OPUS® 5, 10 - 60 cm Columns
OPUS® 45R, OPUS® 60R Columns
Pre-packed Columns
REGULATORY SUPPORT FILE
The information contained in this document is subject to change without notice.
Repligen Corporation makes no warranty of any kind with regard to this material, including, but not
limited to, the implied warranties of merchantability and fitness for a particular purpose.
Repligen Corporation shall not be liable for errors contained herein or for incidental or
consequential damages in connection with the furnishing, performance, or use of this material.
No part of this document may be photocopied, reproduced, or translated to another language
without the prior written consent of Repligen Corporation.
For further information, please contact Repligen Corporation at www.repligen.com.
© 2017 Repligen Corporation. All rights reserved.
The trademarks mentioned herein are the property of Repligen Corporation and/or its affiliate(s) or
their respective owners.
Customer Support
[email protected]
+1-781-250-0111 (option 2)
Technical Support
+1-781-250-0111 (option 3)
[email protected]
Repligen Corporation
41 Seyon Street Building #1, Suite 100
Waltham, MA 02453
www.repligen.com
Contents
1.
2.
Introduction ......................................................................................................................... 6
Product Information ............................................................................................................. 7
2.1 Product Overview ...................................................................................................................... 7
2.2 Product Design ........................................................................................................................... 7
2.3 Certificate of Analysis (CoA) Examples ...................................................................................... 9
2.3.1
Pre-GMP OPUS® Columns Certificate of Analysis (CoA) ................................................. 9
2.3.2
GMP Run Ready OPUS® Columns Certificate of Analysis (CoA) .................................... 10
2.3.3
Certificate of Analysis: Chromatograms ....................................................................... 11
2.4 Column Manufacturing and Packing ........................................................................................ 13
2.5 Materials of Construction: Product Contact ............................................................................ 17
2.6 OPUS® Physical Specifications ................................................................................................. 22
2.7 Column Stability ....................................................................................................................... 23
2.7.1
Warranty ....................................................................................................................... 26
2.8 Material Safety Data Sheet ...................................................................................................... 26
3.
Manufacturing Information ................................................................................................ 27
3.1 Introduction ............................................................................................................................. 27
3.2 Manufacturing Quality Assurance Standards and Policy ......................................................... 27
3.3 Manufacturing Facilities........................................................................................................... 27
3.4 Manufacturing Controls and SOPs ........................................................................................... 27
3.5 OPUS® Column Manufacturing ................................................................................................ 29
3.6 Bioburden and Endotoxin Release Testing .............................................................................. 34
4.
Shipping Qualification......................................................................................................... 35
4.1 Summary .................................................................................................................................. 35
4.2 Introduction ............................................................................................................................. 35
4.3 Method: ISTA 2A and 2B Tests ................................................................................................. 37
5.
4.3.1
ISTA Test Methods ........................................................................................................ 37
4.3.2
Column Efficiency Test Methods .................................................................................. 39
4.3.3
Results: ISTA and Column Efficiency Tests .................................................................... 39
4.3.4
Chromatographic Performance Test Results ................................................................ 40
4.3.5
Conclusion ..................................................................................................................... 40
Extractables and Leachables ............................................................................................... 41
5.1 Introduction and Background .................................................................................................. 41
5.2 OPUS® Extractables Strategy ................................................................................................... 42
5.3 USP<88> Biological Reactivity Tests, In Vivo............................................................................ 42
5.3.1
CFR 21 Part 177 Indirect food Additives: Polymers ...................................................... 43
5.3.2
USP General Chapters 661: Polypropylene Containers ............................................... 43
5.3.3
Animal Free and EMEA 410/01 ..................................................................................... 43
5.4 Extractable Test Protocol and Results ..................................................................................... 44
5.4.1
Extruded PP: OPUS® 10 – 30 cm Columns Only ............................................................ 46
5.4.2
Machined Compression Molded PP: OPUS® 10 – 60/R cm Columns............................ 47
5.4.3
PP Mesh: OPUS® 10 – 60/R cm Columns ...................................................................... 48
5.4.4
P/ E-Glass Composite: OPUS® 45/R – 60/R cm Columns Only ...................................... 49
5.4.5
Platinum Cured Silicone O-Ring: OPUS® 10 – 60/R cm Columns .................................. 50
5.4.6
Platinum Cured Silicone Braided Tubing: OPUS® 10 – 60/R cm Columns .................... 50
5.4.7
Conclusions ................................................................................................................... 51
5.5 Leachables: OPUS® Column Strategy ....................................................................................... 52
5.6 Considerations for Leachables Testing .................................................................................... 52
5.7 References ............................................................................................................................... 53
6.
Appendix ............................................................................................................................ 54
6.1 OPUS® 5, 10-60/R cm ID Material Certificates (available upon request) ................................ 54
6.2 Engineering Drawings .............................................................................................................. 55
6.2.1
OPUS® 5 cm Column ..................................................................................................... 55
6.2.2
OPUS® 10 cm Column ................................................................................................... 56
6.2.3
OPUS® 14 cm ID Column ............................................................................................... 57
6.2.4
OPUS® 20 cm Column ................................................................................................... 58
6.2.5
OPUS® 25 cm Column ................................................................................................... 59
6.2.6
OPUS® 30 cm Column ................................................................................................... 60
6.2.7
OPUS® 45 cm and 45R Column ..................................................................................... 61
6.2.8
OPUS® 60 cm and 60R Column ..................................................................................... 62
6.3 Packaging ................................................................................................................................. 63
6.3.1
OPUS® 5 cm Column Packaging .................................................................................... 63
6.3.2
OPUS® 10 - 14 cm Column Packaging ........................................................................... 64
6.3.3
OPUS® 20 - 30 cm Column Packaging ........................................................................... 65
6.3.4
OPUS® 45 cm Column Packaging .................................................................................. 66
6.3.5
OPUS® 60 cm Column Packaging .................................................................................. 67
List of Tables
Table 2.1
Table 2.2
Table 2.3
Table 2.4
Table 2.5
Table 2.6
Table 2.7
Table 2.8
Table 2.9
Table 3.1
Table 3.2
Table 4.1
Table 4.2
Table 5.1
Table 5.2
OPUS® Pre-GMP and GMP Applications ............................................................................... 8
Product Contact Materials.................................................................................................. 21
Physical Specifications Summary on OPUS® 10 - 30 cm Columns ...................................... 22
Physical Specifications Summary on OPUS® 45R - 60R Columns ....................................... 22
Column Mass (Approximate Weight of Packed Columns).................................................. 23
Stability Study Schedule and Acceptance Criteria .............................................................. 23
Mechanical Stability Test Results ....................................................................................... 24
Performance Stability Study Results .................................................................................. 24
Results of Bioburden and Endotoxin Testing ..................................................................... 25
Repligen Water Specifications Compared with ASTM, USP Purified Water and Water
for Injection ........................................................................................................................ 29
Parts Cleaning Specifications .............................................................................................. 32
ISTA 2A and 2B Testing Conditions (OPUS® 5, 10 – 60 cm Columns) ............................... 37
OPUS® 10 cm, 20 cm and 45 cm Column Performance Data ............................................ 40
Summary of USP <88> Plastics Classes .............................................................................. 42
Polymer List and Regulatory Information.......................................................................... 45
List of Figures
Figure 2.1
Figure 2.2
Figure 2.3
Figure 2.4
Figure 2.5
Figure 2.6
Figure 2.7
Figure 2.8
Figure 2.9
Figure 2.10
Figure 2.11
Figure 2.12
Figure 3.1
Figure 4.1
Figure 4.2
Figure 4.3
Figure 4.4
Figure 4.5
Figure 4.6
Pre-GMP OPUS® Column Certificate of Analysis ................................................................ 9
GMP Run Ready OPUS® Column Certificate of Analysis................................................... 10
OPUS® Certificate of Analysis Testing Conditions and Chromatograms .......................... 11
Example of OPUS® 10-60 cm ID Column Label ................................................................. 12
OPUS® Part Number Format ............................................................................................ 12
Lifting Handles and Input/Output Ports on an OPUS® 20 cm Column ............................. 16
Castor Detail on an OPUS® 45 cm Column ....................................................................... 16
Materials of Construction on OPUS® 5 cm Column ......................................................... 17
Materials of Construction on OPUS® 10-30 cm Columns................................................. 18
Materials of Construction on OPUS® 45-60 cm Columns ................................................ 18
Materials of Construction on OPUS® 45R - 60R Columns ................................................ 19
OPUS® R Port Design and Materials of Construction ....................................................... 19
OPUS Work Order Example (blank) .................................................................................. 30
OPUS® 5 cm Column Shipping Container Design ............................................................. 35
OPUS® 10 - 30 cm Column Shipping Container Design .................................................... 36
OPUS® 45/R - 60/R Column Chipping Container Design .................................................. 36
OPUS® 5 cm Column Compression and Drop Testing ...................................................... 38
OPUS® 20 cm Column Vibrational and Compression Testing .......................................... 38
OPUS® 60/R Column Vibrational, Incline Impact and Drop Testing ................................. 39
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
1. Introduction
The Regulatory Support File (RSF) for OPUS® (Open platform, User-specified) Pre-Packed Columns is
intended to be used as:





A guide for appropriate application use in process development, clinical, and commercial
purification processes
A guide to validation in manufacturing processes
A support reference for CMC submissions for regulatory license approval
A guide for supplier audits
In place of a Drug Master File submission
This regulatory support file covers all column IDs including OPUS® 5, 10, 14, 20, 25, 30, 45, 60, 45R,
60R Columns. Unless otherwise specified all information applicable to OPUS® 45 and 60 designs is
also applicable to OPUS® 45R and 60R designs.
Repligen is committed to providing all relevant technical, manufacturing, and quality information,
however, only non-confidential information is presented in this document. Confidential details may
be made available upon request through a formal confidentiality agreement or as part of a supplier
audit.
Repligen’s Quality Policy
Copies of Repligen’s quality policy, quality manual, and ISO certificate can be found on the following
website, https://www.repligen.com/resources/quality-documents/.
Safety Notices


Follow all local regulations for safe disposal
For laboratory and manufacturing production only
Responsible Official
The individual designated responsible for quality and regulatory affairs for Repligen, and to whom all
correspondence or requests for audits should be addressed.
Senior Director of Quality
Telephone: +1-781.250.0111
Email: [email protected]
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OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
2. Product Information
2.1 Product Overview
OPUS® Pre-packed Columns (Open platform, User-specified ) columns are designed to perform
chromatographic purification of biological molecules as part of the production process in either GMP
or non-GMP applications.
The OPUS® Pre-packed Column platform offers an alternative to traditional self-pack glass columns,
and can be reliably packed with nearly any bioprocessing resin. To accommodate a wide range of
biopharmaceutical applications, OPUS® columns are configurable for bed height and available in a
range of industry standard internal diameters.
2.2 Product Design
The OPUS® 5, 10 – 60/R cm Column platform is designed to meet the requirements of GMP
manufacturing in the pharmaceutical and biopharmaceutical industries for campaign-use
applications.
Platformable
OPUS® Columns are configurable to accommodate a wide range of purification applications for
vaccines, monoclonal antibodies, and recombinant proteins. For example, an end user can configure
an OPUS® Column by choosing a diameter and specifying:
 Column bed height
 Chromatography resin
 Repligen recommended release criteria, or customized release criteria (ex: plate count,
asymmetry, storage solution, etc.)
Quality Standards
In order to meet the needs of GMP manufacturing, OPUS® 5, and 10 – 60/R cm ID columns are
manufactured in the U.S.A. under the following quality standards:
 Repligen maintains an ISO 9001 compliant Quality Management System that is currently certified
by BSI Americas. A copy of the current ISO certification can be downloaded from the following
web address, https://www.repligen.com/resources/quality-documents/.
 All materials in direct fluid contact path meet USP Class VI, and USP <88> requirements for In Vivo
Biological Reactivity
 All columns are packed in a controlled, classified clean room that meets ISO Class 7 Non-Viable
Particulate (NVP) standards
 All fluid contact components are free from materials of animal origin or compliant with EMEA
410/01 Rev 3
In order to provide the most flexibility to end users, OPUS® Pre-Packed columns are available in two
levels for non-GMP applications and GMP applications. See Table 2.1 for more detail. In general,
OPUS® Pre-GMP and GMP Run Ready columns are identical except as noted in Table 2.1. GMP Run
Ready columns come with a resin side sample for incoming resin identity testing at an end-users
facility. OPUS® Pre-GMP columns do not come with a resin side sample.
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Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Table 2.1 OPUS® Pre-GMP and GMP Applications
Pre-GMP
10 – 60/R cm ID’s
GMP Run Ready
5, 10 – 60/R cm ID’s
GMP Level
Catalog Number
X
X
X
X
Lot Number
X
X
Serial Number
X
X
Column Diameter
X
X
Final/Achieved Bed Height
X
X
Chromatography Resin Type
X
X
Chromatography Resin Lot Number
X
X
Shipping/Storage Solution
X
X
Date of Manufacture
X
X
Customer Property Number
X
X
Asymmetry Specification and Result
X
X
Theoretical plate count (N/m) Specification and
Result
Chromatography Release Test Chromatogram
X
X
X
X
ISO 9001 Compliance Statement
X
X
Product Contact Materials Compliance Statement
(animal free, EMEA 410/01, USP Class VI)
X
X
Packing Environment Statement
X
X
Certificate of Analysis Component
Chromatography Resin Control Statement
Copy of Resin Certificate of Analysis
Endotoxin Specification and Test Result
(pass/fail)
Bioburden Specification Test Result (pass/fail)
8
X
X
X
X
X
OPUS® 5, 10 – 60 cm, OPUS® R Columns
2.3
Regulatory Support File
Certificate of Analysis (CoA) Examples
Each OPUS® Pre-packed Column is delivered with a Certificate of Analysis (CoA) with the content
noted in Table 2.1.
2.3.1 Pre-GMP OPUS® Columns Certificate of Analysis (CoA)
Each Pre-GMP column produced is issued a Certificates of Analysis (CoA). Content is derived from
the template information (Figure 2.1) as well as customer required specifications as detailed on the
OPUS® Work Order. The CoA package also includes the resin manufacturer’s CoA which is attached
to the OPUS® Column CoA.
Figure 2.1
9
Pre-GMP OPUS® Column Certificate of Analysis
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
2.3.2 GMP Run Ready OPUS® Columns Certificate of Analysis (CoA)
Each GMP Run Ready column produced is issued a Certificates of Analysis (CoA). Content is derived
from the template information (Figure 2.2) as well as customer required specifications as detailed on
the OPUS® Work Order. The CoA package also includes the resin manufacturer’s CoA which is
attached to the OPUS® Column CoA. In addition, all GMP Run Ready columns are provided with a
chromatography resin side sample which is shipped with the column and resin lot traceability.
Figure 2.2
10
GMP Run Ready OPUS® Column Certificate of Analysis
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
2.3.3 Certificate of Analysis: Chromatograms
For both Pre-GMP, and GMP Run Ready columns, the Certificate of Analysis comes with a second
page detailing the testing conditions and chromatogram. See example below of the second page of
the OPUS® GMP Run Ready CoA.
Figure 2.3
OPUS® Certificate of Analysis Testing Conditions and Chromatograms
Labeling
Each individual OPUS® 10 – 60/R cm ID Column is labeled with the following information:
1. Catalog number
2. Resin type
3. Column Internal Diameter
4. Column Bed Height
5. Date of Manufacture
6. Storage temperature (“ambient” or “2-8 degrees Celsius”)
7. Lot number
8. Serial number
9. Pressure Rating
11
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Figure 2.4
Regulatory Support File
Example of OPUS® 10-60 cm ID Column Label
Each individual 5cm ID GMP Run Ready column is labeled with the following
1. Catalog Number
2. Resin description
3. Lot number
4. Serial number
OPUS® Column Part Numbers
OPUS® Column part numbers are structured so basic column configuration details can be
deciphered. The OPUS® part number system, which is governed by QA-FM-10107, is not unique for
all user specified inputs, and therefore an OPUS® Work Order is generated for every new purchase
order even if the same column/part number is re-ordered. See Figure 2.5 for the OPUS® part
number format.
Figure 2.5
12
OPUS® Part Number Format
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
If for example a customer were to order a 45 x 15 cm GMP Run Ready OPUS® R Column packed with
Repligen-sourced CaptivA® resin, the part number would be, BC-450-CPRI-150-GR. The part number
code works as follows:





The first 2 digits (“BC”) show the resin is Repligen sourced (vs. customer supplied)
The next 3 digits show the nominal column diameter in millimeters (“450”)
The subsequent 4 digits show the unique code for resin being packed (“CPRI”)
The next 3 digits show the target/specified bed height in millimeters (“150”),
The last 1 or 2 digits reference the GMP level (Pre-GMP or GMP Run Ready) as well as if the
column configuration includes an OPUS® R port (“GR”)
2.4 Column Manufacturing and Packing
Obtaining User Specified Column Inputs
All OPUS® columns are manufactured using input from the OPUS® quote request form
(https://www.repligen.com/rfq/), which documents user specified configurable product aspects
such as,



Column details: internal diameter, bed height, resin source, GMP Level
Acceptance criteria (if specified): plate count, asymmetry, pressure vs. flow
Application specific (if specified): maximum working flow rate, maximum working pressure,
preferred storage solution
All fields on the OPUS® Quote Request form are filled in with input from the end user and/or a
Repligen sales professional. The form is then submitted for review prior to the formal quoting
process. Once a purchase order has been submitted and accepted against a formal quotation, an
OPUS® Work Order is drafted by Repligen to formalize the user specified inputs contained in the
quote request form. The Work Order is then sent to the customer for review and approval. Upon
written approval from the customer, the OPUS® Work Order (QA-FM-10016) is finalized and the
column/s is added to the manufacturing schedule. See Section 3 for more information on the
OPUS® Work Order.
Resin Supply
When ordering an OPUS® column, the resin may be supplied by the customer, drop shipped from
the resin manufacturer, or procured through Repligen. If the customer decides to source the resin
and supply it to Repligen for column packing, then the Health and Safety Declaration for Accepting
Customer Supplied Resin form (QA-FM-02-10035) must be completed.
Overview of OPUS® Column Production Processes*
Column Components: All incoming raw materials and custom components are subject to an
incoming inspection procedure. Only the parts in compliance with the criteria set forward in the
approved Raw Materials and Component Specifications documents are released for column
assembly and packing.
Resins: For all resins, Repligen maintains strict material controls including assignment of internal lot
numbers to enable full traceability within batch records consistent with good documentation
practices. The SOPs which govern these procedures are SOP-1094 (Control of Incoming Materials),
13
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
SOP-10042 (Control of Incoming Components) and SOP-10035 (Customer Property). In addition, all
resins are tested for identity (FTIR) prior to release for column packing.
Manufacturing Qualification: The column assembly processes are qualified and documented with
appropriate SOPs and batch records as specified in Repligen’s ISO 9001 Quality Management
System.
Preparation of Column Components: Column parts are washed and cleaned prior to assembly.
Washing and cleaning procedures are qualified and validated.
Column Packing: OPUS® 5, 10 – 60/R cm ID columns are packed in a controlled, classified clean room
that meets ISO Class 7 standards.
Quality Control: Each pre-packed column is individually tested according to the specifications
detailed on the OPUS® Work Order. The specifications and the results of the release tests are
documented on the Certificate of Analysis.
Packaging: Columns are secured by foam packaging material, and shipped in qualified shipping
containers.

The OPUS® 5, and 10 – 30 cm columns are sealed in polyolefin bags in a controlled, classified
clean room that meets ISO Class 7 NVP standards and then packaged in a cardboard box with
foam packaging material. For OPUS® 10 - 30 cm columns, the box is strapped and shipped on a
plastic pallet. See Sections 4 and 6 for more information.

The OPUS® 45R – 60R cm columns are not bagged; however, the inlet and outlet ports are both
capped and secured with SaniSure clamps. All OPUS® 45R – 60R cm columns are shipped in a
custom made wooden crate. All crates are heat treated and stamped with heat treated
assurance. OPUS® 45 and 45R columns ship in the same qualified crate design, and OPUS® 60
and 60R ship in the same qualified crate design. See Sections 4 and 6 for more information.

The box/crate and internal packaging for the OPUS® 5, and 10 - 60/R cm ID columns have been
qualified with standard International Safe Transit Authority (ISTA) tests. For more information
on shipping qualification, please refer to Section 4 for Shipping Qualifications.
*Note: See Section 3 for more detailed information on the OPUS® Column production process.
Reference Documentation
Quality Documentation: Industry standards for document control are followed as per Repligen ISO
9001 Quality Management System. Repligen Quality management documents can be found on the
following website, https://www.repligen.com/resources/quality-documents/.
Technical Specifications: External column dimensions are provided in the user guide and in Section
2.5 (Table 2.3 and 2.4) of this Regulatory Support File. All other column packing specifications and
user specified criteria are documented in the OPUS® Work Order.
User Guide: A user guide for OPUS® 5, 10-60/R columns is available on Repligen’s website, as well as
an instruction guide for unpacking resin using the OPUS® R design. Please visit
https://www.repligen.com/resources/quality-documents/.
Un-packaging Guide: For OPUS®45-60/R columns, an uncrating guide is available on Repligen’s
website. Please visit, https://www.repligen.com/resources/quality-documents/.
14
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
Technical Documents: A variety of supporting technical documents, presentations, and videos can
be found on Repligen’s website by visiting www.repligen.com/opus.
CE-Certificate: EG directive 97/23/EG is not applicable for OPUS® columns, and therefore no
columns will be CE-signed.
Performance
OPUS® columns are designed to provide chromatographic performance equivalent to or better than
traditional self-packed columns. The performance is attained through a semi-automated packing
process and the design of the flow distribution system.



Optimal flow distribution is achieved through a flow distributor design with minimized dead
space volume. Rigorous Computational Fluid Dynamics (CFD) models validated by experiments
have provided evidence this flow distributor design is optimal for uniform radial distribution.
Mathematical modeling and performance testing have verified that the flow distributor design
provides chromatographic performance consistent with traditional columns.
Multi-cycle performance tests have shown that OPUS® columns deliver robust and reproducible
chromatographic results
Note: More information on column performance can be found on at www.repligen.com/opus.
Ease of Use
The OPUS® 5, 10 – 60/R cm ID platform design incorporates ease of use features such as lifting
handles, castors, and industry standard sanitary tri-clamp inlet and outlet connections (see Table for
more information).
Inlet/Outlet Port Locations
The OPUS® 10-60/R column inlet and outlet ports are both located on the top side of the column.

The column inlet and outlet are secured with a tri-clamp fitting designed by SaniSure® to be both
leak-proof and tamper-evident.
The OPUS® 5 cm column design has inlet and outlet ports located at either end of the tube like a
typical lab scale self-pack column design.
15
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
Lifting Handles
OPUS® columns with 14 – 30 cm IDs are designed with handles as shown below. The OPUS® 5, 10,
45/R, and 60/R Columns have no lifting handles. Columns with internal diameters of 5 cm through
30 cm may be lifted safely by one or two operators.
Figure 2.6
Lifting Handles and Input/Output Ports on an OPUS® 20 cm Column
Castors
OPUS® 45/R – 60/R cm ID columns are equipped with twin wheel swivel castors shown below for
enhanced maneuverability. Each castor has a manually engaged wheel lock and is rated to hold
100kg. The bottom caps for OPUS® 45/R and 60/R Columns are designed with grooves to allow
lifting of the columns with straps.
Figure 2.7
16
Castor Detail on an OPUS® 45 cm Column
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
2.5 Materials of Construction: Product Contact
OPUS® 5 and 10 - 60/R cm ID columns are designed using plastics which are best suited for
downstream processing applications. These plastics have been chosen for performance
characteristics including:
Fit for Purpose
 Suitability for pharmaceutical use with process fluid contact
 USP Class VI compatibility
 Low levels of non-toxic extractables
 Free from materials of animal origin and/or compliant with EMEA 410/01
Mechanical Strength
Recommended maximum 4 bar operating pressure for 5, and 10 – 30 cm IDs, and maximum 3 bar
operating pressure for 45/R – 60/R cm ID columns. All columns were designed with a ≥ 2x Factor of
Safety (FOS) in operating pressure.
Thermal Stability: Column construction can support a working temperature range of 2°C to 40°C
based on the general properties of polypropylene as well as OPUS® Column ISTA shipping tests (see
Section 4).
Figure 2.8
17
Materials of Construction: OPUS® 5 cm Column
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Figure 2.9
Materials of Construction: OPUS® 10-30 cm Columns
Figure 2.10 Materials of Construction: OPUS® 45-60 cm Columns
18
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Figure 2.11 Materials of Construction: OPUS® 45R - 60R Columns
Figure 2.12 OPUS® R Port Design and Materials of Construction
19
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
Materials of Construction: Product Contact
OPUS® 5, and 10 – 60/R cm ID columns are made of polymeric materials chosen to provide optimum
biological and chemical compatibility with a vast range of biopharmaceutical manufacturing
strategies. The elegant design of 10 – 60/R cm ID OPUS® columns employ only two product contact
materials, polypropylene and platinum cured silicone. The 5 cm ID columns employ only
polypropylene. All plastics have been certified to comply with United States Pharmacopeia (USP)
Class VI requirements as defined in USP <88> Biological Reactivity Tests and USP <661>
Physicochemical Tests, In Vivo as well as FDA CFR Title 21 Part 177. Furthermore all product contact
plastics are animal free and/or compliant with EMEA 410/01 guidance.
Product Contact Materials Summary
 OPUS® 5, and 10 – 30 cm ID Columns
o The same medical grade polypropylene homo-polymer formulation is used for the
column tube, flow distributors, inlet, outlet, and bed support screens
o The polypropylene bed support screens are made from a medical grade
polypropylene formulation
 Note: the polypropylene bed support screen is ultrasonically welded to the
flow distributor.
o The flow distributor O-rings are made from platinum-cured medical grade silicone
o The return line (10-30cm columns only) is made from platinum-cured, medical grade
silicone, reinforced with a strong polyester fiber

20
OPUS® 45/R – 60/R cm Columns
o Column tubes are made from a 70% w/w E-glass/Polypropylene engineered
composite structure assuring a polypropylene resin rich internal surface. This
material exhibits a high strength-to-weight ratio, excellent toughness, and chemical
resistance.
o Flow distributors, inlet ports, outlet ports, OPUS® R plug, and OPUS® R inside port
are made from the same medical grade polypropylene homo-polymer formulation
o The polypropylene bed support screens are made from a medical grade
polypropylene formulation
 Note: the polypropylene bed support screen is ultrasonically welded to the
flow distributor.
o The flow distributor O-rings, OPUS® R plug O-ring, and the inner/outer OPUS® R
gaskets are made from the same platinum-cured, medical grade silicone
o The return line is made from platinum-cured medical grade silicone, reinforced with
a strong polyester fiber
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Table 2.2 Product Contact Materials
Component
Material
USP <88>
Class
CFR 21 177
Animal
Origin
Column Tube (5,
10-30 cm)
Column Tube (45/R
– 60/R)
Flow Distributors
Inlet and Outlet
Ports
Bed Support
Screens
Flow Distributor ORings
Return Line
Polypropylene
Class VI
177.1520
Animal Free
70% w/w E-Glass / PP engineered
composite structure
Polypropylene
Polypropylene
Class VI
177.1520
Animal Free
Class VI
Class VI
177.1520
177.1520
Animal Free
Animal Free
Polypropylene
Class VI
177.1520
Platinum-cured medical grade silicone
Class VI
177.2600
EMEA
410/01
Animal Free
Platinum-cured medical grade silicone,
reinforced with strong polyester fiber
Class VI
177.2600
Animal Free
OPUS® R Plug, and
Inside Port
Polypropylene
Class VI
177.1520
Animal Free
OPUS® R Inner/
Outer Gaskets, and
Plug O-ring
Platinum-cured medical grade silicone
Class VI
177.2600
Animal Free
Non-Product Contact Materials Summary
 Top and bottom caps: Acrylonitrile Butadiene Styrene (ABS) co-polymer or High Density
Polyethylene (HDPE)
 Side guard: ABS (blue)
 Inlet and outlet port grommets: silicone (blue)
 Handles: polyurethane (blue)
 Castors: Polyamide casing with non-marking grey polyurethane tires
 OPUS® R outer nut and washer: ABS
 OPUS® R BioClamp: glass filled nylon
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Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
2.6 OPUS® Physical Specifications
Table 2.3 Physical Specifications Summary on OPUS® 10 - 30 cm Columns
Column Diameter
Physical
Attributes
5 cm
10 cm
14 cm
20 cm
25 cm
30 cm
Internal cross
section
20.4 cm
Column Body
Pressure Rating
4 Bar
4 Bar
4 Bar
4 Bar
4 Bar
4 Bar
Bed height range
5 – 30 cm
5 – 30 cm
5 – 30 cm
5 – 30 cm
5 – 30 cm
5 – 30 cm
10 cm bed height
0.2L
0.8L
1.5 L
3.1 L
4.9 L
7.1 L
20 cm bed height
0.4L
1.6L
3.1 L
6.3 L
9.8 L
14.1 L
30 cm bed height
0.6L
2.4L
4.6 L
9.4 L
14.7 L
21.2 L
Assembled Column
Height (cm)
~20 + bed
height
~20 + bed
height
~30 + bed
height
~30 + bed
height
~33 + bed
height
~35 + bed
height
Outer Diameter
(including caps)
6.3 cm
16 cm
21 cm
27 cm
33 cm
38 cm
Inlet/Outlet Flow
Path Internal
Diameter
3.18 mm
6.35 mm
6.35 mm
6.35 mm
9.53 mm
9.53 mm
0.125”
0.25”
0.25”
0.25”
0.375”
0.375”
Inlet and Outlet
Port Connectors
¾” mini triclamp
¾” mini triclamp
¾” mini triclamp
¾” mini triclamp
¾” mini triclamp
¾” mini triclamp
2
78.5 cm
2
154 cm
2
314 cm
2
491 cm
2
707 cm
2
Column Volumes
Table 2.4 Physical Specifications Summary on OPUS® 45R - 60R Columns
Column Diameter
Column Diameter
Physical Attributes
45.7 cm (includes R design)
59.9 cm (includes R design)
Internal cross section
1,640 cm
Column Body
2
2,817 cm
2
3 Bar
3 bar
Bed height range
5 – 30 cm
5 – 30 cm
10 cm bed height CV
16 L
28 L
20 cm bed height CV
33 L
56 L
30 cm bed height CV
49 L
84 L
Assembled Column Height (cm)
~ 90 cm
~92 cm
Outer Diameter (including caps)
54 cm
61 cm
Inlet/Outlet Flow Path Internal
Diameter
10.88 mm
19.05 mm
0.43 inches
0.75 inches
¾” mini tri-Clamp
1” tri-Clamp
Pressure Rating
Inlet and Outlet Port Connectors
Per ASME BPE Standards, Current Edition
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Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Table 2.5 Column Mass (Approximate Weight of Packed Columns)
Column Diameter
Bed
5 cm
10 cm
14 cm
20 cm
25 cm
30 cm
45 cm
60 cm
5 cm
1 kg
2 kg
4 kg
6 kg
10 kg
14 kg
69 kg
117 kg
10 cm
1.2 kg
2.5 kg
5 kg
8 kg
13 kg
18 kg
77 kg
131 kg
15 cm
1.4 kg
3 kg
6 kg
10 kg
16 kg
22 kg
86 kg
145 kg
20 cm
1.5 kg
3.5 kg
7 kg
12 kg
19 kg
26 kg
94 kg
159 kg
30 cm
1.9 kg
4 kg
9 kg
16 kg
24 kg
34 kg
110 kg
187 kg
Height
2.7 Column Stability
Repligen conducted a study to assess shelf life stability for OPUS® columns when stored according to
instructions in the user guide. Two different studies ran in parallel over an 18 month period:
 Mechanical stability study: This study looked at the structural integrity of the column assembly at
pre-determined time points over the course of 18 months.
Study design: Three columns of different internal diameters (10 cm, 20 cm, and 30 cm ID) initially
filled with 18.5% EtOH solution up to a 20 cm bed height were pressurized to 4 bar and the
pressure decay was monitored for 60 minutes. During the course of this pressure hold period, the
column was visually inspected for gross failure such as leakage from ports and/or threads, and
general structural integrity. See Table 2.6 for the mechanical stability test schedule and
acceptance criteria. Results are summarized in Table 2.7.
 Chromatographic performance stability study: This study looked at the chromatographic
performance of the large scale columns over an 18 month period when stored at 2-8 Celsius. The
goal of this study was to show no significant performance degradation will occur if a customer
purchases a column and places it on the shelf for up to 18 months. Cold storage was deemed as
“worst case” due to the polypropylene materials becoming more brittle in cold temperatures.
Study Design: Four 20 cm columns were packed with agarose resin to a 15 cm bed height.
Acceptance criteria for the columns is summarized in Table 2.6 at “T=0.” One column was
retested at each of the time intervals and compared with the performance of that specific column
at time zero. The results are summarized in Table 2.8.
Table 2.6 Stability Study Schedule and Acceptance Criteria
Time Interval
T=0
23
Mechanical Stability Criteria
(Empty Columns)
Performance Stability Criteria
(Packed Columns)
Time at Pressure: 60 minutes
Pressure: 4 bar
Pressure decay: < 10%
Visual: No gross defects or leaks
Asymmetry: 0.8 – 1.6
Plate Count: >1500 N/m (100cm/hr)
P vs. F: record baseline (10 psi)
Endotoxin: ≤ 1.0 EU/mL
Bioburden: ≤ 100 CFU/mL
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
T = 3 months
Time at Pressure: 60 minutes
Pressure: 4 bar
Pressure decay: < 10%
Visual: No gross defects or leaks
Asymmetry: 0.8 – 1.6
Plate Count: >1500 N/m (100cm/hr)
P vs. F: record baseline (10 psi)
Endotoxin: ≤ 1.0 EU/mL
Bioburden: ≤ 100 CFU/mL
T = 6 months
Time at Pressure: 60 minutes
Pressure: 4 bar
Pressure decay: < 10%
Visual: No gross defects or leaks
Asymmetry: 0.8 – 1.6
Plate Count: >1500 N/m (100cm/hr)
P vs. F: record baseline (10 psi)
Endotoxin: ≤ 1.0 EU/mL
Bioburden: ≤ 100 CFU/mL
T = 12 months
Time at Pressure: 60 minutes
Pressure: 4 bar
Pressure decay: < 10%
Visual: No gross defects or leaks
T = 18 months
Time at Pressure: 60 minutes
Pressure: 4 bar
Pressure decay: < 10%
Visual: No gross defects or leaks
Asymmetry: 0.8 – 1.6
Plate Count: >1500 N/m (100cm/hr)
P vs. F: record baseline (10 psi)
Endotoxin: ≤ 1.0 EU/mL
Bioburden: ≤ 100 CFU/mL
Asymmetry: 0.8 – 1.6
Plate Count: >1500 N/m (100cm/hr)
P vs. F: record baseline (10 psi)
Endotoxin: ≤ 1.0 EU/mL
Bioburden: ≤ 100 CFU/mL
All columns passed acceptance criteria at each interim time point, as well as at the end of 18
months. The data is summarized in Tables 2.7 and 2.8 below:
Table 2.7 Mechanical Stability Test Results
Column
Configuration
3 months
6 months
12 months
18 months
10 x 20 cm
Pass
Pass
Pass
Pass
20 x 20 cm
Pass
Pass
Pass
Pass
30 x 20 cm
Pass
Pass
Pass
Pass
Table 2.8 Performance Stability Study Results
Column S/N
3 months
0001
N/m Δ = < 15%
As Δ = < 15%
0002
0003
0004
24
6 months
12 months
N/m Δ = < 15%
As Δ = < 15%
N/m Δ = < 15%
As Δ = < 15%
18 months
N/m Δ = < 15%
As Δ = < 15%
N/m Δ = < 15%
As Δ = < 15%
N/m Δ = < 15%
As Δ = < 15%
N/m Δ = < 15%
As Δ = < 15%
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
At the end of 18 months, bioburden for all 4 packed columns (serial numbers 0001 – 0004) was 0
CFU/ml and endotoxin for all 4 packed columns (serial numbers 0001-0004) was <0.1 EU/ml.
Cleanability
OPUS® Columns are used for purification of biological products which have specific regulatory
requirements for bioburden and endotoxin levels. Therefore, a quantitative cleaning investigation
was performed to demonstrate the effectiveness of sanitization using sodium hydroxide as a
cleaning agent.
Method: Several different OPUS® Columns were packed with Sepharose 6FF in 20 cm bed heights.
Each column was loaded with 1 column volume of E. coli bacteria at a concentration of 0.1 OD
(optical density) at 600 nm. The columns were left to incubate at ambient temperature overnight,
and then flushed with reverse osmosis deionized (RODI) water for 2-3 column volumes in downflow. Samples were collected to measure bioburden and endotoxin. A sanitization procedure was
subsequently used as followed:
Sanitization procedure:
• Flush with 1 M sodium hydroxide in up-flow at 100 cm/h for 30 minutes
• Flush with 1 M sodium hydroxide in down-flow at 100 cm/h for 30 minutes
• Recirculation of 1 M sodium hydroxide for 2 hours in up-flow at 100 cm/h
• Incubation of the column in 1 M sodium hydroxide for 1 hour (static sanitization for compete
removal of endotoxins)
• Flush with RODI water at 100 cm/h until neutral pH is achieved
Each column was then left to incubate at ambient temperature overnight prior to pulling samples for
bioburden and endotoxin testing.
Results: Results for bioburden and endotoxin levels from the microbial challenge are outlined in the
table below, which shows the sanitization procedure completely removed bioburden from millions
of CFU to zero CFU in the post-sanitization water rinse. In addition, endotoxin levels were brought
below the limit of detection (0.25 EU/mL) for the assay.
Table 2.9 Results of Bioburden and Endotoxin Testing
Column Diameter
Cleaning Data
0.1 M NaCl
effluent after
overnight E.coli
incubation
0.1 M NaCl post
sanitization
effluent
25
20 cm
30 cm
45 cm
45R cm
60 cm
60R
TNTC
(CFU/Ml)
>0.25
EU/mL
TNTC
(CFU/Ml)
>0.25
EU/mL
TNTC
(CFU/Ml)
>0.25
EU/mL
TNTC
(CFU/Ml)
>0.25
EU/mL
TNTC
(CFU/Ml)
>0.25
EU/mL
TNTC
(CFU/Ml)
>0.25
EU/mL
0 CFU/mL
<0.25
EU/mL
0 CFU/mL
<0.25
EU/mL
0 CFU/mL
<0.25
EU/mL
0 CFU/mL
<0.25
EU/mL
0 CFU/mL
<0.25
EU/mL
0 CFU/mL
<0.25
EU/mL
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
Conclusions: In order to test effectiveness of sanitization on an OPUS® column, a worst case
scenario was devised where the column was loaded with an excess of E. coli culture (a gramnegative, endotoxin producing bacteria). The results of the sanitization protocol demonstrate the
effective removal of bioburden and endotoxin contamination.
2.7.1 Warranty
Repligen aspires to complete customer satisfaction, and has implemented the following warranty
policy for OPUS® Columns.
 If the column arrives at the customer site in damaged condition, Repligen will accept the damage
risk and issue a replacement at no charge.
 If the column fails passing specifications as agreed to on the OPUS® Work Order, Repligen will
conduct troubleshooting efforts and if unsuccessful, will ask for the column to be returned for
further evaluation. If the root cause of the failed test is determined to be a compromised packed
bed, Repligen will pack a replacement at no charge.
 If the column’s packed bed is compromised (i.e. a channel develops) and the root cause is packing,
then Repligen will replace the column at no charge.
2.8 Material Safety Data Sheet
OPUS® columns are made from plastic components only and therefore no MSDS is needed. An
MSDS for the chromatography resin packed into an OPUS® Column may be obtained from the resin
manufacturer.
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OPUS® 5, 10 – 60 cm, OPUS® R Columns
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3. Manufacturing Information
3.1 Introduction
All OPUS® 5, 10 – 60/R cm Columns are manufactured at the Repligen corporate headquarters,
located at 41 Seyon Street, Waltham, Massachusetts 02453, USA. The QA and QC operations are
also based in the same location. Neither the facility nor products manufactured require registration
or market approval. Therefore, Repligen’s column packing facility and products manufactured
herein are not subject to regulatory review or audit by organizations such as the US Food and Drug
Administration or European Medicines Agency.
3.2 Manufacturing Quality Assurance Standards and Policy
Repligen recognizes the need for high quality standards, and has therefore established an ISO 9001
Quality Management System suitable for the needs of our clients and our industry. Refer to Section
1 for Repligen’s Quality Policy.
3.3 Manufacturing Facilities
The OPUS® Column packing suite consists of multiple ISO Class 7 column packing rooms and a
central ISO 8 prep area. Two airlock doorways are maintained, one for people and one for finished
goods and equipment. In general, column parts enter the suite through a validated parts washer or
are cleaned with NaOH followed by a rinse with RODI water. The OPUS® Column suite is completely
segregated from all other product manufacturing at Repligen and is a restricted-access area.
The clean-room environment is controlled and monitored as follows:








Air quality is maintained by 100% HEPA filtered air
Preparation room air quality is tested to ISO Class 8 standards for non-viable particulates
Column packing room air quality is tested to ISO Class 7 standards for non-viable particulates
Room pressure differentials are maintained and monitored according to SOPs
All rooms are on a routine cleaning and disinfection schedule
Access is restricted to authorized personnel only
Gowning is required for entry into controlled areas including a secondary gowning procedure for
entry into the ISO Class 7 packing rooms
Environmental monitoring is performed to check for viable and non-viable contamination
3.4 Manufacturing Controls and SOPs
Training [SOP-1498]: Manufacturing is performed by qualified and trained operators. Training
documentation is maintained by Quality Assurance.
Process Documentation [SOP-1302, SOP-1098]: Repligen manufacturing processes are governed by
an ISO 9001 compliant Quality Management System. All manufacturing work instructions are
contained in controlled documents, which are issued in advance of each manufacturing batch.
Batches and process intermediates are 100% traceable through an internal lot numbering system.
All manufacturing data are recorded by operators at the time of manufacturing. Batch records are
archived for 3 years on site, and then stored off site for a minimum of 10 years.
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OPUS® 5, 10 – 60 cm, OPUS® R Columns
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Raw Materials [SOP-1094]: All raw materials are controlled, and each raw material has a preapproved specification. Receipt of material is verified and released by QA prior to use in
manufacturing.
Customer Property [SOP-10035]: All customer property including customer supplied resin is
documented, tracked, and released prior to the start of packing. Customer property is stored in
segregated areas within Repligen’s warehouse.
Supplier Management [SOP-1496]: Repligen identifies critical suppliers of raw materials and
components based on the impact to the quality of the product they are used to manufacture.
Critical suppliers are subject to a qualification process and are monitored and routinely audited
according to a pre-determined schedule. The supplier audit schedule is established based on critical
supplier audit cycle, supplier performance, past audit results, and business requirements.
Components [SOP-10042]: All components are controlled and each component has a pre-approved
specification. Every receipt of material is verified and released by QA prior to use in manufacturing.
In addition, each OPUS® Column component has a pre-approved engineering drawing, and is subject
to incoming QC inspection, which includes review of materials certificates, and verification of critical
dimensions.
Process Change Management [SOP-1447]: Manufacturing process changes are governed by change
management procedures that include provisions for customer notification of major changes.
Product Storage Control [SOP-MFG-1212; SOP-1263]: Product is stored either at ambient
temperature, or in temperature controlled units as dictated by the packed resin. All temperature
controlled storage units have backup power, 24/7 electronic monitoring, and alarms that are
monitored.
Preventive Maintenance [SOP-1501] and Calibration [SOP-1181]: Equipment and monitoring
devices are controlled through the Repligen Equipment Control process [SOP1171]. Each piece of
equipment is uniquely identified and has a preventive maintenance and/or calibration schedule as
necessary.
High Purity Water [SOP-MFG-1209]: Purified water is supplied to all manufacturing areas from a
Reverse Osmosis/Deionization (RODI) system. The RODI system is fully automated, and provides
high quality water in a continuously circulating loop. The water system design performance
specifications are ASTM Type I Reagent Grade Water, with the addition of low endotoxin and
bioburden specifications (Table 4.1). Water quality is monitored continuously using an on-line TOC
device, and is routinely sampled and tested by Repligen Quality Control.
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OPUS® 5, 10 – 60 cm, OPUS® R Columns
Table 3.1 Repligen Water Specifications Compared with ASTM, USP Purified Water and Water for
Injection
Parameter
ASTM Type I
USP Purified
water
WFI
Repligen
Specification
Conductivity
Endotoxin
Bioburden
pH
TOC
0.05 µS/cm
N/A
N/A
N/A
0.1 ppm
1.3 µS/cm
N/A
100 CFU/mL
N/A
0.5 ppm
1.3 µS/cm
< 0.25 EU/mL
0.1 CFU/mL
5–7
0.5 ppm
< 0.01 mS/cm
< 0.5 EU/mL
≤ 10 CFU/mL
5–7
0.1 ppm
High purity water is one of the key raw materials for any bioprocessing product. Repligen believes
that these specifications, in conjunction with regular maintenance, ensure that the water system
performs at a suitably high quality standard.
3.5 OPUS® Column Manufacturing
Packing Environment and Environmental Controls
All OPUS® columns are packed in ISO Class 7 classified clean rooms and buffers prepared in an ISO 8
classified clean room. The rooms are monitored on a weekly basis for viable contaminants using
TSA settle plates. Microbial contaminants (bacteria) are counted and reported.
Viable contamination limits have been set for the ISO 8 rooms as follows:
Alert Limit: > 20 CFU/plate
Action Limit: > 35 CFU/plate
Viable contamination limits have been set for the ISO 7 rooms as follows:
Alert Limit: > 10 CFU/plate
Action Limit: > 25 CFU/plate
Counts which exceed an alert or action limit are investigated according to SOP-MFG-1207.
The OPUS® manufacturing suite is monitored on a weekly basis for Non-Viable Particles (≥ 0.5 µm).
Each room is monitored in predetermined locations, measuring 1 cubic foot of air over the course of
1 minute.
NVP limits have been set for the ISO Class 8 clean room spaces as follows:
Alert Limit: ≥ 25,000 particles per ft3 (880,000 particles per m3)
Action Limit: ≥ 50,000 particles per ft3 (1,760,000 particles per m3)
ISO 8 Specification: ≤ 100,000 particles per ft3 (3,520,000 particles per m3)
NVP limits have been set for the ISO Class 7 clean room spaces as follows:
Alert Limit: ≥ 2,500 particles per ft3 (88,000 particles per m3)
Action Limit: ≥ 5,000 particles per ft3 (176,000 particles per m3)
ISO 7 Specification: ≤ 10,000 particles per ft3 (352,000 particles per m3)
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OPUS® 5, 10 – 60 cm, OPUS® R Columns
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OPUS® Work Order and User Specified Inputs
Once a purchase order for a column has been received, the OPUS® Work Order (QA-FM-10015) is
created. The OPUS® Work Order compiles information from the purchase order as well as the user
specified inputs which were recorded from the OPUS® quote request form
(https://www.repligen.com/rfq/).
Note: All OPUS® columns are built to order and each column ordered must have a quote request form
and unique Work Order. These forms document critical user specified inputs and therefore cannot
be eliminated from the ordering process. In addition, each OPUS® Work Order is unique to a PO
number and column part number.
The OPUS® Work Order captures a variety of information including the following,
 Quote number, purchase order number and column part number
 Column size, type, and resin
 Column packing method and solutions used
 Column performance release method and specifications (ex: Asymmetry and plate count)
 Revision history
Once all required fields have been populated, Repligen sends the OPUS® Work Order to the
appropriate customer contact for review. If all the details in the document are satisfactory, the
customer signs and dates the form, and then sends the signed form back to Repligen. Once the
signed form is received, Repligen can begin column packing.
Note: Column packing cannot begin without a customer approved work order. See below for an
example of the OPUS® Work Order.
Figure 3.1
30
OPUS Work Order Example (blank)
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
Chromatography Resin Control
All chromatography resins are tested for identity using FTIR prior to being released for production.
A copy of the FTIR spectrum is maintained with the completed batch record. The SOPs governing
chromatography resin control procedures are SOP-1094 (Control of Incoming Materials), SOP-10042
(Control of Incoming Components) and SOP-10035 (Customer Property).
Repligen Supplied Resins
Resins purchased and supplied by Repligen for column packing are controlled as a raw material
according to SOP-1094 (Control of Incoming Materials). Upon arrival, each resin is placed into
quarantine pending disposition by Repligen Quality assurance. Upon release, each batch of resin is
given a unique internal lot number and expiration date to ensure full traceability throughout the
manufacturing process.
Customer Supplied Resins
Repligen’s customer property procedures (SOP-10035) are designed to protect our customer’s
financial and intellectual property interests to prevent unauthorized use, disclosure, or disposal. All
resins shipped to Repligen for column packing must be unused. Each customer supplied resin is
assigned a unique customer property number which is typically linked to a specific purchase order
and part number.
The customer property number is noted on the form entitled, Health and Safety Declaration for
Accepting Customer Supplied Resin, which must be filled out by an end user prior to shipping resin to
Repligen. Upon arrival, the resin is managed according to SOP-10035, which dictates the resin must
be labeled, segregated, and then stored according to the resin vendor’s recommendation. All
customer supplied resin is also tested for identity using FTIR prior to being released for production.
Unused media is either returned or discarded according to the customer’s instructions.
Repligen understands in some instances customers may have a requirement to sample and test a
small aliquot of the resin for identity (ex. FTIR). Unused resin in containers, which have been
sampled for QC testing, are compatible with Repligen’s quality requirements and therefore can be
accepted for column packing.
Resin Preparation
Once the appropriate resin has been released, parts cleaned, and column packing batch record
documentation have been issued, the follow steps occur:
1. Manufacturing operators move sealed resin containers into one of the OPUS® ISO 7 clean
rooms.
Note: only the released resin is allowed in the packing room, and only one resin type at a time
can be present.
2. Manufacturing operators verify the appropriate resin by checking against the OPUS® Work
Order.
3. After verifying the resin, containers are opened for resin preparation (decantation of storage
solution, fines removal, etc.).
4. For OPUS® GMP Run Ready columns only, prior to beginning resin prep an operator removes 1030 mL of resin per resin lot from the original container. This operation is performed using a
sterile pipette and the operator dispenses the resin aliquot into a 60 mL gamma irradiated,
tamper evident PETG (polyethylene terephthalate) bottle. The bottle is then sealed and labeled
with resin name, lot number, part number, date, and Repligen operator initials. In the event
multiple resin lots are packed into a single column, a single side sample of each resin lot will be
taken. Therefore, multiple side samples will be delivered with a GMP Run Ready column if
multiple resin lots are packed.
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OPUS® 5, 10 – 60 cm, OPUS® R Columns
5. After column packing, the resin “QC sample/s” or “resin side sample/s” are stored with the
finished the OPUS® GMP Run Ready column for shipment.
In general, Repligen uses the following approach for slurry preparation and percent solids
determination:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Decant off storage solution
Perform defining of resin as specified by resin MFG.
Suspended resin in packing buffer to target the desired % solids
Combine resin bottles in a holding tank if required
Pull resin samples
Record mass and volume added for density calculations
Spin samples in a centrifuge
Read spin down solids volume
Determine average % solids (solids vol. / total vol.)
Use target compression factor (CF = target column vol./uncompressed resin vol.) as derived by
a. Past empirical data
b. Resin manufacturer recommendations
c. Repligen R&D recommendations
11. Calculate target solids volume to add (target bed volume / CF)
12. Apply % solids (Step 9) and density (Step 6) to target solids calculations (Step 11) to determine
mass of slurry required
13. (Target solids vol. / % solids) * density = mass slurry to dose
Assembly, Packing, and Performance Testing
OPUS® columns are assembled from qualified and controlled components. Inspected and released
component parts are taken from inventory and brought into the ISO 8 classified cleanroom through
an automated parts washer. Parts which do not enter through the parts washer are chemically
cleaned with NaOH, followed by rinse with RODI water to depyrogenate and reduce bioburden.
Both processes have been qualified and validated to the following specifications:
Table 3.2 Parts Cleaning Specifications
Method
Parts Cleaning Specifications
Parts Washer
Bioburden
< 10 cfu/ml
Endotoxin
< 0.5 EU/ml
TOC
< 10 PPM
Conductivity
< 10 uS/cm
pH
5.0 – 7.0
NaOH Soak
< 10 cfu/ml
< 0.25 EU/ml
N/A
< 50 uS/cm
5.0 - 7.0
The following points summarize the major steps which occur during OPUS® Column packing:
1. Solutions and buffers are prepared in the ISO 8 area of the OPUS® clean rooms. All buffers and
solutions are filtered with a 0.2um filter.
2. Packing solutions/buffers and allocated parts, which have been cleaned, are brought into the
designated ISO 7 packing room.
3. All subsequent steps are performed in the designated ISO 7 clean room.
4. The bottom flow distributor with the ultrasonically welded mesh is inserted into the bottom end
of the tube to form a water-tight seal. The flow distributor assembly is then secured in place
with a polypropylene weld or adhesive bond.
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OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
5. The chromatography resin is added to the open ended column by dosing directly into the
column or using a peristaltic pump.
6. The top flow distributor is inserted into the column tube and packing is initiated to establish a
uniform bed. OPUS® columns utilize flow packing, axial compression, and/or a combination of
both methods to achieve a well packed bed. In general, packing protocols are developed in
Repligen’s R&D department and subsequently transferred to the production team.
7. Following the prescribed packing procedure, the top flow distributor is precisely positioned to
create the correct resin compression. Note: Rigid particle resins such as ceramic hydroxyapatite
are not compressed, rather the top flow distributor is positioned so there is no significant gap
between the consolidated resin bed and the flow distributor assembly.
8. Bed performance is tested according to the procedure and specifications as documented on the
OPUS® Work Order. Note: A column may be tested and flow distributor adjusted during the
packing process to ensure optimal performance.
9. Once the final flow distributor position is set and the column has met the performance
specifications (theoretical plates/meter and Asymmetry) as documented on the OPUS® Work
Order, the packing process can conclude.
10. The column is then sanitized using a procedure recommended by the resin manufacturer and/or
as documented on the OPUS® Work Order.
11. Post sanitization, the column is then neutralized (typically with RODI water), and Bioburden or
Endotoxin samples taken (OPUS® GMP Run Ready Columns only).
12. After neutralization, each pre-packed column is put in its final storage solution as documented
on the OPUS® Work Order.
13. The column assembly is then finished by securing the flow distributors in place using a
polypropylene weld or adhesive bond, and assembling the top cap, bottom cap, and side-guard.
Note: The top cap, bottom cap, and side guard serve cosmetic and ergonomic functions, and
therefore do not impact the performance of the column.
14. Inlet and outlet ports are capped and sealed using a tamper evident SaniSure clamp.
15. Each OPUS® 5, 10 – 30 cm Column is sealed in a polyethylene bag before being removed from
the OPUS® cleanroom suite. Note: OPUS® 45/R and 60/R cm Columns are not bagged since they
are on wheels.
16. Columns are then stored according to storage conditions as noted on the OPUS® Work Order.
Client resin verification upon arrival:
Included with each column lot is a copy of the resin vendor’s Certificate of Analysis1 and a small
sample/s (10-30 mL) of resin (GMP Run Ready columns only) intended for incoming quality control
analysis. As described above, in the event multiple resin lots are packed into a column, a resin
aliquot is taken for each resin lot and delivered with the column. Finally, the column label contains
the resin description, and the certificate of analysis for each column indicates the part number and
lot number of the pre-packed resin.
Equipment Used in the Manufacturing of OPUS® Columns:
Wherever possible, all equipment used to pack OPUS® columns is dedicated single use equipment
such as:
 Slurry tanks and carboys
 Single-use liners for buffer tanks
 Single-use platinum cured tubing for pipe transfers
1
In rare cases a resin vendor’s certificate of analysis may not be included with the OPUS CoA package. For
example, when a customer ships custom resin without a CoA to Repligen for packing, Repligen may not be able
to include a resin CoA in the OPUS CoA package if the custom resin CoA is not readily available from the
manufacturer.
33
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
Where reusable components are used in the manufacturing process which might come into contact
with the resin or the inside of the column, Repligen employs validated cleaning protocols to ensure
the risk of cross resin “contamination” is mitigated.
3.6 Bioburden and Endotoxin Release Testing
Columns are tested according to the specifications detailed in the OPUS® Work Order. Bioburden
and endotoxin testing is performed on OPUS® “GMP Run Ready” columns and samples are taken in
RODI water post sanitization and just prior to introducing the storage solution. The release
specifications are as follows:
 Bioburden: <10 CFU/mL
 Endotoxin: <0.25 EU/mL
Repligen performs endotoxin and bioburden testing in-house using the following two methods.
Bioburden assay method
Bioburden is analyzed by a vacuum filtration method. The sample is applied to a sterile filter under
vacuum and then rinsed with peptone water. The filter is collected aseptically and placed onto TSA
media. The plate is placed into an incubator at 32C +/- 2C for 5 days. An analyst reads the plates at
day 3 and day 5 and documents the results. A negative control of the peptone water is also plated
and incubated to demonstrate the reagents used during the analysis were not contaminated.
Endotoxin assay method
Endotoxin is analyzed by gel clot method. Repligen uses a commercially available kit and performs
the test according to the manufacturer’s instructions which have been transcribed into an internal
test procedure. A column rinse sample with a volume of 0.25 mL is introduced to the gel clot tube
and incubated in a 37C water bath. The tubes are then read by an analyst and the data is recorded.
A positive control is run alongside the sample for this assay.
Bioburden and Endotoxin test results are documented on the Certificate of Analysis as a pass/fail
result for each GMP Run Ready column. See Section 2.0 for sample CoA documents.
Note: OPUS® Pre-GMP columns are not tested for bioburden or endotoxin.
34
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
4. Shipping Qualification
4.1 Summary
To certify the packaging, column components, and column performance remains intact during and
after shipping, International Safe Transit Association (ISTA) tests were conducted on a variety of
OPUS® column sizes. A third party certified laboratory performed the shipping tests, and Repligen
tested chromatographic performance pre and post shipping. Results from the studies show the
packaging withstands the stressors of commercial shipping, and chromatographic performance is
maintained.
4.2 Introduction
Objective
The objective of the shipping studies is to demonstrate the custom made packaging (Figures 5.1 and
5.2) and pre-packed columns of multiple diameters arrive intact after worst case shipping
simulations. See Section 6 for engineering drawings of packaging used for each internal diameter
column.
OPUS® columns employ different packaging based on size and weight. To cover the range of
different column dimensions and packaging methods/materials the following column sizes were
evaluated.
 OPUS® 5 cm Column
 OPUS® 10 cm Column (uses identical packaging as the OPUS® 14 cm Column)
 OPUS® 20 cm Column (uses identical packaging as the OPUS® 25, and 30 cm Columns)
 OPUS® 45 (uses identical packaging as the OPUS® 45R Column)
 OPUS® 60 (uses identical packaging as the OPUS® 60R Column)
 OPUS® 60R (representative of the “R” design)
Figure 4.1
35
OPUS® 5 cm Column Shipping Container Design
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Figure 4.2
OPUS® 10 - 30 cm Column Shipping Container Design
Figure 4.3
OPUS® 45/R - 60/R Column Shipping Container Design
Regulatory Support File
Acceptance Criteria
The shipping tests documented in this regulatory support file have two different acceptance criteria
categories as detailed below.

Visual inspection of packaging
Per ISTA guidelines, procedures 2A and 2B call for a simple pass/fail assessment based on a
visual test of packaging materials. This assessment is made by the certified ISTA test facility and
documented in a summary report.

Chromatographic performance
Repligen assessed chromatographic performance by measuring plate count and asymmetry to
compare “pre-shipping” performance with “post-shipping” performance. In order to pass the
chromatographic portion of the test, the minimum post-shipping theoretical plate count and
asymmetry measurements had to be within +/-25% of pre-shipping results.
36
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OPUS® 5, 10 – 60 cm, OPUS® R Columns
4.3 Method: ISTA 2A and 2B Tests
4.3.1 ISTA Test Methods
ISTA Procedure 2A was used for the OPUS® 5 cm ID and 2B2 was used for OPUS® 10 – 60/R cm IDs.
The selection of the two tests has to do with weight and shipping methods (see below).

ISTA Procedure 2A is a worst case simulation test for individual packaged-products shipped in
boxes (“parcel shipments).
ISTA Procedure 2B is a worst case simulation test for individual packaged-products shipped on
pallets

Both tests are used to:
 Evaluate the performance of a packaged product
 Compare relative performance of the package and product design
During the test, the package and product are considered together and not separately.
Tests and Conditions
All studies were performed by Atlas Box and Crate in Sutton, MA per ISTA guidelines. The specific
test conditions are described further in Table 5.1 below. The 5, 10, 20, 45, 60, and 60R columns
were manufactured by Repligen, packaged into their respective shipping containers, picked up by
Atlas, shipped to their certified testing facility, and tested according the applicable standards. After
the tests were complete, Atlas returned the shipping containers to Repligen for post testing analysis.
Table 4.1
ISTA 2A and 2B Testing Conditions (OPUS® 5, 10 – 60 cm Columns)
Test Name
Atmospheric Conditioning
Controlled Temperature and Humidity
Conditioning
Compression Testing
Random Vibration Testing
Incline Impact (2B only)
Drop Testing
2
Test Details
Ambient Conditions for 36 hours

38° ±2°C; Relative Humidity 85% ±5% for 36
hours
 4°C±2°C; RH uncontrolled for 36 hours
248 lbs. (OPUS® 5), 370 lbs. (OPUS® 10), 744 lbs (OPUS®
20), 1728 lbs (OPUS® 45), 2,392 lbs (OPUS® 60), and
2,836 lbs (OPUS® 60 R) on top of crate/box
60 minutes of random vibration
Frequency (Hz)
PSD Level, g2/Hz
1.0
0.0001
4.0
0.01
100.0
0.01
200.0
0.001
Slide crate down ramp and into a wall

Crate dropped 8” to ground (2B)
See, www.ista.org/forms/2Boverview.pdf. Accessed on 02/04/2014
37
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns


Random Vibration Testing
Crate bottom edges dropped 8” to ground (2B)
Box dropped 38 inches to the ground (2A)
60 minutes of random vibration
Frequency (Hz)
PSD Level, g2/Hz
1.0
0.0001
4.0
0.01
100.0
0.01
200.0
0.001
Figure 4.4
OPUS® 5 cm Column Compression and Drop Testing
Figure 4.5
OPUS® 20 cm Column Vibrational and Compression Testing
38
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Figure 4.6
Regulatory Support File
OPUS® 60/R Column Vibrational, Incline Impact and Drop Testing
Visual Inspection
Per ISTA Procedures 2A and 2B, the certified test facility performed a visual pass/fail inspection of
the packaging materials.
4.3.2 Column Efficiency Test Methods
Overview: Column efficiency testing was designed to assess and uncover any discernible differences
in chromatographic performance pre-shipping and post-shipping. Repligen conducted all
chromatographic performance tests.






5 cm Study: 5 cm x 10 cm OPUS® Column packed with Sepharose® 6 Fast Flow
10 – 14 cm Study: 10 cm x 15.3 cm OPUS® Column packed with Q Sepharose® Fast Flow resin
20 – 30 cm Study: 20 cm x 19 cm OPUS® Column packed with a silica based protein A resin
45 cm Study: 45 cm x 21 cm OPUS® Column packed with Q Sepharose® Fast Flow resin
60 cm Study: 60 cm x 20 cm OPUS® Column packed with Sepharose® 6 Fast Flow resin
60R Study: 60 x 20.5 cm OPUS® Column packed with 90% Phenyl Sepharose 6 Fast Flow with
10% SP Sepharose XL
Each column was tested at 100 cm/hr with pulse injection of 1% CV acetone solution, except for the
OPUS® 5 cm Column which was tested at 100 cm/hr using a 0.2M NaCl mobile phase and 2M NaCl
spike.
4.3.3 Results: ISTA and Column Efficiency Tests
Results: Visual Inspection
ISTA test facility:
 After the worst case shipping simulation tests were completed, Atlas visually inspected the
packaging for signs of damage. For all tests, the custom designed OPUS® packaging passed the
visual inspection without any significant signs of damage.
Note: Visual inspection results are documented as part of the ISTA summary reports issued by the
test facility.
Repligen:
 Upon receipt from Atlas Box and Crate, all shipping containers and columns were inspected and
found to be undamaged and intact.
39
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Note: visual inspection results are documented in Repligen’s summary report for each shipping
test
4.3.4 Chromatographic Performance Test Results
The data summarized in Table 5.2 shows the packing efficiency of 10, 20, 45, 60, and 60R OPUS®
columns remain stable following the applicable shipping simulation. Stability is exhibited by a
negligible change in asymmetry and plate count, while meeting the acceptance criteria.
Table 4.2
OPUS® 10 cm, 20 cm and 45 cm Column Performance Data
Column
5 cm ID
10 cm ID
20 cm ID
45 cm ID
60 cm ID
60R
Date
N/m
As
Pass / Fail
Pre-shipping
2479
1.5
PASS
Post-shipping
3108
1.5
PASS
Pre-shipping
2936
1.2
PASS
Post-shipping
2889
1.2
PASS
Pre-shipping
Post-shipping
Pre-shipping
Post-shipping
Pre-shipping
Post-shipping
Pre-shipping
Post-shipping
4121
5526
2886
2800
3144
2702
3367
3373
1.1
1.1
1.2
1.1
1.3
1.4
1.0
1.0
PASS
PASS
PASS
PASS
PASS
PASS
PASS
PASS
*Pre-ship and post-ship test flow rates vary slightly due to manual flow control of testing set-up.
4.3.5 Conclusion
In summary, the following was observed post worst case shipping simulation:
 No significant damage to the shipping containers
 No damage to the column structures
 No discernable damage to the packed beds
 No significant differences in chromatographic performance
Therefore, OPUS® columns designed and tested by Repligen for chromatographic performance, and
the shipping containers designed and tested in conjunction with Atlas Box and Crate, demonstrate
suitable robustness for surviving the harsh environments of commercial shipping.
40
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
5. Extractables and Leachables
5.1 Introduction and Background
Plastic materials have been used in the manufacturing of therapeutics for many decades. Over the
last 15 years, focused product development by many vendors and biotechnology companies has
resulted in a plethora of single-use technologies. During this time, the industry has witnessed the
development and adoption of critical disposable and single-use technologies like mixers, bioreactors,
filters, and connectors. As a result, standards and best practices for evaluating component safety
have been set for the selection and qualification of plastics.
In general, plastics used in biopharmaceutical manufacturing have low defined extractables and
have been determined to be non-toxic at equivalent therapeutic doses. Many base standards used
for guidance have been set by regulatory publications including USP, CFR 21, and EMEA. These basic
standards have been elaborated on by industry organizations like the Bio-Process Systems Alliance
(BPSA) and Parenteral Drug Association (PDA) as well as product manufacturers through the
publication of best practices of testing and assessment of data. In addition, end user therapeutic
manufacturers have become more demanding in their analytical requirements, assessment of data,
determination of risk, and minimum threshold for meeting internal standards.
Repligen is sensitive to the demands of the industry and will therefore supply relevant and
applicable information about the plastics used in the product contact components of OPUS®
columns. In accordance with industry standards, Repligen uses the definitions for extractables and
leachables as stated in the 2007 BPSA document, "Recommendations for Extractables and
Leachables Testing: Part 1.”
Extractables: Chemical compounds that migrate from any product-contact material when exposed
to an appropriate solvent under exaggerated conditions of time and temperature.
Leachables: Chemical compounds, typically a subset of extractables that migrate into a drug
formulation from any product contact material as a result of direct contact under normal process
conditions.
There is a general consensus that it is the responsibility of the product technology vendor to provide
an extractable data package. In recent years there have been efforts to standardize the testing
procedures for extractables, and wherever possible it is Repligen’s intent to comply with the
standardization efforts. In addition, in compliance with CFR 21, Part 211.65, OPUS® columns are
designed such that all product contact materials are not reactive, additive, or absorptive so as to
alter the safety, identity, strength, quality, or purity of the drug product beyond established
requirements.
Therefore, using the BPSA guidance as a backdrop, Repligen has designed an extractables program
to produce a robust data package by conducting extractables testing using three solvents as well as
exaggerated time and temperature conditions. Solvents were chosen for their common usage in
chromatography columns. Leachables, however, are considered to be process specific and the
responsibility of the end user to define within specific process parameters.
41
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OPUS® 5, 10 – 60 cm, OPUS® R Columns
5.2 OPUS® Extractables Strategy
Based on the above discussion, Repligen has applied the following philosophy in its approach to
developing a meaningful extractables and leachables package for OPUS® columns:
1. All plastics used will be certified to meet four criteria (see Sections 3.2.1–3.2.4 for more detail):
a) Certified to meet USP <88> Biological Reactivity Tests, In Vivo (USP Class VI)
b) Certified to meet CFR 21 Part 177 Indirect food Additives: Polymers
i.
Sec. 177.1520 Olefin polymers (Polypropylene)
ii.
Sec. 177.2600 Rubber articles intended for repeated use (Silicone)
c) USP General Chapters 661: Polypropylene Containers
d) Certified Animal Free or compliant with EMEA 410/01
2. Extractables from the OPUS® 5, and 10 – 60/R cm Column platform were determined according
to an approved written experimental rationale for exaggerated time and temperature conditions
and tested against an approved protocol.
3. Leachables from the OPUS® 5, and 10 – 60/R cm Column platform: Repligen will not conduct,
nor present data for leachables in this Regulatory Support File for any process specific solution
beyond what is determined in the extractables testing. Repligen will on request, support client
based leachable testing by providing component test materials.
5.3 USP<88> Biological Reactivity Tests, In Vivo
Six plastic classes are defined in Table 3.1. This classification is based on responses to a series of in
vivo tests for which extracts, materials, and routes of administration are specified. These tests are
directly related to the intended end-use of the plastic articles.
Table 5.1
Summary of USP <88> Plastics Classes
Plastic Classes
Tests to be Conducted
I
II
III
IV
V
VI
Extract
Species
Procedure
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
USP 0.9% NaCl
X
X
X
X
X
X
X
X
X
Mouse
Rabbit
Mouse
Rabbit
Mouse
Rabbit
Mouse
Rabbit
Rabbit
Systemic-Intravenous
Intracutaneous Irritation
Systemic-Intravenous
Intracutaneous Irritation
Systemic-Intravenous
Intracutaneous Irritation
Systemic-Intravenous
Intracutaneous Irritation
Intramuscular
(7 day, no Histopathology)
42
1:20 EtOH/NaCl
PEG 400
Cottonseed Oil
Muscle Implant
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
Acute Systemic Toxicity Test
Purpose: In-vivo systemic tests evaluate the impairment or activation of a system rather than the
impairment of individual cells or organs. In “acute” systemic toxicity tests, the test material (extract)
is tested for systemic toxic effects as a result of a single, acute exposure. This test is designed to
evaluate systemic responses to the extracts of materials following injection into mice.
Irritation Test: Intracutaneous Irritation Test
Purpose: The irritation tests are in-vivo screening tests to evaluate the potential of test materials or
their extracts to cause irritation on the exposed part of the body. This test is designed to evaluate
local responses to the extracts of materials following intracutaneous injection into rabbits.
Implantation Test: Intramuscular
Purpose: Implant studies evaluate the local pathological effects on living tissue at both the gross and
microscopic level of a test article surgically implanted into an appropriate implant site. The
implantation test is designed for the evaluation of plastic materials and other polymeric materials in
direct contact with living tissue.
5.3.1 CFR 21 Part 177 Indirect food Additives: Polymers
Subpart B: Substances for Use as Basic Components of Single and Repeated Use Food Contact
Surfaces. Section 177.1520 – Olefin Polymers (Applied to Polypropylene).
The olefin polymers from polypropylene referenced in CFR 21 Part 177 Sec. 177.1520 may be safely
used as articles or components of articles intended for use in contact with food, subject to the
provisions of this section.
Subpart C: Substances for use only as components of articles intended for repeated use Sec.
177.2600, and rubber articles intended for repeated use (applied to silicone).
Rubber articles intended for repeated use may be safely used in producing, manufacturing, packing,
processing, preparing, treating, packaging, transporting, or holding food, subject to the provisions of
this section.
5.3.2 USP General Chapters 661: Polypropylene Containers
The standards and test provided in this section characterize polypropylene containers produced
from homopolymers or co-polymers that are suitable for packaging dry solid or liquid oral dosage
forms.
5.3.3 Animal Free and EMEA 410/01
Note: This is for guidance on minimizing the risk of transmitting animal spongiform encephalopathy
agents via human and veterinary medicinal products.
Scientific principles for minimizing risk (EMEA 410/01): Use of materials from ‘non TSE-relevant
animal species’ or non-animal origin is preferred. If materials from ‘TSE-relevant animal species’
have to be used, consideration should be given to all the necessary measures to minimize the risk of
transmission of TSE.
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OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
5.4 Extractable Test Protocol and Results
By Michael Ruberto, Ph.D.
Background
Repligen has performed polymer deformulation and extractables testing on the product contact
components of their OPUS® columns. This data has been consolidated into a format that will be
suitable for use in the OPUS® product literature.
Extractables and Leachables
Materials
The materials used to fabricate single-use processing equipment for biopharmaceutical
manufacturing are often polymers, such as plastic or elastomers (rubber), as opposed to the
traditional metal or glass. Polymers offer more versatility, since they are light-weight, flexible and
much more durable than their traditional counterparts. Plastic and rubber are also disposable, so
issues associated with cleaning and its validation are often avoidable. Whenever there is contact
between a material of construction for a manufacturing component and therapeutic, there is always
the possibility for chemicals from the material to migrate or leach into the drug. All materials can
produce leachables.
Leachables are the chemicals that migrate from single-use processing equipment into the various
components of the drug product during manufacturing. Extractables are chemicals entities, organic
and inorganic, that can be extracted from single-use processing equipment using common
laboratory solvents in controlled experiments. They represent the worst case scenario and are used
as a tool to predict the types of leachables that can be encountered during pharmaceutical
production. So, extractables are the “potentials” and leachables are the “actuals.”
An effective way to minimize and control leachables is to use well characterized materials to
fabricate the manufacturing equipment. The OPUS® column product contact materials are mainly
constructed from polypropylene (PP) homopolymers and platinum cured silicone. PP homopolymer
is much less prone to leachables than other types of polyolefins due to its mechanical and physical
properties (such as melting point, glass transition temperature, molecular weight distribution, and
percent crystallinity.) All of these important polymer characteristics have been measured and
benchmarked for each PP product contact component and can be used as a quality control measure
to ensure that all incoming raw materials have similar properties. This can help to ensure consistent,
batch-to-batch leachables profiles for the OPUS® product contact components. The additives
package has also been determined for each polymer in an effort to predict and control leachables.
The platinum cured silicone components are very durable materials that are often used in medical
applications. These silicone elastomers are amorphous polymers that usually do not require
formulation with additives such as phthalates, antioxidants, or heat and light stabilizers. This less
complex formulation greatly reduces the risk of leachables. The silicone polymers have also been
fortified with silica fillers to provide the essential mechanical properties required for the OPUS®
chromatography applications. As in the case of the PP components, the mechanical and physical
properties of the platinum cured silicone gaskets and tubing have all been measured and
benchmarked. All polymers used to construct the product contact components have met the
requirements of a USP Class VI polymer and are regulated for food contact application according to
21CFR Part 177 Indirect Food Additives. The specific polymer and regulatory information is
summarized in the table below.
44
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Table 5.2
Polymer List and Regulatory Information
Component
Column Tubes
45/R – 60/R cm
Column Tubes
10-30 cm IDs
Material
USP
70% w/w EGlass / PP
Homopolymer
Composite
Structure
Class VI
USP <88>
Extruded PP
Homopolymer
Class VI
USP <88>
CFR 21 177
177.1520
Animal
Origin
Animal Free
Additives
Primary Antioxidant
Processing Aid
177.1520
Animal Free
Primary Antioxidant
Secondary
Antioxidant
Processing Aid
Flow Distributors
5, 10 – 60/R
Compression
Molded PP
Homopolymer
Class VI
USP <88>
177.1520
Animal Free
Acid and Metal
Scavengers
Primary Antioxidant
Secondary
Antioxidant
Processing Aid
Inlet and Outlet
Ports, OPUS® R
Plug, OPUS® R
Inside Port
Compression
Molded PP
Homopolymer
Class VI
USP<88>
177.1520
Animal Free
Acid and Metal
Scavengers
Primary Antioxidant
Secondary
Antioxidant
Processing Aid
Bed Support
Screens 5, 1060/R
PP Woven Mesh
Class VI
USP<88>
177.1520
EMEA
410/01
Acid / Metal
Scavengers
Primary Antioxidant
Secondary
Antioxidant
Hindered Amine
Processing Aid
Flow Distributor
O-Rings, OPUS® R
Plug O-Ring,
OPUS® R
Inner/Outer
Gaskets
Return Line, 1060/R
45
Platinum Cured
Silicone
Class VI
177.2600
Animal Free
Acid and Metal
Scavengers
Silica Filler
Platinum Cured
Silicone
PET Braiding
Class VI
177.2600
Animal Free
Silica Filler
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Testing
The polymers utilized in medical and pharmaceutical applications should be compliant with the
appropriate USP guidelines and it is recommended that they meet the USP Class VI testing
requirements. The appropriate extractables and leachables (E&L) testing programs should be
implemented for the bioprocessing materials that come into direct contact with components of the
drug formulation. Three industry groups have published “Best Practices” for conducting this testing.
Several presentations and publications were prepared by the Product Quality Research Institute
(PQRI) for the evaluation and safety assessment of extractables and leachables in packaging for
various drug dosage forms of high risk. These recommendations apply to the primary and secondary
packaging associated with these pharmaceutical products. The BioProcess Systems Alliance (BPSA)
and BioPhorum Operation Group (BPOG) have also published technical guideline for evaluating the
risk associated with extractables and leachables specifically for single-use processing equipment.
The Repligen approach to E&L testing is that it is the responsibility of the product technology vendor
to provide a technical extractable package. Leachables, on the other hand, are considered to be
process specific and the responsibility of the end user to define with specific process solutions. With
that in mind, Repligen has designed an extractables program to produce a robust data package by
conducting extractables testing using three solvents under exaggerated conditions of contact. The
materials of contact in the OPUS® Column platform:






Extruded PP (5, and 10 – 30 cm tubes only)
Polypropylene / E-Glass Composite (OPUS® 45/R – 60/R cm tubes only)
Machined Compression Molded PP
Polypropylene Mesh
Platinum Cured Silicone O-Rings
Platinum Cured Silicone Braided Tubing
Each were extracted with USP Water, 20% Ethanol, and 2.2% Benzyl Alcohol for 72 hours at 40oC.
The extracts were analyzed for semi-volatiles by GC/MS, non-volatiles by LC/PDA/MS, and inorganics
by ICP-MS. In addition, the neat OPUS® components were analyzed for volatiles by Headspace
GC/MS. The data generated from this comprehensive series of extractables testing is detailed
below.
5.4.1 Extruded PP: OPUS® 10 – 30 cm Columns Only
Volatiles by Headspace GC/MS
Extractables
Hydrocarbon <C9
Hydrocarbon <C9
µg/g
1.66
1.47
Source of extractables - The hydrocarbons can be traced back to low molecular weight oligomers
present in the PP from incomplete polymerization or polymer degradation reactions. The
percentages of low molecular weight oligomers have been benchmarked and are monitored for the
OPUS® Column polymer components to ensure a consistent extractables profile.
Semi-Volatiles by GC/MS
46
Extractable
Water (µg/g)
-------
<1
2.2% Benzyl Alcohol
(µg/g)
<1
20% Ethanol
(µg/g)
<1
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Non-Volatiles by UPLC/PDA/MS
Extractable
Water (µg/g)
Unknown
Unknown
1.84
2.86
2.2% Benzyl Alcohol
(µg/g)
1.83
4.15
20% Ethanol
(µg/g)
3.83
10.19
Inorganics by ICP-MS
Extractable
Water (µg/g)
Phosphorous
Sodium
Calcium
Silicon
< 4.514
< 1.128
1.858
4.022
2.2% Benzyl Alcohol
(µg/g)
< 24.784
1.922
2.780
1.418
20% Ethanol
(µg/g)
< 4.636
< 1.159
2.086
1.011
Source of extractables - Sodium and Calcium can be traced back to the metal stearates and oxides
used to scavenge residual catalysts and acid byproducts in the polymer. Silica is due to the siloxane
based lubricant used in the polymer manufacturing.
5.4.2 Machined Compression Molded PP: OPUS® 10 – 60/R cm Columns
Volatiles by Headspace GC/MS
Extractables
-------
µg/g
<1
Semi-Volatiles by GC/MS
Extractable
Water (µg/g)
-------
<1
2.2% Benzyl Alcohol
(µg/g)
<1
20% Ethanol
(µg/g)
<1
Non-Volatiles by UPLC/PDA/MS
Extractable
Water (µg/g)
Unknown
Unknown
Unknown
Unknown
2.74
1.84
2.75
<1
2.2% Benzyl Alcohol
(µg/g)
<1
<1
4.14
<1
20% Ethanol
(µg/g)
1.93
<1
9.86
4.38
Inorganics by ICP-MS
47
Extractable
Water (µg/g)
Phosphorous
Sodium
Calcium
Silicon
< 4.626
< 1.157
2.233
3.615
2.2% Benzyl Alcohol
(µg/g)
< 4.766
< 1.191
1.630
1.687
20% Ethanol
(µg/g)
< 23.588
1.414
2.197
<1
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Source of extractables - Sodium and Calcium can be traced back to the metal stearates and oxides
used to scavenge residual catalysts and acid byproducts in the polymer. Silica is due to the siloxane
based lubricant used in the polymer manufacturing.
5.4.3 PP Mesh: OPUS® 10 – 60/R cm Columns
Volatiles by Headspace GC/MS
Extractables
-------
µg/g
<1
Semi-Volatiles by GC/MS
Extractable
------Extractable
Various Pegylated
Compounds
Unknown
Unknown
Unknown
Water (µg/g)
2.2% Benzyl Alcohol
(µg/g)
<1
<1
Non-Volatiles by UPLC/PDA/MS
Water (µg/g)
2.2% Benzyl Alcohol
(µg/g)
1 – 150
1 – 108
<1
1.50
<1
1.12
2.62
<1
20% Ethanol
(µg/g)
<1
20% Ethanol
(µg/g)
1 - 315
2.06
2.42
3.84
The Pegylated extractables displayed a characteristic mass distribution of 44 amu increments. The
empirical formulae for the prominent ions observed for these compounds ranged from C15H33O8 C40H82NO13.
Inorganics by ICP-MS
Extractable
Water (µg/g)
Phosphorous
Sodium
Calcium
Silicon
< 4.797
2.739
1.855
3.233
2.2% Benzyl Alcohol
(µg/g)
< 24.385
5.090
2.322
1.474
20% Ethanol
(µg/g)
< 4.95
2.075
1.829
<1
Source of extractables - Sodium and Calcium can be traced back to the metal stearates and oxides
used to scavenge residual catalysts and acid byproducts in the polymer. Silica is due to the siloxane
based lubricant used in the polymer manufacturing.
48
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
5.4.4 P/ E-Glass Composite: OPUS® 45/R – 60/R cm Columns Only
Volatiles by Headspace GC/MS
Extractables
Hydrocarbon <C9
µg/g
2.84
Source of extractables – The hydrocarbons can be traced back to low molecular weight oligomers
present in the PP from incomplete polymerization or polymer degradation reactions. The
percentages of low molecular weight oligomers have been benchmarked and are monitored for the
OPUS® column polymer components to ensure a consistent extractables profile.
Semi-Volatiles by GC/MS
Extractable
Water (µg/g)
-------
<1
2.2% Benzyl Alcohol
(µg/g)
<1
20% Ethanol
(µg/g)
<1
Non-Volatiles by UPLC/PDA/MS
Extractable
Water (µg/g)
<1
2.2% Benzyl Alcohol
(µg/g)
<1
20% Ethanol
(µg/g)
1.13
Pegylated
Compound
Unknown
Unknown
24.15
<1
<1
<1
<1
1.01
The Pegylated extractables displayed a characteristic mass distribution of 44 amu increments. Two
mass distributions within the single chromatographic peak were detected. The empirical formulae
for the prominent ions observed for these compounds ranged from C15H33O8 - C19H44NO10.
The unknown peak in the water extract was detected by LC/PDA. UPLC with fraction collection was
used to isolate this unknown. The fraction was evaporated to dryness and re-analyzed by both
GC/MS and LC/MS however no observable MS spectrum could be observed. NMR analysis of the
fraction was inconclusive since significant signal could not be generated.
Extractable
Boron
Phosphorous
Sodium
Calcium
Silicon
Inorganics by ICP-MS
Water (µg/g)
2.2% Benzyl Alcohol
(µg/g)
1.110
1.941
< 23.128
28.175
6.624
5.822
8.488
9.445
25.994
30.921
20% Ethanol
(µg/g)
1.323
27.841
4.413
9.415
21.182
Source of extractables – Sodium and Calcium can be traced back to the metal stearates and oxides
used to scavenge residual catalysts and acid byproducts in the polymer. Silica, Boron, and
Phosphorous are common elements found in borosilicate and borophosphosilicate glass.
49
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
5.4.5 Platinum Cured Silicone O-Ring: OPUS® 10 – 60/R cm Columns
Volatiles by Headspace GC/MS
Extractables
-------
µg/g
<1
Semi-Volatiles by GC/MS
Extractable
Water (µg/g)
-------
<1
2.2% Benzyl Alcohol
(µg/g)
<1
20% Ethanol
(µg/g)
<1
Non-Volatiles by UPLC/PDA/MS
Extractable
Water (µg/g)
Unknown
Unknown
<1
1.33
2.2% Benzyl Alcohol
(µg/g)
<1
1.87
20% Ethanol
(µg/g)
3.00
4.32
Inorganics by ICP-MS
Extractable
Water (µg/g)
Potassium
Phosphorous
Sodium
Calcium
Silicon
< 0.454
< 4.710
< 2.272
1.183
19.344
2.2% Benzyl Alcohol
(µg/g)
< 0.442
< 22.482
1.579
1.370
15.626
20% Ethanol
(µg/g)
9.989
< 4.858
< 1.073
1.075
19.365
Source of extractables – A silica based filler is used to provide enhanced mechanical properties to
the platinum cured silicone polymer. The filler is the primary source of inorganic based extractables
from this component.
5.4.6 Platinum Cured Silicone Braided Tubing: OPUS® 10 – 60/R cm Columns
Volatiles by Headspace GC/MS
Extractables
Decamethylcyclopentasiloxane
µg/g
1.09
Source of extractables - Decamethylcyclopentasiloxane is most likely present in the low molecular
weight silicone based processing lubricant used during tubing manufacturing.
50
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Semi-Volatiles by GC/MS
Extractable
------Extractable
Unknown
Unknown
Unknown
Unknown
Water (µg/g)
2.2% Benzyl Alcohol
(µg/g)
<1
<1
Non-Volatiles by UPLC/PDA/MS
Water (µg/g)
2.2% Benzyl Alcohol
(µg/g)
30.73
<1
<1
<1
<1
<1
1.52
2.66
20% Ethanol
(µg/g)
<1
20% Ethanol
(µg/g)
<1
3.86
1.91
6.95
The unknown peak in the water extract was detected by LC/PDA. UPLC with fraction collection was
used to isolate this unknown. The fraction was evaporated to dryness and re-analyzed by both
GC/MS and LC/MS however no observable MS spectrum could be observed. NMR analysis of the
fraction was inconclusive since significant signal could not be generated.
Inorganics by ICP-MS
Extractable
Water (µg/g)
2.2% Benzyl Alcohol
20% Ethanol
(µg/g)
(µg/g)
Phosphorous
< 4.710
< 22.482
< 4.858
Sodium
51.538
4.316
5.344
Calcium
1.269
1.316
1.561
Silicon
26.584
36.007
53.586
Source of extractables – A silica based filler is used to provide enhanced mechanical properties to
the platinum cured silicone polymer. The filler is the primary source of inorganic based extractables
from this component.
5.4.7 Conclusions
The product contact materials used in OPUS® pre-packed chromatography columns meet the
requirements of a USP Class VI plastic and are regulated for food contact applications. Each polymer
has been hand selected based on its mechanical / physical properties, inherent stability, and low
potential risk for leachables. Only those polymer additives that are functionally necessary are
present in the OPUS® product contact components. This has been confirmed experimentally
through a complete quantitative analysis of the additives package in each polymer. Extractables
testing has been conducted for the product contact components using conditions of 40ºC for 72
hours in three solvents: USP water, 20% ethanol, and 2.2% benzyl alcohol. The extracts were
analyzed for volatiles, semi-volatiles, non-volatiles, and metals. The identified extractables were
correlated back to their source of origin in the OPUS® component so that they can be controlled
during manufacturing. Structure elucidation was performed on the unknowns and empirical
formulae were proposed when possible. The physical properties of the polymers that have the
most influence over leachables (such as melting point, glass transition temperature, percent
crystallinity, and molecular weight distribution) have been benchmarked to ensure a consistent
batch-to-batch leachables profile for these components and a well-managed supply chain for raw
51
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
materials used in their construction. The result is a chromatography column which has achieved a
minimization and control of leachables through comprehensive material characterization, quality
control, and extractables testing.
5.5 Leachables: OPUS® Column Strategy
The extractables information in this regulatory support file is designed to be the foundation of a
leachable substances therapeutic safety assessment. The data presented represent an extractables
profile of what might be extracted from an OPUS® Column under extreme exaggerated conditions
(prolonged exposure at high temperature).
Role of the End User
Each process is different, and therefore must be evaluated for impact of leachables. In many cases,
the data provided by an extractables test can be used to create a risk based assessment to support a
leachables program.
Role of Repligen
Repligen will provide suitable component test materials and upon request to support application
and process specific leachables testing.
5.6 Considerations for Leachables Testing
Purpose
To assess the safety risk posed to patients through exposure to low levels of chemical entities
extracted from plastics in the manufacturing process.
Role of the “model solvent” extraction test
In general, the model extraction vehicles in a standard extractables test will likely show all of the
materials which could possibly be extracted from a plastic product. Model stream extraction
vehicles are chosen for their ability to extract compounds from plastics as well as their relevance to
the test application (chromatography in this case). The results of extractable tests can be compiled
and analyzed to create a risk based approach for conducting (or not conducting) a leachables study.
Chromatography: An assessment of application impact
In the case of chromatography the method from start to finish should be considered, however, a risk
analysis should focus on the elution fluid, which in most cases will be an aqueous solution. Although
a pre-packed chromatography column will see solvents such as 0.5N NaOH, phosphoric acid, high
and low pH additives, and high salt conditions, in general none of these compounds or additives are
meant to pass into the final product pool. In addition, impact to the final product pool is limited
due to multiple chromatography or filtration steps which help to eliminate extractables throughout
a typical downstream process. Therefore, to assess the impact of other solvents in addition to the
elution solvent, extractables and leachables studies can be carried out with the proposed
purification methods in mind. This will enable a thorough understanding of the impact of the
chromatography steps as it pertains to leachables in the final product pool.
52
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
5.7 References
“Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal
Drug Products”, Product Quality Research Institute, Arlington VA, September 8, 2006
D. Jenke PQRI PODP Workshop Feb.22-23, 2011
PQRI Review Article – PDA J Pharm Sci and Tech 2013, 67 430-447
Bio-Process Systems Alliance: www.bpsalliance.org . Formed in 2005 as an industry-led corporate
member trade association dedicated to encouraging and accelerating the adoption of single use
manufacturing technologies used in the production of biopharmaceuticals and vaccines.
Parenteral Drug Association: www.pda.org . The leading global provider of science, technology and
regulatory information and education for the pharmaceutical and biopharmaceutical community.
Founded in 1946 as a nonprofit organization, PDA is committed to developing scientifically sound,
practical technical information and resources to advance science and regulation through the
expertise of its more than 9,500 members worldwide.
Recommendations for Extractables and Leachables Testing - Part 1: Introduction, Regulatory Issues
and Risk Assessment
Bioprocess Systems Alliance; Bioprocess International 5(11): p36-49 December 2007
Recommendations for Extractables and Leachables Testing - Part 2: Executing a Program
Bioprocess Systems Alliance; Bioprocess International 6(1): p44-53 January 2008
USP General Chapters <88> Biological Reactivity tests, In Vivo
Toxicon USP <88> “Class Tests
Estimation of toxic hazard – A decision tree approach. G.M. Cramer and R.A Ford
Fd Cosmet.Toxicol. Vol16 pp.255-276 Pergamon Press 1978
Threshold of Toxicological Concern Concept in Risk Assessment. R Kroes, J Kleiner and A Renwick
Toxicological Sciences 86(2), 226-230; 2005
Parenteral Drug Association: Assessment of E/L from Bags, Tubings and Filters
53
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
6. Appendix
6.1 OPUS® 5, 10-60/R cm ID Material Certificates (available upon request)
Refer to Section 2 for a summary of the product contact materials. The following documents are
available upon request. Please email our Customer Service department at [email protected] for
more information:

5, 10-30 cm ID Column Tube, 10-60/R cm ID Flow Distributors, Inlet Port, Return Port, and Outlet
Port: Class VI Documentation

5, 10–30 cm ID Column Tube, 10–60 cm ID Flow Distributors, Inlet Port, Return Port, and Outlet
Port: Animal Origin Documentation

5, 10–30 cm ID Column Tube, 10–60 cm ID Flow Distributors, Inlet Port, Return Port, and Outlet
Port: Component Quality Documentation (21 CFR 177)

5, 10–60 cm ID Bed Support Screens: Class VI Documentation

5, 10–60 cm ID Bed Support Screens: Animal Origin Documentation

5, 10–60 cm ID Bed Support Screens: Component Quality Statements (21 CFR 177)

5, 10–60 cm ID O-Rings: Class VI Documentation

5, 10–60 cm ID O-Rings: Animal Origin Documentation

5, 10–60 cm ID O-Rings: Component Quality Documentation (21 CFR 177)

10–60 cm ID Return Line: Class VI Documentation, Component Quality Statements (21 CFR 177)

10–60 cm ID Return Line: Animal Origin Statements

45-60 cm ID Tube: Animal Free Statement
54
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.2 Engineering Drawings
6.2.1 OPUS® 5 cm Column
55
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.2.2 OPUS® 10 cm Column
56
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.2.3 OPUS® 14 cm ID Column
57
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.2.4 OPUS® 20 cm Column
58
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.2.5 OPUS® 25 cm Column
59
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.2.6 OPUS® 30 cm Column
60
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.2.7 OPUS® 45 cm and 45R Column
61
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.2.8 OPUS® 60 cm and 60R Column
62
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.3 Packaging
6.3.1 OPUS® 5 cm Column Packaging
Box design
Packaging inserts
63
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.3.2 OPUS® 10 - 14 cm Column Packaging
64
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.3.3 OPUS® 20 - 30 cm Column Packaging
65
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.3.4 OPUS® 45 cm Column Packaging
66
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
6.3.5 OPUS® 60 cm Column Packaging
67
Regulatory Support File
OPUS® 5, 10 – 60 cm, OPUS® R Columns
Regulatory Support File
Index
B
M
Bioburden.......... 3, 5, 10, 25, 27, 31, 35, 36, 37
Material Safety Data Sheet ....................... 3, 29
Materials of Construction ... 3, 5, 19, 20, 21, 22
C
P
Certificate of Analysis .. 3, 5, 10, 11, 12, 13, 16,
36, 37
Cleanability....................................................26
Packaging .................... 4, 16, 66, 67, 68, 69, 70
Pre-GMP................................ 3, 5, 8, 10, 11, 37
E
Q
Endotoxin .......... 3, 5, 10, 25, 27, 31, 35, 36, 37
Extractables.... 3, 44, 45, 47, 49, 50, 51, 52, 53,
54, 56
Quality........... 3, 7, 8, 16, 29, 30, 33, 49, 56, 57
S
G
Shipping .............................. 3, 5, 10, 16, 38, 39
Stability ......................... 3, 5, 19, 24, 25, 26, 43
GMP Run Ready . 3, 5, 8, 10, 12, 13, 15, 34, 35,
36, 37
W
L
Leachables............... 3, 4, 44, 45, 47, 49, 55, 56
68
Warranty ................................................... 3, 27
Work Order .... 5, 11, 12, 14, 15, 16, 28, 32, 33,
34, 35, 36