Quality Management at DSMZ

1. Quality Management at DSMZ Implementation of an International Recognised Quality Standard covering Management of Experience and Protection of Diversity: DIN EN ISO 9001:2000

2. TOPICS NORMS AND STANDARDS APPLICABLE TO BIOTECHNOLOGY DECISION OF DSMZ IMPLEMENTATION OUTLOOK: OECD-BRC

3. Available standards for biotechnology

4. Focus of interest(s) Capabilityof product(s) Demands of interest groups Decision for a certain standard • The decision for the appropriate standard depends on various interests and options: • The own focus: what is the primary concern? • The capability of products: what possibility is given by the own products and services? • The demands of interest groups: what are the expectations of customers, stakeholders and employees?

5. Focus of interest Options – alternative standards Product centered interests -> ISO Guide 34 „General requirements for the competence of reference material producers“ Institution centered interests -> ISO 9001 „Quality management systems – Requirements“ Process centered interests -> ISO 17025 "General Requirements for the Competence of Testing and Calibration Laboratories"

6. living material recurrent properties Capability of product(s) unrestricted reproducibility numerous, diverse products completely defined characteristics limited number of similar products handling with standard methods Options – alternative standards The capability of the products and services need to be analyzed to decide if a product or process or management related standard is appropriate to ensure quality. The more products and services a company is dealing with, the more essential is a coordinated management system. The less products and services a company is dealing with, the more useful could a concentration on these single processes or products itself be for ensuring quality.

7. focus of interest Options – alternative standards • Individual Product -> ISO Guide 34 • Accreditation that deals directly with Certified Reference Material Manufacturers. • All methods that the Manufacturer uses to certify their standards must be validated and proven to be accurate. • Requires that an „uncertainty", which includes all of the sources of error involved in certifying the standard, be reported on the Certificate of Analysis. Furthermore, the Certificate of Analysis itself must observe stricter requirements • Conclusion:Guide 34 provides the highest and most rigorous level of quality assurance, confidently stating that the manufacturer's standards are produced correctly and competently. • Individual Process -> ISO 17025 • Certifies that quality-oriented tests are performed correctly. These tests establish that the product is indeed a quality product. • All aspects of quotations and contracts, the Research and Design operation, and Manufacturing and Quality Control activities are examined by this standard. The qualification, education, and training of all associates are scrutinized against their job responsibilities. Even the qualifications of vendors and collaborators are checked, as well as every Quality Critical specification and purity requirement. • Conclusion: • To be ISO 17025 certified, a company must not only be consistent, but must also be proficient in testing the quality of their products

8. focus of interest Options – alternative standards • Institutional Processes -> ISO 9001 • Certifies that a company has official written procedures and training documentation in the areas of customer service, product design, manufacturing, analysis, certification, packaging, shipping, and accounting. • This credential is very customer service oriented. Every complaint is documented and corrective and preventive measures must be put into place. • Conclusion:An ISO 9001 certification assures well defined management processes as a basis for quality and qualification. As long as a company is consistent in its documented actions, it can remain ISO 9001:2000 certified. • SUMMARY: • Product centered interests with ISO Guide 34 • -> concerns a single product with its characteristics, manufacturing process and parameters • -> quality as a result of exhaustive material knowledge and unchanging processes • Process centered interests with ISO 17025 • -> concerns a single manufacturing or service process with its parameters • -> quality as a result of perfectly described and uniformly operating procedures • Institution centered interests with ISO 9001 • -> concerns an institution or a branch with its managing processes • -> quality as a result of coordinated managing processes and described operating procedures

9. Focus of interest(s) Capabilityof product(s) Demands of interest groups Decision for ISO 9001 standard at DSMZ • Focus of interest: • institution related quality management system connecting all DSMZ branches • formalising and consorting existing operating procedures and creating a comprehensive framework for security, training and infrastructure • Capability of products: • a quality management system for living, highly diverse products and individual services • maintain scientific approach in the collection and maintenance of the biological material • Demands of interest groups: • fulfil the OECD requirements for BRCs • guarantee the stakeholder an efficient management

10. Overview to the 8 fundamentals of ISO 9001 • 1. Focus on your customers • Organizations rely on customers. • Therefore: • Organizations must understand customer needs. • Organizations must meet customer requirements. • Organizations must exceed customer expectations. • 2. Provide leadership • Organizations rely on leaders. • Therefore: • Leaders must establish a unity of purpose and set the direction the organization should take. • Leaders must create an environment that encourages people to achieve the organization's objectives. • 3. Involve your people • Organizations rely on people. • Therefore: • Organizations must encourage the involvement of people at all levels. • Organizations must help people to develop and use their abilities. • 4. Use a process approach • Organizations are more efficient and effective when they use a process approach. • Therefore: • Organizations must use a process approach to manage activities and related resources.

11. Overview to the 8 fundamentals of ISO 9001 • 5. Take a systems approach • Organizations are more efficient and effective when they use a systems approach. • Therefore: • Organizations must identify interrelated processes and treat them as a system. • Organizations must use a systems approach to manage their interrelated processes. • 6. Encourage continuous improvement • Organizations are more efficient and effective when they continually try to improve. • Therefore: • Organizations must make a permanent commitment to continually improve • their overall performance. • 7. Get the facts before you decide • Organizations perform better when their decisions are based on facts.  • Therefore: • Organizations must base decisions on the analysis of factual information and data. • 8. Work with your suppliers • Organizations depend on their suppliers to help them create value. • Therefore: • Organizations must maintain a mutually beneficial relationship with their suppliers.

12. Decision for ISO 9001 standard at DSMZ • The system should support • establishing an international quality standard: • for quality policy, ~ planning, ~ control, ~ demonstration and ~ assurance • to determine responsibility for management levels and employees • to define the organisation processes and resources • structuring and management of expertise • employee focus and ~ qualification • objective orientation • continuous improvement processes and analysis methods • protection of different interests and ensuring diversity • customer focus • product stability and traceability • transparency • advantages of DIN EN ISO 9001:2000 covering all demands

13. ISO 9001 is: ISO 9001 is not: ISO 9001 as a living and continuously growing system fixing unchangeable laboratory procedures establishing managing procedures describing laboratory procedures defining complete product parameters continuous improvement restricted to single processes or products ruling laboratory procedures securing infrastructure assuring staff qualification trainings enabling an institution to develop structures, strategies and procedures defining and parametrically fixing a product

14. Challenges at DSMZ establishing the QMS • Internal and product related challenges: • perpetuation of highly flexible work groups • preservation of the characteristic traits of each branch (Micro-Organisms, Plant Cell Cultures, Human and Animal Cell Cultures, Plant Viruses) • assuring the scientific potential and expert knowledge • unrestricted scope for design in science • integration of the peripheral equipment and infrastructure in highly qualified processes • standardisation of quality measures of all 4 domains within 1 guiding principle • transparency of the internal organisation and fortification of communication • systematically and continuous improvement and implementation of synergies between the domains

15. Realisation in 3 steps Step 1: • definition of quality aspects and quality manual • definition of quality programs • definition of process library (SOPs for laboratory and management procedures) • establishing a quality management team (representatives of all branches and domains) Step 2: • creation of master business procedures • creation of meta procedures (meta SOPs) for laboratories • fixing organisation charts and process network • document releases and staff training • methods for weak-point analysis Step 3: • customer opinion poll • laboratory audits • internal audit • start of electronic process management and recording • certification audit

16. Example step 2: Meta Procedures; Network Input by CABRI CABRI process description DSMZ integration in SOP

17. Process evaluation to straighten interfaces between working groups Workflow SOP Process stability within homogeneous process routes Example step 2: straighten workflows

19. Realisation Example: Periphery and Infrastructure • Integration of peripheral equipment and infrastructure in highly qualified processes: • labelling and batching, release and storage system (electronically based) • media • chemical • products • unified handling of records concerning the equipment • maintenance and analysis for e. g. • incubators • refrigerators and freezers • internal trainings for laboratory devices • programs for cleaning, hygiene, security, qualification and house keeping • facility management • 226 procedures, records and guides have been settled to assure • quality and security in laboratory and management processes • all procedures will be continuously revised andthe system is • continuously extended by new procedures and applicable standards

20. Realisation experience • Staff member responded differently and critically to the decision of implementing an ISO 9001 quality management system: Concerns • about loosing scientific basis and scope for development • that SOPs will reduce scope for decision making • of accumulation of documentation • of time consuming process • that formalisation is oppositional to a culture collection’s entity • Expectations • growing together of the branches • reduce redundancy • harmonisation of similar laboratory processes and security standards • transparent decisions • open communication platforms • participation of all hierarchical layers to decision making processes • not all concerns proved true and some emerged as less affecting • not all expectations are achieved today but are on their way

21. Conclusion • Implementing an ISO 9001 QMS • does take it’s time • is an ongoing process • is a chance to structural harmonisation • is not a restraint for science • can be adjusted for the speciality of biological material • is a basis and solid starting point for further thoughts for accreditation of some processes according to ISO 17025 or of some biological products for reference material according to ISO Guide 34.

22. Annex 1: Overview Quality Management Systems

23. „House of Quality“ Model QMS Modules for Biological Resource Centres complementary elements - as applicable complementary elements - as applicable complementary elements - as applicable Service Activities Large Scale Activities Scientific Activities GLP (OECD Series) Principles of GLP and Compliance Monitoring GLP (OECD Series) Principles of GLP and Compliance Monitoring GLP (OECD Series) GMP (FDA / EMEA Guides) ISO Guide 34 Quality system guidelines for the production of reference materials EN 12128:1998 Laboratories for research, development and analysis – Containment levels of microbiology laboratories, areas of risk, localities and physical safety requirements EN 1619:1996 Large-scale process and production – General requirements for management and organisation for strain conservation procedures ISO 17025:2000 General requirements for the competence of testing and calibration laboratories EN 12307:1997 Large-scale process and production – Guidance for good practice , procedures, training and control for personnel EN 12740:1999 Laboratories for research, development and analysis – Guidance for handling, inactivating and testing of waste ISO 15189:2003 Medical laboratories - Particular requirements for quality and competence EN 12741:1999 Laboratories for research, development and analysis – Guidance for biotechnology laboratory operations EN 12461:1998 Large-scale process and production – Guidance for the handling, inactivating and testing of waste ISO 7218:1996 Microbiology of food and animal feeding stuffs – General requirements for management and organisation for strain conservation procedures EN 12738:1999 Laboratories for research, development and analysis – Guidance for containment of animals inoculated with microorganisms in experiments EN 12460:1998 Large-scale process and production – Guidance on equipment selection and installation on accordance with the biological risk ISO 14644 ff Cleanrooms and associated controlled environments ISO 10006 QM - Guidelines to quality in project management ISO 9001:2000 Quality Management System Requirements ISO 9001:2000 Quality Management System Requirements SOP / documentation system (e.g. CABRI Guidelines for Bacteria and Archea, Fungi, Yeast, Plasmids, Phages, Animal and Human Cells, DNA probes, Plant Cells, Plant Viruses | Biological Security of Devices and Equipment EN 12296, 12297 and 12289 -> EN 12347, 12469, 12884, 12885 etc. | SO 9126 Information technology - Software Product Evaluation - Quality characteristics and guidelines for their use Biosafety in Microbiological and Biomedical Laboratories (CDC/NIH Manual) | WHO Laboratory Biosafety Manual | Cartagena Protocol on Biosafety to the Convention on Biological Diversity | Biological and Toxin Weapons Convention (BTWC) | Chemical Weapons Convention (CWC) | Dual Use Regulation (EG 1334/2000 | UN Model Regulations (Orange Book) | ICAO (Technical Instructions) | IATA DGR | UPU (International Postal Convention) | ADR, RID, IMO | Council Directive 2000/54/EC on the protection of workers from risks related to exposure to biological agents at work

24. Quality Management related links: International Organization for Standardization (ISO) http://www.iso.org The American National Standards Institute (ANSI) http://www.ansi.org/ European Committee for Standardization (CEN) http://www.cenorm.org/ European Co-operation for Accreditation http://www.european-accreditation.org International Laboratory Accreditation Cooperation (ILAC) http://www.ilac.org/ The American Association for Laboratory Accreditation http://www.a2la.org OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring http://www.oecd.org/document/63/0,2340,en_2649_34381_2346175_1_1_1_1,00.html

25. Annex 2: OECD – BRC guidelines

26. OECD BRC–Initiative as a basis for establishing an accredited DSMZ Quality Management System

27. Definition of a BRC acc. to OECD Biological Resource Centres - Quality and Expertise for Biological Information and Materials - Functions Public Mandatory Culturable Organisms Viable, not yet Culturable Organisms Legal and Protection Services Preservation and Provision of Biological Resources | Databases Diversity of Biological Resources Intellectual property rights (IPR) protection Co-Ordination and Unifying Catalogues Tissues Collections Related Bioinformatics Cells Protection of human, animal, plant and environmental health and safety Ethical protection of the rights of individuals and patients Replicable Parts Structural Information cDNAs Import/export regulations / Material transfer agreements Physiological Information Viruses Private industry’s protection of investments and industrial secrecy Molecular Information Plasmids Customers / Applications Genomes R&D Applications Ensuring Education and Training Information on Resources Electronic Tools and Analysis Medical Performance of R&D on Biological Resources Human Cells Environmental Resources for Political Formulation Animal Cells Agricultural Resources for Public Information Plant Cells Industrial Scientific Micro-Organisms Conservation of Biodiversity Service Providing Information & Data Bases Repository

28. BRC Quality Standards – OECD Position • To achieve quality assurance, common standards of practice must be implemented that deal with the following major issues: • • Quality management/quality assurance systems that are unified across national borders. • • Authenticity of biological materials, databases and bioinformatics and accuracy of labelling. • • Processing of cultures, cell lines, and genetic constructs, including procedures and standards for ensuring their long-term stability and quality. • • Accuracy of the data collected and supplied. • • Expertise and training ofhuman resources, particularly of a new generation of taxonomists able to reconcile existing knowledge with modern techniques and information technology. • Sharing of expertise among centres through co-ordination and networking. • Support the development of an accreditation system for BRCs based upon scientifically acceptable objective international criteria for quality, expertise and financial stability.

29. Thank you for your attention !