BPSA Technical Guides For SingleUse Systems used In BioPharmaceutical Manufacturing

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BPSA Technical Guides For Single-Use Systems
used In Bio-Pharmaceutical Manufacturing

• Roberta Morris
• Dir. Marketing Product Development Charter
  Medical, Ltd.
• Director,BioProcess Systems Alliance (BPSA)

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Overview

• The Bio-Process Systems Alliance (BPSA)
• Published Guides and Recommendations
• Component Quality Tests
• Extractables and Leachables
• Irradiation and Sterilization
• Disposal Guide

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What is BPSA?Bio-Process Systems Alliance

• An organization representing suppliers of
• Disposable process components
• Single Use Systems
• Services to the biopharmaceutical industry
• Special purpose group within the Society of the
  Plastics Industry, Inc. (SPI)

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BPSA Objectives

• Implementation
• Encourage and facilitate adoption of single-use
  systems in biopharmaceutical manufacturing
• Information
• Communicate industry best practices to
  biopharmaceutical manufacturers, regulatory
  bodies and non-government organizations
• Quality
• Establish industry consensus guidelines and
  standards for the manufacture and use of
  single-use process components and systems

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BPSA Members Include
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BPSA Publications

• Component Quality Test Matrices (Parts 1 2)
• BioProcess Intl May June, 2007
• Irradiation and Sterilization Validation (Parts 1
  2)
• BioProcess Intl Sept Oct, 2007
• Disposal Guide
• BioProcess Intl Nov, 2007
• Extractables and Leachables
• BioProcess Intl Dec, 2007 (Part 1)
• BioProcess Intl Jan, 2008 (Part 2)

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BPSA Component Quality Test Matrices

• Component Subcommittees
• Films and containers (bags)
• Filter capsules
• Tubing
• Connectors
• Quick connects, fittings, clamps
• Aseptic/sterile connectors

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BPSA Component Quality Test Matrices

• Actions
• Reviewed current quality tests and methods by
  system component
• Compiled consensus Matrix of Quality Tests and
  References for bioprocess system components

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Component Quality Test Matrices
Applicable References

• Many applied test and performance references are
  not specific to bioprocess components
• Drug and biologic GMP regulations and guidances
• Pharmacopoeial standards and info. chapters
• Medical device standards (e.g. AAMI, ANSI, ISO)
• References sourced from related fields
• Medical Devices
• Sterile implantables
• Blood product transfusion systems
• Pharmaceuticals and Biologicals
• Final dosage containers
• Processing equipment, e.g. sterilizing filters

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Component Quality Test Matrices
Standard Methods in Use

• 21 CFR 177 Code of Federal Regulations
• AAMI Association for the Advancement of Medical
  Instrumentation
• ANSI American National Standards Institute
• ASME BPE American Society of Mechanical
  Engineers, Bioprocessing Equipment
• ASTM - American Society for Testing and
  Materials
• EP European Pharmacopoeia

Cont.
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Component Quality Test Matrices
Standard Methods in Use (cont.)

• ISO International Standardization Organization
• ISTA International Safe Transit Association
• FTMS Federal Test Method Standard
• NIH National Institutes of Health
• JP Japanese Pharmacopoeia
• BP British Pharmacopoeia
• USP United States Pharmacopoeia

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Component Quality Test Matrices
Outline

• Test type and general description
• Test reference
• Standard or guidance
• Test frequency
• Qualification, intermittent, lot release
• Summary description

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Component Quality Test Matrices
Films and Containers

• Qualification Test Methods include

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Component Quality Test Matrices
Filter Capsules

• Qualification Test Methods include

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Component Quality Test Matrices
Tubing

• Qualification Test Methods include

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Component Quality Test Matrices
Connectors and Fittings

• Qualification Test Methods include

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Component Quality Test Matrices
Summary

• Defines consensus quality criteria and methods
  applied by BPSA members
• Minimum quality criteria for component selection
• Reference sources and applicability

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Irradiation and Sterilization

• Standards for validation of sterilization
  by gamma irradiation are established
• ASTM International
• ANSI / AAMI / ISO 11137 (2006)
• AAMI TIR33
• Recognized by regulatory agencies
• Application to biopharma process scale systems
  can be costly and complex
• Less burdensome alternate approaches
  may be application

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Irradiation and Sterilization

• Purpose
• Provide an overview on microbial control and
  sterilization by gamma irradiation
• Key terms and definitions
• Options and recommendations
• Microbial control vs. sterilization validation
• Sterilization validation
• ANSI / AAMI / ISO 11137 (2006) standard
• Application to bioprocess systems

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Goal
Irradiation and Sterilization

• Educate and enable readers to
• Understand meaning of
• Microbial control
• and
• Validated sterility
• Differentiate where each is applicable
• Make educated decisions about which will be
  sufficient or required

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Basics of Gamma Irradiation
Irradiation and Sterilization

• Electromagnetic radiation (higher energy than
  x-rays)
• Emitted from radionuclides, e.g. Cobalt 60
• Breaks DNA Microbial Lethality
• Provides benefits in safety, time and cost
• No residual radioactivity, no quarantine for
  out-gassing
• Minimal waste byproducts
• Well-defined operating parameters
• Ensures accurate dosing
• Repeated radiation of single-use
  systems/components should be avoided

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Basics of Sterilization by Gamma
Irradiation and Sterilization

• Sterility Assurance Level (SAL)
• Probability of a non-sterile unit (not simply 0
  cfu / unit)
• Typically validated to SAL lt10-6 (lt1 non-sterile
  unit / million)
• Dosages (kiloGrey, kGy, 0.1 megaRad, obsolete)
• Bioburden (cfu) generally low and non-resistant
• lt8-10 kGy typically adequate to achieve 0 cfu /
  unit
• gt25-50 kGy generally applied to achieve SAL lt10-6
• Sterility
• 0 cfu / sample ? sterile
• Sterility validated SAL (typically lt10-6)

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Microbial Control vs. Sterilization
Irradiation and Sterilization

• Validation of sterility of bioprocess systems can
  be costly and burdensome
• Consider microbial control by irradiation as an
  alternative to a sterile label claim
• gt25 kGy provides equivalent lethality without
  quantified sterility assurance level (SAL)
  required for validated sterile claim
• Sterile claim may not be required

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Single-Use Biopharmaceutical Process
Figure courtesy Pall Life Sciences
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Microbial Control and Sterilization
Irradiation and Sterilization

• gt25 kGy dose typically sufficient to
• Eliminate viable bioburden (0 cfu / unit)
• Provide high level of microbial control
• Single-use systems often used with non-sterile
  processes
• Low to 0 cfu / unit adequate
• Validated sterile claim (SAL10-6) not required
• Adequately qualified as microbially controlled

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Irradiation and Sterilization
Examples

• Sterile claim
• Mammalian cell culture media, additives
• Sterile process, sterile API (bulk)
• Sterile fill (finished dosage)
• Irradiated for microbial control
• Process development
• Bacterial fermentation additives (some)
• Chromatography buffers
• Diafiltration buffers
• Any process not claimed as sterile

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Current Standards for Sterile Validation
Irradiation and Sterilization

• ANSI/AAMI/ISO 111372006 (Parts 1 3)
• Method 1 and Method 2
• VDmax - Substantiation of two pre-established
  irradiation sterilization dosages
• 15 kGy and 25 kGy
• AAMI TIR332005
• VDmax - Flexibility of 7 additional dosages
• 17.5, 20, 22.5, 27.5, 30, 32.5 and 35 kGy

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Approaches to Validation Testing
Irradiation and Sterilization

• Single-use bioprocess systems / components pose
  technical challenges
• Size and complexity
• Relatively high cost/system
• Small batch sizes
• Alternate strategies to minimize validation
  described in ANSI/AAMI/ISO 11137
• Master Product
• Equivalent Product
• Simulated Product

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Approaches to Testing Large Systems
Irradiation and Sterilization

• Large articles are difficult to manipulate
  aseptically
• Bioprocess systems/components may be expensive
• Need to balance desire to ensure technical
  correctness with desire to avoid false results

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Approaches to Testing Large Systems
Irradiation and Sterilization

• Entire system
• Validate sterility of external system
• Product packaging as containment device
• Difficult to validate internal fluid path
• System portion only
• Fluid Path
• Sectioning of a large product

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Summary - Key Decisions
Irradiation and Sterilization

• Microbial Control or Sterile Claim?
• Irradiation only
• Claim gamma dosage for microbial control
• Irradiation Validation of Sterility (SAL lt10-6)
• Bioburden analysis of gt30 units
• Sterility testing of gt10 units
• Quarterly audits of gt10 units for bioburden and
  gt10 units for sterility to maintain Sterile claim
• If sterility validation
• Product/packaging or fluid path only?
• Model / equivalent / simulated product?

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Photo courtesy Sartorius Stedim Biotech
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Regulations

• FDA Title 21 of the Code of Federal Regulations
  (CFR) Part 211.65 (1)
• Equipment shall be constructed so that surfaces
  that contact components, in-process materials, or
  drug products shall not be reactive, additive, or
  absorptive so as to alter the safety, identity,
  strength, quality, or purity of the drug product
  beyond the official or other established
  requirements.

CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED
PHARMACEUTICALS - Equipment Construction
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Regulatory Guidance

• FDA ICH Q7
• Equipment should be constructed so that
  surfaces that contact raw materials,
  intermediates, or APIs do not alter the quality
  of the intermediates and APIs beyond the official
  or other established specifications.

GOOD MANUFACTURING PRACTICE GUIDANCE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS
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Definitions
Extractables and Leachables

• Extractables Chemical compounds that migrate
  from any product contact material, including
  elastomeric, plastic, glass, stainless steel or
  coating components when exposed to an appropriate
  solvent under exaggerated conditions of time and
  temperature.
• Leachables - Chemical compounds, typically a
  subset of extractables, that migrate into the
  drug formulation from any product contact
  material, including elastomeric, plastic, glass,
  stainless steel or coating components as a result
  of direct contact with the drug formulation under
  normal process conditions or accelerated storage
  conditions and are found in the final
  drug product.

Conceptually the same as for final
container/closures
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Relationship
Extractables and Leachables

• Extractables include
• Known additives
• Impurities in additives and polymers
• Reaction products of material with extraction
  solvents

Extractables

• Leachables include
• Known extractables
• Extractables that are chemically modified by drug
  formulation

Leachables
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Processing Materials
Extractables and Leachables

• Process systems can have many more individual
  product contact materials/components than
  container/closures
• Many of the components are custom packaged
  Bag from Vendor A
• Tubing from Vendor B
• Filter from Vendor C
• Connectors from Vendor D
• Complete EL assessment for each component can be
  a daunting task

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Extractables and Leachables
Purpose

• Provide an overview for single use components and
  systems
• Guide for suppliers, users and regulators
• Key terms and definitions
• Regulations and guidances
• Application to bioprocess systems
• Recommend extraction solvents, methods
• Suggest analytical methods
• Typical extractable materials

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Extractables and Leachables
Goals

• Learn from what others have done
• PQRI Study the science of EL is universal
• Learn from earlier single use system
• Filters
• Adapt to address the present and future
• Educate vendors and end-users so that
  expectations and responsibilities are clear

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Additl Relevant Documents
Extractables and Leachables

• 1999 CDER Container Closure Guidance
• Not applicable to processing materials
• Classes of drug formulations
• Inhalation, Parenterals gt Ophthalmics, Topical
• 2005 EMEA Guideline For Plastic Immediate
  Packaging Material
• PDA TR 26 Sterilizing Filtration of Liquids
• 21 CFR Part 177 Indirect Food Additives
  Polymers (GRAS)

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Program for Extractables - Overall Goals
Extractables and Leachables

• Keep within the concepts that have been developed
  by the current science for extractables and
  leachables
• Modify, where appropriate, for processing
  materials
• Provide a framework to help guide users
• Understand there may be more than one way to
  address the issue of extractables and leachables

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Single-Use Biopharmaceutical Process
Figure courtesy Pall Life Sciences
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First, Understand Your Process
Extractables and Leachables

• RD Studies
• Process descriptions, Batch records
• SOPs
• Technical reports
• Batch analysis
• Data trending
• Create comprehensive list of operating parameters
  at each step

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Process System Considerations
Extractables and Leachables

• Materials
• Filter membrane
• Filter assembly
• Prefilters
• Piping / Tubing
• Tanks / Bags
• Connectors
• Formulation
• Solvent
• Composition

• Preparation
• Sterilization
• Pre-flush
• Process
• Contact time, temp
• Mode (batch or fill)
• Batch size
• Position
• Filling or upstream
• Drug dose, regimen
• Dilution, frequency

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Create a List of Product Contact Materials
Extractables and Leachables

• Any material that has the potential to migrate
  into the final product
• List begins upstream with the starting buffers
• List finishes with materials used directly before
  the final fill of containers
• Can include
• Tubing
• Bags
• Filters
• Connectors
• O-rings

• Tangential flow cassettes
• Syringes
• Chromatography resins
• Final bulk storage vessels

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Risk Assessment
Extractables and Leachables
Initiate Extractables and Leachables Evaluation
Does material have product contact?
No
Yes
No action

• Risk Factors
• Compatibility of Material
• Location in process
• Nature of product
• Surface Area
• Contact temp., time
• Pretreatment steps

Relevant Risk?
Include vendor data and make justification for no
testing
No
Yes
Continue to Extractables
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Perform Risk Assessment
Extractables and Leachables

• Goal is to determine the product contact
  materials that have the greatest potential for an
  objectionable level of leachables
• Must be performed using criteria that are
  specific to the end user cannot be generalized
  between applications
• Best performed early in the process development
  when changes are more easily addressed

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Risk Factor 1 - Material Compatibility
Extractables and Leachables

• Most biopharmaceutical products are aqueous and
  therefore are compatible with many materials
• Most biopharmaceutical materials pass
  USP lt87gt or lt88gt Biological Toxicity testing
• But first, obtain manufacturers recommended
  operating parameters such as pH, temperature,
  pressure
• Check to be sure material is being used within
  the recommended normal operating ranges

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Risk Factor 2 - Proximity to Final Product
Extractables and Leachables

• Location directly upstream of final fill has
  direct risk to final product
• Location upstream in process MAY have a reduced
  risk
• This is true if there are steps where
  contaminants can leave the process
• Diafiltration diafiltrate volume can be 100x
  the process volume
• Lyophilization volatiles may be removed
• Ideally, supporting data should be obtained

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Risk Factors 3 and 4
Extractables and Leachables

• Solution Composition
• Extreme pH
• Higher organic or alcohol content
• Surfactants
• Components with High Surface Area/Volume Ratio
• Filters porous structure leads to area much
  larger than filtration area
• Smaller process volume usually has higher surface
  area/volume ratio

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Risk Factors 5 and 6
Extractables and Leachables

• Contact time and temperature
• Pretreatment steps
• Sterilization (e.g., gamma, ethylene oxide,
  autoclave, H202 vapor) tends to increase
  leachables
• Rinsing prior to product contact tends to lower
  leachables

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What to do with the Risk Factors
Extractables and Leachables

• Create priorities for testing
• If a change is needed, better to find out soon
• Weigh according to use-specific criteria
• Example the presence of surfactants may be
  considered a high risk for leachables,
  requiring more testing

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What to do with the Risk Factors
Extractables and Leachables

• If determine no relevant regulatory or safety
  risk for a specific product contact / material
  interaction
• Submit vendor information for regulatory filings
• If there is relevant risk
• Proceed to extractables evaluation

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Evaluation of Extractables
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Extractables Data
Extractables and Leachables

• Determine if extractables data is available from
  vendor or other reference source
• The most useful extractables data is a
  comprehensive list of potential leachables
• Goal of extractables testing is to identify
  potential leachable compounds
• Less vendor data does not necessarily mean less
  extractables or leachables
• A vendor who performs high quality extractables
  testing and identifies many extractables should
  be admired

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Characteristics of High Quality Data
Extractables and Leachables

• Extraction performed with at least two solvents
  at extreme conditions with respect to time,
  temperature, surface area/volume ratio and
  pretreatment steps
• Suggest water and low MW alcohol
• Where relevant, also or alternately a low MW
  organic
• Solvents or extraction conditions should not
  chemically or mechanically degrade polymer

Extreme relative to actual product and process
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EL Analytical Methods
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Characteristics of High Quality Data
Extractables and Leachables

• Analysis with specific analytical methods
• HPLC-UV-MS
• GC-MS
• Other specific methods as appropriate
  (e.g. ICP, Headspace GC)
• Non-specific methods such as FTIR, TOC, NVR, pH
  may also be helpful to estimate total
  extractables
• FTIR can detect compounds that are not otherwise
  found (e.g., oligomers).

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Extractables Data Evaluation
Extractables and Leachables

• Assess toxicity based on worst-case extractables
  data
• Many processing material applications have a high
  dilution factor
• Extractables tests are conducted with high
  surface area to volume ratios
• Process materials can have surface area to
  process volume ratios 1000s of times lower
• Relatively high concentration of extractables may
  be acceptable when converted to dosage
• Must be evaluated case by case

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What if Vendor Data is Not Available?
Extractables and Leachables

• Convince vendor to provide data
• Perform extractables tests
• Could be resource intensive
  if process has many
  product
  contact materials
• OR
• Proceed directly to leachables
  testing

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Leachables Testing
Extractables and Leachables
Leachable Testing Necessary
Leachables Detected?
Submit Leachables Data
Perform Leachable Testing
No
Yes
Identify and Quantitate Leachables and Assess
Toxicity
Submit Leachables Data
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Leachables Testing
Extractables and Leachables

• Should be performed on materials for which
  extractables data does not eliminate toxicity
  risk
• Ideally performed with process formulation
• Alternatively With
• Suitable models
• Analysis methods should be same or based on
  methods used for extractables testing

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Proposed Roles and Responsibilities
Extractables and Leachables

• Suppliers
• Provide high quality extractables ( leachables?)
  data
• Characterize/identify, quantify, source
• Users
• Assess utility of supplier data, generate additl
  data as needed, assess toxicity, product impact
  of leachables
• Provide regulators with extractables data and
  leachables assessment for process and drug
  product
• Identify, quantify, source, safety, stability,
  etc.
• Users and Suppliers
• Collaborate to correlate leachables with
  extractables data as needed

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Disposal of Single-Use Bioprocess Systems
The Education Committee of the BioProcess Systems
Alliance
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Typical Single-Use System and Composition

• 2,500 L bag 3-7 layers
• PE, EVA, polyamide?
• 3-15 M of tubing
• Silicone rubber or thermoplastic
  elastomer, typically 3/8 ID X
  5/8 OD
• Filter capsules
• Shells ABS, polysulfone, polypropylene,
  polyester?
• Membranes PES, PVDF, Nylon?
• Fittings, connectors, clamps
• ABS, polysulfone, polycarbonate, polypropylene?

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Factors to be considered in selecting a method
of disposal

• Current practice with
  non-process disposables
  (labware, cleaning supplies, etc.)
• Local agency requirements, guidelines, and
  available options
• Volume and weight
• Biohazard level
• Recycle-ability

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Disposal Options

• Landfill, untreated
• Landfill, treated
• Grind, autoclave, and landfill
• Recycle
• Incinerate
• Incineration with generation of steam or
  electricity
• Pyrolysis

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BPSA Guides and Recommendations

• Component Quality Test Matrices
• Part 1 - BioProcess Intl April, 2007
• Part 2 - BioProcess Intl May, 2007
• Guide to Irradiation and Sterilization
• Part 1 - BioProcess Intl Sept, 2007
• Part 2 - BioProcess Intl Oct, 2007
• Guide to Disposal
• BioProcess Intl Nov, 2007
• Recommendations for Extractables and Leachables
• Part 1 - BioProcess Intl Dec, 2007
• Part 2 - BioProcess Intl Jan, 2008

www.bpsalliance.org
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Whats Next?

• Integrate end-user company members
• Develop supplemental information with more
  detailed options and case studies
• Provide input for development of PDA
  Technical Reports on Single-Use Manufacturing

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www.bpsalliance.org
Speaker Roberta Morris

rmorris_at_lydall.com BPSA Executive Director Kevin
Ott
kott_at_socplas.org
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Questions