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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
Page 1
MEMBERS
Page 2
MEMBERS
“RECOMMENDATIONS FOR
TESTING, EVALUATION AND
CONTROL OF PARTICULATES
FROM SINGLE-USE PROCESS
EQUIPMENT”
BPOG Webinar
15 January 2015
The Final Product
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
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.
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.
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.
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
Common Understanding
End users to convey their specific
particulate requirements.
Suppliers can demonstrate their
capabilities.
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
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
PART I INTRODUCTION
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
PART II PARTICLE RISK
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.”
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
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)
What are the Risks of Particles?
for the Patients
for the Product
for the Process
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?
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?
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?
• Location of Particle
o External surface
o Embedded
o Process Contact Surface
What are the Risks of Particles?
PART III PARTICLE CHARACTERISTICS
&
QUANTIFICATION
• Particle Definition
• Type of Particle
• Particle Characteristics
Particle Characterization
Type of Particles
Intrinsic (native to the SUT)
Extrinsic (foreign to the SUT)
Known
Unknown - MOST CONCERNING
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
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
Particle Size
Visible Gray Zone
1µm 50µm 150µm
Sub-visible
visible
gray zone
Visible
100µm
Particle Size
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.
PART IV PARTICLE MEASUREMENT
METHODS
Particle Measurement
Visual Inspection
Liquid Measurement Methods
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.
Liquid Measurement Methods
Light obscuration (USP <788>)
Light scattering
Laser Diffraction
Membrane Microscopy (USP <788>)
Electron microscopy
Dynamic Imaging (MFI)
PART V SINGLE-USE TECHNOLOGY
LIFECYCLE
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.
Particulate Management Program
Fishbone of potential sources
Each sub component
Each Process Step
people
methods
machine
environmentmeasurements
SUT Lifecycle
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
SUT Lifecycle
SUT Lifecycle
SUT Lifecycle
Chain of Responsibility
Each stage of the supply chain is
responsible
The Final assembly provider is
responsible.
Particulate Capabilities
What can be delivered?
Routinely?
PART VI METHODS OF CONTROL FOR
SUPPLIERS
Methods of Control for Suppliers
• Raw Components
• Clean Room Operation
• Clean Room Performance
• Manufacture of the SUT
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.
Clean Room Maintenance/Controls
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)
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
PART VII PARTICULATE EVALUATION
AS PART OF END USER
MANUFACTURING
Particulate Evaluation: End-User
• Processing Considerations
• Best Practices for Handling SU
Components
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)
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
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.
PART VIII DEVIATION RESPONSE
• When in the lifecycle is the particle
observed?
• Where is the particle observed?
• Particle Investigation Steps
Deviation Response/Mitigation
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
WHERE is the particle Observed?
On or In the SUT?
Outer Package
Inner Package
Exterior of the SUT
Within the Product/Process Contact
Surface
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
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.
Summary
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.
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.
But a lot did not make it into the
particulate paper…
…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!
What are the Next Steps?
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.
Next Steps
6. Establish supplier/end-user Quality
Agreements of SUT Acceptance Criteria.
How Can You Buy the Paper?
Contact Jeanette McCool
or Kevin Ott at
or visit:
www.bpsalliance.org
Cost: $295
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.
If You Build It…
BPSA has made a big contribution.
What is next?
Who can help?
How can you help?
Discussion
More is needed.
Do we do it? Or do we hand it off to
someone else?
Did we miss anything?
Your thoughts?