GOOD MANUFACTURING PRACTICES IN A QUALITY WORLD

1. GOOD MANUFACTURING PRACTICESIN A QUALITY WORLD Gordon Harnack President, Oracle Consulting Group Tucson, AZ www.fdamaze.com

2. The Discussion Plan • Definitions • General Discussion • Drugs & Biologics • Devices • In Vitro Diagnostics • Food • Cosmetics • GMP Specifics – Device GMPs

3. What are Good Manufacturing Practices (GMP)? • Good Manufacturing Practice regulation is a set of regulations, codes, and guidelines for the manufacture of drugs (known as medicinal products in Europe), medical devices, diagnostic products, foods products and Active Pharmaceutical Ingredients (APIs). • http://en.wikipedia.org/wiki/Good_Manufacturing_Practice

4. What are Current Good Manufacturing Practices (cGMP)? • Good Manufacturing Practice implemented in 1976 for the manufacture of products that are under FDA jurisdiction, including pharmaceuticals, biological products and medical devices. Current Good Manufacturing Practice ensures that finished products have the correct identity, strength, quality and purity characteristics they are represented to have, and have not been altered during processing, packaging, or handling. It requires extensive use of documentation and strict reconciliation of inventory. • www.sciteclabs.com/dictionary.html

5. Why GMP Regulations? • The Federal Food, Drug & Cosmetic Act authorizes such regulations • Title 21, Chapter 9, FFD&C Act has 17 references to GMPs • FDA’s mechanism to implement oversight of any “manufacturing” operation • Establishes FDA’s “minimal” manufacturing control expectations • Make management the chief “jailable” officer • Absent GMP regulations – fall back on FFDC Act!

6. FDA’S ExpectationsRelated to Firm Size • The larger the firm the greater FDA expectations • However, even the smallest firm MUST address every aspect of applicable FDA regulations.

7. What FDA Centers deal with Drug GMPs? • Center for Biologics Evaluation & Research (CBER) • Center for Drug Evaluation & Research (CDER) • Center for Veterinary Medicine (CVM) CDER states: “Useful to manufacturers of components used in the manufacture of these products”

8. What Types of Firms are Exempt from Drug GMPs? • Drug wholesalers, retailers, pharmacies & hospitals unless engaged in manufacturing operations beyond the usual dispensing or selling of drugs at retail • Compounders of drugs – pharmacists & physicians Note: Compounded drugs must still be composed of FDA approved components. Note: Some products are exempt from certain elements of Drug GMP.

9. What Types of Firms are Exempt from Drug GMP Regulations? (cont) • Manufacturers of active pharmaceutical ingredients (APIs) & bulk drugs are exempt from cGMP REGULATIONS but NOT cGMP requirements of the FFDC Act! • FDA cites API manufacturers for violations of the ACT, not drug GMP regulations • FDA’s GMP regulations are used as “guidance” during inspections. • FDA claims to be working on specific API GMPs

10. Drug GMPs Apply to • Prescription & OTC drugs, including homeopathic drugs • Manufacturing facilities of ALL sizes • Investigational drugs for clinical trials • Foreign produced drugs distributed in the U.S.

11. Drug GMPs • 21 CFR § 210 - cGMP in Manufacturing, Processing, or Holding of Drugs; General • 21 CFR 211 - cGMP Practice for Finished Pharmaceuticals • 21 CFR 210 & 211 – 300+ “shalls”

12. Drug GMPs (continued) • Applicability • GMP of §’s 210 – 226 & §’s 600 – 680 supplement – not supersede each other, unless otherwise directed • Compliance failures  adulterated drug product

13. Drug GMPs (continued) • Proposed new drug cGMPs will model FDA’s intent to integrate QS & RISK MANAGEMENT…& to harmonize with other non-drug regulatory systems & ISO 9000 • FDA states that a robust modern QS must embrace the concept that: “Quality should be built into the product, and testing alone cannot be relied on to ensure product quality.”

14. Drug GMPs (continued) • GMP Regulations specific to CBER regulated products • 21 CFR 606 – Current GMP for blood & blood products • 21 CFR 610 – General biological products standards • 21 CFR 630 – General requirements for blood, blood components & blood derivatives • 21 CFR 640 – Additional standards for human blood and blood products • 21 CFR 660 – Additional standards for diagnostic substances for laboratory tests • 21 CFR 680 – Additional standards for miscellaneous products

15. Medical Device GMPs • QUALITY SYSTEM REGULATIONS • 21 CFR § 820 - 200+ “shalls” • Control each phase of manufacturing • Harmonized with ISO 9000 • Greater emphasis on compliant handling, corrective & preventive actions, & labeling

16. What Types of Firms are Exempted from Device GMPs? • Component manufacturers Note: Some individual TYPES of devices are exempt from some elements of GMP regulations, for example: Many Class I devices, like tongue depressors, are typically exempted from all GMPs except records (820.180) & complaint files (820.198).

17. In Vitro Devices GMPs • 21 CFR 809 – In vitro diagnostic products for human use - approximately 25 “shalls”

18. Cosmetic GMPs – No Specific GMP Regulations • Regulated under the FFDC Act for: • Labeling • Ingredients • Contaminants • Processing • Packaging, or • Shipping and handling

19. Current Good Food Manufacturing Practices • 21 CFR 110 – approximately 95 “shalls” • Focus on • Sanitary/Unsanitary conditions • Personnel, Equipment & Buildings • Production/Process Controls • Raw materials • Water • Storage • Warehousing & distribution

20. Now a Close Examination of Medical Device GMPs

21. What Types of Firms are Subject to Device GMPs? • Remanufacturers • Custom Device Manufacturers • Contract Manufacturers • Contract Testing Labs • Repackagers, Relabelers & Specification Developers • Manufacturers of Accessories • Initial Distributors

22. Management responsibility Quality system controls Training controls Design/Development controls Document & data controls Purchasing controls Product identification & traceability controls Process and manufacturing controls Inspection & testing controls Inspection, measuring, & test equipment controls Process Validation Labels & Labeling Acceptance controls Non-conforming product controls Corrective & preventive action controls Handling, storage, packaging, preservation & delivery controls Quality record controls Installation & Servicing controls Complaint Handling controls Statistical technique controls Medical Device GMP20 Elements

23. Management Controls • Management shall: • Establish its policy and objectives for, and commitment to quality… • Policy is understood • Implemented • Maintained at all levels • Establish & maintain adequate organizational structure – ensuring that devices are designed & produced in regulatory compliance • Establish & maintain appropriate responsibility, authority & interrelations of all personnel… • Provide adequate resources… • Appoint a Management Representative…

24. Management Controls (continued) • Management shall: • Require the Management Representative to review the suitability & effectiveness of the QS at defined intervals to ensure… • Establish a quality plan that defines quality practices, resources & activities… • Establish how requirements for quality are met. • Establish & maintain QS procedures…

25. Quality System Controls • Establish procedures for quality audits … • Sufficient personnel with necessary education, background, training & experience to…

26. Training Controls • Establish procedures to identify training needs & ensure all personnel are trained to adequately perform their assigned responsibilities… • Personnel shall be made aware of device defects which may occur from improper performance… • Personnel performing verification/validation activities shall be made aware of defects & errors that may be encountered…

27. Planning Requirements Specifications Verification Validation Change Control Review Transfer Design History File (DHF) Design Controls

28. Design Risk Analysis • “Safety requirements should be commensurate with the hazards that can result from a system failure.” • FDA expects that all individual hazards, including SW, be identified and either eliminated or reduced to acceptable levels during the device’s design & development • FMEAs & Fault Trees

29. “Human Factors” in Device Design • FDA's site on human factors www.fda.gov/cdrh/humanfactors • See “Fitting Human Factors in the Product Development Process” published in the January 2006 Medical Device & Diagnostic Industry magazine – available as a “pdf”… www.agilisconsulting.com/pdf/HumanFactorsandtheProductDevelopmentProcess.pdf

30. What are Human Factors? • Human factors (HF) is the study of how people use technology. The interaction of human abilities, expectations, and limitations, with work environments and system design. • The term “human factors engineering” (HFE) refers to the application of human factors principles to the design of devices and systems. It is often interchanged with the terms "human engineering," "usability engineering," or "ergonomics." • The goal of HFE is to design devices that users accept willingly and operate safely in realistic conditions. In medical applications, HFE helps improve human performance and reduce the risks associated with use error. • In many cases, HFE focuses on the device user interface (also called the UI or the man-machine interface). The user interface includes all components and accessories necessary to operate and properly maintain the device, including the controls, displays, software, logic of operation, labels, and instructions.

31. Document & Data Controls • Establish & Maintain procedures (EMP) to control ALL documents required by regulations…including • Document review, approval & distribution • Document changes…

32. Purchasing Controls • EMP to ensure that ALL purchased or otherwise received product & services conform to SPECIFIED REQUIREMENTS…including • Evaluation of suppliers, contractors & consultants • Establish & maintain data that clearly describe or reference SPECIFIED REQUIREMENTS…including quality requirements

33. Product ID & Traceability Controls • EMP for identifying product during ALL stages of receipt, production, distribution & installation • Devices intended for surgical implant, life sustaining or supporting…whose failure when properly used can be expected to result in significant injury shall be identified with a control number…

34. Process & Manufacturing Controls • Manufacturer shall develop, conduct, control & monitor production processes to ensure that a device conforms specifications… • Establish & maintain process control procedures that describe all necessary controls…

35. Production & Process Controls (continued) • Process controls shall include: • Documented instructions, SOPs, & methods that define & control production • Monitoring & control of process parameters, component & device characteristics • Compliance with specified standards or codes • Approval of processes & equipment • Criteria for workmanship expressed in documented standards or by identified & approved samples

36. Production & Process Controls (continued) • EMP to control ALL changes to specifications, methods, processes or procedures… • Where environmental conditions can have any adverse effect on product quality…EMP to adequately control those conditions… • EMP for health, cleanliness, personnel practices & clothing of personnel…

37. Production & Process Controls (continued) • EMP to prevent contamination of equipment or product… • Provide buildings of suitable design & with sufficient space to perform necessary operations, prevent mix-ups & assure orderly handling

38. Production & Process Controls (continued) • Ensure that ALL equipment used in manufacturing process meets its specified requirements… • Equipment is properly installed, maintained, adjusted, cleaned & used • Establish & maintain schedules for equipment adjustment, cleaning or other maintenance… • Conduct periodic inspections • Ensure limitations/tolerances are posted

39. Production & Process Controls (continued) • Where manufacturing material could be expected to have adverse effects…EMP for the use & removal of those materials… • Validate any computers or automated data processing systems used

40. Inspection & Testing Controls • Manufacturers shall ensure that ALL inspection, measuring & test equipment is suitable & is capable of producing valid results… • EMP to ensure equipment is routinely calibrated, inspected, checked & maintained…

41. Inspection, Measuring & Test Equipment Controls • Calibration procedures shall include specific directions & limits for accuracy & precision… • Accuracy & precision failures shall require remedial action to reestablish the limits & assess adverse effect(s) on product quality… • Calibration standards used shall be traceable… • Calibration records shall include equipment ID, dates, individuals, & the next calibration date

42. Process Validation • Where the results of processes cannot be FULLY verified by inspection & test, the process shall be validated according to established procedures • EMP to monitor & control validated process parameters, controlling: • Personnel, records & changes

43. Label, Labeling & Packaging • EMP to control labeling activities, including label: • Integrity • Inspection • Storage • Operations • Control number

44. Packaging • Manufacturer shall ensure that packaging & shipping containers are designed & constructed to protect the device from alteration or damage…

45. Acceptance Controls • EMP for inspections, tests or other verifications as acceptance of: • Incoming product against specified requirements • In-process product against specified requirements • Finished devices to ensure EACH production run, lot or batch meets acceptance criteria

46. Acceptance Controls (continued) • Manufacturer shall: • Document acceptance activities, including: • Activities performed • Dates • Results • Signatures of individuals • If appropriate, equipment used • Identify acceptance status throughout the processes..

47. Non-conforming Product Controls • EMP to control non-conforming product (NCP) • Procedures shall control ID, documentation, evaluation, segregation & disposition of NCP • Evaluation shall include determining any need for an investigation & the persons/organizations responsible for the NCP

48. NCP Controls (continued) • EMP that define the responsibility for review & the authority for the disposition of NCP • Procedures shall control: • Reviews & dispositions • Records shall document any justification for use of NCP & signatures of authorizers • Rework shall include appropriate retesting, reevaluation & adverse effects assessment to ensure the product meets specifications

49. Corrective & Preventive Action Controls • EMP for implementing CAPAs, including: • Analyzing processes, work ops, concessions, audits, records, complaints, returns, & other sources of quality data • Use of appropriate statistical methods • Investigating nonconformances to product processes & the QS • Identifying action(s) needed to correct or prevent recurrence of nonconformances

50. CAPA Controls (continued) • CAPA procedures shall require: • Verification or validation of CAPAs to ensure their effectiveness & that they do not adversely affect the finished device • Implementing & recording changes in methods & procedures needed to correct & prevent quality problems • Ensuring information identified is disseminated to all appropriate individuals • Submitting records for management review