ISO 13485:2003 certified FDA cGMP compliant FDA ASR Lic. No. 3003830126 California FDB # 52386

cGMP Oligonucleotides:Custom Manufacturing Solutions for Molecular DiagnosticsDNA & RNA Oligonucleotides Probes, Primers & Assay Sets Custom Fill & Finish Services

Custom ASR Oligonucleotides for CLIA Labs Analytical Services GMP Compliance to FDA QSR

Classified Cleanroom Environment

BENEFITS OF A EUROGENTEC PARTNERSHIP

During the past months our team has carefully evaluated

many different (suppliers)...a few of the key success crite-

ria which your team impressed us with (were): quality of

your products, your responsiveness and receptivity in ad-

dressing our many questions and your impressive GMP

facilities and Quality Management Systems.

- Quote from a major North American diagnostic client

1

Experience true partnership with EurogentecWith over 20 years experience, Eurogentec is a leading supplier of high-quality reagents and custom-synthesized oligonucleotides

for genomic research to scientists around the globe. Our state-of-the-art cleanroom facilities meet Class 100,000 (ISO 8) and

Class 10,000 (ISO 7) standards. Eurogentec’s Quality Management System (QMS) is fully compliant with the cGMP Quality System

Regulation (QSR) and is ISO 13485:2003 certified. Manufacturing sites located in Europe, North America and Asia offer customized

global solutions providing redundancy and harmonization of experience, processes and facilities. This guarantees an uninterrupted

supply of high-quality GMP-level oligonucleotides as components for DNA- and RNA-based molecular diagnostic assays.

Complete Custom Solutions: Benefits of a Eurogentec PartnershipChoosing a manufacturing partner early in the assay development process is an important step towards successful product

commercialization. Eurogentec’s ability to provide a complete custom solution makes the difference.

EXPERIENCE

> Over 23 years experience in oligo synthesis

> Over 16 years GMP manufacturing experience

> Fully trained and skilled staff

> Expert synthesis & purification chemists

QUALITY COMMITMENT

> Organization-wide QMS implementation

> Comprehensive risk analysis and mitigation

> ISO 13485 Medical Device QMS certification

> Classified cleanroom facility

PROCESS FLEXIBILITY

> Licensed for all standard probe formats

> Large inventory of licensed modifications

> Research, Pre-Diagnostic & Diagnostic processes

> Custom QC release & final documentation

SUPPLY CHAIN RELIABILITY

> Global manufacturing sites

> Harmonized QMS

> Optimized and validated instruments & processes

> Full traceability for regulatory compliance

REGULATORY COMPLIANCE

> Full compliance to FDA cGMP/QSR (21 CFR Part 820)

> EU IVD Directive 98/79 EC compliance

> Comprehensive archival batch records

COMPLETE CUSTOM SOLUTIONS

> Fill & finish

> Assay set assembly

> GMP Taq DNA polymerases and mastermixes

> Collaborative project development

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Good Manufacturing Practices & Regulatory Compliance—To GMP or Not to GMP1

Primers and probes are critical components of molecular diagnostic assays. Performance parameters like detection limit and

specificity will differ significantly with variations in oligonucleotide quality. Good quality must be built in during the manufacturing

process and GMP prevents errors that cannot be eliminated through quality control of the finished product. As a consequence,

incoming quality control (IQC) is not an adequate replacement for GMP manufacturing of critical components. For example, IQC

is likely to miss low-level cross-contamination, variations in impurities and small sequence errors. These variations could result

in failing to meet the IVD performance characteristics required for use in certain patient samples e.g., detection limit or specificity.

Manufacturing in a GMP facility documented with comprehensive batch records reduces the risks associated with such errors.

The Eurogentec SolutionEurogentec ensures exceptional product quality by manufacturing in

classified cleanrooms and use of an ISO 13485-certified and GMP com-

pliant QMS. Although not strictly required by regulatory authority, the use

of cleanrooms ensures that all parameters are controlled, monitored

and fully documented. This unique level of compliance ensures a high

standard of quality, exceptional lot-to-lot reproducibility and fully docu-

mented traceability including archiving batch records upon final QC

release of products.

Our clients may have additional requirements that exceed our stan-

dard regulatory compliance systems. These may include requests for

custom analytical, purification or QC protocols, expanded batch record

documentation and backup facilities to ensure an uninterrupted product

supply stream. We are able to provide our partners with custom-tailored

plans that accommodate their unique compliance requirements.

1IVD Technology, June 2008, pp. 18-20 and July 2008, pp. 18–20. On the web at www.devicelink.com

A QMS certified by an independent organization

against an international standard such as ISO

13485 is an appropriate means to assess the

quality of a supplier’s manufacturing process

and the level of GMP compliance.

The FDA encourages suppliers of critical IVD

components to embrace GMP. Primers and

probes supplied to a clinical laboratory for in-

clusion into a Lab Developed Test (LDT) can be

considered as Analyte Specific Reagents (ASRs)

and are required to be manufactured under

GMP conditions.

Technical and regulatory experts are available for

client consultation.

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Manufacturing Processes & Options—Flexible Custom SolutionsManufacturing Processes—Documentation requirements differ significantly as products progress from Discovery and

Feasibility to Validation and Commercialization. Eurogentec partners choose from three progressively detailed levels of documen-

tation and overall quality assurance appropriate for each phase of product development and commercialization:

DIAGNOSTIC Oligos—appropriate for Validation and Commercial-

ization. These oligos will be made according to Eurogentec’s Di-

agnostic GMP/QSR manufacturing process, which is certified to

the medical device quality standard ISO 13485:2003 and compliant

to FDA’s Quality System Regulations (21 CFR Part 820) and the

European IVD Directive 98/79 EC. The production process takes

place in a dedicated GMP cleanroom facility (class 100,000 (ISO

8)), using fully optimized and validated QC methods and equip-

ment. All aspects of the manufacturing process are monitored

and documented resulting in a formal batch record which is ar-

chived for 5 years. After review of the batch record, an authorized

QC representative releases the product. Client is supplied with a

Certificate of Analysis; all relevant QC data are attached.

PRE-DIAGNOSTIC Oligos—priced between Research Oligos and

Diagnostic Oligos and appropriate for Design Control and early

Validation phases of assay development. These oligos will be

made according to the same process as the Diagnostic oligos with

the exception of documentation and ISO 13485 certification. Only

basic aspects of the manufacturing process are monitored and

documented resulting in a condensed batch record which is ar-

chived for 5 years. After review of the batch record, an authorized

QC representative releases the product. Client is supplied with a

Certificate of Analysis; all relevant QC data are attached.

RESEARCH Oligos—most cost-effective option but not appropri-

ate for commercial diagnostic applications and only suitable for

Discovery and Feasability phases. ISO 9001 certified but not cGMP

compliant. Client is supplied with a Technical Data Sheet.

TO GMP OR NOT TO GMP

> Oligos are critical diagnostic assay components

> Incoming QC is not a replacement for GMP

> GMP significantly mitigates manufacturing risks

> FDA encourages suppliers to embrace GMP

> Eurogentec is ISO 13485 certified and fully GMP compliant

CERTIFICATION, LICENSES & COMPLIANCE

> ISO 13485 Certification

> FDA ASR Lic. No. 3003830126

> FDA 21 CFR Part 820 cGMP Compliance

> Calif. Dept. of Public Health FDB Lic. 52386

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Manufacturing Options—Clients can choose from many manufac-

turing options. We are able to provide our partners with custom-tailored

programs that accommodate their unique compliance requirements.

SYNTHESIS

> Synthesis scale from 1 µmol to several mmol

> Dedicated equipment and reagents

> Development of custom modifications

> Custom mixes of backbones and chimeric oligonucleotides

PURIFICATION

Diagnostic assays and the regulations governing their use demand

oligonucleotides that meet target purity levels. We have developed

optimized purification protocols for a number of techniques and of-

fer several purification options, one or more of which can be selected

depending on client requirements:

> Ion exchange HPLC (IE-HPLC)

> Reverse-phase HPLC (RP-HPLC)

> PAGE

> Ultrafiltration

STANDARD MODIFICATIONS

> Biotin > Thiol

> Digoxigenin > Linkers, spacers

> DNP > Unique amidites

> LNA® > Wobbles

> Phosphate > Fluorescent dyes

> Amine > Quenchers

STANDARD PROBE FORMATS

> TaqMan®

> Molecular Beacons

> Scorpions®

PURITY IS MORE THAN A NUMBER!

Purity determination can be quite subjec-

tive. Reported values depend on the specific

equipment, columns, buffers, buffer gradi-

ents and integration parameters used during

analysis. Establishing the appropriate level of

oligo purity for a given assay ensures balance

between cost (excessive purification incurs

added cost) and performance (insufficient

purity degrades functionality).

FEATURE BENEFIT

Harmonized cGMP sites in Europe, North America & Asia Uninterrupted and reliable oligo supply

Classified cleanroom manufacturing environment Contamination mitigation

Manufacturing according to cGMP/QSR guidelines FDA regulatory compliance

All sites ISO 13485 certified Exceeds regulatory requirements

Continuous risk management process Mitigate manufacturing errors

Instrument & QC method validation Lot-to-lot reproducibility

Various synthesis scales, modifications, purification & QC options Flexible and cost-effective client solutions

Custom processes for each phase of product life cycle Flexibility and cost effectiveness

Stringent product release QC criteria Consistent lot-to-lot reproducibility

Flexible fill & finish options Customized manufacturing and component assembly

Additional capabilities (GMP Taq polymerases and mastermixes) Complete cGMP solution

Comprehensive batch records Full process traceability

Dedicated account contact person Continuous project oversight and real-time status updates

Custom Solutions from Eurogentec

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QC RELEASE METHODS

We offer a selection of QC release methods, any of which can be

incorporated into the final QC release documentation.

Typical QC Release Methods

> Final mass determination (release by O.D., µmol, µgram)

> Physical inspection

> MALDI-TOF, ESI- and LC-Mass Spectrometry

> Ion exchange HPLC (IE-HPLC)

> Reverse-phase HPLC (RP-HPLC)

> Capillary Gel Electrophoresis (CGE)

Optional QC Release Methods

> Direct sequencing using enzymatic cleavage and MALDI-TOF MS

> Enzymatic tests for DNA-enzyme conjugates

> Probe/dye activity: fluorescence, signal-to-noise ratio, melting

profile for Molecular Beacons

> Bioburden

Customized QC Release Methods

> QC release methods based on specific client requirements

Product Stability Testing

> Stability testing of oligonucleotides following standard or

user-customized procedures

Custom Formulation Options

> Customized mixtures of individual oligonucleotides

> Conjugated oligonucleotides

(HRP, AP, synthetic peptides, proteins)

> Lyophilized, dried or in solution (H2O or custom buffer)

> Bulk or aliquoted into tubes or plates

> Customized fill & finish

> GMP Taq DNA polymerases & mastermixes

> Customized packaging and labeling

DEDICATED PURIFICATION COLUMNS RECOMMENDED

Although not specifically required by regulatory

guidelines, we strongly advise dedicated HPLC

purfication columns for our clients’ commercial

products. Columns can be dedicated to a single

oligonucleotide or a group of oligonucleotides de-

pending on the final assay formulation. Dedicated

columns are stored on-site and can be used for

multiple purification runs.

OLIGO SEQUENCE VERIFICATION

Upon request, or as a requirement for FDA

compliance, we can perform direct sequence

analysis using enzymatic cleavage and MAL-

DI-TOF analysis.

Certificates of Analysis and Archived Batch Records

A Certificate of Analysis (including results and selected data supporting final product release) is

supplied with each oligonucleotide. Our Diagnostic process is monitored utilizing detailed checklists

resulting in a comprehensive batch record ensuring full traceability. Our Pre-Diagnostic process is

monitored utilizing less detailed checklists resulting in an abridged batch record. Both batch records are

archived for five years.

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Classified Cleanrooms—Exceeding Regulatory RequirementsEnvironmental and oligonucleotide cross-contamination present an enormous risk to manufacturers of molecular diagnostic

assays. Although not required for compliance to either the cGMP guidelines or the ISO 13485 QMS, Eurogentec determined that

the best approach for minimizing this source of risk was to build a dedicated and self-contained cleanroom facility.

Our GMP facilities incorporate a secure key card system for access to the manufacturing floor and feature full segregation of syn-

thesis, cleavage/deprotection, purification and fill & finish activities. Access to the various cleanrooms of different classes (Class

100,000 (ISO 8) and 10,000 (ISO 7) with Class 100 (ISO 5) working zones) requires airlock pass-through and a strict gowning policy.

Risk Management & Quality AssuranceAs required by the ISO 13485 standard, Eurogentec has implemented a comprehensive risk management system to control and

minimize oligonucleotide manufacturing risks. This process is based on the FMEA (Failure Mode and Effects Analysis) which is a

process used to identify possible failure modes, determine their potential effect(s) on product manufacturing and identify actions

to mitigate those failures. A rating classification of High, Medium and Low is used to evaluate level of severity, occurrence and

likelihood of detection of each risk.

The outcome of risk management actions resulting from FMEA analysis is represented in the diagrams shown below. 100% of

all high-risk and 85% of the medium risks have been successfully converted to a lower risk category.

GMP CLASSIFIED CLEANROOM MANUFACTURING FACILITY

Controlled Key Card Access Personnel Airlock Mandatory Gowning

Material Pass-through Airlock Class 100,000 Facility Class 10,000 Room

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Controlled Upstream Processes

> Regular vendor screening & audits

> Inbound material quarantine, conformity testing and QA release

Quality Management System (QMS)

> Certified to ISO 13485

> Exceeds FDA 21 CFR Part 820 standards

> Knowledgeable and experienced Quality Management Team

> Commitment to quality and continuous improvement

Exhaustive Environmental Controls

> Classified cleanroom environment and 24/7 monitoring

> Strict process segregation

> Key card airlock access and logging system

> Strict employee gowning policy

Commitment to Total Quality

> IQ/OQ/PQ maintenance and calibration standards

> Dedicated cGMP instrumentation and equipment

> Stringent document change control procedures

> Deviation control management

> Process control management

> Proprietary and exhaustive analytical method validation

> Independent QC product release department

> Routine and regular internal audits

> Client quality audits

> Comprehensive sample retention program

> Detailed batch records ensuring full traceability

Comprehensive risk management

minimizes potential impact on

manufacturing and downstream

processes.

Partnering with Eurogentec—The Process

Confidentiality Agreements

We treat all details including oligonucleotide sequences, probe formats, manu-

facturing specifications, product formulations and business plans with utmost

confidentiality.

Client Consultation

We encourage regular face-to-face meetings or online teleconferences to

ensure clear understanding of manufacturing requirements and specifications.

In addition, our technical experts are available for consultation on all aspects of

oligonucleotide manufacturing and regulatory compliance.

Supplier Questionnaires and Audits

We encourage site visits and formal audits of our facilities. Please discuss sub-

mission of Supplier/Vendor Questionnaires or arrangements for on-site facility

audits with your IVD representative.

Quotations

Quotations are typically short-term guarantees of pricing based on product

descriptions, manufacturing specifications, shipping and delivery information.

Pilot Studies for Evaluation and Validation

Evaluation and validation projects are key components of the vendor evaluation

process and we work closely with you to provide these services.

Supply or Purchase Agreements

Supply or Purchase Agreements typically guarantee pricing for one or more

years, can include discounted pricing based on annualized usage forecasts, can

incorporate our partners’ detailed and comprehensive customized manufactur-

ing specifications and may contain additional client terms and conditions.

Dedicated Account Contact Person

A dedicated Account Contact Person acts as your advocate in the production

plant, monitors all aspects of the production process and will provide you with

frequent real-time updates during each production run. Clients are also provid-

ed a confidential email address that goes directly to the Account Contact Person

to ensure a rapid response to all inquiries.

LNA® is a registered trademark of Exiqon A/SScorpions® is a registered trademark of DxS Ltd.TaqMan® is a registered trademark of Applied Biosystems, Inc.

Eurogentec NA services clients throughout the Americas.

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Fully Certified and Harmonized Global Manufacturing Sites

Europe—Corporate HeadquartersEurogentec S.A.

Liège Science Park

Rue Bois Saint-Jean 5

Seraing 4102

Belgium

Tel: +32-4-372-7400

Fax: +32-4-372-7500

Email: ivd@eurogentec.com

AsiaNippon EGT Co., Ltd.

1-1-25, Arakawa

Toyama 930-0982

Japan

Tel: +81-76-411-02-77

Fax: +81-76-452-03-99

Website: www.n-egt.com

Email: info@n-egt.com

11111 Flintkote Avenue / San Diego, CA 92121-1222

Toll free 1 (877) 387-6436 / Tel. +1 (858) 793-2661 / Fax +1 (858) 793-2666

Email: ivd.na@eurogentec.com / Website: www.eurogentec.com

Eurogentec North America, Inc.