Quality Management SystemsInterpretation and Application for

GMP Manufacturing of Diagnostic Oligos

Peter Haima

Contents

• IVD & Regulatory needs for GMP• Good Manufacturing Practices• EUROGENTEC’s Quality Vision• Building a GMP QMS • One GMP QMS – flexible solutions• To GMP or not to GMP• Quality beyond QMS• Summary

IVD environmentOligo quality is critical for assay performance

• Accuracy• Precision• Repeatability• Specificity• Detection Limit• Quantitation Limit• Linearity• Range• Robustness

Regulatory environment

• Medical Device Manufacturer (MDM) needs to have a QMS in compliance with GMPs: – FDA 21 CFR Part 820

– IVD Directive 98/79 EEC: CE marking

• MDM needs to ensure that a supplier of oligosuses an appropriate QMS

• In practice: MDMs require their kit components (e.g. oligos) to be made under GMP

• Not the highest purity

• Not just Quality Control at the end

Assuring highest quality oligosGood Manufacturing Practices (GMP)

Environmental Control

OrderEntry

Syn-thesis

CleavageDeprotection

Purifi-cation

QC FillLabel

Release

Quality Management of entire process

Eurogentec

• Producing research oligos since 1987• BELGIUM :QMS - ISO 9001 certified (2000/3/6)• USA (SD) :QMS - ISO 9001 certified since 2004• Asia (Singapore & Japan)• Large-scale & IVD oligos since 2003• Upgrading our research production facility and

QMS for IVD was initiated to meet customer requests (partnership/audits)

• Need for IVD Quality Vision arose in 2006

Global Quality Vision

Oligos are critical IVD kit components.

Therefore our Facility and QMS

should be fully compliant with

ISO 13485:2003

&

FDA 21 CFR part 820.

GMP QMSFrom ISO9001 to ISO 13485

-Documenting procedures

-Validating all methods

-Controlling production process

-Extensive quality records

-Ensuring traceability of operators, equipment, raw materials, facility

-Incoming QC raw materials

-Environment control (bioburden/contamination)

ISO 13485

• QMS compliant with ISO13485 & 21 CFR 820

• Process control through use of checklists and SOPs, followed by sign-off of every step.

• Establish full traceability

• Release of batch record, certificate of analysis and final product by QC-authorized person.

• Prevent cross-contamination / Mix-ups

– Clean rooms for production (class 10-1000,000) and segregation of all critical steps

– Access via airlocks, gowning policy

GMP Oligo Manufacturing

GMP Oligo Facility

One GMP QMS-flexible solutionsfrom R to D to C

Dx-Light oligos

Research oligos Dx oligos

1st Ideas Feasibility Prototyping CommercializationValidation

Phase 0 Phase 1 Phase 2 Phase 3 Phase 4R&D

Bridging the gap between D & C

GMP with condensed documentation > lower costs

GMP or non-GMP? Quality

• MDMs use GMP oligos• Can incoming QC replace a GMP process?• FDA (§ 820.50): quality of a product is achieved

through proper control of the manufacture of that product.

• WHO: Good quality must be built in during the manufacturing process; GMP prevents errors that cannot be eliminated through quality control of the finished product.

� Quality cannot be fully tested into products afterwards!

GMP or non-GMP? Risk Management

• ISO14971 lists hazards associated with medical devices in normal/fault conditions

• Hazards like non-specificity or reduced sensitivity may impact patient health

• Manufacture of critical assay components with a GMP process will reduce that risk

• Absence of GMP will increase the risk � Use of GMP oligos is an effective measure to

reduce the risks potentially impacting patient health

GMP or non-GMP? Financial

GMP vs. Research: 40-mer FAM beacon

0%

20%

40%

60%

80%

100%

120%

1 10 100 1000 10000

nmol yield

PriceGMP

Research

Quality beyond GMP• Partnership:

– Understand customer needs, R&D projects & end-products (incl. red flags)

– Consult and advise customer– Promote use of dedicated purification columns– Align analytical release specs with functional

performance (rely on customer feedback)– Agree on clear specifications and methods to verify– Have supply agreement in place

• Use external MD consultants for audits & gap analyses

• Learning by doing, continuous improvement• Offer special QC methods

“Despite all efforts and precautions…Things Happen”

Uninterrupted supply through harmonization and redundancy of four production sites

San Diego

Belgium

Japan

Singapore

Summary

• Oligo quality is critical for the diagnostic performance of an IVD assay

• Only GMP assures highest quality, reduces potential risks for patients, is not expensive

• EUROGENTEC’s GMP - QMS for diagnostic oligos is compliant with FDA 21 CFR 820 & ISO 13485:2003

• Many measures beyond QMS have been implemented to further enhance the quality of our services

• Different levels of documentation are offered, appropriate for each phase of product development(R > D > C).

Acknowledgements For years of hard work to upgrade our

production facility and QMS to GMP level

• Anne-Françoise Emontspohl (QMS) • Diego Messina (QC & QMS)• Luc Marion (Manufacturing Manager)• Gottfried Proess (Manufacturing Director)• Team Leaders

– David Kusinda (synthesis TL)– Dario Largana (purification TL)– Giovanna Traini (fill & finish TL)– Benoît Lacroix (large scale TL)– Isabelle Leroy (QC TL)

• Production operators

Quality Management Systems

Interpretation and Application for

GMP Manufacturing

of Diagnostic Oligos

Peter Haima

Nucleic Acid Technologies, 4-5 December 2007