

Table 3: Time (minutes) required for SU crossflow filtration

Wetware Installation Fill Supplies

Flush/Equlibrate

First Concentration Diafiltration

Second Concentration and External

Recovery Teardown50 30 20/20 120 120 30 30


and total process times are described below for upstream and downstream unit operations because they are representative of the five different unit operations used.

Crossflow Filtration: The unit operation set-up included prefilled feed and buffer tanks, three pumps, a 1.4m2 SU self-contained Hydrosart® CF filter, and receiving waste and flush tanks. The FlexAct was also connected to load cells, in-line flow meters, and a conductivity sensor for precise first and second feed concentration with a 10× diafiltrate exchange in between. Total crossflow filtration time for 200 L of 5 g/L to 6.2 Kg (approximately 150 g/L) of recovered protein solution was eight hours (Table 3) with a total installation time and teardown time of 80 minutes. This crossflow set-up can be used at 15-L to 200-L recirculation volumes.

Buffer and Media Preparation: The unit operation set-up included a mixing skid, pump, SU Sartopore® 2 filter capsules, and receiving tank(s). For both buffer and media preparation operations, the FlexAct used a flow sensor because that is a more cost-efficient approach than using a load cell. To save time, the modular unit was connected to an automated supply magnetic mixer and a SU pH or conductivity sensor for automatic pH adjustment or homogeneous indication. This buffer and media preparation set-up can be performed at 50-L to 1,000-L scales. Total preparation time for 500 L of media and buffer was six hours and

10 mins and three hours and 40 mins, respectively (Table 4, with a wetware and teardown time of 80 minutes.

Virus Removal: The FlexAct set-up included one supply and a flushing/ equilibration skid, pump, SU Virosart HF filter capsule, and a receiving skid. Total operation time for processing 200 L was four hours and 10 minutes (Table 5) with an installation time of 60 minutes and teardown time of 20 minutes. This virus removal set-up can be used at 50-L to 1,000-L scales.

In summary, using the FlexAct enabled buffer and media preparation operations times for 500 L of between four and six hours, with set-up time of just one hour and teardown of only 20 minutes. In the crossflow filtration and virus removal unit operations at 200 L, total operational time is four to eight hours, with installation times of between 50 minutes to one hour and teardown times of 30 minutes. This is significantly shorter than the time it would take to set up these unit

Table 4: Time (minutes) required for SU 500-L buffer and media preparation performed by a single trained operator

Application Type

Wetware Installation Preflush Prefill

Powder Add

Mix and Adjust

Filter Transfer

Wetware Teardown

Buffer Preparation

60 20 30 30 30 30 20

Media Preparation

60 20 30 30 180 30 20

Table 6: Feature and benefits of the FlexAct process platform based on the smart modular package unit approach

Features Manufacturing Benefits Industry Benefits

Mobile modular, multi-application package unit

Easy to use in ballroom facilities with skids for SU unit operationCost-effective and saves space as only need one module to run six different upstream and downstream unit operations

Smaller manufacturing footprint and lower CAPEX costs with potential to reduce footprint by estimated 45-75% (5, 9) and CAPEX costs by 67% (5)

Intelligent COM design for rapid wetware installation and teardown times (1-1.5 hours average)

Flexibility to changeover scale and unit operation quickly and simply allows multi-product facility useSaves time and costs associated with SIP, CIP and validation tasks

Potential to run 42% more batches per year (6) and respond quickly to fluctuating/ changing market/product demandsRequires fewer staff could reduce headcount by around 13% (15)

Automation hardware follows industrial standards (Siemens) and interfaces with Emerson’s Delta-V, Rockwell’s Allen Bradley products, and Siemens’ SIMATIC PCS7

Easier integration of automated components and devices at the process management levelSecure data transfer which facilitates PAT and data analytics

Reduces IT costs and staff headcount. Offers effort savings of potentially 50-75% with SU implementation time (13, 14)

Touch screen HMI and software based on industrial engineering principles (ISA/ANSI-88)

Simple to set up recipe driven and standardizes operations to manufacture consistent product

Robust processes reduce costs of operator training and batch failures offers potential for 23 - 32% reduction in the CoGs (6, 5)

CTO design space Supports users in SU unit operation design and set-up to prevent connectivity, filter sizing, and mass balance errors

Standardizing process could reduce training time/costs, staff numbers, material variants and stock housing requirements. Could also improve supply chain network and delivery times

All steps from wetware installation to postprocess teardown are guided by recipe operator messages. This reduces set-up time and manual assembly errors because the modular package unit provides CLEAR operational GUIDANCE for the correct configuration.

Table 5: Time (minutes) required for SU virus removal

Wetware Installation Preflush

Equlibration Filtration Postflush Post-IT Offline

Wetware Teardown

60 25 5 60 30 60 30


operations with reusable components, for which SIP and CIP activities would take many hours, indicating that using SU technology with a modular package unit incorporating an industrial automation platform is time efficient, offering fast, flexible manufacturing and quick changeover between unit operations.

Manufacturing and Industry BenefitsBecause smart modular package units such as the FlexAct units can run prequalified and tested recipes, users can rapidly integrate SSB and other manufacturers’ SU technology in bioprocess operations, achieving faster installations with reduced downtime. Table 6 summarizes manufacturing and industry benefits that can be achieved using this modular unit.

Addressing the Needs of an Expanding Global Market Integrating automation and single-use technology at the process-management level is enabling biopharmaceutical companies and CDMOs to perform rapid unit operations and changeovers at different scales with a range of different types of biologics, using manufacturing facilities with increasingly smaller footprints. The next step, after automating unit operations, is an integrated SU quality by design (QbD) solution from seed train through to drug substance, with secure open architecture to allow remote preventive maintenance and predictive services to effect repairs or diagnose faults, as well as enable

seamless chemometrics, data analytics, cloud solutions, and machine learning. This intelligent SU facility will offer biopharmaceutical companies the potential to react flexibly and scalably to changing market demands and aligns with the industry’s drive to significantly reduce CAPEX and OPEX associated with manufacturing life-saving biopharmaceuticals to an expanding global market.

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8 Shukla AA, et al. Single-Use Disposable Technologies for Biopharmaceutical Manufacturing. Trends Biotechnol. 31(3) 2013:147–154.

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about/amgen-singapore/amgen-singapore-manufacturing-capabilities.

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11 WuXi Biologics Starts Up Large-Scale, Single-Use Biomanufacturing Facility. BioPharm Int. 2017; http://www.biopharminternational.com/wuxi-biologics-starts-large-scale-single-use-biomanufacturing-facility.

12 ISA-88.00.02-2001. Batch Control Part 2: Data Structures and Guidelines for Languages; https://www.isa.org/store/products/product-detail/?productId=116687.

13 Holm T. Aufwandsbewertung im Engineering Modularer Prozessanlagen. Hamburg: Helmut-Schmidt-Universität Bibliothek, 2016: 61-63.

14 Claes M. Evaluation of Automation-Related Project Work Packages for Integration of Modular Package Units in PCS7; personal communication.

15 Levine H, et al. Single-Use Technology and Modular Construction. BioProcess Int. 11(4)s 2013: 41–45. c

Corresponding author Burkhard Joksch is Senior Manager Software and Automation, [email protected]. Stuart Tindal is Product Marketing Manager FlexAct at Sartorius Stedim Biotech, Goettingen, Germany; +49.551.308.0.

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Parenteral pharmaceuticals must be “essentially free” from visible particulate matter (1). In the production of

biopharmaceuticals with single-use systems (SUS), biocompatibility requires controlling interactions between drug substances/products and SUS surfaces to ensure drug product quality and patient safety with regard to extractables/leachables and particulate matter. Any particulate matter stuck to fluid-contacting surfaces of process components could wash off and contaminate process fluids. Depending on system configuration, a final drug product could be at risk for particulate matter from SUS. Risk assessments take into account potential particle sources (e.g., ingredients, SUS surfaces, final containers) and particle sinks (filtration and other purification steps) throughout an entire manufacturing process. Applications of SUS

downstream of final filters presents the highest risk scenario, in which direct contact between drug substance/product and SUS components occurs. For example, applications of SUS in final fill and finish operations, aseptic vaccine production, or processing steps in the manufacture of cell and gene therapy products present the highest risks for potential particulate matter in final drug products as described in the guidelines for SUS particle risk assessment from the Bio-Process Systems Alliance (BPSA) (2).

“Clean-build” manufacturing of SUS components and assemblies in cleanrooms reduces particulate matter risks. Also, suppliers usually inspect

SUS for particles during manufacturing, and end users typically inspect them before application as well. However, the turbidity of some SUS components makes visual inspection of their interior surfaces difficult. Given the size and complexity of many SUS assemblies, particles visible in final drug products (typically ≥100 µm) might not be seen in a visual inspection. A method is needed that extracts and measures particles present on SUS interior surfaces for a realistic assessment of particulate matter risk (2).

Historically, the most common particle measurement method applied to SUS is that described in chapter

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Visible Particulate Matter in Single-Use BagsFrom Measurement to PreventionKlaus Wormuth, Melanie Gauthier, Mathieu Labedan, Veronique Cantin, Fanny Gaston, Manon Thaust, Nelly Montenay, and Magali Barbaroux

PRODUCT FOCUS: All biologics

PROCESS FOCUS: Production, downstream processing

WHO SHOULD READ: QA/QC, manufacturing

KEYWORDS: Disposables, raw materials, quality control, analytical, biocompatibility

LEVEL: Intermediate








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<788> of the US Pharmacopeia, so most SUS manufacturers claim that their SUS equipment meets USP <788> specifications (3). However, as detailed in a recent article, USP <788> is a standard for measurement of subvisible particles (10–100 µm) in final drug products, not for extraction and measurement of particles from SUS (4). Clearly missing is a standardized approach for liquid extraction of SUS surfaces and subsequent particle measurement. Currently, the ASTM International E55.04 committee on general biopharmaceutical standards is working toward developing a standard practice, but as of today no such standard exists.

To get an approximate sense of the degree of particle cleanliness currently available in polymer-based SUS bioprocess containers (“bags”), we measured visible particles (≥100 µm) in a small sampling of commercially available 20-L SUS bags. In a cleanroom, we partially filled the bags with purified water and agitated them, then filtered the resulting extracts onto filter membranes to collect particles. For measuring particles by “membrane microscopy,” we used an automated microscope to scan the filter membranes and image analysis methods to count and size the collected particles. We further analyzed a select number of membranes with infrared microscopy to identify chemically and thus classify the particles.

All SUS bags examined contained measurable amounts of visible particles, of which textile fibers and cellulose particles were most commonly found in six out of eight products. Because of our small sample size, no broad conclusions can be made regarding the level and type of visible particulate matter expected to be found in SUS bags. However, analysis of the types of particles we found indicates that implementation of SUS manufacturing process improvements probably would decrease the levels of visible particulate matter found inside SUS bags examined herein.

Materials and MethodsWe chose a sampling of 20-L SUS bags from eight product lines currently on the market for this study (Table 1). To extract particles from the bags, we filled each one with 1 L purified filtered water in a cleanroom environment (a laboratory that meets ISO 7 particle levels). With the tubing ports stoppered, we agitated the bags horizontally 20 times. Then we filtered liquid extract (water plus extracted particles) from those bags onto membrane filters and counted all collected particles ≥100 µm using a microscope with image analysis software. Background particle counts were measured both before and after each set of measurements (applying the same procedures but without the bag), all results of which were insignificant (<5%) relative to measured values.

To classify the particles, we compared spectra from infrared microscopy of the particles with those in a large database of reference spectra. Note that only a sampling of

particles was identified and classified: We analyzed only a select number of filter membranes but categorized all particles ≥100 µm on each chosen membrane.

Results and DiscussionCounting, Sizing, and Identification of Visible Particles in Single-Use Bags: All bags tested contained particles ≥100 µm (Table 1, Figure 1). The average visible particle counts per bag ranged by a factor of about 35 between the lowest and highest levels found (Table 1). In a general sense, the more particles we measured, the greater was the variability in counts from bag to bag — as indicated by larger ranges in Figure 1.

The bag product with the largest number of particles (Product C) presented a significant measurement challenge with the membrane microscopy method. Large numbers of thin white particles were extracted from the Product C bags, and those particles exhibited low contrast on white filter membranes. The image analysis software sometimes struggled to define such particle boundaries, so the counts obtained were somewhat less accurate than those for other types of particles with higher contrast.

Infrared microscopy measurements and observations of physical morphology (shape, color) guided us in classifying particles (Table 2). For bag products A, B, D, E, and H, 80–95% of the particles we found fell into the two classifications of textile fibers and cellulose particles. For bag product F, >50% of the particles found were plastic related, and bag product G contained roughly equal amounts of textile fibers, cellulose, and plastic

Table 1: Average particle counts (≥100 µm) for 20-L SUS bags (*nominal bag volume)

Bag ProductNumber of

Bags TestedAverage Number of

Particles ≥100 µm (per bag)Average Number of

Particles ≥100 µm (per L)*A 10 37.5 1.9B 10 15.7 0.8C 5 237.2 11.9D 16 6.7 0.3E 15 10.3 0.5F 5 10.4 0.5G 5 11.4 0.6H 5 10.8 0.5

To get an approximate sense of the degree of PARTICLE CLEANLINESS currently available in polymer-based single-use bioprocess containers, we measured visible particles (≥100 µm) in a small sampling of commercially available 20-L bags.


particles. Bag product C contained large numbers of thin white particles (94% of the particles found) as mentioned above, and comparison with reference infrared spectra suggested that these particles are probably ethylene bis(stearamide) or a related compound. Measurable amounts of protein particles (e.g., hair or skin flakes) also were found in products B, C, E, and F. Other particles found at lower concentrations included plastic materials (synthetic polymers), glass fibers, and a few metallic particles (Table 2).

Possible Approaches for Reduction of Visible Particle Levels in SUS Bags: Identification and classification of particles obtained from SUS bags aids in our search for potential sources of particles in SUS manufacturing. Textile fibers likely come from cleanroom

technicians’ street clothes or perhaps fibrous wipes used to clean surfaces. Improved gowning procedures and elimination of fibrous wipes in cleanrooms probably would reduce levels of such textile fibers. Potential measures to reduce cellulose particles (from paper or cardboard) would involve eliminating paper documentation in cleanrooms and carefully controlling cardboard packaging sources (e.g., double bag packaging of incoming components). Reduction of risk from protein particles (hair and skin) normally comes with improved protective gowning and hygiene discipline.

As opposed to the “extrinsic” particles discussed above, “intrinsic” particles generated by SUS processes and components could require changes in cleaning and maintenance procedures for manufacturing process

machinery — or in more extreme cases, replacement of existing production systems with cleaner alternatives. The plastic particles (and perhaps some of the “other” types listed in Table 2) could be generated through cutting, welding, and assembly processes, as well as machinery wear. Incoming materials and components require tight quality control.

In addition to analysis of the potential sources of particles found in SUS bags discussed herein, successful particle reduction efforts require a holistic and risk-based strategy. At Sartorius Stedim Biotech, our Particle Prevention Program (P3) focuses on five strategic factors: quality by design, supplier quality, cleanroom processes, inspection processes, and measurement methods. Quality by design for new products focuses on evaluation of materials and processes that shed fewer particles than others. Supplier quality efforts emphasize improved understanding of our component manufacturing processes and implementation of controls at component manufacturing sites. Overall analyses of complex cleanroom processes for SUS manufacturing requires periodic risk assessments and disciplined implementation of corrective and preventive actions (CAPA). In addition, inspection processes must use “best practices” for lighting, scanning, timing, and inspector training. Finally, qualified methods to assess particle

Figure 1: Number of particles (≥100 µm) per liter of nominal bag volume for eight 20-L SUS bag products

0

5

10

15

20

25

30

35Pa

rtic

les

per L

iter (

Nom

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Bag

Vol

ume)

A B C D E F G H Bag Product Type

Generation of INTRINSIC particles could require changes in cleaning and maintenance procedures for SUS manufacturing process machinery — or in more extreme cases, replacement of existing production systems with cleaner alternatives.


levels quantitatively within SUS assemblies (extraction, sizing, counting, and identification) as shown here generate crucial data that help drive continuous improvement efforts to reduce particle levels.

“Visible” Particles (≥100 µm) Found with Microscopy Are Not Necessarily Visible to the Unaided Eye: Extraction and membrane filtration concentrates low amounts of particles onto relatively small membrane surface areas, making those particles readily accessible for measurement. Liquid particle counting methods as in USP <788> (light obscuration) and more recently developed flow-imaging methods (high-speed camera systems) are challenged by sampling issues and the difficulty of accurately counting dilute amounts of particles in a liquid extract. In a study of small particles (>0.7 µm) extracted from 1-L SUS bags and measured by flow imaging, large numbers of very small particles were found, but only in some cases were significant amounts of particles ≥25 µm detected (5). A fraction of those particles may have fallen into the “visible” range (≥100 µm), but that size class was not studied specifically.

It is important not to draw broad conclusions about the cleanliness of SUS products based on the small set of data from the small number of bag products we tested. And remember that many of “visible” particles (≥100 µm) detected by liquid extraction combined with the membrane microscopy are not likely

to be visible by unaided human eyes during inspection of SUS components.

A Path to ImprovementThis study shows how extraction and measurement of particles from the interior surfaces of 20-L polymer-based SUS bags reveals that all bag products tested contained detectable levels of particles within the visible size range. Classification of the types of particles found in the bags suggests that tightened SUS manufacturing controls — probably achievable through implementation of relatively straightforward process improvements — should reduce the levels of particles found in future systems.

References1 USP <790> Visible Particulates in

Injections. US Pharmacopeial Convention, Inc.: North Bethesda, MD, April 2015.

2 The 2014 Particulates Guide: Recommendations for Testing, Evaluation, and Control of Particulates from Single-Use Process Equipment. Bio-Process Systems Alliance (Society of Chemical Manufacturers and Affiliates): Arlington, VA, 2014; http://bpsalliance.org/technical-guides.

3 USP <788> Particulate Matter in Injections. US Pharmacopeial Convention, Inc.: North Bethesda, MD, July 2012.

4 Vogel JE, Wormuth K. Particulate Contamination in Single-Use Systems: Challenges of Detection, Measurement, and Continuous Improvement. BioProcess Int. 15(9) 2017: 16–20.

5 Johnson MW. Understanding Particles in Single-Use Bags. BioProcess Int. 12(4) 2014: supplement. c

Corresponding author Klaus Wormuth is lead scientist, particles, at Sartorius Stedim Biotech GmbH in Göttingen, Germany; 49(0)551-3082610, [email protected]. Melanie Gauthier is a materials engineer; Mathieu Labedan is a business manager; Veronique Cantin and Manon Thaust are laboratory technicians; Fanny Gaston is a particles laboratory scientist; Nelly Montenay is manager of product development; and Magali Barbaroux is head of bag technologies, all at Sartorius Stedim Biotech in Aubagne, France.


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Table 2: Particle type classification (≥100 µm); textile fiber = fibers likely from clothing (infrared: cotton, acrylic, and polyester), cellulose = particle or fiber with paper or cardboard morphology (infrared: cellulose), protein = fibers with hair morphology, or thin translucent particles (infrared: protein), plastic = synthetic polymers (other than textile fibers)

Bag Product

Total Particles Analyzed

Textile Fibers (%) Cellulose (%) Protein (%) Plastic (%) Other (%)

A 28 57 29 0 8 GF 7B 79 15 73 6 1 GF 4C 112 3 0 2 1 EBS 94; UK 1

D 21 43 52 0 0 UK 5E 52 15 71 8 4 Metal 7F 35 9 29 3 57 Paint 3G 29 35 31 0 26 GF 3; UK 10H 28 32 50 0 18 0

GF = glass fiber; EBS = infrared analysis suggests ethylene bis(stearamide) or a related compound; metal = shiny metallic; paint = likely paint chip; UK = unknown (not able to identify)

Qualified methods to assess particle levels quantitatively within SUS assemblies (extraction, sizing, counting, and identification) as shown here generate CRUCIAL DATA that help drive continuous improvement efforts to reduce particle levels.

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For more than 20 years, single-use technologies (SUTs) have had widespread application in the biopharmaceutical industry,

initially for buffer and media storage. Because of their recognized advantages and numerous technological advances (e.g., bioreactors, mixers, probes, and needles), SUTs now are considered increasingly for critical steps such as formulation, bulk drug-substance storage, bulk transport, and final drug-product filling. Thus, integrity assurance is becoming a major concern for biomanufacturers.

However, current regulations focus on primary packaging (e.g., vials and syringes) or secondary packaging (e.g., capsules and stoppers), without taking into account assemblies used in bioproduction. Initiatives and revisions to current regulations still are under way (1–4) to propose good practices concerning the integrity of single-use systems (SUS).

In the absence of a regulatory framework or guideline specifically applicable to SUS used in bioproduction, experts continue to

recommend a traditional risk management approach (5). Scientific understanding of the critical size of a defect presenting a risk of liquid leakage and/or microbial contamination is a prerequisite for any integrity assurance strategy. Then it is necessary to conduct in-depth studies to correlate the physical integrity test methods (and their detection limit) with the critical defect sizes that lead to liquid leaks and/or microbial contamination in real-life and worst-case conditions.

Definition and Regulatory FrameworkThe concept of container–closure integrity covers the ability of an enclosed container to maintain a drug product’s sterility and quality throughout its lifecycle. This includes both physical (lack of content leakage) and microbial (lack of bacterial

penetration) integrity. The concept is well known for primary packaging but has so far been poorly treated for single-use assemblies used in bioproduction (6–7).

USP <1207> for sterile product packaging-integrity evaluation was revised in 2016 (9). It is an informative chapter (good practice) and not a directive. It applies mainly to primary packaging, but could also cover containers used in liquid handling, preparation, and manufacture. The chapter describes test methods and states that a deterministic approach is preferred. This document introduces the concept of maximum allowable leakage limit (MALL), which corresponds to the greatest leak size tolerable that poses no risk to product safety. Thus, an integral container must have no defect greater than the MALL.

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Integrity Redefined Consistent Robustness and Integrity Testing Lead to Enhanced Process Integrity and Patient SafetyMarc Hogreve, Carole Langlois, Katell Mignot, and Jean-Marc Cappia



WHO SHOULD READ: QA/QC, manufacturing, regulatory

KEYWORDS: Disposables, failure mode analysis, MALL limits, integrity testing, leak testing

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Therefore, it is essential to characterize the MALL accurately to minimize risk of leak occurrence and to detect leak presence reliably. This requires identifying critical steps and understanding influencing factors.

Failure Mode Analysis (AMDEC/FMEA)As part of risk analysis, identification and understanding of failure modes that may lead to a defect in the integrity of SUS is a prerequisite for implementing a reliable control strategy. This analysis must be carried out by both suppliers and end-users of SUS.

Control of SUS raw materials and components and all manufacturing process stages (according to the rules of quality by design, QbD) leading to the release of a finished disposable product are the suppliers’ responsibility. Validation and/or qualification of assemblies, packaging, sterilization, and transport also must

have been carried out. This systematic approach, accompanied by strict controls in production and an integrity test at the end of production, must guarantee the perfect conformity of a finished single-use product with established specifications (and with particular robustness and barrier properties).

At end-user facilities, SUS are received, stored, deconditioned, and manipulated, all of which introduce new risks of integrity failure. Visual inspection (at reception and before use) and good training of operators on proper manipulation of these systems are necessary. Implementation of complementary tests, such as the point-of-use leak test, may be required depending on the criticality of application. Figure 1 shows the complexity of the SUS lifecycle and validation, qualification, and control steps to ensure integrity.

Single-Use System Integrity Testing Science With the new revision of the USP <1207> chapter (9), the approach has been raised to develop physical integrity test methods with detection limits that can be correlated to a disposable container’s barrier requirements (e.g., liquid leaks and microbial ingress). Such MALLs should be defined specifically for packaging configurations and their use.

In previous studies, researchers tried to establish the respective MALLs on different container systems, but mostly with artificial capillary leaks (10–13). Those data are valuable to represent channel leaks in welds, seals, or hose-barb connections. However, an important failure mode in a single-use system is not represented: pinhole defects in bag film. Thus we at Sartorius Stedim Biotech (SSB) have launched several scientific studies to characterize the leak behavior in flexible film materials.

Because the use conditions for SUS vary extensively based on application (e.g., shipping, storage, or mixing), SSB decided to work on a theoretical model that allows the prediction of the MALL for any use. Starting with identification of worst-case pressure conditions, bacterial challenge concentration, and typical liquid-model solutions, we set up studies for microbial ingress and liquid-leak testing on our Stedim 71 and Stedim 80 film materials. We started tests with extreme pressures

Table 1: Overview of test results for microbial ingress and liquid leak testing

Pressure (mbar) FilmNo Liquid Leak for

No Microbial IngressWater TSB0 Stedim 80 (PE) Not tested Not tested 15 μm0 Stedim 71 (EVA) Not tested Not tested 30 μm

70 Stedim 80 (PE) 3 μm Ongoing 10 μm70 Stedim 71 (EVA) Ongoing Ongoing Ongoing150 Stedim 80 (PE) Planned Planned Planned150 Stedim 71 (EVA) Planned Planned Planned300 Stedim 80 (PE) 2 μm 2 um 1 μm300 Stedim 71 (EVA) Ongoing Ongoing 2 μm

Figure 1: Life cycle of a single-use system

Quality by designQuality risk management

Initial validationQualification

Manufacturing Shipping(empty) Storage Unpacking

HandlingFilling

StorageShipping

(filled) Resin Film Bag Sterilization

Packaging integrityVisual inspection

Operator trainingPoint-of-use leak test

Shippingvalidation

Quality systemValidation guides and quality statementsQualification reportsCertificates of release/sterility/integrity

Leak test 100% (bag chamber)Visual inspection 100%Integrity testing 100%

(finished product)Packaging and shipping validation

Material Control Process Control Quality Control

Component Assembly


differentials of 0 mbar (atmospheric) and 300 mbar with water-for-injection (WFI ) and trypticase soy broth (TSB) as model solutions.

For the microbial ingress testing, TSB-filled test containers were prepared with defective film coupons with several defect sizes from 1 µm to 100 µm. If necessary, the containers were pressurized and subjected to a bacterial aerosol challenge of 106 CFU/cm2 for three hours. Afterward, all samples were incubated for 14 days at 30–35 °C, then visual microbial growth was reported. Chosen concentration represents a worst-case scenario, based on current good manufacturing practice (CGMP) specifications for surfaces in ISO7 and ISO8, augmented by six logs. For the liquid-leak test, containers were filled with different model solutions, prepared with similar film coupons, pressurized, and held for 30 days. A liquid drop was observed on

liquid tracer paper and visual growth was reported. Table 1 lists results obtained so far for different conditions.

Based on these first test results, we can establish a theoretical model to predict the MALL for all applications based on the applied pressure and liquid characteristics. Figure 2 shows this model for our Stedim 71 film material based on ethylene-vinyl acetate (EVA), including estimated MALLs for different applications. So far, the model shows an estimated MALL of 2 µm for worst-case, high-pressure conditions. For medium-pressure applications, validity of the model will be improved by further testing at intermediate pressure points of 70 mbar and 150 mbar.

Single-Use System Integrity Testing Technologies For decades, the biopharmaceutical industry has used penetration tests (dye

ingress and microbial ingress) to verify the integrity of primary packaging. These probabilistic methods can be applied to SUS in validation or investigation steps. However, they are not applicable to perform 100% testing that may be required in production (at a supplier) or at the point of use (at an end user).

Two deterministic analytical methods applicable to single-use assemblies are described in USP <1207>: the pressure-drop test and the helium gas tracer test (14, 15). They are used to control physical integrity with fairly wide detection ranges. Correlation to the microbial ingress and liquid leak tests then allows an analyst to demonstrate microbial integrity.

The MALL of 2 μm estimated from our microbial-ingress and liquid-leak testing inspired us to develop and offer a highly sensitive, physical, and nondestructive integrity test method based on helium gas tracer technology. This is performed as a 100% release test in our manufacturing process to guarantee inherent integrity of SUS shipped to end-users. In addition, robustly validated point-of-use leak and integrity tests (based on pressure decay measurement) complement release testing to confirm a single-use system’s integrity directly before use.

In our helium-based integrity test, we place single-use assemblies in a sealed vacuum test chamber and connect them to the helium filling line. The vacuum chamber ensures an appropriate vacuum and helium background level to achieve the best level of detection (LoD). A mass spectrometer measures the rate of increase in the concentration of helium

Figure 2: Predictive model for use-case related MALLs

Max

imu

m A

llow

able

Leak

age

Lim

it (μ

m)

Pressure Applied (mbar)

35

30

25

20

15

10

5

00 100 200 300

Storage Application

10–25 μm

Shipping Application2–10 μm

Model with current data (extreme points)

Expected model withfull data set

Figure 3: Test chamber design

Restraining Plate + Porous Spacer

Single-Use AssemblyFilled with Helium

Restraining Plate + Porous Spacer

Vacuum Chamber + Gas Tracer

Filtered Helium

To identify MALLs for single-use bag systems, it is CRUCIAL to understand the bacterial penetration and liquid-flow mechanisms through components and materials used for those systems.


that passes through defects in a single-use system.

A patented integrity test with a special pumping technique ensures proper test sample evacuation and reduces stress on a bag assembly by lowering the internal pressure of the bag and the external chamber pressure (16). The test chamber is equipped with restraining plates and porous spacers to provide mechanical support for the assembly during the test and prevent masking effects caused by direct contact between the film surface and stainless steel plate (Figure 3). This mechanical support enables testing with small inflation volumes and higher test gas pressures to achieve the highest sensitivity of 2 µm.

Because design-specific characteristics of single-use systems (e.g., number of connections, surface area, and materials of construction) can affect leak rate, it is important to determine helium leak-rate acceptance criteria by comparing the baseline of conforming products with leak rates given by defective assemblies. Permeation of helium through a bag-film surface and tubing material can

increase helium concentration significantly in a chamber during the test and thus should be evaluated thoroughly.

Sartorius Stedim Biotech selected this technology for nondestructive testing of finished products for all SUS intended for use in commercial manufacturing of drug substances and products. A comprehensive validation study with >700 tests performed on a large number of product types has been used to validate this test method with a six-sigma confidence interval across our two-dimensional (2D) bag product families. Our study included different types of deliberately calibrated artificial leaks to create positive controls. The reproducibility and precision of our validated method allows use of SUS in critical process steps to reduce risks associated with introducing a defective consumable into processes, which can jeopardize system sterility. Further development will make this testing available for three-dimensional (3D) bag assemblies up to 650 L in 2020.

For testing SUS integrity at points of use, SSB offers different solutions,

depending on the application and product family. A range of methods is available to detect leaks in single-use bag assemblies. Some of those require an assembly to be placed in a separate device for testing; others can be applied after installation of a bag into its final container. Less complex small- to mid-range volume bag assemblies can be tested in a separate device (including a system to restrain a bag). That improves LoD significantly, thus providing a point-of-use integrity test with sensitivity that can be correlated to microbial ingress and liquid leaks. For complex and large-volume single-use bag assemblies, performing a point-of-use leak test after installation and immediately before use is the best solution to save high-value product and production time and reduce additional risk of bag damage after the test.

With our FlexAct BT bag tester solution and its design to rigidly restrain a bag used with our Sartocheck 4 plus bag tester, Sartorius Stedim Biotech provides a robust test setup to detect defects down to 10 μm on our Flexboy and Flexsafe 2D product families. As shown herein, this leak size can be correlated to the MALL for storage applications and therefore give additional integrity assurance for the storage of high-value bulk drug substances and products. The Sartockeck 4 plus bag tester also can be used to perform point-of-use leak testing on nearly all our 3D bag families, including Flexsafe STR and Flexsafe systems for storage, shipping, and mixing. All pressure decay test methods have been validated extensively with a

The MALL of 2 μm estimated from our microbial-ingress and liquid-leak testing inspired us to develop and offer a highly sensitive, physical, and nondestructive INTEGRITY TEST method based on helium gas tracer technology.


six-sigma confidence interval using positive and negative controls.

The Right Test MethodA consistent and reliable integrity control strategy must be based on initial risk analysis before the implementation of QbD to ensure the intrinsic and consistent robustness of single-use systems and mastery of all stages of a manufacturing process. In-depth knowledge of factors that can affect SUS integrity in real-life conditions and the understanding of liquid leakage mechanisms (and their correlation with microbial penetration) are paramount. They allow biomanufacturers to define scientifically appropriate detection thresholds for the risks of associated loss of integrity.

Appropriate and validated physical test methods and protocols then can be put into place (both at supplier and end-user sites) to cover different types of potential failures and support visual inspection and good practices. The MALL value to ensure integrity of a SUS depends on the process step in which that system is to be used and the stresses that it will have to endure (e.g., pressure, shocks, and contact time). In such cases, a risk analysis should be conducted to determine the type of test to be implemented and the target detection threshold. Doing so enables implementation of the appropriate single-use solution. It may be necessary to implement the most sensitive test method (helium 2 μm) for critical applications (e.g., transport of bulk drug substance or drug product).

References1 PDA Technical Report 27:

Pharmaceutical Package Integrity. Parenteral Drug Association: Bethesda, MD, 1998.

2 ASTM WK64337: Standard Practice for Integrity Assurance and Testing of Single-Use Systems. ASTM International: West Conshohocken, PA, 2018.

3 ASTM WK64975: Test Method for Microbial Ingress Testing on Single-Use Systems. ASTM International: West Conshohocken, PA, 2018.

4 Design, Control, and Monitoring of Single-Use Systems for Integrity Assurance.

Bio-Process Systems Alliance: Arlington, VA, 2017.

5 ICH Q9: Quality Risk Management. Fed. Register 71(106) 2006: 2105–2106.

6 Annex 1: Manufacture of Sterile Medicinal Products. EudraLex: The Rules Governing, Medicinal Products in the European Union, Volume 4. The European Commission: Brussels, Belgium, 2010.

7 21 CFR 211.94: Drug Product Containers and Closures. Fed. Register 81, 2016: 81697.

8 Guidance for Industry: Container and Closure Integrity Testing in lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products. US Food and Drug Administration: Silver Spring, MD, 2008.

9 USP <1207> Sterile Product Packaging-Integrity Evaluation; USP <1207.1> Package Integrity and Test Method Selection; USP <1207.1> Package Integrity Leak Test Technologies; USP <1207.3> Package Seal Quality Test Methods. US Pharmacopeia–National Formulary. US Pharmacopeial Convention: North Bethesda, MD.

10 Morton DK, et al. Quantitative and Mechanistic Measurements of Container/Closure Integrity: Bubble, Liquid, and Microbial Leakage Tests. J. Paren. Sci. Technol. 43(3) 1989: 104–108.

11 Kirsch LE, Nguyen L, Moeckly CS. Pharmaceutical Container Closure Integrity 1: Mass Spectrometry-Based Helium Leak Rate Detection for Rubber-Stoppered Glass Vials. PDA J. Pharm. Sci. Technol. 51(5) 1997: 187–194.

12 Gibney MJ. Predicting Package Defects: Quantification Of Critical Leak Size. Virginia Tech, 2000.

13 Keller SW. Determination of the Leak Size Critical To Package Sterility Maintenance. Virginia Tech, 1998.

14 ASTM F2095: Standard Leak Test for Pressure Decay Leak Test for Nonporous Flexible Packages with and without Restraining Plates. ASTM International: West Conshohocken, PA, 2013.

15 ASTM F2391-05: Standard Test Method for measuring Package and Seal Integrity using Helium as the Tracer Gas. ASTM International: West Conshohocken, PA, 2011.

16 Hogreve M. Sartorius Stedim Biotech GmbH, Deutsches Patent und Markenamt (German Patent and Trademark Office) DE102014013522B4. 30 March 2017. cCorresponding author Marc Hogreve is senior scientist of Integrity Testing ([email protected]); 49-551-308-3752, at Sartorius Stedim Biotech GmbH in Göttingen, Germany. Carole Langlois is marketing manager, Traditional Vaccines; Katell Mignot is a subject matter expert, Single Use Technologies; and Jean-Marc Cappia is head of Segment Marketing Vaccines, at Sartorius Stedim Biotech in Aubagne, France.

FlexAct, Flexboy, Flexsafe, Flexsafe STR, and Sartocheck are registered trademarks of Sartorius Stedim Biotech GmbH.


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A s the complexity of biopharmaceutical manufacturing increases (1), supply partnership

management is becoming key to the successful continuous supply of drugs for patients. To prevent drug shortages, ensure robust recall management, and to seek to provide drug treatment to patients wherever they are located, the biopharmaceutical industry is building greater transparency into its vendor supply chains and developing supplier–end‑user partnerships with best practices inspired from other sectors such as the automotive or electronics industries. As a leading international supplier, Sartorius Stedim Biotech (SSB) is developing global supply chain management as a strategic goal for supporting the growth and expansion of the biopharmaceutical industry.

The Supply Chain As a Strategic FunctionSupply chains support commercialand/or manufacturing activities. If well‑defined and implemented, they can offer strategic advantages by

providing transparent partnerships with end users. Thus, vendors and end users are investing more time and effort into establishing and managing their supply chains.

With the need to speed up development of new therapies and make drugs more widely available and affordable, single‑use technologies are an integral part of industrial biomanufacturing processes. Increasingly global operations require highly reliable delivery times and dedicated supply chain organization.

What Is the Supply Chain? In supply chain discussions, often what first comes to mind is the transportation of goods or the procurement of products, services, and raw materials. But a supply chain is much more than that.

The best definition of everything that encompasses a supply chain comes from the American Production and Inventory Control Society (APICS) (2), now known as the Association for Operations Management. The APICS describes a supply chain as a global network ensuring the coordinated movement of components or products

to an end user through information flows, physical and cash flows. The APICS proposes an operational model known as the SCOR (supply chain operations reference) model, which comprises seven elements: the supplier, the processor, the customer, the material flow, the material return flow, the monetary transaction flow, and the planning and coordination activity of an entire process (Figure 1).

Operating a Global Supply ChainSSB uses the SCOR model, which identifies three organizational levels to consider (Figure 2). This is one of the most widely used models in the biopharmaceutical industry and has been used successfully in other sectors such as the food and beverage and small‑molecule pharmaceutical industries. It allows organizations to adapt best practices for supply chain management both internally and externally for global implementation.

SSB’s global supply chain has been defined by considering not only the geographical and geopolitical context,

SUPPLIER SIDE

Going Beyond the Simple Customer–Supplier RelationshipEnsuring a High-Quality Supply Chain Through Transparent PartnershipsClaudio Catallo



WHO SHOULD READ: Sales and operations, manufacturing, QA/QC and logistics specialists

KEYWORDS: Supply chain management, SCOR model, ERP systems, operational excellence, single-use products












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LEVEL: Intermediate












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LEVEL: Intermediate


The clear objective is to reduce delivery times and transportation risks by LOCATING CLOSER to customers based outside Europe and by specializing factories as centers of excellence for components or assembly.

market segmentation, and dynamics, but also product type. Organizational configurations then are adapted to the needs and constraints of specific regions. The locations of manufacturing units and which products they have to produce also are defined. For each component, the best “make or buy” policy is considered. At a regional level, the best distribution model is defined and implemented.

The supply chain of SSB manufacturing plants (third level of the SCOR model) is managed by a local team of supply chain experts who are in charge of each manufacturing plant’s end‑to‑end supply chain. That includes procuring raw materials, planning for production and managing scheduling, and overseeing the logistics of material flow through the facility (raw materials, work in process, and finished goods). Each production plant has its own warehouse for storage of raw materials and finished products, which also is managed by a local supply chain team.

Finally, network coordination is organized by arranging information, product, timing, and payment flows from supplier to customer. In short, this is where all processes are organized for order management, raw material procurement, production planning, and delivery of finished products directly to customers or through a distribution center.

SSB offers its customers different supply chain processes according to their specific needs. The process will be different for an off‑the‑shelf catalogue product that is generally in stock from that of a custom product or a prototype that has to be developed. Using an organizational model allows a response to all variations, regardless of a customer’s location. Using an enterprise resource planning (ERP) system manages order processing, procurement, planning, logistics, sterilization of products, and final delivery wherever customers are located.

Ensuring Supply chain CapacityAdoption of single‑use technology in the biopharmaceutical industry is a true success story and has encouraged single‑use technology suppliers to

support their customers’ growth through close support and robust industrial strategies. Service rates, costs, and quality of supply are the three key factors in this market.

SSB has significantly strengthened its global capabilities with a footprint of more than seven manufacturing plants globally (Figure 3). With almost 10,000 m² of cleanroom space, SSB’s capacity has been increased by over 60% in the past two years, notably with the opening of a factory in Beijing, China, and an extension to facilities at Göttingen, Germany. Additionally, a 12,000‑m² distribution center has been opened in Aubagne, France. It includes a cleanroom where the “kits” of raw materials and components used for manufacturing are prepared and sent to production lines at the plant. Our partner base (including the need for sterilization capacities) also has doubled, and SSB is pursuing a strict back‑up program to ensure continuity of services for the highly regulated biopharmaceutical market. Today, SSB relies on a network of nine sterilization sites, with plans for doubling that capacity again by 2021.

Global Supply Chain Management To support its customers further, SSB has created a dedicated global supply chain team. This team is in charge of process improvement and implementing SSB’s 2025 industrial strategy, as well as supporting customers by proposing collaboration projects within partnerships. Experienced specialists make it a priority to monitor and optimize the service rate offered to customers and

ensure expansion of industrial facilities in line with market demand. The team also manages details of customer collaboration projects, such as setting up security stocks or adjusting deadlines based on forecasts and location of customers’ delivery points.

By 2025, SSB will strengthen production capacity significantly in North America and Asia to offer an industrial facility that can be totally substitutable (as a back‑up). The clear objective is to reduce delivery times and transportation risks by locating closer to customers based outside Europe and by dedicating factories as centers of excellence for components or assembly. Organizing facilities and technologies through a platform approach focused on separate manufacturing steps will enable groups to increase levels of standardization and reduce manufacturing redundancies, while maintaining a wide range of solution configurations available to customers today.

Therefore, SSB will continue to invest in its facilities and offer additional

Figure 1: Overview of supply chain operations reference (SCOR) model

Materials

Cash

Planning

Supplier M Manufacturer M Customer


equipment and manufacturing processes around the world to ensure continuity of supply to customers. For the purposes of risk management, SSB already has proposed qualifying multiple sites in parallel for strengthening the assurance of supply through established business continuity planning. Taking responsibility for finding the best production slots in our plants and balancing global capacities quarterly will ensure that all customers benefit from SSB’s global supply network.

Single ERP Platform Global supply chain management principles can be applied through a common data‑manufacturing system. SSB is completing implementation of a single ERP platform for all plants and sales subsidiaries. This will provide complete visibility and consistency of data among different entities with clear advantages in terms of information processing speed and simplification of customer order‑processing activities.

For customers, this translates to more reliable delivery times and faster responses to their queries.

Today, a customer order received by a sales subsidiary is entered into the ERP system, which generates a production order for the plant that takes charge of the request, as well as an order for raw materials that is sent to the approved supplier. Therefore, all these activities are integrated efficiently in the ERP platform.

For stock products, each shipment automatically translates into a production order to restore the correct level of stock. That offers clear advantages for customers in terms of delivery times. An integrated part of the digitalization strategy is the introduction of an APS (advanced planning and scheduling) system. It will make management of sales‑forecasting, planning, and production‑scheduling processes even more integrated and efficient, resulting in further optimization of processes that will directly improve the levels of service provided to customers.

Assurance of SupplyTo guarantee supply for customers, SSB simultaneously operates in different sectors such as supply‑risk management, business‑continuity planning, and dual manufacturing.

Supply-Risk Management: We have implemented a real‑time analysis tool

and a team dedicated to estimate supply risks based on demand and available capacities from our suppliers. To enhance levels of transparency, we recommend this tool to customer orders that guaranteed, reliable long‑term supplies. With the help of this service, redundancy plans have been implemented for all critical components, such as tubes and films.

In terms of dual manufacturing, most products from SSB can be made in at least two different locations. Plans are under way to extend this dual manufacturing capability to all SSB products. To cope with events such as Hurricane Maria (which hit the island of Puerto Rico in 2017), SB expanded its network in North America by opening an additional logistic platform at Miami, FL, where a six‑month security stock is maintained for the most critical of our products manufactured in Yauco (PR). If unexpected circumstances occur again, critical product supply will continue for the period of time necessary to restore production capacity.

Sales and Operational PlanningPart of a supply chain best practice is implementing a sales and operational planning (S&OP) process to guarantee assurance of supply. Every month SSB’s demand‑planning team draws up sales forecasts for the coming few months. This team uses statistical tools

Figure 2: The framework levels of a SCOR model

SupplyChain

Level 1: Sets scope and context,geographies, segments, and products

Plan

M1Make build

to stock

M2Make build

to order

M3Make engineer

to orderLevel 2: Identifies major configurations within geographies, segments, and products

Level 3: Identifies key business activities within a configuration

M2.01Schedule

productionactivities

M2.02Issue

product

M2.03Produce and test

M2.04Package

M2.05Stage

product

M2.06Release product

to deliver

Source Make Deliver

Return

Most products from Sartorius Stedim Biotech can be made in at least TWO DIFFERENT LOCATIONS.

Supply Network

Redefined.


A global manufacturing footprint along with end-to-end process control leads to strong assurance of quality supply.

Benefit from high quality, robust change control and long-term business continuity through our unique supply network.




please visitWWW.SARTORIUS.COM/SINGLE-USE-

EXPERTS

and maintains continuous contact with key customers to assess their future needs. On the basis of those data, required production capacity is calculated to meet those needs. The process allows verification of production capacity to determine whether it is in line with market demand. When it is not, the team has time to adjust and distribute a production load over several facilities.

The S&OP process is based on a precise sequence of steps, repeated every month. This process enables the necessary decisions to ensure the best use of production capacity and, if necessary, adjust it to market demand. Through this process, SSB maintains and improves lead time of deliveries and delivery reliability.

Manufacturing OperationsGlobal supply chain success relies on robust and reliable manufacturing operations. Because of the importance of having a strong global manufacturing base, SSB has developed a supply chain network in which single‑use technologies are manufactured in seven production plants (Figure 3).

The ERP system manages end‑to‑end supply chain processes for each production plant. Customer orders automatically translate into production orders, and resulting raw‑material orders for suppliers are managed through material requirement planning (MRP). Every production step, from raw material selection to final‑product assembly, is recorded in the ERP. This allows managers to track the status of each individual sales order and to take prompt remedial action if a deviation from the initial schedule occurs.

Material planners keep every delivery of raw materials and their security stock levels under control through specific reports to guarantee the correct supply to production lines. The service level of suppliers is measured and monitored. All deviations are discussed by the strategic sourcing team, and specific actions are implemented when required.

Production planners also use specific reports to follow the status of production batches, reviewing batch sequences and prioritizing for specific committed delivery deadlines. Flow of materials and layout of production lines

are inspired by the principles and rules of lean manufacturing. Yield efficiency of production lines increases through continuous improvement. This translates for customers into lead times and service levels that will be in line with their needs. A global team of continuous‑improvement experts supports this process, working day to day in each manufacturing plant to improve performance.

Product Distribution SSB uses a capillary distribution network comprising logistics hubs and local warehouses from which products can be shipped to customers worldwide. Transport requirements such as sea shipment, air, truck, or a combination of those are chosen to accommodate customer needs. Logistics hubs are managed directly by SSB or by industry professionals who guarantee standards and levels of service that customers need. Similar to production plants, all the operations of reception, storage, packaging, and shipping in logistics hubs and warehouses are managed by the ERP. The system also provides all required shipping documentation. Assisted by optical scanners that read barcodes on packaging, that ensures collection and shipment of correct products, assuring the right level of service to customers.

Encouraging Operational Excellence Operating a successful global supply chain is complex and requires expert

teams and integration of digitalization across many sales, manufacturing, and distribution sites. As an innovative partner to the biopharmaceutical industry working on advanced technologies for decades, SSB is well aware of the importance of supply chain management and continues to keep operational excellence as its priority. This approach allows product supply and demand to be aligned with current and changing market needs, helping the company provide its best service for customers and patients in an expanding global biopharmaceutical market.

References 1 BioPhorum. Biomanufacturing

Technology Roadmap Report, 2017; https://www.biophorum.com/wp-content/uploads/2017/11/Biomanufacturing-Technology-Roadmap.pdf.

2 APICS Dictionary; http://www.apics.org/apics-for-individuals/publications-and-research/apics-dictionary. cCorresponding author Claudio Catallo is head of global supply chain management FMT at Sartorius Stedim Biotech, phone: 39-335-6021013, [email protected].

Figure 3: Global network of SSB’s manufacturing sites

Göttingen

Beijing

YaucoLourdes

M’Hamdia

Aubagne

Tagelswangen


S ingle-use systems (SUSs) offer significant process advantages over stainless steel systems and find increasing application in

biopharmaceutical processing. However, shifting from stainless steel to SUS polymer materials raises concerns about potential risks to drug product purity from leachable chemicals and particulate matter. Here, we focus on evaluating potential risks from particulate matter embedded in single-use polymer films used in production of SUS bioprocess bags.

Polymer films make up a large portion of the surface area of single-use bags. They must meet stringent requirements not required for typical packaging films: high mechanical integrity and low levels of leachable chemicals. Consequently, typical single-use films are relatively thick and contain much-reduced levels of chemical

additives (processing aids and stabilizers). But reduction of additives may result in a higher probability of finding gel particles embedded within the film. Gel particles are nodules of polymer material — unmixed or “unmelted” polymer resin with perhaps increased cross-linking or molecular weight — that appear as “fish-eye” shaped defects in the film (1). Figure 1 shows an example of a gel particle embedded in a single-use film, as observed from the exterior surface of the film, and also upon cross-sectioning

through the gel particle. High temperatures within an extrusion process can chemically degrade gel particles, which then become amber, brown, or black. In addition, the industrial scale and complex nature of film-extrusion processes also increase the risk that foreign particulate matter other than gel particles might become embedded in SUS films.

Are embedded particles in single-use films cosmetic defects, or do they represent a significant risk to bioprocess reliability (the sterile integrity of a process) or risk to product

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Embedded Particles in Single-Use Bags Risk to Bag Integrity and Drug Product Purity, or Only a Cosmetic Defect?Klaus Wormuth, Lucie Delaunay, Veronique Gissinger, Nelly Montenay, and Magali Barbaroux


PROCESS FOCUS: Process development and manufacturing

WHO SHOULD READ: QA/QC, manufacturing, analytical

KEYWORDS: Disposables, pressure, leachables, extractables, risk analysis

LEVEL: Intermediate








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LEVEL: Intermediate








SUPPLIER SIDE






LEVEL: Intermediate








SUPPLIER SIDE






LEVEL: Intermediate


purity? In an attempt to quantify risks to film integrity and product purity, we applied a unique pressure-burst test to single-use films with varying sizes of embedded gel particles. Here we describe a worst-case scenario regarding leachable chemicals from embedded particles.

Pressure-Burst Test of Film IntegrityA pressure-burst test was applied to both Flexboy (polyvinyl acetate-based) and Flexsafe (polyethylene-based) SUS films from Sartorius Stedim Biotech. As shown in Figure 2, a disk of SUS film

material was clamped onto the test apparatus, then the air pressure on the interior (contact layer) side of the film was increased until the film burst, and the maximum pressure at burst was noted.

Gel particles of increasing size were centered on the SUS film disk, burst pressure was measured, and the result was compared with film samples without particle gels. Gel size (equivalent circular area in square millimeters) was measured by comparison with a TAPPI size chart. The results for Flexboy films show that gel particles up to and greater than 2 mm2 in area do not change the burst pressure — and for Flexsafe films, only gel particles greater than 4 mm2 in area marginally reduce burst pressure (Figure 3). Note that in both cases, large gel particles were difficult to find, and for Flexboy films only one gel >2 mm2 was found. Thus, in this case, no statistical analysis was possible (Figure 3).

Rather than a tensile-stress test that applies stress in only one direction along a film, the pressure-burst test generates “membrane stresses”: tangential stresses radiating within the film in all radial directions (2). Within the time frame of the measurement, as the stress in the film exceeds the yield

stress, the film begins to thin, and eventually it ruptures (Figure 2). Note that the pressure-burst test generates extreme stresses and strains, with burst pressures ranging from about 3 bar to nearly 6 bar (Figure 3), which are much higher pressures than experienced in real process applications.

Our results clearly show that only large gel particles (2–4 mm2 in area, or 1–2 mm in diameter) begin to affect burst test results — and those gel sizes are much larger than the typical minimum detection capabilities for on-line camera inspection systems used in film extrusion processes. Thus, the risk from embedded gel particles to single-use film integrity appears to be small.

Leachable Chemical Risk AssessmentAlthough an extractables chemical assessment of a SUS film yields a list of known potential leachable chemicals from that film, foreign particles embedded in films could contain unknown potential leachable chemicals. However, a risk assessment for potential contamination of the process fluid, drug substance, or drug product must take into account the volume of the embedded particles (and thus the amount of potential unknown

Figure 1: Microscope images of gel particle in SUS film (area = 1.5 mm2); (top) view of film surface, (bottom) cross-section cut through gel

Figure 2: Pressure-burst test; (left) apparatus and film disk, (right) film after burst; (below) example pressure-burst test measurement with maximum pressure at burst = 6 bar

Pres

sure

(bar

)

8

6

4

2

00 5 10 15Time (seconds)

The results clearly show that ONLY LARGE gel particles begin to affect burst test results.


chemical leachables) relative to the volume of the film and relative to the volume of the drug substance or drug product in the SUS bag.

As an example, for a 20-L SUS bag, the total volume of SUS film material is approximately 300 cm3. The largest gel particle analyzed in the pressure-burst test results (2-mm diameter) would have a spherical volume of only 0.004 cm3. Even for an SUS bag contaminated with large amounts of such large particles, the volume fraction of particles in the bag film will still be small. For example, if the particles were 0.1% of the film volume (0.3 cm3), that would be equivalent to 75 particles of 2-mm diameter. This would be an extremely large number of particles, especially noticeable upon visual inspection of a 20-L SUS bag.

Such a worst-case scenario is exacerbated if 10% of the volume of the 75 particles (0.03 cm3) is considered to be leachable and ends up dissolved in

the 20 L (20,000 cm3) of process fluid/drug substance/drug product in a 20-L SUS bag. But even in such an extremely unlikely worst-case scenario, the concentration of potential leachable chemicals from embedded particles in the drug substance or drug product would be only about 1 ppm (1 mg/L).

Certainly, this type of risk analysis must be performed specific to the actual drug substance or drug product volumes and relative to the location (criticality) of a given SUS bag within a biopharmaceutical process. However, the example risk analysis above suggests that it is highly unlikely for potential leachable chemicals from embedded particles within SUS films ever to reach concentrations that would raise concerns and require a chemical analysis.

Low Risk to Film IntegrityEven under the extreme stresses and strains generated in the pressure burst

test, only very large embedded particles had any marginal impact on SUS film integrity. In addition, even under extreme worst-case assumptions, calculations suggest that only very low concentrations of potential leachable chemicals from particles embedded within SUS could end up in drug products. Also important to note is that camera inspection systems on SUS film extruders do reliably detect embedded particles, and researchers generally try to control the cleanliness of the SUS film extrusion process. In summary, the risk from embedded particles in SUS films to SUS bag integrity and drug product purity is likely to be very low.

References1 ASTM D883-00. Standard

Terminology Relating to Plastics. ASTM International; https://www.astm.org/Standards/D883.htm.

2 Tseng HH, Lai FS, Lee CK. Pneumatic Bursting Characteristics of Plastics Films. Polym. Eng. Sci. 33(8) 1993: 504. c

Corresponding author Klaus Wormuth ([email protected]) is a principal scientist at Sartorius Stedim Biotech GmbH in Göttingen, Germany. Lucie Delaunay is project manager, Veronique Gissinger is a laboratory technician, Nelly Montenay is film and material platform manager, and Magali Barbaroux is in corporate research, at Sartorius Stedim Biotech, Aubagne, France.

Figure 3: Effect of gel particle size on burst pressure; (top) Flexboy film, burst pressure as a function of gel size (equivalent circular area), reference = no gel; (bottom) Flexsafe film, burst pressure as a function of gel size (equivalent circular area), reference = no gel

Pres

sure

Max

(bar

)

4

3

2

1

0

Referencen = 22

Gels ≤2 mm2

n = 30

Gels >2 mm2

n = 1

Pres

sure

Max

(bar

)

Gel Size

Referencen = 28

<0.3 mm2

n = 60.3–1 mm2

n = 351–2 mm2

n = 112 mm2

n = 114 mm2

n = 3>4 mm2

n = 8

6

5

4

3

2

1

0


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The Foundations for

Single-Use Manufacturing.

Redefined from A–Z.

In the past, biopharma companies were struggling with various risk factors which kept them from implementing single-use solutions.

With our solid single-use foundation for biomanufacturing processes we are solving all of these challenges simultaneously. Our fully integrated single-use platform connects an exclusive approach in biocompatibility, state-of-the-art integrity control and testing as well as a unique automation platform and supply network.

This strategy provides flexibility and acceleration which leads to a cost-effective process that ensures the quality of your biologics and enhances patient safety.


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Sartorius Stedim Biotech GmbHAugust-Spindler-Str. 1137079 Göttingen, Germany www.sartorius-stedim.com