This document summarizes a report published by the Bio-Process Systems Alliance (BPSA) regarding recommendations for testing, evaluation, and control of particulates from single-use process equipment. The BPSA is a trade association that facilitates implementation of single-use technologies through various initiatives. The report was created by a working group consisting of subject matter experts from single-use technology suppliers and end users. It provides guidance on characterizing and minimizing particulate levels throughout the lifecycle of single-use technologies, including manufacturing, storage, handling and end use. It also discusses investigation and mitigation of particulate deviations. The BPSA recommends further work to develop standardized measurement methods, application-specific requirements, a catalog of particle types,

2. Bio-Process Systems Alliance
 Trade association of suppliers and users: 46 Members
 Facilitates implementation of single-use via:
 Networking opportunities
 Safe harbor for dialogue
among industry business leaders
 End-user / supplier forums
 Best practice guides/projects
 Extractables; Particulates; Integrity; Change

3. Page 1
MEMBERS

4. Page 2
MEMBERS

5. “RECOMMENDATIONS FOR
TESTING, EVALUATION AND
CONTROL OF PARTICULATES
FROM SINGLE-USE PROCESS
EQUIPMENT”
BPOG Webinar
15 January 2015

6. The Final Product

7. The Team
Csilla Kollar, Dow Corning Corp.
Mark A. Petrich, Merck & Co., Inc.
Eric Isberg, Entegris
Ernie Jenness, EMD Millipore
Helene Pora, Pall Life Sciences
James D. Vogel, The BioProcess
Institute
John Stover, AdvantaPure/New Age
Industries
Ken Davis, Value Plastics, Inc.
Kirsten Strahlendorf, Sanofi Pasteur
Mike Johnson, Entegris
Patrick Evrard, GSK Vaccines
Maureen Eustis, The BioProcess Institute

8. Discussion
 How BPSA got here?
 Some History
 The Effort…The Team and Methods.
 Details of the Paper
 Recommended Next Steps
 BPSA Recommendations
 Panel Discussion
 Efforts in Standards Organizations.

9. Recognized a Need
 Concerns for particulate contamination
discussed at 2011, 2012 and 2013 BPSA Int’l
Single-Use Summits (ISUS).
 2013 formed working group of SMEs from SUT
supplier and end user companies to discuss
and recommend best practices.
 Dozens of meetings held over 9-months to
balance all considerations from both sides.

10. Document Overview
 Educational document for suppliers and end
users in the Single-Use Technology (SUT)
Industry
 Guide to characterization and determination
of levels and types of particles in SUTs
 Recommends procedures to achieve
minimal levels of particles in SUTs.

11. The Intent
 Help the BPSA members navigate this
complex topic throughout the lifecycle of
the SUT.
 New to--and familiar with--SUT
 End Users and Suppliers

12. Common Understanding
 End users to convey their specific
particulate requirements.
 Suppliers can demonstrate their
capabilities.

13. Common Goal
“The goal of end users, regulators, and
standards-setting organizations should be to
minimize particulates in drug products, without
placing unnecessary expectations on suppliers
for minimal safety gains. Improving the
manufacturing quality will reduce the risk of
harm to patients from particle contamination.”
--Langille, Stephen E., Particulate Matter in Injectable Drug Products, PDA J Pharm Sci Tech 2013

14. Table of Contents
Part I: Introduction
Part II: Particle Risk
Part III: Particle Characteristics & Quantification
Part IV: Particle Measurement Methods
Part V: Single-Use Technology Lifecycle
Part VI: Methods of Control for Suppliers
Part VII: Particulate Evaluation as Part of End User
Manufacturing
Part VIII: Deviation Response/Mitigation Plans
Part IX: Summary and Conclusion
Part X: BPSA-recommended Next Steps
Part XI: Terms and Definitions
Part XII: References

15. PART I
INTRODUCTION

16. Common Goal
“The goal of end users, regulators, and
standards-setting organizations should be to
minimize particulates in drug products, without
placing unnecessary expectations on suppliers
for minimal safety gains. Improving the
manufacturing quality will reduce the risk of
harm to patients from particle contamination.”
--Langille, Stephen E., Particulate Matter in Injectable Drug Products, PDA J Pharm Sci Tech 2013

17. PART II
PARTICLE RISK

18. Definition of “Particle”
“A particle is loose mobile matter or
embedded matter that is unintentionally
present in/on the single-use
component/assembly and potentially
may contact or may end up in the
process/product fluid.”

19. Comparison
 Multi-use Equipment
o Usually cleaned and rinsed before sterilization
o Rinse removes particles; soil, cleaners,
environmental contaminants
 Single-Use Equipment
o Received as Ready-To-Use
What’s in the SUT may end up in the process
media
o Usually not rinsed prior to sterilization
o Particles may be generated during the products
lifecycle

20. Risk
 Fewer is Better!
 Well documented in the regulations.
o “Surfaces…shall not be reactive, additive or
absorptive”
(CFR 211.65)
o “All surfaces…free of surface solids”
(CFR 600.11)

21. What are the Risks of Particles?
 for the Patients
 for the Product
 for the Process

22.  Patients
o Obstruction of blood vessels
o Over-taxation of immune system
o Incompatibility with arterial system
o Level of risk is based on factors such as the route
of drug delivery (IV, SC, IM), age/health of patient,
frequency of dosage, characterization of the
particle
What are the Risks of Particles?

23.  Product
o Safety
o Effectiveness
o Chemical structure
o Top cause of recalls in 2012
o Level of risk can be based on the product;
Vaccines, mAbs, Cell Therapies, Intermediate
What are the Risks of Particles?

24.  Process
o Media/Buffer Prep
o Upstream: Fermentation, Separation
o Downstream: Purification, Drug Substance Storage
o Final Fill
o Is there a filter downstream of the process?
o Is it storage or transfer of process media?
o What is the exposure time?
What are the Risks of Particles?

25. • Location of Particle
o External surface
o Embedded
o Process Contact Surface
What are the Risks of Particles?

26. PART III
PARTICLE CHARACTERISTICS
&
QUANTIFICATION

27. • Particle Definition
• Type of Particle
• Particle Characteristics
Particle Characterization

28. Type of Particles
 Intrinsic (native to the SUT)
 Extrinsic (foreign to the SUT)
 Known
 Unknown - MOST CONCERNING

29. Particle Characteristics
 Size
o Visible or sub-visible
 Shape
o Spherical or angular
 Hardness
o Soft/deformable or hard/brittle
 Texture
o Smooth or rough
 Chemical Composition
o Inert or toxic
o Intrinsic or extrinsic
 Quantity

30. Particle Size
 Visible (>50-100 microns)
o USP <1>
o USP <790> (<1790>)
o EP 2.9.20
o JP 6.06
 Sub-visible
o USP <788>
10 and 25 micron

31. Particle Size
 Visible Gray Zone
1µm 50µm 150µm
Sub-visible
visible
gray zone
Visible
100µm

32. Particle Size

33. Particle Size
 The BPSA suggests the 100-micron size be the
benchmark for differentiating between visible and
sub-visible particles.
 The draft USP monographs have clearly defined
visible particles as being >100 microns.

34. PART IV
PARTICLE MEASUREMENT
METHODS

35. Particle Measurement
 Visual Inspection
 Liquid Measurement Methods

36. Visual Inspection
Typical attributes inspected for are:
 Component arrangements are verified;
 Connections are verified to be secure;
 Embedded particles/gels;
 Film creases;
 Exterior particles are observed and removed;
 Finished goods are inspected for internal particles
where possible, e.g. clear and translucent
components; and
 Actions are taken based on inspections and may
include discarding the single-use assembly.

37. Liquid Measurement Methods
 Light obscuration (USP <788>)
 Light scattering
 Laser Diffraction
 Membrane Microscopy (USP <788>)
 Electron microscopy
 Dynamic Imaging (MFI)

38. PART V
SINGLE-USE TECHNOLOGY
LIFECYCLE

39. Single-Use Lifecycle
 Each step of the SUT’s lifecycle can
contribute to the potential for additional
particulates.
 A proper Particulate Management Program
will minimize these contributions and keep
the levels as low as possible.
 Process steps can be added, e.g. filtration,
to reduce SUT’s particulate levels.

40. Particulate Management Program
 Fishbone of potential sources
 Each sub component
 Each Process Step
people
methods
machine
environment
measurements

41. SUT Lifecycle

42. SUPPLIER
 Raw materials of the components (resins,
compounds);
 Preparation of equipment (cleaning and/or
sanitization) for manufacturing components
or assemblies;
 Fabrication of each individual component.
(bag film, tubing, connectors, O-ring, filter
membrane);
 Assembly of the sub-assembly (bag with
ports, filter capsule, connector);
 Assembly of the final assembly (bag
assembly, transfer assembly, filling
assembly);
 Packaging;
 Transportation and handling; and
 Sterilization (irradiation).
END USER
 Receipt;
 Quality inspection;
 Storage;
 Transfer to the production area;
 Removal of packaging (may
occur at various stages);
 Preparation (e.g., rinsing,
autoclaving);
 Use; and
 Disposal.
SUT Lifecycle

43. SUT Lifecycle

44. SUT Lifecycle

45. SUT Lifecycle

46. Chain of Responsibility
 Each stage of the supply chain is
responsible
 The Final assembly provider is
responsible.

47. Particulate Capabilities
What can be delivered?
Routinely?

48. PART VI
METHODS OF CONTROL FOR
SUPPLIERS

49. Methods of Control for Suppliers
• Raw Components
• Clean Room Operation
• Clean Room Performance
• Manufacture of the SUT

50. Requirements
 Manufacturing processes designed to minimize the risk of particle
generation, introduction or inclusion into the finished assembly;
 Maintaining proper preventative maintenance of manufacturing
equipment;
 Ensuring cleanliness of materials and people entering the
cleanroom;
 Controlling flow of materials and personnel within the
manufacturing environment;
 Providing operator training;
 Demanding cleanroom gowning;
 Ensuring cleanroom maintenance and control;
 Inspecting product, including up to 100% in-process surveillance
and lot release testing;
 Recording performance trending for both the cleanroom operation
and the manufactured SUT; and
 Documenting non-conformance, root cause analysis and
corrective/preventative actions.

51. Clean Room Maintenance/Controls

52. Recommendations
 Apply risk-adjusted and science-based approach
 Particulate control is everyone’s responsibility –
not just the final integrator’s
 ISO Class 8 or better for component providers unless
thorough risk analysis concludes this is not needed (post-
production cleaning possible)
 ISO Class 7 or lower for assembly integration unless
thorough risk analysis concludes this is not needed (pre-
use flush possible or end-use doesn’t require low
particulate claims)

53. Conclusions
 Quality has to be built in – can’t rely of final test
 Particulate control – both visible and sub-visible – in single-use
assemblies is feasible
 Awareness regarding particulate contamination has increased
tremendously – requirements for critical applications will get even
more stringent
 Instituting the following…
 Appropriate incoming material controls
 Material /personnel workflow in/out of clean rooms
 Environmental monitoring
 Appropriate gowning/de-gowning processes
 In-process inspection
 Robust OOS investigation and CA/PA procedures
… will result in meeting/exceeding user expectations for particulate
contamination

54. PART VII
PARTICULATE EVALUATION
AS PART OF END USER
MANUFACTURING

55. Particulate Evaluation: End-User
• Processing Considerations
• Best Practices for Handling SU
Components

56. Potential Sources
Source type Manufacturing-induced source
Processing materials and raw
material ingredients/ product
Particulates from the single-use component can interact with components of a protein
solution to form precipitates.6 These can be further exacerbated by process conditions
and/or type of single-use component
Manufacturing activities Connecting and disconnecting assemblies
Using fiber-shedding filters with zero-to-minimal flushing
Limited use of rinsing/washing/flushing steps
Valve use
Pump use
Onsite or site-to-site transportation conditions and containers
Mismatched components, non-optimal component-equipment integration
Mixing components chafing inside of container or impeller parts/bearings
Rough handling
Regular equipment/processing aid wear
Abrasive product (e.g. undissolved aluminum salts)
Manufacturing environment Open system applications of single-use
Personnel Handling of SUT assembly or part(s)

57. Processing Considerations
 Mixing speed;
 Number of connections made during the
process;
 Storage times and temperatures;
 Line clamping or valve use;
 Pumping/spallation;
 Rinsing/flushing/washing steps; and
 General handling practices

58. Best Practices for Handling Single-
Use Components
1. Cover sharp parts. Do not remove
supplier’s protective coverings until
necessary.
2. During storage, bags should be
contained in a hard-shelled container
or, at minimum, covered with a sealed
outer bag. Lines should be secured
as appropriate, especially when
freezing.
3. Flush the systems, especially those
that contain filters or fiber-shedding
components, where possible.
4. Avoid over-processing: over-mixing,
or over-handling of
components/assembly.
5. Avoid pulling, flattening, rubbing,
squeezing, flexing, or twisting of
components/assembly.
6. Optimize the welding and sealing
conditions to avoid “flashing” or
inadequate welds.
7. Keep product fluid contact path as short
and with as few components as possible.
8. Do not lift items by their tubing
connections.
9. Minimize the stress on tubing junctions.
Avoid sharp bend radii.
10.Do not allow sharp objects to be used in
the same area as single-use components.
11.Match peristaltic pump tubing type and
dimensions to pump heads, process
duration, and process fluids. Do not
exceed anticipated tubing life.
12.Minimize surfaces that can rub together
during shipping, storage, or use.

59. PART VIII
DEVIATION RESPONSE

60. • When in the lifecycle is the particle
observed?
• Where is the particle observed?
• Particle Investigation Steps
Deviation Response/Mitigation

61. WHEN in the Life Cycle a
Particle is Observed?
 Supplier
 Subcomponent manufacturing
 QC prior to packaging
 After packaging and before shipment
 End User
 Incoming receiving
 Point of use
 Before use
 During Use
 After Processing is complete

62. WHERE is the particle Observed?
On or In the SUT?
 Outer Package
 Inner Package
 Exterior of the SUT
 Within the Product/Process Contact
Surface

63. Particle Investigation Steps
Detect Report Hold the Lot
Compare to
Catalog
Capture &
Characterize
Quarantine
Determine
Root Cause
Assess
Impact
Prepare
Investigative
Report
Review and
CAPA

64. Summary & Conclusion
There are four primary areas that must be managed
in order to ensure robust control of particulates in
single-use systems:
1. Cleanliness of the incoming materials;
2. Cleanliness of the manufacturing steps and assembly
processes;
3. Cleanliness of the operators and associated gowning;
and
4. Cleanroom facility and equipment maintenance and
controls.

65. Summary

66. Summary
 Particle Control is everyone’s responsibility.
 Quality must be built-in.
 Proper systems to minimize particulates
 Continuous Improvement for the full SUT lifecycle
 Track Results
 Show the particle control process is improving.

67. What We Did
 Listened to concerns of BPSA Members
(suppliers and end users)
 Formed working group of SMEs (suppliers and
end users)
 Held weekly phone meetings for 9 months often
involving very spirited “debates”
 Developed best practices and recommendations
 Resulted in BPSA Paper.

68. But a lot did not make it into the
particulate paper…

69. …because of…
 Some lack of consensus
 Very In-depth discussions
 Attempts to keep the paper
a manageable length.
 Deadlines!
We’re making progress, but a lot of
content still needs to be addressed!

70. What are the Next Steps?

71. Next Steps
1. Need SUT Particulate Measurement Method.
2. Better defined application-specific requirements.
3. Create industry-wide catalog of particles.
4. Conduct particulate generation studies.
5. Create a formal SUT Best Practices Guide.
6. Establish supplier/end-user Quality Agreements
of SUT Acceptance Criteria.

72. Next Steps
6. Establish supplier/end-user Quality
Agreements of SUT Acceptance Criteria.

73. How Can You Buy the Paper?
 Contact Jeanette McCool
or Kevin Ott at
 mccoolj@socma.com
 ottk@socma.com
or visit:
www.bpsalliance.org
 Cost: $295

74. Other Happenings…
In addition to the BPSA project:
 USP-787, 790, 1787, 1790
 ASME-BPE added particulate content to the
Non-Mandatory Appendix portion of the ASME-
BPE 2014 Standard resulting from discussion by
their Particulate Task Group…More to come
 ASTM has two work streams creating a draft of a
standard related to particulate currently under
review.

75. If You Build It…
 BPSA has made a big contribution.
 What is next?
 Who can help?
 How can you help?

76. Discussion
 More is needed.
 Do we do it? Or do we hand it off to
someone else?
 Did we miss anything?
 Your thoughts?