Bio-Manufacturing Practices Short Course in Biotechnology

1. Steve Pondell Director of Manufacturing, Encysive Pharmaceuticals Principal, Integrated BioTech Solutions August 8, 2008 Bio-Manufacturing PracticesShort Course in Biotechnology S. Pondell, Aug, 2008 Integrated BioTech Solutions

2. Part 1: Biotech Regulatory Environment S. Pondell, Aug, 2008 Integrated BioTech Solutions

3. What is Biotechnology? • Webster’s definition: • The manipulation (as through genetic engineering) of living organisms or their components to produce useful usually commercial products (as pest resistant crops, new bacterial strains, or novel pharmaceuticals); also: any various applications of biological science used in such manipulation S. Pondell, Aug, 2008 Integrated BioTech Solutions

4. What is Biotechnology? • Contemporary Examples: • Genetically-engineered drugs • Genetically-engineered crops • Small to medium size life science companies • Alternative fuels • Organisms for environmental control • Nanotechnology related to health care • Medical devices S. Pondell, Aug, 2008 Integrated BioTech Solutions

5. Regulatory Environment • Rules, guidelines or laws formulated by a governmental agency to guide or control products in the public realm • All companies operate in some type of regulatory environment • Because of biotech’s potential impact to public health, it tends to be more highly regulated that other industries S. Pondell, Aug, 2008 Integrated BioTech Solutions

6. U.S. Biotech Regulating Bodies • Food and Drug Administration (FDA) • Environmental Protection Agency (EPA) • Department of Agriculture • Patent and Trademark Office • Drug Enforcement Agency (DEA) S. Pondell, Aug, 2008 Integrated BioTech Solutions

7. Foreign Agencies • EMEA (Europe FDA) • Therapeutic Products Division (Canada FDA) • Therapeutic Goods Administration (Australia FDA) • Ministry of Health (Japan FDA) S. Pondell, Aug, 2008 Integrated BioTech Solutions

8. How Do Agencies Regulate? • Congress passes laws • Clean Water Act • Food, Drug and Cosmetic Act • Agencies create regulations • Mandatory • Agencies create guidelines • Strongly suggested • Agencies audit for compliance to regulations and guidelines • Agencies take enforcement actions for non-compliance S. Pondell, Aug, 2008 Integrated BioTech Solutions

9. Development and Approval Process Pre-clinical Research Clinical Research Clinical Studies Phase 1 Phase 2 Phase 3 IND Post-marketing Marketing Application Review Discovery / Screening Phase 4 Animal Testing S. Pondell, Aug, 2008 Integrated BioTech Solutions

10. Typical TimelinesDiscovery to Commercial • Alternate fuels 1 yr • Pesticide 3-5 yrs • Environmental remediator 3-5 yrs • Medical device 2-5 yrs • Small molecule drug 8-10 yrs • Biologic drug 10-12 yrs • Generic drug 2-3 yrs S. Pondell, Aug, 2008 Integrated BioTech Solutions

11. Compliance • GLPs (Good Laboratory Practices) • Pre-clinical, EPA • GCPs (Good Clinical Practices) • Clinical studies • GMPs (Good Manufacturing Practices) • Production and distribution of drugs and devices for human use • Written into Federal Register – mandatory regulations S. Pondell, Aug, 2008 Integrated BioTech Solutions

12. Compliance • Guidelines • Non-mandatory • Provides acceptable ways to meet regulations • Guidelines can become regulations S. Pondell, Aug, 2008 Integrated BioTech Solutions

13. Compliance • Companies self-police • Quality Unit is responsible • Top management also held responsible • Procedures, documentation and training • Agencies audit on regular basis S. Pondell, Aug, 2008 Integrated BioTech Solutions

14. Enforcement • Non-compliance • Found during audit or review • Official notification • Withholding of approvals • Withdrawal of product from market • Seizure of product • Legal action • Consent decree • Personal liability of top management • Debar S. Pondell, Aug, 2008 Integrated BioTech Solutions

15. Part 2: cGMP’scurrent Good Manufacturing Practices S. Pondell, Aug, 2008 Integrated BioTech Solutions

16. History of FDA • In 1202, King John of England proclaimed the first English food law, which prohibited adulteration of bread with such ingredients as ground peas or beans. • In 19th century, physicians were scarce and poorly educated and many people put their faith in patent medicines, pitched by traveling salesmen as drugs and miracle cure devices. • Ingredients secret • Efficacy questionable in many cases • Food, Drug and Cosmetic Act of 1906 created FDA • Significant revision in 1936 and again in 1960’s S. Pondell, Aug, 2008 Integrated BioTech Solutions

17. What are cGMP’s? • current Good Manufacturing Practices • Developed from a series of manufacturing mishaps in the 1960’s and 1970’s • Found in Code of Federal Regulations, Title 21, Parts 210 and 211 (for drugs) and Part 820 (for devices) • Applicable for drugs manufactured for human use, including investigational drugs S. Pondell, Aug, 2008 Integrated BioTech Solutions

18. What do cGMPs do? • Assure the following: • Identity • Purity • Safety • Effectiveness • Potency • Of drug products • Assure that these qualities are met • Consistently • Over life of product S. Pondell, Aug, 2008 Integrated BioTech Solutions

19. Sections of cGMP’s for Drugs • A. General Provisions • B. Organization and Personnel • C. Buildings and Facilities • D. Equipment • E. Control of Components and Drug Product Containers and Closures • F. Production and Process Controls • G. Packaging and Labeling Controls • H. Holding and Distribution • I. Laboratory Controls • J. Records and Reports • K. Returned and Salvaged Drug Products S. Pondell, Aug, 2008 Integrated BioTech Solutions

20. A. General Provisions • Minimum requirements • Applies to drug products • Additional detail for biologically derives products • Parts 600-680 • Additional detail for products derived from human cells or tissue • Part 1271 • Over-the-counter drugs exempted • Nutraceuticals exempted S. Pondell, Aug, 2008 Integrated BioTech Solutions

21. B. Organization and Personnel • Must have “quality unit” • Must have adequate laboratories • Must have adequate personnel for task, trained to perform task, and trained in GMP’s • Supervisors must have adequate education, training and experience to perform task • Adequate clothing and personal hygiene so as not to compromise product • Consultants must have adequate education, training and experience to perform task S. Pondell, Aug, 2008 Integrated BioTech Solutions

22. C. Buildings and Facilities • Adequate number and size • Good product flow so as to avoid mix-ups or contamination • Adequate lighting, ventilation and plumbing • Adequate sewage, refuse, washing and toilet facilities • Sanitation • Maintenance S. Pondell, Aug, 2008 Integrated BioTech Solutions

23. D. Equipment • Design, size and location suitable for task • Constructed of materials that are non-reactive with product • Maintained to avoid product contamination • Control of computer systems to assure consistent operation • Appropriate filters to avoid product contamination or reaction S. Pondell, Aug, 2008 Integrated BioTech Solutions

24. E. Control of Components and Drug Product Containers and Closures • Components received, tested and stored to prevent contamination • Each batch tested and approved prior to use • First in/first out • Retested periodically • Containers and closures provide appropriate protection for product and are non-reactive S. Pondell, Aug, 2008 Integrated BioTech Solutions

25. F. Production and Process Controls • Written procedures – written and followed • Approved batch record describing manufacturing process • Calculate yields at appropriate steps • Equipment identified as to status • Product appropriately sampled and tested • Time limits on production activities • Control of microbial contamination • Reprocessing controlled S. Pondell, Aug, 2008 Integrated BioTech Solutions

26. G. Packaging and Labeling Controls • Appropriate controls during receipt and storage to prevent mix-ups • Issuance controlled, and quantities reconciled • Correct labels applied to product • Lot number, expiration date • Tamper-evident packaging for OTC • Inspected and sampled during production • Expiry date supported by testing S. Pondell, Aug, 2008 Integrated BioTech Solutions

27. H. Holding and Distribution • Warehousing • Control of quarantined product prior to release • Appropriate temperature and humidity controls as needed by product • Distribution • First in/first out • Traceability of lot distribution in case of recall S. Pondell, Aug, 2008 Integrated BioTech Solutions

28. I. Laboratory Controls • Specifications, standards, instruments as necessary to assure identity, safety, efficacy, potency and purity of product • All product tested and released prior to distribution • Products routinely tested for stability • Reserve samples • Penicillin contamination avoidance S. Pondell, Aug, 2008 Integrated BioTech Solutions

29. J. Records and Reports • Production and laboratory records must be maintained for life of product • Equipment cleaning and use logs • Lot records regarding quantity, test results and labels • Master production and control records • Batch-specific production and control records • Record review • Laboratory records • Distribution records • Complaint files S. Pondell, Aug, 2008 Integrated BioTech Solutions

30. K. Returned and Salvaged Drug Products • Returned product must be held and evaluated prior to re-distribution • Must have assurances of proper storage • Packages must be intact S. Pondell, Aug, 2008 Integrated BioTech Solutions

31. International Harmonization • cGMPs exist in all major markets • Europe • Japan • US • International Conference on Harmonization has aligned cGMPs between major markets • Interpretation can still be issue • Emphasis different from market to market S. Pondell, Aug, 2008 Integrated BioTech Solutions

32. What is Validation? • Definition • Documented evidence that provides a high degree of assurance that a specific process, facility, or support system will consistently produce a product meeting its predetermined specifications and quality attributes. S. Pondell, Aug, 2008 Integrated BioTech Solutions

33. Part of cGMP’s? • Biologics and Pharmaceuticals – NO • CFR 210/211 • Medical Devices – YES • CFR 820 • BUT, FDA expects and requires validation in all cases • Validation helps assure that products are pure, safe and effective S. Pondell, Aug, 2008 Integrated BioTech Solutions

34. Where did it come from? • Originally from need to consistently control sterilization cycles for injectable solutions • Expanded over years to include utilities and equipment • Further expansion to processes, methods and computers • Latest expansion has been cleaning of equipment S. Pondell, Aug, 2008 Integrated BioTech Solutions

35. The Parts of Validation • Design qualification • Installation qualification • Operating qualification • Process qualification • Re-qualification S. Pondell, Aug, 2008 Integrated BioTech Solutions

36. What Gets Validated? • Facilities • Utilities • Equipment • Computer Control Systems • Test Methods • Process • Cleaning • Operators? S. Pondell, Aug, 2008 Integrated BioTech Solutions

37. The Parts of a Qualification • Protocol • Written pre-defined acceptance criteria • A description of procedures (and tests) to be conducted, data to be collected, and methods to be utilized. • Criteria by which a successful validation will be judged S. Pondell, Aug, 2008 Integrated BioTech Solutions

38. The Parts of a Qualification • Results and Report • Written compilation of results • Actual, traceable data • Evaluation against pre-defined criteria • Explanation and justification of deviations • Conclusion supporting or refuting a successful validation S. Pondell, Aug, 2008 Integrated BioTech Solutions

39. Part 3: Quality Assurance/Quality Control S. Pondell, Aug, 2008 Integrated BioTech Solutions

40. What is Quality Assurance (QA) • Quality Assurance (QA) is • the activity of providing evidence needed to establish confidence among all concerned, • that the quality-related activities are being performed effectively. • All those planned or systematic actions necessary to provide adequate confidence that a product or service will satisfy given requirements for quality. • Quality Assurance is a part and consistent pair of quality management proving fact-based external confidence to customers and other stakeholders that product meets needs, expectations, and other requirements. • QA (quality assurance) assures the existence and effectiveness of procedures that attempt to make sure - in advance - that the expected levels of quality will be reached S. Pondell, Aug, 2008 Integrated BioTech Solutions

41. What is Quality control (QC)? • Quality control (QC) is • a procedure or set of procedures intended to ensure that a manufactured product or performed service adheres to a defined set of quality criteria or meets the requirements of the client or customer. • Refers most commonly to a department which analyses raw materials, intermediates, and final product S. Pondell, Aug, 2008 Integrated BioTech Solutions

42. Role of Quality assurance in the pharmaceutical industry • Quality Assurance is a vital part of drug development in the small pharmaceutical environment. It is the department which is responsible for ensuring that all the appropriate procedures have been followed and documented so that clinical progress can be made. • Quality Assurance and Management are responsible, in FDA’s eyes, for assuring that products manufactured are safe, pure and efficacious. S. Pondell, Aug, 2008 Integrated BioTech Solutions

43. Types of Quality Systems • QbD – Quality by Design • ISO 9001/14001 – More generic than cGMP’s • Apply to variety of industries • TQM – Total Quality Management • Six Sigma • Originally developed for electronics industry (Motorola) S. Pondell, Aug, 2008 Integrated BioTech Solutions

44. Sigma Sigma is a metric or mathematical/statistical term which defines how often a process fails to meet requirements. Six Sigma is defined as a process which produces only 3.4 product defects per million opportunities (DPMO) to produce a defect. DPMO or PPMSigma Level 308,537 2 66,807 3 6,210 4 233 5 3.4 6 S. Pondell, Aug, 2008 Integrated BioTech Solutions

45. A Six Sigma Process S. Pondell, Aug, 2008 Integrated BioTech Solutions

46. Six Sigma A defined methodology for reducing process variation and a mathematical term for defining the number of defects produced by a process compared to the number of opportunities to create a defect. S. Pondell, Aug, 2008 Integrated BioTech Solutions

47. How does it work? • Utilizes data to statistically determine where and to what extreme process variability exists. • Step wise improvements are established to generate savings by reducing process variability. • Focus is on: • Reducing the cost to produce ▫ Reduce cycle time or downtimes • ▫ Improve yields • ▫ Reduce variability • ▫ Manufacturing costs • Customer needs S. Pondell, Aug, 2008 Integrated BioTech Solutions

48. DMAIC Process Lean Six Sigma methodology utilizes a rigorous procedure called DMAIC on each input of a process and thereby controls the final output or product. S. Pondell, Aug, 2008 Integrated BioTech Solutions

49. Metrics • The organization and charting of collected data to determine how well a process is performing. • Typically each key process input is measured to determine how the actual compares to the expected. (i.e. theoretical, average, goal) • The sequential charting of multiple data points determines the trend and variability of the process. • Key Process Inputs and Key Process Outputs are measured. S. Pondell, Aug, 2008 Integrated BioTech Solutions

50. Ways to Improve Efficiency • Decrease variability. • Decrease defects. • Decrease time span. • Process variability and defects are the prime enemies of efficiency. • Time waste is different from material waste in that time waste can never be salvaged. • Process time traps must be identified and removed. S. Pondell, Aug, 2008 Integrated BioTech Solutions