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

mccoolj@socma.com

ottk@socma.com

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?