Quality Management Systems

Interpretation and Application for

Custom Manufacturing

of Diagnostic Oligos

Peter Haima

TIDES 2007

Contents, version 1

Contents

• Quality beyond QMS

• Special QC methods

• Despite all efforts and precautions ……

• Summary

• IVD & Regulatory environment.

• Eurogentec environment & Quality Vision

• Building an IVD QMS

• One IVD QMS – flexible solutions

IVD environmentOligo quality is critical for IVD assays

• Accuracy

• Precision

• Repeatability

• Intermediate Precision

• Specificity

• Detection Limit

• Quantitation Limit

• Linearity

• Range

• Robustness

Regulatory environment

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

• CMO is encouraged to be in compliance

• MDM needs to ensure that CMO uses an appropriate QMS

Regulatory environment

• Medical Device Manufacturer (MDM) needs to have a QMS in compliance with IVD Directive 98/79 EEC: CE mark

• ISO 9001:2000 QMS is not generally accepted as adequate for MDM.

• ISO 13485:2003 is a standard specific to medical device QMS, supplementing ISO 9001:2000.

• MDM maintaining a QMS complying to ISO13485 is complying to the IVDD 98/79 EEC

• MDM needs to ensure that CMO uses an appropriate QMS, that meets their requirements (ISO 9001:2000 is seen as inadequate)

Eurogentec environment

• 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 oligos since 2002

• IVD oligos since early 2004

• Upgrading our research production facility and QMS for IVD was initiated to meet customer requests (partnership/audits)

• Need for IVD Quality Vision arose

Global Quality Vision

Oligos are critical IVD kit components. Therefore our Facility and QMS

should be compliant with

ISO 13485:2003

21 CFR 820

Building from

ISO

900

1: 2

003

ISO

134

85:2

003

FDA

21

CFR

820

ISO

900

1: 2

000

ISO

134

85:2

003

21 C

FR 8

20

Main objectives ofIVD QMS• Quality Assurance: reliability of production process and end product

• Prevent cross-contamination / Mix-ups

• Establish traceability to include:– Facility

– Equipment

– Operators

– Raw materials

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

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

Main characteristics - IVD QMS

• Highly documented QMS (procedures, checklists, batch r.)

• Qualification and validation of equipment, processes, (analytical) methods & software

• Qualify critical raw material vendors and IQC

• High traceability

• Review of all documentation before final release of product by QC authorized person

• Dedicated zones (suites) for IVD production, restricted access via airlocks, specific gowning & cleaning, project segregation

One IVD 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

Quality beyond QMS

• 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

• Hire personnel from Dx companies

• Use external MD consultants for audits & gap analyses

• Learning by doing, continuous improvement

• Offer special QC methods

– Direct Oligo Sequencing by enzymatic cleavage and Mass Spec.

– Melting profile analysis of Molecular beacons

4086.0 5419.2 6752.4 8085.6 9418.8 10752.0

Mass (m /z)

0

8191.9

0

10

20

30

40

50

60

70

80

90

100

% In

tens

ity

Sp ec #1=>BC=>SM 25=>M C[BP = 7343.3, 8192]

7349.6

4266 5315 6364 7413 8462 9511

Mass (m /z)

0

2721.4

0

10

20

30

40

50

60

70

80

90

100

% In

tens

ity

Spec #1=>BC=> SM 25[BP = 7054.1, 272 1]

7057.2

7348.0

6765.7

6461.6

3726.0 4748.2 5770.4 6792.6 7814.8 8837.0

Mass (m /z)

0

4500.9

0

10

20

30

40

50

60

70

80

90

100

% In

tens

ity

Sp ec #1=>BC=>SM 25=>M C[BP = 6458.9, 4501]

6462.16156.5

5851.2

6767.3

5562.37058.9

5273.8

4970.0

Sequence determinationby exonuclease digestion and mass spec.

Enzyme Peak # Mass obs Mass diff Base Sequence 5'-3'

SVP 1 24 7348,0 290,8 C GGAATATTGCTGGTGATCCTTTCC 23 7057,2 291,5 C GGAATATTGCTGGTGATCCTTTC 22 6765,7 GGAATATTGCTGGTGATCCTTT

SVP 2 22 6767,3 305,2 T GGAATATTGCTGGTGATCCTTT 21 6462,1 305,6 T GGAATATTGCTGGTGATCCTT 20 6156,5 305,3 T GGAATATTGCTGGTGATCCT 19 5851,2 288,9 C GGAATATTGCTGGTGATCC 18 5562,3 GGAATATTGCTGGTGATC

SVP 3 18 5562,0 289,8 C GGAATATTGCTGGTGATC 17 5272,2 304,6 T GGAATATTGCTGGTGAT 16 4967,6 312,8 A GGAATATTGCTGGTGA 15 4654,8 328,4 G GGAATATTGCTGGTG 14 4326,4 304,4 T GGAATATTGCTGGT 13 4022,0 328,5 G GGAATATTGCTGG 12 3693,5 328,6 G GGAATATTGCTG 11 3364,9 303,8 T GGAATATTGCT 10 3061,1 GGAATATTGC

SVP 4 10 3066,6 289,2 C GGAATATTGC 9 2777,4 328,9 G GGAATATTG 8 2448,5 304,3 T GGAATATT 7 2144,2 304,3 T GGAATAT 6 1839,9 GGAATA

SVP 5 6 1838,4 312,5 A GGAATA 5 1525,9 304,3 T GGAAT 4 1221,6 GGAA

BSP 1 5 6062,2 GGAA 4 6374,3 312,1 A GGAA

BSP 2 4 6378,1 GGA 3 6691,5 313,4 A GGA 2 7020,8 329,3 G GG 1 7351,0 330,2 G G

Molecular Beacon QCMelting profile and S/N ratio

0%

20%

40%

60%

80%

100%

120%

25 35 45 55 65

Temperature (°C)

Nor

mal

ized

fluo

resc

ence

“Despite all efforts and precautions…Things Happen”Fall back options with different production sites

San Diego

Belgium

Japan

Singapore

Summary

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

• We have built an IVD QMS for diagnostic oligos in compliance with 21 CFR Part 820 & ISO 13485:2003

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

• Even higher levels of GMPs are now being implemented for the manufacturing of therapeutic oligos

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 (Production)

• 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

• MD consultants

QMS Team

IVD Team

Quality Management Systems

Interpretation and Application for

Custom Manufacturing

of Diagnostic Oligos

Peter Haima

TIDES 2007