Validation Guide For Thermo Scientific HyClone Single

Transcription

Validation Guide
For Thermo Scientific HyClone
Single-Use Mixer (S.U.M.) Systems
For use in biopharmaceutical applications
Validation Guide
For Thermo Scientific HyClone
Single-Use Mixer (S.U.M.) Systems
Rev. 1.0
Preface
MANUAL NUMBER
1.0
--
REV
ECR/ECN
Thermo Scientific
06/22/09
Date
Description
By S. Parkinson
Single-Use Mixer (S.U.M.)
ii
Table of Contents
Thermo Scientific
Section 1
Validation Overview
1.1 Introduction.......................................................................................1
1.2 Scope.................................................................................................1
Section 2
Qualification Test Methods
2.1 Introduction.......................................................................................2
2.2 ASTM................................................................................................2
ASTM D882................................................................................2
ASTM D1003..............................................................................2
ASTM D3985..............................................................................2
ASTM E1640..............................................................................2
ASTM F1249...............................................................................3
2.3 EP......................................................................................................3
EP <3.2.2.1>................................................................................3
2.4 ISO....................................................................................................3
ISO 10993-4................................................................................3
2.5 USP...................................................................................................3
USP <85>....................................................................................3
USP <87>....................................................................................4
USP <88>....................................................................................4
USP <661>..................................................................................4
USP <788>..................................................................................4
2.6 Test Protocols.....................................................................................5
Puncture Resistance......................................................................5
Seal Integrity................................................................................5
2.7 Animal Derived Component Statement.............................................5
CIS Example................................................................................7
Section 3
Standard Component Librabry
3.1 Introduction.......................................................................................8
Physical Data...............................................................................8
Biological Compatibility..............................................................8
Chemical Compatibility...............................................................9
Standard Component Library Summary.....................................10
iii
Thermo Scientific
Section 4
BPC System Design Qualification
4.1 Introduction.....................................................................................12
4.2 DQ Development............................................................................12
DQ Test Plan.............................................................................12
Risk Assessment.........................................................................12
Design Optimization..................................................................12
4.3 DQ Verification...............................................................................13
DQ Build...................................................................................13
DQ Test Report.........................................................................13
Section 5
BPC System Operational Qualification
5.1 Introduction.....................................................................................14
5.2 OQ Process Development................................................................14
OQ Test Plan.............................................................................14
Risk Assessment.........................................................................14
Process Control..........................................................................14
5.3 OQ Process Development................................................................14
OQ Build...................................................................................15
Risk Assessment.........................................................................15
Process Control..........................................................................15
Section 6
BPC System Validation
6.1 Introduction.....................................................................................16
6.2 Process Qualification........................................................................16
6.3 Sterility Assurance............................................................................16
6.4 Endotoxin and Particulate................................................................16
6.5 Functionality....................................................................................17
Mixing Components..................................................................17
System Functionality..................................................................29
Temperature...............................................................................30
Shipping.....................................................................................34
Mixing Application Studies........................................................35
Section 7
Quality Control
7.1 Introduction.....................................................................................44
7.2 Inspection........................................................................................44
Incoming Inspection..................................................................44
In-Process Inspections and Testing.............................................44
7.3 BPC Lot Record Release and Certificate of Analysis ........................45
7.4 Sample C of A..................................................................................46
7.5 Traceability.......................................................................................47
7.6 Shelf Life..........................................................................................47
7.7 Film Fact Sheets (CX5-14 and CX3-9).............................................48
7.8 USP Class VI Data...........................................................................49
7.9 Sample Certificate of Irradiation......................................................50
iv
Thermo Scientific
Section 8
Regulatory
8.1 General............................................................................................51
8.2 BioProcess Container™ Systems (BPC).............................................51
Section 9
Appendix
9.1 References........................................................................................52
9.2 Abbreviations and Acronyms............................................................52
9.3 Film Component Information Package............................................54
9.4 Pall Kleenpak Validation Information.............................................104
Section 1
Validation Overview
Section 1 Validation Overview
1.1 Introduction
1.2 Scope
The bioprocess industry increasingly relies on single-use flexible containers
for the critical functions of packaging, delivery, transport, storing and
processing of biopharmaceutical liquids and powders. Flexible container
systems consist of plastic films, ports, tubing, fittings and end treatments.
Performance of a specific container system in a particular application
depends on the material and manufacturing quality, as well as the
conditions and constraints imposed by the application. The integrity of
stored contents depends primarily on the characteristics of the film, the
largest component (product contact surface area) of any flexible container
system. This document contains the experimental data and supporting
information that can assist in selecting and qualifying the optimal
bioprocess container system for a specific application.
This validation guide contains standard Thermo Scientific HyClone
Single-Use Mixer (S.U.M.) component lists, test methods and results,
product design verification methods, operational qualification methods,
quality control, validation and regulatory information.
This validation guide is good for one year from publication. The Standard
Component Library is subject to change without notice. As of the date of
this publication the data is current and correct.
Thermo Scientific
Section 2
Section 2 Qualification Test Methods
2.1 Introduction
2.2 ASTM
ASTM D882
Thermo Scientific
A number of tests are performed regularly to validate components for
BioProcessing Container systems, including the Single-Use Mixer. Listed
below are some of the test standards and methods used to validate the
physical and chemical properties and the biocompatibility of HyClone®
BPC systems and components.
American Society for Testing and Materials
Standard Test Method for Tensile Properties of Thin Plastic Sheeting:
This test method covers the determination of tensile properties of plastics
in the form of thin sheeting, including film (less than 1.0 mm [0.04 in.]
in thickness). Test coupons (1”x5”) were obtained from the container
material and seams.
ASTM D1003
Standard Test Method for Haze and Luminous Transmittance of
Transparent Plastics: This test method covers the evaluation of specific
light transmitting and wide-angle, light-scattering properties of planar
sections of materials such as essentially transparent plastic.
ASTM D3985
Standard Test Method for Oxygen Gas Transmission Rate through Plastic
Film and Sheeting Using a Coulometric Sensor: This test method covers
a procedure for determination of the steady-state rate of transmission
of oxygen gas through plastics in the form of film, sheeting, laminates,
coextrusions or plastic-coated papers or fabrics. Gas permeability was
measured at 23°C with 50 percent relative humidity (RH) on the
outside of the film and 100 percent RH on the inside of the film to
simulate actual use conditions for a fluid storage container in an ambient
environment. Oxygen permeability was also measured at 0 percent RH on
both sides to simulate idealized conditions.
ASTM E1640
Standard Test Method for Assignment of the Glass Transition Temperature
by Dynamic Mechanical Analysis: This test method covers the assignment
of a glass transition temperature (Tg) of materials using dynamic
mechanical analyzers. It is applicable to thermoplastic polymers, thermoset
polymers, and partially crystalline materials that are thermally stable in
the glass transition region and have an elastic modulus in the range of 0.5
MPa to 100 GPa.
Section 2
ASTM F1249
2.3 EP
EP <3.2.2.1>
2.4 ISO
ISO 10993-4
2.5 USP
USP <85>
Thermo Scientific
Standard Test Method for Water Vapor Transmission Rate (WVTR)
Through Plastic Film and Sheeting Using a Modulated Infrared Sensor:
Water vapor transmission rates were measured according to ASTM
F1249-01. Water vapor permeability was measured at 5°C and 23°C
with 0 percent RH on the outside and 100 percent RH on the inside to
simulate worstcase use conditions for a fluid storage container.
European Pharmacopoeia (EP)
The EP <3.2.2.1> is a set of physicochemical material tests, which includes
the following: appearance, acidity, alkalinity, absorbance, reducing
substances and transparency.
International Organization for Standardization
This test provides general requirements for evaluating the interactions of
medical devices with blood. It describes a classification of medical and
dental devices that are intended for use in contact with blood, based on
the intended use and duration of contact as defined in
ISO 10993-1. It covers the fundamental principles governing the
evaluation of the interaction of devices with blood, the rationale for
structured selection of tests according to specific categories, together with
the principles and scientific basis of these tests.
United States Pharmacopoeia (USP)
Bacterial Endotoxin Testing: Limulus Amebocyte Lysate (LAL) testing is
done to evaluate the presence of bacterial endotoxins in or on a sample.
This test is used to detect or quantify bacterial endotoxins that may be
present in or on the sample of the article(s) to which the test is applied.
It uses the LAL obtained from the aqueous extracts of circulating
amebocytes of horseshoe crab, which has been prepared and characterized
for use as an LAL reagent. There are two types of techniques for this
test: the gel-clot techniques, which are based on gel formation, and the
photometric techniques.
Section 2
USP <87>
Biological Reactivity Test, in vitro: This category of test evaluates
biological reactivity of mammalian cell cultures to polymeric materials.
Biocompatible materials should not show cell lysis or toxicity. USP <87>
describes two methods to test for cytotoxicity: the Agar Diffusion Test and
the Elution Test.
The Agar Diffusion Test is designed for elastomeric closures in a variety
of shapes. The agar layer acts as a cushion to protect the cells from
mechanical damage while allowing the diffusion of leachable chemicals
from the polymeric specimens. Extracts of materials that are to be tested
are applied to a piece of filter paper.
The Elution Test is designed for the evaluation of extracts of polymeric
materials. The procedure allows for extraction of the specimens at
physiological or non-physiological temperatures for varying time
intervals. It is appropriate for high-density materials and for dose-response
evaluations.
USP <88>
Biological Reactivity, in vivo: The standard used is USP Class VI
Biological Tests for Plastics. This is a series of three tests that evaluate
biological reactivity of animals to polymeric material: systemic toxicity,
intracutaneous reactivity and implantation.
The Systemic Injection Test and the Intracutaneous Test are designed
to determine the systemic and local, respectively, biological responses
of animals to plastics and other polymers by the single dose injection of
specific extracts prepared from a sample.
The Implantation Test is designed to evaluate the reaction of living tissue
to the plastic and other polymers by the implantation of the sample itself
into animal tissue.
Thermo Scientific
USP <661>
Containers Testing: This set of tests evaluates the physical and chemical
properties of plastics and their extracts. The Physicochemical testing of
plastics includes the following: heavy metals, buffer capacity, non-volatile
residue and residue on ignition.
USP <788>
Particulate Matter: Particulate matter consists of mobile, randomly
sourced, extraneous substances that cannot be quantified by chemical
analysis due to the small amount of material that it represents and to
its heterogeneous composition. The Light Obscuration Particle Count
Test (LOPCT) is done to evaluate the presence of particulates in or on a
sample.
Section 2
2.6 Test Protocols
Puncture Resistance
Quality testing is preformed to validate the quality of Thermo Scientific
HyClone BPC systems during the design phase and production process.
Components and overall systems are regularly tested to ensure the
processes and materials used in the manufacturing of BPC systems meet
high-quality expectations.
Puncture resistance testing predicts the durability of the BPC film while in
use. Since the film has a large surface area, it is most susceptible to damage
by impact with another object. Films with high-puncture resistance
correspond to materials that can absorb the energy of an impact by both
resistance to deformation and increased elongation. A film with high
puncture resistance offers superior resistance to damage, thereby providing
increased protection to the container’s contents.
Puncture resistance, measured in energy units, evaluates the film strength
and extensibility properties. Puncture resistance is similar to tensile
toughness, which measures the amount of energy absorbed by a material
under loading. High puncture resistance improves the durability and
reliability of the flexible bioprocess container by enabling it to resist
damage during handling, storage and shipment of product.
Puncture resistance was measured using an Instron tensile test machine
equipped with a 6 inch diameter annular fixture. Film was secured within
the fixture and punctured using a 0.5 inch diameter probe at a test speed
of 20 in/min. The total force and energy absorbed by the film during
puncture is measured.
Seal Integrity
2.7 Animal Derived
Component
Statement
Thermo Scientific
Routine seal integrity testing is performed on representative BPC chamber
samples to ensure that functional strength requirements are met. These
tests include seam peel, hydrostatic, and leak / burst testing.
Definition of Animal Origin and Statement of Policy Regarding Animal
Derived Component Free (ADCF) Products.
Animal Origin Definition: The current working definition of “Animal
Origin” is something derived directly from animal tissue.
Section 2
Incidental Contact Substances In Certain Raw Materials:
It is recognized that certain raw materials may be derived from non-animal
sources such as microbial fermentation. Some of these may utilize animal
origin peptides or other components in fermentation or purification
processes. However, these are incidental contact materials and are not
the original source of derivation. In these limited cases, we undertake
to document supplier certifications of source, country of origin and risk
reduction steps relating to incidental contact substances.
ADCF Status of Packaging and Product Contact Materials:
Plastics materials may contain additives used as release agents or as antislip or anti-block processing aids produced from bovine tallow. These
substances (such as calcium stearate) are incorporated into resins to
facilitate the production and processing of the resin material. While
certain plastic contact surfaces like filters, connectors, tank liners and
tubing will have limited exposure time to Thermo Scientific HyClone
products, the greatest surface-to-product contact areas and product
residence times will be with the chamber films. Two chamber film
options for long-term storage of product are offered. Our CX series of
films (CX3-9 and CX5-14) do not have animal derived components and
are considered ADCF. We provided animal origin questionnaires to our
plastic component suppliers and incorporate the response information
into our QA database. Additionally, we are working with key filter and
other plastics suppliers to encourage them to move to ADCF plastics
where feasible.
Thermo Scientific
Section 2
Component Information Summary
Description: BPC: 50, 200, 500, 1000 and 2000 L S.U.M. II Open Top, Bottom Drain Tank Liner
SH30762.04, SH30762.01, SH30762.02,
Part Number: SH30762.03 and SH30762.05
Customer: N/A
Unapproved Drawing: N/A
Drawing Number: 13460
Revision: B
Change Date: N/A
Listed below are the components of the BioProcess Container. All components listed are considered standard unless otherwise indicated. The standard components that come
in contact with the product have been validated for biocompatibility. They have all passed the USP <88> Class VI Plastics testing. The components that are non-product contact
are not tested for biocompatibility.
PRIMARY CONTACT COMPONENTS
Part Number
SH2B0894.04
SV20536.01
SV20522.01
SH2B0894.01
SV20536.01
SV20522.01
SH2B0894.02
SV20536.01
SV20522.01
SH2B0894.03
SV20536.01
SV20522.01
SH2B0949.01
SV20536.01
SV20522.01
Description
TANK LINER: 50 L S.U.M. II (CX3-9)
FILM: HyQ CX3-9
FITTING: Port, 1"
FILM: HyQ CX3-9
FITTING: Port, 1"
FILM: HyQ CX3-9
FITTING: Port, 1"
FILM: HyQ CX3-9
FITTING: Port, 1"
FILM: HyQ CX3-9
FITTING: Port, 1"
Material
See Subassembly Below
CX3 - 9 LDPE
Low Density Polyethylene
CX3 - 9 LDPE
CX3 - 9 LDPE
CX3 - 9 LDPE
CX3 - 9 LDPE
ADCF*
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
EMEA/410
Compliant**
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Processing
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Material
Polypropylene
Polycarbonate
Polycarbonate
Styrene-Ethylene ButyleneStyrene (SEBS)/
Polypropylene Blend
Platinum Cured Silicone
ADCF*
No
No
No
EMEA/410
Compliant**
Yes
Yes
Yes
Processing
Exceeds EU Requirements
Yes
Yes
Yes
Yes
N/A
N/A
Material
Polyester
ADCF*
N/A
EMEA/410
Compliant**
N/A
SECONDARY CONTACT COMPONENTS
Part Number
SV20548.03
SV20037.30
SV20037.32
Description
FITTING: Diptube Connector, 7/8" x 1/2" x 1/2"
FITTING: Quick Connect, Insert 1/2" (MPX)
FITTING: Quick Connect, Cap (MPX)
SV20678.10
SV20019.25
TUBING: 1/2" ID x 1/8" Wall
TUBING: 7/8" ID x 1/8" Wall
NON-PRODUCT CONTACT COMPONENTS
Part Number
SV20031.03
Description
FASTENER: Snapper Clamp, 1/2" - 3/4" OD Tube
* Yes = Animal Derived Component Free (ADCF). * No = Components are Animal Derived. ND = No Data Available. N/A = Non Product Contact or Non Applicable.
** Yes = AD Components Exceeds EU Requirements found in EMEA /410/ 01 Rev. 2. ** No = AD Components do not exceed EMEA/410/01 Rev 2
This information was obtained from resin and/or component manufacturers and is accurate to the best of our knowledge
BPC Technical Specialist
Thermo Scientific
1-Jun-09
Date
HyClone Laboratories, Inc.
Logan, Utah
435-792-8000
925 West 1800 South
84321
435-792-8001 fax
www.thermo.com/hyclone
Section 3
Standard Component Library
Section 3 Standard Component
Library
3.1 Introduction
The Standard Component Library of qualified parts is maintained to keep
the manufacturing of BPC systems at a high standard. The characteristics
of each component relate directly to the ability of a container system to
maintain product integrity and perform as required. In addition, knowing
the characteristics of each component guides the selection of an optimal
container system for a specific application. The standard component
library will assist the end user in identifying which configuration of
components will best meet their requirements. Qualification testing is
performed on individual components, not the finished product.
Physical Data
Flexible container systems consist of four basic types of components:
film, tubing, fittings and end treatments. The performance of a specific
container system in a particular application depends primarily on its
component parts. standard product contact materials tolerate up to 38
kGy (3.8 MRad) of gamma irradiation without loss of integrity.
Biological Compatibility
Several test standards are available to show biocompatibility, including
United States Pharmacopoeia (USP), ISO, European Pharmacopoeia
(EP) and Japanese Pharmacopoeia. Listed below are the test results for
the Standard Components Library. Components are tested post gamma
irradiation >50 kGy.
Thermo Scientific
Section 3
Chemical Compatibility
The film, being the largest component of any flexible container system,
warrants particular attention in the selection process. BPCs are made
of several film types with polyethylene (PE) product contact layers
that demonstrate chemical compatibility in a variety of bioprocessing
applications. Chemical compatibility data were obtained from resin
suppliers, technical publications, and field and in-house testing. Ratings
are based on physical test results after exposure to a specific environment
for a specific time period. The chemical compatibility data listed here is
intended to be used as a general guideline only.
Variability in temperature, exposure time, concentration, loading and
any other applicable condition may increase or decrease chemical attack.
It is strongly recommended that customers conduct testing under their
specific requirements or end-use conditions. For additional information
on compatibility with specific chemicals, please contact you sales
representative for Thermo Scientific HyClone products. The chemical
compatibility data on the following tables must be viewed with the
following caveats:
•
•
•
Storage condition variability (for example, time and
temperature).
Many chemicals may be compatible at lower concentrations.
This information does not correlate to extractables and
leachables.
Resin Legend
HDPE
High Density Polyethylene
PVDF
Polyvinylidene fluoride
LDPE
NPC
Non Product Contact
PC
Polycarbonate
PEI
Polyether Imide
TPE
Thermoplastic Elastomer
with Polypropylene base
PCCE
Poly(cyclohexylene din ethylene
cyclohexanedicarboxylate)
PP
Polypropylene
PS
Polysulfone
AC
Acrylic
PVC
Polyvinyl chloride
SI
Silicone
PTFE
Teflon PTFE 850A
NR
Nitrite Rubber
PUR
Polyurethylene
SS
Stainless Steel
SEBS
Styrene-Ethylene Butylene Styrene
S
Steel
ND
No Data
Rating Legend
E = Excellent , no discernible attack (<5% chance in physical properties)
G = Good, no significant attack, slight discoloration (5-15% chance in physical properties)
F = Fair, mild attack, limited use recommended (15-30% chance in physical properties)
X = Not Acceptable, aggressive or severe attack ( > 40% chance in physical properties)
ND = No Data
n/a = Not Applicable NG = Not Given NT = Not Tested
Thermo Scientific
Section 3
SV20247
SV20245
SV20189
SV20179
SV20178
Unitized SIP Adapter
Double SIP Adapter
Double SIP Adapter
Double SIP Adapter
Sanitary Gasket
Tri-Clamp to Hose Barb Adapter
End Cap
Quick Connector
Quick Connector
SI
SI
SI
SI
PVDF
PVDF
Yes
Yes
Yes
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
ND
Pass
ND
Pass
ND
Pass
Pass
Pass
Pass
Pass
ND
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
ND
3.2.2.1
3.2.2.1
3.2.2.1
Yes
Yes
Yes
-80 to 60 C
-80 to 60 C
-80 to 60 C
E
G
E
E
G
E
E
G
F
E
G
E
E
F
G
F
E
G
F
E
E
E
G
E
G
E
E
E
E
F
F
F
F
F
F
F
F
F
G
G
F
F
F
E
E
E
F
E
E
E
E
E
E
E
E
E
E
F
F
F
E
G
E
E
E
X
G
X
E
G
G
E
E
E
E
G
G
G
G
G
G
G
G
G
X
G
G
G
G
ND
ND
E
G
ND
ND
E
E
E
F
E
ND
ND
ND
G
G
G
ND
E
ND
F
ND
E
E
E
E
E
G
E
E
E
E
X
X
X
X
X
X
X
X
X
G
G
X
X
X
E
E
E
X
E
E
E
G
G
F
E
ND
E
E
X
X
X
E
X
ND
F
ND
F
X
X
X
X
F
X
X
G
X
E
E
E
ND
F
ND
E
ND
X
X
X
X
ND
X
ND
X
ND
ND
X
ND
E
E
G
E
E
E
E
E
E
E
E
E
E
E
E
E
X
G
E
E
E
ND
ND
E
E
G
G
E
E
E
E
E
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
E
E
X
X
X
X
X
G
G
G
X
X
X
X
X
E
X
ND
G
ND
E
X
X
X
E
X
ND
G
ND
E
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
E
E
X
X
X
X
X
E
E
G
X
ND
Salts
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
F
F
X
X
X
X
X
X
X
G
X
Vegetable Oils
E
E
E
E
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ND
ND
E
X
X
X
E
X
X
X
E
Kentones
Essential Oils
Esters
Physical /
Mechanical
Pass
Pass
Pass
E
E
X
E
E
E
E
F
F
F
F
F
F
F
F
F
G
G
F
F
F
E
E
E
F
X
X
E
E
E
E
E
Glycols
Hydrocarbons
Amines
Biocompatibility
Pass
Pass
Pass
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
G
X
X
X
E
E
X
X
X
X
X
X
X
F
X
F
F
F
E
G
E
E
ND
X
X
X
E
X
F
E
F
X
G
E
E
E
E
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
E
X
X
X
E
G
G
E
E
X
X
X
E
X
ND
F
ND
E
X
X
X
X
F
F
E
F
-50 to 230 C
ND
-80 to 204 C
-73 to 135 C
-48 to 72 C
-51 to 135 C
-50 to 45 C
-67 to 135 C
E
G
-73 to 135 C
-40 to 121 C
Yes
ND
Yes
Yes
Yes
No
Yes
ND
-40 to 148 C
Yes
Yes
n/a
Yes
n/a
3.1.9
n/a
n/a
n/a
n/a
n/a
3.2.9
n/a
F
F
F
F
X
X
X
X
X
X
X
X
X
G
X
X
X
X
E
E
F
X
G
G
F
F
F
E
F
n/a
n/a
Pass
n/a
n/a
n/a
Pass
n/a
Pass
Pass
Pass
Pass
ND
Pass
Pass
Pass
ND
Pass
Pass
ND
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
ND
ND
Pass
Pass
Pass
Pass
Pass
ND
ND
ND
ND
ND
ND
ND
ND
Pass
Pass
Pass
ND
ND
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
ND
Pass
Alkalis
-62 to 129 C
-62 to 129 C
-62 to 129 C
-62 to 129 C
-50 to 230 C
-60 to 260 C
-60 to 260 C
-60 to 260 C
-60 to 260 C
-60 to 260 C
-60 to 260 C
-60 to 260 C
-60 to 260 C
10 to 40 C
10 to 40 C
10 to 40 C
-60 to 260 C
-60 to 260 C
-73 to 135 C
-73 to 135 C
-62 to 129 C
-50 to 230 C
Up to 60 C
Up to 60 C
-62 to 129 C
-17 to 135 C
-17 to 135 C
-80 to 60 C
-62 to 129 C
Aldehydes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
ND
Yes
ND
Yes
ND
Yes
No
No
No
Yes
ND
No
No
Yes
Yes
Yes
Yes
Yes
No
No
Yes
Yes
Acids
Alcohols
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Working
Temperature
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Pass
Pass
Pass
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Pass
ADCF
Pass
Pass
Pass
Pass
Pass
ND
ND
ND
ND
ND
ND
ND
ND
Pass
Pass
Pass
ND
ND
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
European
Pharmacopoeia EP
Standard Components Library Summary
SV20249
SI
AC
PUR
SI
Pass
Pass
Pass
Pass
Pass
Pass
Pass
ND
Pass
ND
Pass
ND
Pass
Pass
Pass
Pass
Pass
ND
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
ISO 10993-4
Sterilization
Resin ID
Resin Family
Pass
Pass
Pass
SV20261
SmartSite Luer Lock Needle Free Valve
SI
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
Yes
Yes
Yes
Yes
Yes
Yes
No
No
Yes
No
No
No
Yes
Physicochemical
USP < 661>
Part Identification
Part Description
Pass
Pass
Pass
HyQ CX5-14
No
No
No
SV20535
Part Number
Film
Yes
Yes
Yes
LDPE
PCCE
LDPE
Affinity PL 1880
Eastman ECTEL
Affinity PL 1880
HyQ CX3-9
Tubing
SV20536
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
SI
Yes
Tubing
Amesil 50
SF1416
TyGon 3350
C-Flex R70-082
Tygon S-50-HL
Pharmed BPT
Engage 8180
Pharmapure
SV20019
End Treatments
SV20271
Double SIP Adapter
SEBS
SEBS
PVDF
SI
PC
PC
PVDF
PP
PP
LDPE
PS
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
C-Flex R70-374-000
Yes
SV20274
SIP Adapter
Tri-Clamp Tank Adapter
Luer Lock
Unitized SIP Adapter
Nylon Clamp
Luer Lock
End Plug
End Plug
Luer Lock
Sanitary Connector
Steam Thru Connector
SV20037.01, .04, .23
-.32, .43
SV20037.20-.22, .33,
.34, .37-.42, .44
SV20293
SV20299
SV20404
SV20412
SV20420
SV20421
SV20449
SV20503
SV20507
SV20519
SV20616
*250 L S.U.B. Only
Bacterial Endotoxin
USP <85>
10
Thermo Scientific
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
SEBS
PVC
TPE
LDPE
ND
Yes
Cytotoxicity
USP <87>
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
SEBS
Udel P -1700-MG11
GE Lexan HPS1-1124
USP Class VI
USP <88>
Tubing
Tubing
Tubing
Tubing
Tubing
Tubing
Pre-Cut Tubing
PC
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
SIP / Autoclave
Compatible
SV20063
SV20157
SV20259
SV20651
SV20706
SV20678
SV20749
PS
Kynar 720
Kynar 1000HD
Kynar 720
Kynar 1000HD
Amesil 50
Sanitech 50
Sanitech 50
Lim 6045
Sanitech 50
Lim 6045
Sanitech 50
Lim 6045
Sanitech 50
NG
NG
NG
Sanitech 50
Lim 6045
C-Flex R70-082
C-Flex R70-082
Kynar 1000HD
Amesil 50
Makrolon 2558-550115
Kynar 1000HD
Profax PD626
Profax PD626
Engage 8402
Udel P-1700-MG11
Gamma Stable
Section 3
ND
ND
n/a
n/a
ND
No
Yes
Yes
Yes
Yes
Yes
No
Up to 60 C
Up to 60 C
-80 to 60 C
< 200 C
< 110 C
< 110 C
< 175 C
-50 to 45 C
‘-50 to 45 C
3 to 40 C
F
G
G
E
F
E
E
X
E
E
G
X
X
X
E
G
E
E
X
X
X
E
E
X
F
X
F
F
X
X
X
F
X
X
X
X
X
X
X
F
X
F
F
E
X
F
F
X
F
E
X
X
X
ND
X
F
E
G
E
E
E
F
X
X
E
E
X
E
E
E
E
E
E
E
E
E
E
E
E
E
F
E
E
X
F
F
X
X
E
E
X
E
ND
E
X
F
ND
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
F
E
E
E
F
E
E
E
E
E
E
E
E
F
G
G
G
X
G
E
ND
F
E
E
E
E
E
E
F
E
F
F
E
E
F
F
G
F
E
ND
G
ND
E
ND
ND
F
E
F
F
G
E
E
X
X
E
E
F
E
G
G
G
G
G
F
G
F
F
E
G
F
F
X
F
E
E
X
E
E
E
E
F
G
F
F
X
E
E
X
X
X
ND
X
G
E
E
E
E
E
E
G
E
G
G
E
E
G
G
X
G
E
X
X
X
X
X
X
G
E
G
G
X
G
G
E
X
G
X
E
X
G
G
X
G
X
X
X
X
E
E
E
E
X
X
G
G
G
G
X
X
X
X
G
G
E
X
X
X
G
E
E
X
X
X
G
X
X
X
X
X
G
X
G
G
E
X
G
G
X
G
E
X
X
X
X
X
X
X
X
X
X
X
X
E
X
X
X
X
X
E
X
X
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
G
E
X
X
X
G
E
G
G
G
G
G
G
G
G
G
E
G
G
G
X
G
E
X
X
X
E
X
X
E
Salts
E
ND
G
E
E
Vegetable Oils
X
ND
X
G
E
Kentones
Essential Oils
Esters
Physical /
Mechanical
Yes
n/a
n/a
n/a
NPC
NPC
Yes
Yes
Yes
-62 to 129 C
G
G
G
G
G
G
E
G
E
E
E
G
E
E
X
E
E
X
X
X
E
X
E
E
Glycols
Hydrocarbons
Amines
Biocompatibility
ND
n/a
n/a
n/a
Yes
Up to 60 C
F
F
F
F
F
E
F
E
E
E
F
E
E
X
E
E
G
X
Alkalis
Sterilization
Resin ID
ND
Resin Family
Pass
n/a
Yes
-17 to 135 C
-17 to 135 C
-17 to 135 C
-17 to 135 C
-17 to 135 C
-80 to 60 C
-17 to 135 C
-60 to 110 C
-60 to 110 C
Up to 260 C
-17 to 135 C
-50 to 70 C
121 - 126 C
< 175 C
< 110 C
2 to 160 C
15 to 40 C
< 82 C
X
G
G
E
E
Aldehydes
G
n/a
No
No
No
No
No
Yes
No
Yes
Yes
ND
No
No
Yes
Yes
Yes
Yes
ND
ND
-50 to 230 C
-20 to 200 C
-40 to 40 C
-50 to 70 C
2 to 160 C
Acids
Alcohols
F
n/a
n/a
n/a
ND
n/a
n/a
ND
n/a
n/a
n/a
ND
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Yes
Yes
Yes
No
Yes
Working
Temperature
E
n/a
n/a
n/a
n/a
n/a
NPC
NPC
ADCF
Part Identification
Part Description
Yes
n/a
Yes
NT
NG
NT
NT
NT
Pass
NT
NT
PC
NT
NT
NT
Pass
NT
NT
Yes
Pass
Pass
Engage 8411
No
No
LDPE
Yes
Pass
Pass
Pass
Pass
Pass
Pass
Pass
n/a
Dow Engage
8130 / 8411
No
Yes
Yes
Yes
Pass
Pass
Pass
NT
PE
Yes
Yes
Yes
Yes
Pass
Pass
Pass
Pass
n/a
n/a
n/a
n/a
Borealis HD810MO
Huntsman H2153
Huntsman H2153
Amesil 50 LSR -60
No
No
No
Pass
NT
NT
NT
Pass
PP
HDPE
HDPE
SI
PE
PS
Yes
Yes
Yes
Pass
Pass
n/a
n/a
n/a
Huntsman PE 2053
Yes
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
NT
n/a
NT
NT
Pass
NT
NT
Pass
n/a
Pass
Pass
Pass
PC
PC
LDPE
Yes
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
NT
n/a
NT
NT
Pass
NT
NT
Pass
n/a
n/a
Kynar 1000HD
No
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
n/a
ND
ND
Pass
Pass
Pass
Pass
n/a
Pass
PVDF
Yes
No
No
No
No
No
No
No
No
No
Yes
No
No
Yes
Yes
Yes
Yes
No
No
Yes
No
Yes
No
Yes
n/a
ISO 10993-4
Pass
PC
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Physicochemical
USP < 661>
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Profax PD626
Profax PD626
Profax PD626
Profax PD626
Profax PD626
Engage 8402
Profax PD626
BP Solvay G60-25-144
BP Solvay G60-25-144
Teflon PTFE 850A
Profax PD626
Dowlex IP10
DuPont Tyvek 1073B
Amesil 50 LSR -60
Huntsman H2153
316L
NG
NG
Bacterial Endotoxin
USP <85>
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
Pass
ND
Pass
NT
n/a
NT
NT
PP
PP
PP
PP
PP
LDPE
PP
HDPE
HDPE
PTFE
PP
HDPE
HDPE
SI
HDPE
SS
PC
SI
Yes
Yes
Yes
Yes
Yes
Cytotoxicity
USP <87>
n/a
n/a
n/a
n/a
n/a
Amesil 50
FKM E51406
GE Lexan HPM 1944
Dowlex IP10
316L
USP Class VI
USP <88>
Pass
NT
NT
Pass
n/a
SI
Viton
PC
HDPE
SS
S
NR
European
Pharmacopoeia EP
Standard Components Library Summary (continued)
Part Number
SV20665
Y-Connector
Injection Tee
1 “ Port Plate
Straight Connector
T-Connector
Y-Connector
Y-Connector
Straight Connector
T-Connector
Straight Connector
Y-Connector
Luer Lock
Elbow Connector
1” Port Plate
Diptube Connector
Stir Bar lock Ring
Stir Bar Dish
Stir Bar
Double Elbow Connector
1 1/2” Tri-Clamp
Sparge Membrane
Temperature Sample Port
1000 L Impeller
Ferrules for Diptube
Aseptic Connector Male
Aseptic Connector Male /Female
End Cap
50L and 250L 1/2” Port
50L Sparge 31/4” Flange
250L Sparge 61/2 “ Flange
Fitting 38 mm Endcap
50L Impeller
250L Impeller
Temperature Sample Port
Pinch Clamp
Tubing Clamp
End Treatments (continued)
SV20668
SV20716.01
SV20716.02
SV20716.03
SV20722
SV20735
SV20733*
SV20750
SV20031
SV20664
SV20052
SV20219
SV20290
SV20401
SV20402
SV20403
SV20422
SV20423
SV20504
SV20505
SV20506
SV20507
SV20510
SV20522
SV20548
SV20571
SV20572
SV20573
SV20650
SV20667
SV20712
SV20750
SV20784
SV20787
Disposable Pressure Transducer
Fittings
SV20796
Bioreactor Gasket
Bioreactor V-Rings Seals
Bioreactor Seal Cup
Bioreactor Bearing Port
Bioreactor Hub
Bioreactor Bearing
Bioreactor Dust Cover
SIP / Autoclave
Compatible
11
Thermo Scientific
S.U.B. Assemblies
SV20724
SV20725
SV20731
SV20732
SV20737
SV20747
SV20736
*250 L S.U.B. Only
Gamma Stable
Section 4
Section 4 BPC System Design
Qualification
4.1 Introduction
4.2 DQ Development
DQ Test Plan
Risk Assessment
Design Optimization
Thermo Scientific
The Design Qualification (DQ) phase consists of design development
and design verification. The DQ process ensures new BPC components,
products or systems meet the design requirements. DQ is an integral part
of the development process ensuring that quality and reliability is designed
into each BPC we manufacture.
Design development follows a formal design control process which
establishes the design and process requirements. Design requirements
include, but are not limited to the following categories: physical,
performance, material, reliability, manufacturing, packaging and
regulatory. Product designs are developed via a 3-D model and then
optimized through engineering analysis, risk assessment, reliability
assessment and prototype evaluation.
The DQ test plan outlines the verification testing that ensures products
meet the design requirements for reliability and risk assessment. Products
are initially designed with a 2x safety factor. The reliability to which
designs and processes meet these requirements is a minimum of 90
percent reliability and 90 percent confidence, with a goal of achieving
99.99 percent reliability with 90 percent confidence.
Risk assessment is performed using design failure modes and effects
analysis (DFMEA). This tool identifies and prioritizes the potential failure
modes and their effects and the current controls. The results are used to
establish design improvements that eliminate or minimize the risk of the
potential failure modes or effects.
The design is optimized through several techniques, including design
of experiments (DOE)–which is a multi-variable analysis used to define
and optimize critical design features and characteristics. Finite elemental
analysis (FEA)–which evaluates the deformation and loading of a
product or part 3-D model through a set of simple structural elements,
interconnected at a finite number of nodes. The governing equations for
the approximate structure can be solved exactly providing approximate
solutions to the real product or part. Reliability assessment is performed
using stress-strength analysis, Weibull analysis and other reliability tools
to ensure product reliability. Prototype and conceptual model designs are
verified by evaluating machined components, stereo lithography (SLA)
and cast urethane parts.
12
Section 4
4.3 DQ Verification
DQ Build
DQ Test Report
Thermo Scientific
The design verification phase of the DQ is the building, testing and
reporting of the product to the DQ test plan. The results of the testing
are summarized in the DQ report and the results then support the initial
drawings and specifications.
The DQ build generates parts on prototype production equipment
according to preliminary process procedures. Alternative processes that
will not be utilized in the operational qualification process may be used
in the DQ build to verify the design. Design verification may then be
completed in the operational qualification.
The DQ testing verifies that the design meets the requirements. The DQ
test report summarizes the test results and engineering analysis.
13
Section 5
Section 5 BPC System Operational
Qualification
5.1 Introduction
5.2 OQ Process
Development
The process development phase of the OQ includes development
of equipment, processes, product and material flow. It also includes
optimization of processes and material flow, development of process
control, risk assessment, parameter optimization and confirmation.
OQ Test Plan
The OQ test plan outlines the qualification testing of the product to
assure that the design and processes meet the product’s requirements.
The reliability to which designs and processes meet the requirements is a
minimum of 90 percent reliability and 90 percent confidence with a goal
of achieving 99.99 percent reliability with 90 percent confidence.
Risk Assessment
Risk assessment is performed using process failure modes and effects
analysis (PFMEA). PFMEA is a tool that identifies and prioritizes the
potential failure modes and their effects and the process controls. The
results are used to minimize potential failure modes and establish process
improvements that eliminate or minimize potential failure modes.
Process Control
To optimize production processes, Design of Experiments (DOE) are
performed. The results of these experiments are used to refine parameters
in the Process Control Document (PCD). PCDs are established to
control the process to assure that requirements or specifications are met.
Work instruction documents (WID) are also outlined during process
development.
5.3 OQ Process
Verification
Thermo Scientific
The Operational Qualification (OQ) phase consists of process
development and process qualification. The OQ ensures products
meet design and process requirements. The OQ is an integral part of
the development process assuring quality is designed into each BPC
manufactured.
The process verification phase of the OQ is the building, testing and
reporting of the product to the OQ test plan. The results of these tests are
summarized in the OQ report with those results then supporting the final
approval of the specifications, work instruction documents and process
control documents.
14
Section 5
OQ Build
OQ Test Report
Document Release
Thermo Scientific
The OQ build is designed to build parts on the production equipment
according to procedures developed during process development and to
train production personnel to the production documentation. Production
documentation does not need to be released at this point.
The OQ testing verifies production products meet specification
requirements. The OQ test report summarizes the results.
The production documentation is released based on successful OQ testing.
Documentation includes WIDs, drawings and specifications.
15
Section 6
Validation
Section 6 Validation
6.1 Introduction
Product and process validations have been developed and implemented as
defined in the BPC Validation Master Plan, and is in compliance with the
concepts of cGMP for medical devices. Meaningful product validations
demonstrate compliance with release criteria and approved product claims.
Process validation provides opportunities to improve production processes.
BPC irradiation, endotoxin and particulate validation is based on current
testing standards. These tests evaluate manufacturing conditions as well as
product cleanliness and consistency.
6.2 Process
Qualification
6.3 Sterility
Assurance
6.4 Endotoxin and
Particulate
Thermo Scientific
Process Qualification (PQ) consists of a production build and validation
testing when a new product or change in manufacturing process
is introduced. The production build takes place under the defined
specification. The acceptance criteria set from the OQ results or DOE are
utilized as the requirements for validation testing. BPC systems are tested
functionally when applicable. Validation testing verifies and confirms that
product manufactured according to the PCD meets the acceptance criteria
set by BPC engineering during the OQ phase. Pending validation results,
the product produced during the production build may be saleable.
Validation of the gamma irradiation Sterility Assurance Level (SAL) for
the BPC product family is performed as per ANSI/AAMI/ISO 111372:2006 guideline. The standard outlines the VDmax25 test methods
following the use of a “simulated product.” The test kit consists of a
200 L chamber and a representative sample of connectors and tubing used
on standard BPC products. This BPC and assembly is referred to as the
“monster bag” and evaluates a worstcase configuration for sterility. This
method validates a minimum irradiation dose of 25 kGy for all products
and provides an SAL of 10-6.
Process validations and monitoring are established for endotoxin and
particulate for the manufacture of BPC systems. Particulate (USP 788)
and endotoxin (USP 85) assays in conjunction with bioburden testing
on sample flexible containers to demonstrate product consistency are
performed. BPC test samples consistently meet or exceed the acceptance
criteria.
16
Section 6
Validation
6.5 Functionality
Mixing Components
Descriptions of the design of the Single-Use Mixer (S.U.M.) BPC are
provided in the following sections. Some individual components of the
S.U.M. were utilized directly from the Thermo Scientific HyClone
Single-Use Bioreactor (S.U.B.) design and the corresponding testing
results are included here.
Individual Component
Designs
Descriptions of the design of individual components of the S.U.M. are
provided in the following sections.
Bearing Port Design
The following section details the individual components comprising the
bearing/hub assembly. See labeled schematic below for components.
Figure 6.1 Bearing/hub assembly
Highlights of the bearing port design include the following:
• Under-cut lip which allows snap in feature of the seal-cup.
• Locating lip to interface with drive motor housing.
• Tortuous sterility path when fully assembled with all components.
• Polyethylene construction for seal capability with bag film.
Seal Cup Design
Thermo Scientific
Highlights of the design are the following:
• Seven snap legs. These legs take minimal force to snap in seal cup
to bearing port, but a larger force to remove seal cup.
• Three concentric rings for seal and gasket placement.
• ADCF polycarbonate construction.
17
Section 6
Validation
V-Ring Seals
Gasket
Bearings
Dust Cover
Hub Design
Impeller Design
Details of the seal are as follows:
• High wear resistance Viton construction.
• Reliable sealing capabilities.
• ADCF construction.
Silicone gasket provides a seal between bearing port and contact fluids.
Details of the gasket:
• ADCF construction.
• Molded from qualified Silicone.
Hub assembly design makes use of two sealed bearings. This locks the hub
to the bearing port and eliminates the failure mode of the hub slipping
and causing seal misalignment.
An oil seal used as a dust cover to enclose the assembly.
Stainless steel construction due to product contact nature. This piece
provides the hollow pass through for the drive shaft to couple with the
mixing impeller. Provides sealing counter faces for the v-ring seals.
• Stainless 316 construction.
• Hexagon profile couples with drive shaft.
• Sealing counter faces: machined to a high quality polished surface.
The geometry of each impeller was defined by the following guidelines:
• Style: Pitched Blade
• Impeller Diameter: 5.75”, 7.875” or 9.875”
• Blade Angle: 45°
• Number of Blades: 3
• Impeller Tubing: ADCF, C-Flex
Figure 6.2 Impeller and tubing design
Chamber Design
Thermo Scientific
The chamber design met Design Input requirements for geometry and
porting requirements.
18
Section 6
Validation
Individual
Component
Evaluation
Bearing Port Evaluation
(S.U.B. Testing)
Seal Cup
The following figure is a cross sectional view of the bearing assembly and a
three-dimensional view of the seal cup.
Figure 6.3 Seal cup design
Seal Cup Engagement Test
This evaluation was to verify that all snap legs on the seal cup were
properly seated in the bearing port. A total of 46 hub assemblies were
evaluated. There were 24 samples evaluated upon completion of full
functional testing and 22 pre-gamma samples upon completion of leak/
burst testing. The 24 samples evaluated were post-gamma, while the
remaining 22 samples were pre-gamma. Results were that all legs were
fully seated except those legs that were either partially or fully located
in the lifter gap. Those legs did flex out into their relaxed free state and
would be captured by the undercut lip if it had existed in that area.
All samples met the requirement of no unseated engagement legs.
Thermo Scientific
19
Section 6
Validation
Seal Cup Disengagement
Test
This testing was done to determine the forces required to disengage the
fully seated seal cup from the bearing port. Samples tested were pregamma and consisted only of the bearing port and seal cup. Samples were
fixed on the Instron, and tested under tensile load at a crosshead speed of
5 in/min. No requirements were set for this test and it was conducted for
information only.
Results below show an average removal force of 277.5 lbf with a standard
deviation of 26.3 lbf. The large standard deviation results from the varying
loads due to the random alignment of the seal cup leg relative to the
bearing port. The resulting lower 3-σ value of 198.6 lbf is acceptable due
to no tensile load being applied to the seal cup during use.
Seal Cup Disengagement
1/27/2006
Rate: 5 in/min
Sample
lbf
1
2
3
4
5
6
7
8
9
10
293.3
281.9
267.5
300.1
322.2
242.8
255.0
293.8
278.3
240.3
Stats
ave
stdev
min
max
277.5
26.3
240.3
322.2
Table 6.1 Seal cup disengagement results
V-Seal Wear Evaluation
Thermo Scientific
The installation parameters of the v-ring seals are critical to the
functionality of the system. The critical parameters being the stretch of
the inner diameter of the seal and the compression of the lip. This lead to
optimization of the seal installation for the S.U.M. application through
extensive testing evaluating stretch and lip compression. The resulting seal
final assembly performed as intended.
20
Section 6
Validation
Figure 6.4 Hub assembly cross-section
Sterility Testing of Hub
Assemblies
A final sterility run was conducted on a total of seven samples. Samples 14 contained the product contact 35 mm seal only, samples 5-7 contained
the upper 50 mm seal only (see Figures 6.5 and 6.6). This arrangement
allowed testing and demonstrating reliability with single seals, thus when
multiple seals are used in the final configuration they are redundancies to
the system to improve reliability. Hub assemblies were sealed into sample
bags that were then filled with TSB by the liquid media group. Access
holes were drilled into the port bodies to directly challenge the seals with
positive growth media. House air was filtered into the bags to create a
positive pressure environment. Testing was conducted in the validation
incubation room.
Figure 6.5 Tests #10-1 to 10-4, Product contact V-seal only
Thermo Scientific
21
Section 6
Validation
Figure 6.6 Tests #10-5 to 10-7, Non Product contact v-seal only
Samples were tested over a five month period resulting in a total of
28.9 million revolutions. The design requirement is 120 RPM for 21
days, which equates to 3.63 million revolutions. All samples met the
requirement of no sterility failures.
Gasket Pressure Test
Hub Sub-Assembly Testing
Thermo Scientific
This testing was conducted to test the square profile gasket. Samples were
molded out of silicone. In use, the gasket will experience an approximate
pressure range of 0.5-1.0 psi. Testing was limited to 40 psi maximum
due to safety concerns. Results show that all samples were tested up to 40
psi with no leaks. All samples passed the requirement of >5 psi without
leakage.
This testing was to evaluate the hub assembly for functionality and
durability. A total of eight samples were assembled in the clean room and
gamma irradiated. The hub assembly was tested for seven days at 360
rpm. This resulted in the required number of revolutions based upon
the 21-day run at 120 rpm requirement established in the design input.
Testing was accomplished on prototype test stands; samples did not house
a drive shaft, impeller, and were not sealed into a BPC. Results were that
all samples functioned properly with no issues and all engagement legs
were fully seated. Samples were taken apart upon testing conclusion and
were visually evaluated. Results show that the v-ring seals demonstrated a
consistent wear pattern and performed as intended. No abnormalities were
noted.
22
Section 6
Validation
Impeller to Hub Tubing Pull
Test
Testing was performed to evaluate the connection of the impeller tubing
to the impeller on one end and the stainless hub on the other end. The
tubing tested was 0.75” ID, 1/8” wall ADCF C-Flex, supplied from the
vendor at a specified pre-cut length. A total of ten samples were scheduled
for testing; one sample was not tested. The samples were tested after
the supported burst testing. Samples were tested to verify that the pull
strength of the connection exceeded normal forces during drive shaft
insertion into the impeller assembly.
Assembled BPC Evaluation
(S.U.B./S.U.M. Testing)
NOTE: The following tests on BPCs are equivalent for the S.U.B and
S.U.M.
Visual Inspection
Dimensional Inspection
Eleven 50 L and eleven 250 L assembled S.U.B./S.U.M. BPCs were
visually inspected. All containers met the visual requirements for
appearance, quality and workmanship. There were no abnormalities noted.
Dimensional inspection was performed on 11 each of the 50 and 250 L
finished S.U.B./S.U.M. BPCs. All measurements were within drawing
specifications for both S.U.B./S.U.M.s.
Leak/Burst Test –
Unsupported
Leak and burst testing was performed on the 50 and 250 L S.U.B. BPC in
an unsupported condition. Testing procedures included filling the S.U.B./
S.U.M. BPC to 1 psi and holding for two minutes. All units passed the
test requirements with no issues. Average leak hold pressures for the 50
and 250 L S.U.B.s were 1.17 and 1.13 psi. Average maximum pressures
were 3.23 for the 50 L and 1.82 psi for the 250 L S.U.B.
Container Burst Strength
Test – Supported
Leak/Burst Tests were performed on the 50 and 250 L S.U.B. BPCs,
supported in the corresponding size S.U.B. tank. Testing procedures
included filling the S.U.B. BPC to 1 psi and holding for two minutes. All
of the S.U.B./S.U.M. BPCs passed the test requirements. Average leak
hold pressures for the supported 50 and 250 L S.U.B. BPCs were 1.154
and 1.064 psi, respectively. Average maximum pressures were 6.758 psi for
the 50 L and 4.07 psi for the 250 L S.U.B. BPC.
Three samples of the 250 L S.U.B. BPC were burst upon conclusion of a
21 day functional sterility test. S.U.B./S.U.M. BPCs were pressurized in
order to generate burst data for liquid filled and supported conditions at
an operating temperature of 37°C. Results below show location of burst
to be in the headspace of the bag. The three samples passed the burst
requirement of no seam failures.
Thermo Scientific
23
Section 6
Validation
Sample
Burst Location
1
2
3
Bearing port
Top seam
Top seam
Max
Pressure
3.21
3.59
3.69
Failure Type
(Material/Seam)
Material
Material
Material
Pass/Fail
Pass
Pass
Pass
Table 6.2 Half volume burst testing – 250 L S.U.B.
Film and Port Weld Seam
Strengths
Peel tests were performed on all welded seams (film-to-film and portto-film). All weld seam strengths met standard S.U.B./S.U.M. BPC
requirements according to our control methods for manufacturing the 50
and 250 L S.U.B.s.
Hardware Evaluation
Summary
A qualification of the hardware for the 200, 500, 1000 L Single-Use
Mixers (S.U.M.) was conducted to qualify the design and process used in
the manufacture of this product. The key elements of the design are listed
below:
• Stainless steel outer support container
• Portable cart or dolly
• BPC chamber to drive interface
• Drive shaft
• Mixer motor
• Motor controller
• Electrical box or panel
Qualification test results demonstrated that the materials, methods, and
processes established produce S.U.M. hardware units that meet or exceed
all requirements.
Visual Inspection and
Dimensionals
Four units of each size were inspected and found to be in conformance
to the drawings. All welds and mechanical connections were secure
with no defects or anomalies. Surface finish and passivation were also in
compliance with the drawings. All hardware met the visual requirements
for appearance, quality and workmanship. There were no anomalies noted.
The overall dimensions of the units were measured and found to conform
to the drawing and met all other design requirements of the footprint,
height, and BPC interface fit. The S.U.M. systems provided for a
bottom drain port along with space for a top fill port, meeting design
requirements. The following table provides the results of the dimensional
verification (all units in inches).
Thermo Scientific
24
Section 6
Validation
Dimensional
Test*
Tank ID
Cart
Width
Tank
Bottom to
floor
200 L Spec
21.3
34.0
Tolerance
1.0
1.0
200 L Actual
21.3
34.5
500 L Spec
31.5
34.0
Tolerance
1.0
1.0
500 L Actual
30.8
34.5
1000 L Spec
42.2
38.7
Tolerance
1.0
1.0
1000 L Actual
41.5
39.0
*all measurements taken with calibrated tape
7.0
1.0
7.3
7.0
1.0
7.0
7.0
1.0
7.0
Height
(Inside)
44.0
1.0
43.3
57.0
1.0
56.3
54.0
1.0
54.3
Cart
Height (w/out
Length (w/
Height
motor mount
Electrical Box)
(w/ motor)
block)
47
53.50
62.2
2
0.50
2
47
53.25
62
52.3
66.20
75.2
2
0.50
2
52
66.00
75
58.3
64.00
74.1
2
0.50
2
59
64.00
74
Motor Mount
Channel Offset
from cart center
Back of channel
to tank center
0.00
0.50
0.00
3.00
0.50
3.25
6.00
0.50
6.00
14.40
0.50
14.75
19.20
0.50
18.75
23.70
0.50
23.50
Table 6.3 Dimensional verification of S.U.M. hardware
Motor Functionality
Seven units were operated from 70-350 rpm at nominal volume with
an aqueous solution. Test results indicated that all units demonstrated
acceptable variable speed control and maintained selected speeds. The
following table shows the results from the S.U.M. motor calibration for
the 200 L S.U.M. at maximum and minimum volumes.
S.U.M. Hardware Calibration (120 VAC - 60 Hz)
Verify: VFD Parameters
Rated Speed: 1725
Calibration Factor: 172.5
Slip Factor: 0
Supply voltage: 120
200 L S.U.M. - (70-169 rpm)
Volume
200 L
RPM (output) RPM (actual)
10
7.90
20
16.80
30
25.70
40
36.60
50
43.50
60
52.30
70
61.20
80
70.10
90
79.00
100
88.00
110
96.90
120
105.90
130
114.80
140
123.80
150
132.70
160
141.80
170
150.70
180
159.60
190
168.50
200
178.00
Error %
21%
16%
14%
9%
13%
13%
13%
12%
12%
12%
12%
12%
12%
12%
12%
11%
11%
11%
11%
11%
200 L S.U.M. - (70-169 rpm)
Volume
100 L
RPM (output) RPM (actual)
10
7.90
20
16.70
30
25.70
40
34.50
50
43.40
60
52.20
70
61.10
80
70.10
90
78.90
100
87.90
110
96.80
120
105.80
130
114.80
140
123.70
150
132.70
160
142.00
170
150.90
180
159.80
190
168.70
200
177.60
Error %
21%
17%
14%
14%
13%
13%
13%
12%
12%
12%
12%
12%
12%
12%
12%
11%
11%
11%
11%
11%
Table 6.4 S.U.M. Motor calibration
Thermo Scientific
25
Section 6
Validation
Motor Functionality
Measurement of motor operating temperature was conducted at high
mixing speed while mixing water. The motor temperature reached steady
state after one hour and the results of the tests can be seen in Table 6.5 for
the 1000 L unit.
1000 L
RPM
150
200
250
300
350
Motor Temperature (˚F)
106.5
110.5
112.4
112.7
121.6
Table 6.5 Motor temperature at various rpm
Unit Mobility
System Functionality
Minimum Volume
Determination
Six units (two of each size) were moved by a single operator with and
without fluid (filled to nominal volume). Units were moved on a level
cement floor by a single operator; however it is recommended that two
operators move the 1000 L unit for safety.
Three units (200 L, 500 L, and 1000 L) were tested in five sequential 4day runs at 128 percent rated RPM. The S.U.M. BPC units were loaded
into the hardware. No interface issues were observed with the S.U.M.
BPCs and the hardware at the coupler block, drive shaft, drain port,
and other lines sets on the BPC. All units met or exceeded performance
requirements.
The mixing range is defined at 100 percent nominal volume for the upper
limit, while the lower limit is based on having enough liquid above the
impeller to prevent extreme cavitations. Submersing the impeller prevents
shock loading of the system, which may result in premature component
failure. Table 6.6 shows the minimum fluid volume requirements based on
minimum fluid heights. The data indicate that minimum volume is tank
geometry based.
Minimum Volume
System
S.U.M.
(with plastic
vessel)
S.U.M.
(with
stainless
steel vessel)
System
Size (L)
Minimum
Volume (L)
200
500
1000
50
200
500
1000
2000
100
250
500
12
40
100
200
400
Percent
Distance from
Minimum
of Total Impeller to Bottom Volume
Volume
of Tank (cm)
Height (cm)
50%
50%
50%
24%
20%
20%
20%
20%
17.5
19.8
21.6
4.8
7.6
7.1
11.4
10.2
50.8
57.2
55.9
12.4
19.8
22.4
23.1
27.9
Volume per
Distance
Above Cone
(L/cm)
2.4
5.0
9.1
1.0
2.0
4.5
8.7
14.2
Table 6.6 Minimum volumes
Thermo Scientific
26
Section 6
Validation
Fluid Velocities
A BPC was installed into each hardware system and filled to minimum
volume and then to maximum volume. Fluid Velocity was measured in
the tank(s) using a SpeedTech knot meter sensor, which has an accuracy
of ±.05 m/s. The sensor was mounted approximately 30 degrees from
vertical. Data was recorded at four positions in the tank approximately 10
inches apart (vertically).
Figure 6.7 Fluid vectors and flow rate sampling points
Fluid Velocity S.U.M.
0.6
0.5
2 0 0 L m a x vo lu m e
m/s
0.4
5 0 0 L m a x vo lu m e
1 0 0 0 L m a x vo lu m e
0.3
2 0 0 L m in
5 0 0 L m in
0.2
1 0 0 0 L m in
0.1
0
1
2
3
4
Tank Locaon
Graph 6.1 Fluid velocities in the S.U.M. by sampling location
Mixing System Durability
Thermo Scientific
Each BPC was allowed to mix for a minimum 90-hour time period
to evaluate the durability of the BPC and components. All BPCs were
gamma irradiated at a 25-38 kGy level. All systems were run at 130
percent of the rated RPM (increased the motor temp by approximately
10°F). Four samples of each size were run for 90+ hours or 7.5x longer
than the 12 hour requirement.
27
Section 6
Validation
Hub Durability
Impeller Durability
With properly loaded BPCs, there were no hub failures experienced.
Visual inspections of the impeller show no deformation of the impeller.
Hardware Motor
The Brothers BF2SW30-005TL4AX ½” HP motors performed well.
There is an increase in motor temperature as the motor RPM increases.
The motor temperature increases approximately one degree Fahrenheit for
every 10 RPM. It is not recommended that the motor be overdriven so the
VFD value was set to 100 percent of rating (i.e. 360 RPM max).
Drive Shaft
The drive shaft met or exceeded requirements. The wear on the drive shaft
hex was measures at .004 inch wear after 30 days at 450 RPM. This met
the maximum wear requirement of .010 inch. The impeller (at its nominal
location) is 6.25 inches from the inside edge of the tank, at a maximum
drive shaft deflection the clearance would be reduced to 2 inches leaving
enough room for functional operation of the impeller.
500 L Force vs. RPM
18
16
Lbs Force
14
12
10
Max Volume lbs force
Min Volume lbs force
8
6
4
2
0
100
150
200
250
300
350
400
450
500
RPM
Graph 6.2 Drive shaft force at various rpm
System Force Loading
Thermo Scientific
Drive shaft axial load forces were measured in the mixing system by
mounting the motor on a load cell. Forces were measured with 150 -lbf
capacity load cell, which have an accuracy of ±1.5-lbf.
28
Section 6
Validation
Graph 6.3 Finite element analysis of drive shaft axial force
S.U.M. Functional
Testing
System Functionality
Thermo Scientific
Please see the Mixing and Validation Studies section for more functional
testing data.
Systems were tested for reliability by running the units at full volume for
extended time periods to establish system reliability. Test results indicated
that the system demonstrated a reliability of at least 0.99999 (z-score >4)
based on a 12-hour mixing time requirement and testing units for 10-days
each (no failures).
29
Section 6
Validation
Temperature
Temperature Control (Jacketed S.U.M. Hardware)
Heating: Chilled water in a range of 2-8°C was added to the BPC system
at nominal working volume. Using the Jacket and an external Sentra
Temperature Control Unit (TCU) set at 40°C, the water was heated to
37°C. Calibrated temperature probes were placed in the fluid and adjacent
to the thermal blanket in various locations.
Heat times at nominal volume were as follows:
50 L: from 5 - 40°C = 109 minutes
200 L: from 3 - 37°C = 116 minutes.
500 L: from 5.5 - 37°C = 177 minutes.
1000 L: from 3.5 - 37°C = 367 minutes
2000 L: from 3 - 37°C = 625 minutes
200 L Docking S.U.M. Tank: from 5 - 40°C = 140 minutes
Temperature variation at equilibrium was demonstrated at less than 0.1°C.
The following graphs show the results in detail.
NOTE: These results are examples of those obtained in our test conditions
only. Results will vary depending on test conditions.
50 L S.U.M. II Temperature Map
4 5 .0 0
4 0 .0 0
3 5 .0 0
3 0 .0 0
2 5 .0 0
2 0 .0 0
1 5 .0 0
1 0 .0 0
5 .0 0
0 .0 0
2 6 -Jan 2009
1 5 :3 6 :0 0
2 6 -Jan2009
1 6 :4 8 :0 0
2 6 -Ja n 2009
1 8 :0 0 :0 0
A ve ra g e R o o m T em p e ra tu re
2 6 -Ja n 2009
1 9 :1 2 :0 0
2 6 -Jan 2009
2 0 :2 4 :0 0
2 6 -Ja n 2009
2 1 :3 6 :0 0
A ve ra g e Me dia T e m p era tu re
2 6 -Ja n2009
2 2 :4 8 :0 0
2 7 -Ja n 2009
0 0 :0 0 :0 0
2 7 -Ja n 2009
0 1 :1 2 :0 0
A ve ra g e V e ssel W a ll Tempera tu re
Graph 6.4 50 L S.U.M. II Temperature Map
Thermo Scientific
30
Section 6
Validation
2 0 0 L S U M II J a c k e t Te m p e r a tu r e M a p p i n g
45.00
40.00
Tempurature (Deg C)
35.00
BTM JACKET
30.00
MID JACKET
TOP JACKET
Bottom
25.00
BTM MEDIA
MID MEDIA
20.00
TOP MEDIA
INLET
OUTLET
15.00
AMBIENT
10.00
5.00
0.00
1
11
21
31
41
51
61
71
81
91
101
111
121
131
141
151
Minutes
Graph 6.5 200 L S.U.M. II Jacket Temperature Mapping
5 0 0 L S U M II J a c k e t Te m p e r a tu r e M a p p i n g
45.00
40.00
35.00
BTM JACKET
Tempurature (Deg C)
30.00
MID JACKET
TOP JACKET
Bottom
25.00
BTM MEDIA
MID MEDIA
20.00
TOP MEDIA
INLET
OUTLET
15.00
AMBIENT
10.00
5.00
0.00
1
26
51
76
101
126
151
176
201
226
251
276
301
326
351
376
401
426
451
476
Minutes
Thermo Scientific
31
Section 6
Validation
1 0 0 0 L S U M II J a c k e t T e m p e r a tu r e M a p p i n g
45.00
40.00
35.00
BTM JACKET
Tempurature (Deg C)
30.00
MID JACKET
TOP JACKET
Bottom
25.00
BTM MEDIA
MID MEDIA
20.00
TOP MEDIA
INLET
OUTLET
15.00
AMBIENT
10.00
5.00
0.00
1
26
51
76
101
126
151
176
201
226
251
276
301
326
351
376
401
Minutes
2000 L S.U.M. Jacket Tank Temperature Map
45.00
40.00
Temperature (C)
35.00
30.00
25.00
20.00
15.00
10.00
5.00
0.00
0
200
400
600
800
1000
1200
Minutes
Jkt-Btm
Jkt-Mid
Jkt-Top
Tank-Btm
Media-Btm
Media-Mid
Media-Top
Inlet
O utlet
Ambient
Thermo Scientific
32
Section 6
Validation
2 0 0L D o c k in g S u m
T a n k T e m p e r a tu r e M a p
4 5. 0 0
4 0. 0 0
Tempurature (Deg C)
3 5. 0 0
3 0. 0 0
2 5. 0 0
2 0. 0 0
1 5. 0 0
1 0. 0 0
5. 0 0
0. 0 0
0
20
40
60
80
1 00
1 20
14 0
16 0
18 0
200
Minutes
Jkt - Btm
Jkt - Mid
Jkt - Top
Tank - Btm
Media BTM
Media MID
Media TOP
Inlet
Outlet
Ambient
Graph 6.9 200 L Docking Tank Temperature Mapping
5 00 L S U M
J a c k e t T a n k T e m p e r a tu r e M a p
45 . 0 0
40 . 0 0
Tempurature (Deg C)
35 . 0 0
30 . 0 0
25 . 0 0
20 . 0 0
15 . 0 0
10 . 0 0
5. 0 0
0. 0 0
0
50
10 0
15 0
20 0
25 0
3 00
3 50
4 00
Minutes
Jkt - Btm
Jkt - Mid
Tank - Top
Tank - Btm
Media -Btm
Media - Mid
Media - Top
Outlet
Inlet
Ambient
Graph 6.10 200 L Docking Tank Temperature Mapping
Thermo Scientific
33
Section 6
Validation
1 0 0 0 L D o c k in g S U M
T a n k T e m p e r a tu r e M a p
45.00
101A - T01
Tempurature (Deg C)
40.00
102A - T02
103A - T03
35.00
104A - T04
Jkt - Btm
30.00
Jkt - Mid
25.00
Jkt - Top
20.00
Tank - Btm
15.00
Media - Mid
Media -Btm
Media - Top
10.00
Inlet
Outlet
5.00
0.00
Ambient
0
100
200
300
400
500
600
700
Minutes
Graph 6.11 1000 L Docking Tank Temperature Map
Shipping
Based on the ISTA requirements, all 7 S.U.M. units tested passed ground
transportation testing with an equivalent 150-180 minutes of random
vibration (Grms level of 0.52) simulated testing. All units also shipped to
actual destinations without incident.
Size (L)
Quantity
200
200
500
1000
1
1
2
3
Shipping Type/
Distance (miles)
Truck/2300+ miles
Truck/1500 miles
Truck/1500 miles
Truck/1500 miles
ISTA Equivalent/Required
Test Time (minutes)
180
150
150
150
Table 6.7 ISTA Shipping
Docking S.U.M. hardware was packaged according to the packaging
specification (see example of packaging in Figure 6.8) and subjected to the
ISTA 1E test protocol for vibration. The assembly and shipping container
was inspected for damage and functionality at the beginning and at the end
of the testing. Visual inspection and functional testing results indicated that
the packaging provides proper protection for distribution of the hardware.
Figure 6.8
Thermo Scientific
34
Section 6
Validation
Mixing Application
Studies
Materials and Methods
The S.U.M. BPC was placed in the hardware according to the instructions
in the S.U.M. User Guide except for air inflation of the BPC. The prepared
S.U.M. was filled to 100 percent nominal volume with process water.
Mixing speeds were established by a visual inspection allowing a vortex of
medium scale (non-violent). In this instance, 330 RPM was utilized. The
agitation was then stopped until the start of each separate study.
A stainless steel bar fitted with three separate silicone tubes was placed into
the BPC out of the way of the impeller. The three tubes were situated at
such locations along the bar to allow for samples to be taken from the top,
middle, and bottom of the liquid.
The powders for each section of this study were added through the powder
port. To represent a worst case scenario, mixing was not initiated until all
of the powder was added.
For the NaCl, RPMI and albumin sections, samples were collected at
one minute increments for the first eight minutes and every four minutes
thereafter for one hour including time zero when the mixing process
began. For the remaining sections, samples were collected every four
minutes for one hour including time zero. Each sample was analyzed at a
later time for osmolality, pH, and/or other parameters as described below.
Table 6.8 shows the components mixed and analytics performed to
demonstrate mixing. With the exception of glycerol all mixing materials
were added in powder form. The 50, 200, 500, 500, 1000 and 2000 L
S.U.M. units were used with all mixing materials excerpt the maltose and
glycerol which were used with the 50 L S.U.M. only.
NOTE: Due to the low solubility of maltose at room temperature (25°C),
water for this section of the study was first heated to 65°C. As the powder
was added, the temperature dropped rapidly and was held at or near 40°C
for the entire hour.
Mixing
Material
Solution
Concentration
NaCl
1M
Osmolality, conductivity
RPMI
1x
Osmolality, conductivity, pH, UV-Vis absorbance, metabolite profile
CDM4CHO
1x
Osmolality, conductivity, pH, metabolite profile
Albumin
0.1%
Absorbance, osmolality, protein analysis
Maltose
Concentrate
60%
Specific gravity, osmolality (50L S.U.M. only)
Glycerol
10%
Specific gravity, osmolality (50L S.U.M. only)
Analytics
Table 6.8
Thermo Scientific
35
Section 6
Validation
The following charts show the results obtained. They demonstrate rapid
and scalable mixing of the materials used.
Mixing Evalua�ons
1M Sodium Chloride Prepara�on
2500
Osmolality (mOsm/kg)
2000
1500
1000
500
0
0
10
20
30
40
50
60
70
Time (minutes)
50 L S.U.M.
200 L S.U.M.
500 L S.U.M.
1000 L S.U.M.
2000 L S.U.M.
Graph 6.12 Mixing evaluations
Mixing Evalua�ons
1M Sodium Chloride Prepara�on
120
Conduc�vity (mS/cm)
100
80
60
40
20
0
0
10
20
30
40
50
60
70
Time (minutes)
50 L S.U.M.
200 L S.U.M.
500 L S.U.M.
1000 L S.U.M.
2000 L S.U.M.
Thermo Scientific
36
Section 6
Validation
Mixing Evalua�ons
0.1% Albumin (Powder-Liquid)
Protein Concentra�on (Bradford, g/L)
1200
1000
800
600
400
200
0
0
10
20
30
40
50
60
70
Time (minutes)
50 L S.U.M.
200 L S.U.M.
500 L S.U.M.
1000 L S.U.M.
2000 L S.U.M.
Mixing Evalua�ons
0.1% Albumin (Powder-Liquid)
180
160
140
120
100
80
60
40
20
0
0
10
20
30
40
50
60
70
Time (minutes)
50 L S.U.M.
200 L S.U.M.
500 L S.U.M.
1000 L S.U.M.
2000 L S.U.M.
Thermo Scientific
37
Section 6
Validation
Mixing Evalua�ons
1X RPMI Cell Culture Medium (Powder-Liquid)
8.5
8.4
pH
8.3
8.2
8.1
8
7.9
0
10
20
30
40
50
60
70
60
70
Time (minutes)
50 L S.U.M.
200 L S.U.M.
500 L S.U.M.
1000 L S.U.M.
Mixing Evalua�ons
350
300
250
200
150
100
50
0
0
10
20
30
40
50
Time (minutes)
50 L S.U.M.
200 L S.U.M.
500 L S.U.M.
1000 L S.U.M.
2000 L S.U.M.
Thermo Scientific
38
Section 6
Validation
Mixing Evalua�ons
0.6
UV/Vis (558 nm)
0.5
0.4
0.3
0.2
0.1
0
0
10
20
30
40
50
60
70
60
70
Time (minutes)
50 L S.U.M.
200 L S.U.M.
500 L S.U.M.
Mixing Evalua�ons
2.5
Glucose (g/L)
2
1.5
1
0.5
0
0
10
20
30
40
50
Time (minutes)
50 L S.U.M.
200 L S.U.M.
500 L S.U.M.
1000 L S.U.M.
2000 L S.U.M.
Thermo Scientific
39
Section 6
Validation
Mixing Evalua�ons
8.6
8.4
8.2
pH
8
7.8
7.6
7.4
7.2
0
10
20
30
40
50
60
70
80
Time (minutes)
50 L S.U.M.
200 L S.U.M.
500 L S.U.M.
1000 L S.U.M.
2000 L S.U.M.
Mixing Evalua�ons
1X CDM4CHO Cell Culture Medium
350
300
250
200
150
100
50
0
0
10
20
30
40
50
60
70
80
Time (minutes)
50 L S.U.M.
200 L S.U.M.
500 L S.U.M.
1000 L S.U.M.
2000 L S.U.M.
Thermo Scientific
40
Section 6
Validation
Mixing Evalua�ons
14
Conduc�vity (mS/cm)
12
10
8
6
4
2
0
0
10
20
30
40
50
60
70
80
Time (minutes)
50 L S.U.M.
Mixing Evalua�ons
9
8
7
Glucose (g/L)
6
5
4
3
2
1
0
0
10
20
30
40
50
60
70
Time (minutes)
50 L S.U.M.
200 L S.U.M.
500 L S.U.M.
1000 L S.U.M.
Thermo Scientific
41
Section 6
Validation
Powder-Liquid Mixing - 60% maltose
Osmolality
3000
2800
2600
mOsm/kg
2400
2200
2000
1800
1600
1400
1200
1000
0
10
20
30
40
50
60
Time (minutes)
Bottom
Middle
Top
Powder-Liquid Mixing - 60% maltose
Specific Gravity
55
50
%Brix
45
40
35
30
25
0
10
20
30
40
50
60
Time (minutes)
Bottom
Middle
Top
Thermo Scientific
42
Section 6
Validation
Liquid-Liquid Mixing - 10% glycerol
Osmolality
1550
mOsm/kg
1500
1450
1400
1350
1300
0
10
20
30
40
50
60
50
60
Time (minutes)
Bottom
Middle
Top
Liquid-Liquid Mixing - 10% glycerol
Specific Gravity
12
11
%Brix
10
9
8
7
6
0
10
20
30
40
Time (minutes)
Bottom
Middle
Top
Thermo Scientific
43
Section 7
Quality Control
Section 7 Quality Control
7.1 Introduction
7.2 Inspection
Only the highest quality components are used in the manufacture of
HyClone S.U.M. Each component is given a unique part number and
has a controlled material specification. In addition, we actively promote
communication with vendors, conduct audits of vendors and maintain a
vendor evaluation program.
Incoming components are quarantined until they have met the approved
component specification’s criteria. During the inspection process, lot
numbers and part numbers are recorded for traceability purposes. Once
components have satisfied the requirements in the specification they are
released into inventory by QC personnel.
In-process inspections and testing take place during the manufacturing
process to ensure that each production run of BPC systems is being
manufactured to the approved specifications.
Incoming Inspection
Component
In-Process Inspections
and Testing
Thermo Scientific
Film
Inspection
• Contamination
• Gels or carbons
• Width and gusset dimensions
• Film thickness
• Tensile strength
• Chemical composition using
FT-IR Spectrometer
Ports, fittings, tubing, end
treatments
•
Flexible container chambers
Inspection
• Appearance
• Seam and port seal strength
• Dimensional Analysis
• Leak and burst testing
Finished flexible containers
•
•
•
•
•
•
Appearance and visual
inspection
Dimensional analysis
Correctness
Completeness
Particulate debris
Defects and damage
Correct packaging
44
Section 7
Quality Control
7.3 BPC Lot
Record Release
and Certificate of
Analysis
Production control process ensures traceability for each lot of
BPC systems. The process control document becomes the stepwise
manufacturing record, which physically accompanies the lot through
manufacturing. At the end of the production process Quality Assurance
reviews the lot record for completeness and correctness prior to release of
the lot. At this time a Certificate of Analysis (COA) is issued.
Lot record review
• Bill of Materials
• Certificate of Irradiation
• Production quality inspections
• Production integrity testing
• Labels
• Deviations
• Certificate of Analysis
Thermo Scientific
Certificate of Analysis
• Product name
• Catalog number
• Lot number
• Expiration date
• Irradiation dosage
45
7.4 Sample C of A
CERTIFICATE OF ANALYSIS
Standard BioProcess Container™ Systems
Product:
HyQtainer® BioProcess Container™:
XXX Liter
Lot#: AAANNNN
Catalog#:SH30XXX.XX Expiration Date: MMM/YYYY
======================================================================
Test
Specification
Units
Results
======================================================================
Irradiation Dose
25 – 38
kGy
Pass
x
Inspection:
x
Biological Reactivity: All product contact materials have passed USP Class VI testing (USP <88>).
x
Cytotoxicity: All HyClone product contact films have passed Cytotoxicity testing (USP <87> MEM Elution).
x
Physicochemical: All HyClone product contact films have passed USP Physicochemical Tests for Plastics
x
EP Testing: All HyClone product contact films have passed EP <3.2.2.1> “Plastic Containers for Aqueous
x
Endotoxin: Samples of representative BioProcess Container Systems are routinely tested in periodic
This lot of BioProcess Container Systems has been 100% visually inspected per specification.
(USP <661>).
Solutions for Parenteral Infusion”.
validations for the presence of endotoxin per the USP Bacterial Endotoxin Test (USP <85>).
Aqueous extracts contained < 0.25 EU/ml as determined by the Limulus Amebocyte Lysate Test (LAL).
x
Particulate:
x
Sterility:
Samples of representative BioProcess Container Systems have been routinely tested in
periodic validations and have passed requirements per Particulate Matter in Injections Light Obscuration
Particulate Count Test (USP <788>).
Routine sterility testing is performed on representative samples of HyClone BioProcess Container
Systems following ANSI/AAMI/ISO 11137 guidelines. Periodic validation has determined that an irradiation
dose of 25 – 38 kGy provides a minimum Sterility Assurance Level (SAL) of 10 –6 for product contact
surfaces.
_______________________________________
Quality Control Department / Date Issued
Thermo Scientific
Logan, Utah
435-792-8000
925 West 1800 South
84321
435-792-8001 fax
46
Section 7
Quality Control
7.5 Traceability
Traceability is maintained on BPC Systems and components.
7.6 Shelf Life
Standard Chambers
Shelf life of BPC systems is based on real-time stability and accelerated
aging tests performed during product development. All Standard BPC
systems have a three-year expiration date from date of irradiation.
Custom Chambers with
Standard Components
Customization is available on all Standard BPC’s. Custom chambers
with standard components can have a shelf life equal to a Standard BPC
system, which is based on real-time stability and accelerated aging tests
performed on the standard components during product development. All
Custom chambers with standard components on the BPC systems can
receive a three-year expiration date from date of manufacture if requested
by the customer.
Custom Chambers with
Custom Components
Customization to our Standard BPC’s to meet the specifications of our
customers is available. Custom designs with custom components receive a
manufacture date on the Certificate of Analysis. Shelf life data may not be
available for some custom items requested by the customer or supplied by
the customer.
Thermo Scientific
47
Section 7
Quality Control
7.7 Film Fact Sheet
CX5-14
Thermo Scientific HyClone CX5-14 film is a five-layer, 14 mil cast film
produced in a cGMP facility. The outer layer is a polyester elastomer
coextruded with an ethyl vinyl alcohol (EVOH) barrier layer and an ultralow density polyethylene product contact layer.
CX5-14 is manufactured using no animal derived components.
Property
Physical Data
Tensile Strength
Elongation
Yield Strength
Secant Modulus
Toughness
Puncture Resistance
Seam Strength
O2 Tranmission Rate
CO2 Tranmission Rate
Moisture Vapor
Tranmission Rate
Haze
Figure 7-1
Schematic Cross-Section
Figure 7-2
Schematic 3-D View
Test Protocol
Average Values
ASTM D882
ASTM D882
ASTM D882
ASTM D882
ASTM D882
HyClone
ASTM D882
ASTM D3985
50% RH Outside,
100% RH Inside, 23ºC
Mocon
50% RH Outside,
ASTM F1249
0% RH Outside,
ASTM D1003
(Outside Dry/Inside Wet)
ASTM E1640
2893 psi
710%
1279 psi
35 ksi
414 lbf-in.
132 lbf-in.
29 lbf/in.
0.019
cc/100 in.2/24 hr.
19.4 MPa
0.036
cc/100 in.2/24 hr.
0.56
cc/m2/24 hr.
0.022
g/100 in.2/24 hr.
0.34
g/m2/24 hr.
8.8 MPa
242 MPa
4.7 kN-cm
1.5 kN-cm
51.1 N/cm
0.29
cc/m2/24 hr.
20%
Glass Transition
-30ºF
Temperature
Film Gauge
0.014 in.
Film Contact Material
Polyethylene
Temperature Range*
-112 to 140ºF
Sterilizable
5.0 Mrad
Biocompatibility Data (Post Gamma Irradiation, >50 kGy)
USP Class VI
USP <88>
Pass
Cytotoxicity
USP <87>
Pass
Bacterial Endotoxin
USP <85>
0.006 EU/mL
Heavy Metals
USP <661>
<1 ppm
Buffering Capacity
USP <661>
<1 mL
Non-Volatile Residue
USP <661>
<1 mg
Residue on Ignition
USP <661>
<1 mg
Hemolysis
ISO 10993-4
Nonhemolytic
Appearance
EP <3.2.2.1>
Pass
Acidity and Alkalinity
EP <3.2.2.1>
Pass
Absorbance
EP <3.2.2.1>
Pass
Reducing Substances
EP <3.2.2.1>
Pass
Transparency
EP <3.2.2.1>
Pass
-34.4ºC
356 μm
-80 to 60ºC
50 kGy
* Sub-zero conditions require proper support and handling.
Leachables and Extractables Testing
Extensive testing has been performed on the CX range of films using
standard solutions. Information is available upon request.
Thermo Scientific
48
Section 7
Quality Control
Film Fact Sheet
CX3-9
Thermo Scientific HyClone CX3-9 film is a three-layer, 9 mil cast film
produced in a cGMP facility. The outer layer is a polyester elastomer
coextruded with an ultra-low density polyethylene product contact layer.
CX3-9 is manufactured using no animal derived components.
Property
Test Protocol
Average Values
Tensile Strength
ASTM D882
4300 psi
Elongation
ASTM D882
1100%
Yield Strength
ASTM D882
900 psi
6 MPa
Secant Modulus
ASTM D882
8 ksi
57 MPa
Toughness
ASTM D882
435 lbf-in.
4.9 kN-cm
Puncture Resistance
HyClone
85 lbf-in.
0.94 kN-cm
Seam Strength
ASTM D882
13 lbf/in.
Moisture Vapor
Tranmission Rate
ASTM F1249
0% RH Outside,
0.06 g/100 in. /
24 hr.
0.9 g/m2/24 hr.
Film Gauge
0.009 in.
229 μm
Film Contact Material
Polyethylene
Temperature Range*
-112 to 140ºF
-80 to 60ºC
Sterilizable
5.0 Mrad
50 kGy
Physical Data
Figure 7-3
Schematic Cross-Section
Figure 7-4
Schematic 3-D View
30 MPa
23 N/cm
2
Biocompatibility Data (Post Gamma Irradiation, >50 kGy)
USP Class VI
USP <88>
Pass
Cytotoxicity
USP <87>
Pass
Bacterial Endotoxin
USP <85>
<0.005 EU/mL
Heavy Metals
USP <661>
<1 ppm
Buffering Capacity
USP <661>
<1 mL
USP <661>
<1 mg
Residue on Ignition
USP <661>
<1 mg
Hemolysis
ISO 10993-4
Pass
Appearance
EP <3.2.2.1>
Pass
Acidity and Alkalinity
EP <3.2.2.1>
Pass
Absorbance
EP <3.2.2.1>
0.0055 units
Reducing Substances
EP <3.2.2.1>
<0.1 mL
Transparency
EP <3.2.2.1>
Pass
*Sub-zero conditions require proper support and handling.
7.8 USP Class VI Data
Thermo Scientific
For USP Class VI Data refer to Appendix section 9.3 Film Component
Information Package.
49
Section 7
Quality Control
7.9 Sample
Certificate of
Irradiation
Thermo Scientific
50
Section 8
Regulatory
Section 8 Regulatory
8.1 General
We annually register with the Food and Drug Administration (FDA) as a
Medical Device Establishment to be a manufacturer and contract
manufacturer of medical devices for sera and media products.
As a manufacturer of medical devices for human use, our facilities are
inspected by the Food and Drug Administration for compliance with
current Good Manufacturing Practices (cGMP) as listed in 21 CFR
Chapter 1 Part 820, Quality System Regulation.
The intended use statements and promotional materials define the
regulatory status of Thermo Scientific HyClone products and verbal
claims associated with them. The medical devices are listed with the Food
and Drug Administration using Form FDA 2892. Class I medical devices
are not licensed by the FDA. Serum and media for cell culture use are
also exempt from pre-market notification requirements (21 CFR 864).
They may be used as a component in the manufacture of a device or
drug that requires licensing. It is the responsibility of the device or drug
manufacturer to determine if serum and/or cell culture media are suitable
for their application.
8.2 BioProcess
Container Systems
(BPC)
Although we have implemented the same cGMP compliant quality system
for BPC manufacture and the BPC facility is covered by our ISO 9001
registration, BPC systems are not considered medical devices. The FDA
does not regulate flexible containers.
Master files are submitted to the FDA to provide requested proprietary
information. The FDA may review a master file in conjunction with
the review of a customer’s product after we have authorized the review
in a written letter to the FDA. A master file on BPC systems has been
submitted to the FDA along with subsequent updates to that master file.
FDA CBER has given the BPC systems master file the designation
BB-MF-6657. Master files are not released to customers.
Thermo Scientific
51
Section 9
Appendix
Section 9 Appendix
9.1 Validation
References
9.2 Abbreviations
and Acronyms
Validation References:
•
•
•
•
•
•
U.S. Pharmacopoeia
European Pharmacopoeia
ASTM
ANSI/AAMI/ISO 11137
ANSI/AAMI/ISO 15843: 2000
ANSI/AAMI/ISO TIR27: 2001
%EL
Percent elongation
AAMI
Association for the Advancement of Medical Instrumentation
ADCF
Animal Derived Component Free
ANSI
American National Standards Institute
ASTM
American Society for Testing and Materials
BPC
BioProcess Container
C
Celsius
cGMP
Current Good Manufacturing Practices
COA
Certificate of Analysis
DFMEA Design Failure Mode Effect Analysis
Thermo Scientific
DOE
Design of Experiments
DV
Design Verification
EP
European Pharmacopoeia
CBER
Center for Biologics Evaluation and Research
F
Fahrenheit
FDA
Food and Drug Administration
FEA
Finite Element Analysis
g
Gram
GPa
Giga Pascal
h
Hour
52
Section 9
Appendix
in Inch
in/min
Inches per minute
ISO
International Organization for Standardization
kGy
Kilo Gray
L
Liter
LAL
Limulus Amebocyte Lysate
lbf
Pound-force
MPa
Mega Pascal
ml
Milliliter
OQ
Operational Qualification
PC
Polycarbonate
PCD
Process Control Document
PE
Polyethylene
PFMEA Process Failure Modes and Effects Analysis
Thermo Scientific
PP
Polypropylene
PQ
Process Qualification
PS
Polysulfone
psi
Pounds per square inch
PVC
Polyvinyl chloride
RH
Relative Humidity
Tg
Glass Transition Temperature
USP
United States Pharmacopoeia
UTS
Ultimate Tensile Strength
VIP
Validation Information Package
WID
Work Instruction Document
WVTR
Water Vapor Transmission Rate
53
Section 9
Appendix
9.3 Film Component
Information Package
Component Information Package
BioProcess Container Systems
Biological Compatibility Testing
Material: CX5-14 SV20535.01 / Lot 3 MH03160FX035
Lab Report #: 04C43926, 04T45009 and 04T45650
Component: Film
USP <88> Class VI Biological Reactivity Tests in Vivo
x USP Systemic Toxicity Study in the Mouse
x USP Intracutaneous Toxicity Study in the Rabbit
x USP Muscle Implantation Study in the Rabbit
USP <87> Biological Reactivity Tests in Vitro Cytoxicity
x USP Agar Diffusion
x USP Elution Method
USP <85> Bacterial Endotoxin using Kinetic – LAL
x Based on USP requirement for WFI
USP <661> Physicochemical Testing of Plastic Containers (Aqueous
Extract)
x
x
x
x
Residue on Ignition
Heavy Metals
Buffering Capacity
ISO 10993-4 Hemolysis
EP <3.2.2.1> Physicochemical Tests
x
x
x
x
x
x
x
Appearance
Initial Color of Solution
Acidity
Alkalinity
Absorbance
Reducing Substance
Transparency
Test articles were gamma-irradiated at a dosage of 56.8-61.7 kGy (see Isomedix
irradiation run ID 15411 A and B), and then submitted to a certified independent
laboratory for biological compatibility testing (see NAMSA, lab report numbers
04C43926, 04T45009 and 04T45650). Test results indicate that the material met or
exceeded the USP, ISO and EP requirements.
Thermo Scientific
Logan, Utah
435-792-8000
925 West 1800 South
84321
435-792-8001 fax
54

Validation Guide For Thermo Scientific HyClone Single

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