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

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

What are Good Manufacturing Practices (GMP)? n n Good Manufacturing Practice regulation is a What are Good Manufacturing Practices (GMP)? n n 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 3

What are Current Good Manufacturing Practices (c. GMP)? n n Good Manufacturing Practice implemented What are Current Good Manufacturing Practices (c. GMP)? n n 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 4

Why GMP Regulations? n The Federal Food, Drug & Cosmetic Act authorizes such regulations Why GMP Regulations? n The Federal Food, Drug & Cosmetic Act authorizes such regulations ¡ n n 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! 5

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

What FDA Centers deal with Drug GMPs? n n n Center for Biologics Evaluation What FDA Centers deal with Drug GMPs? n n n 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” 7

What Types of Firms are Exempt from Drug GMPs? n Drug wholesalers, retailers, pharmacies What Types of Firms are Exempt from Drug GMPs? n 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. 8

What Types of Firms are Exempt from Drug GMP Regulations? (cont) n Manufacturers of What Types of Firms are Exempt from Drug GMP Regulations? (cont) n Manufacturers of active pharmaceutical ingredients (APIs) & bulk drugs are exempt from c. GMP REGULATIONS but NOT c. GMP 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 9

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

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

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

Drug GMPs (continued) n n Proposed new drug c. GMPs will model FDA’s intent Drug GMPs (continued) n n Proposed new drug c. GMPs 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. ” 13

Drug GMPs (continued) n GMP Regulations specific to CBER regulated products ¡ ¡ ¡ Drug GMPs (continued) n 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 14

Medical Device GMPs n n n QUALITY SYSTEM REGULATIONS 21 CFR § 820 - Medical Device GMPs n n n 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 15

What Types of Firms are Exempted from Device GMPs? n Component manufacturers Note: Some What Types of Firms are Exempted from Device GMPs? n 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). 16

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

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

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

Now a Close Examination of Medical Device GMPs 20 Now a Close Examination of Medical Device GMPs 20

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

Medical Device GMP 20 Elements n n n Management responsibility Quality system controls Training Medical Device GMP 20 Elements n n n 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 n n n n 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 22

Management Controls n Management shall: ¡ Establish its policy and objectives for, and commitment Management Controls n Management shall: ¡ Establish its policy and objectives for, and commitment to quality… n n n ¡ ¡ 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… 23

Management Controls (continued) n Management shall: ¡ ¡ Require the Management Representative to review Management Controls (continued) n 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… 24

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

Training Controls n Establish procedures to identify training needs & ensure all personnel are Training Controls n 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… 26

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

Design Risk Analysis n n “Safety requirements should be commensurate with the hazards that Design Risk Analysis n n “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 28

“Human Factors” in Device Design FDA's site on human factors www. fda. gov/cdrh/humanfactors n “Human Factors” in Device Design FDA's site on human factors www. fda. gov/cdrh/humanfactors n 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/Human. Factor sandthe. Product. Development. Process. pdf n 29

What are Human Factors? n n Human factors (HF) is the study of how What are Human Factors? n n 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. 30

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

Purchasing Controls n EMP to ensure that ALL purchased or otherwise received product & Purchasing Controls n 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 32

Product ID & Traceability Controls n n EMP for identifying product during ALL stages Product ID & Traceability Controls n n 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… 33

Process & Manufacturing Controls n n Manufacturer shall develop, conduct, control & monitor production Process & Manufacturing Controls n n 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… 34

Production & Process Controls (continued) n Process controls shall include: ¡ ¡ ¡ Documented Production & Process Controls (continued) n 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 35

Production & Process Controls (continued) n n n EMP to control ALL changes to Production & Process Controls (continued) n n n 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… 36

Production & Process Controls (continued) n n EMP to prevent contamination of equipment or Production & Process Controls (continued) n n 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 37

Production & Process Controls (continued) n n Ensure that ALL equipment used in manufacturing Production & Process Controls (continued) n n 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 38

Production & Process Controls (continued) n n Where manufacturing material could be expected to Production & Process Controls (continued) n n 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 39

Inspection & Testing Controls n n Manufacturers shall ensure that ALL inspection, measuring & Inspection & Testing Controls n n 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… 40

Inspection, Measuring & Test Equipment Controls n n Calibration procedures shall include specific directions Inspection, Measuring & Test Equipment Controls n n 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 41

Process Validation n n Where the results of processes cannot be FULLY verified by Process Validation n n 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 42

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

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

Acceptance Controls n EMP for inspections, tests or other verifications as acceptance of: ¡ Acceptance Controls n 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 45

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

Non-conforming Product Controls n n n EMP to control non-conforming product (NCP) Procedures shall Non-conforming Product Controls n n n 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 47

NCP Controls (continued) n n EMP that define the responsibility for review & the NCP Controls (continued) n n 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 48

Corrective & Preventive Action Controls n EMP for implementing CAPAs, including: ¡ ¡ Analyzing Corrective & Preventive Action Controls n 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 49

CAPA Controls (continued) n CAPA procedures shall require: ¡ ¡ Verification or validation of CAPA Controls (continued) n 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 50

Handling, Storage, Preservation & Delivery Controls n EMP to: ¡ ¡ ¡ Control storage Handling, Storage, Preservation & Delivery Controls n EMP to: ¡ ¡ ¡ Control storage areas to prevent mix-ups, damage, deterioration, contamination or other adverse effects Control product requiring stock rotation Control receipt from & dispatch to storage areas 51

Delivery Controls n EMP to: ¡ ¡ Ensure only approved devices are released POs Delivery Controls n EMP to: ¡ ¡ Ensure only approved devices are released POs are reviewed to ensure ambiguities & errors are resolved… Ensure stock that deteriorates over time is properly controlled & expired devices are not distributed Maintain distribution records that ID n n n Name & address of initial consignee Date, ID & quantity of devices shipped Any control numbers used 52

Quality Record Controls n n n All required records shall be maintained at the Quality Record Controls n n n All required records shall be maintained at the manufacturing location or other location that is reasonably accessible for FDA inspection, review & copying Records deemed confidential may be so marked All required records shall be retained for the device’s expected life – but in no case less than 2 years from the date of release 53

Quality Records – Quality System Records (QSR) n Manufacturers shall maintain a quality system Quality Records – Quality System Records (QSR) n Manufacturers shall maintain a quality system record (QSR) that includes ¡ Procedures and records of activities required by FDA regulation that are not specific to a particular type of device, including: n n SOP creation & numbering SOPs Training SOPs and records Purchasing SOPs and records Supplier assessment SOPs and records 54

Quality Records – Device Master Record (DMR) n Maintain an approved DMR, including: ¡ Quality Records – Device Master Record (DMR) n Maintain an approved DMR, including: ¡ ¡ ¡ Device specifications – drawings, composition, formulation, component specifications & SW specifications Product process specifications – equipment specs, production methods, production SOPs & environmental specs QA SOPs, QA specs, acceptance criteria & QA equipment Packaging & labeling specs, & methods Installation, maintenance & servicing SOPs 55

Quality Records – Device History Record (DHR) n EMP that ensure the DHR documents Quality Records – Device History Record (DHR) n EMP that ensure the DHR documents devices were manufactured in accordance with the DMR & FDA regulations, the DHR includes: ¡ ¡ ¡ Date(s) & quantity of manufactured devices Quantity released for distribution Acceptance records Primary ID label & labeling Any device ID & control number(s) used 56

Installation & Servicing Controls n n n EMP for adequate installation, inspection instructions & Installation & Servicing Controls n n n EMP for adequate installation, inspection instructions & any needed test activities Procedures shall ensure proper installation & device performance after installation Installation SOPs shall be distributed appropriately 57

Installation & Servicing Controls n Procedures shall require: ¡ ¡ ¡ Installation personnel perform Installation & Servicing Controls n Procedures shall require: ¡ ¡ ¡ Installation personnel perform any required testing in accordance with manufacturers instructions & document the inspection & testing to demonstrate proper installation Specified servicing requirements follow established & maintained SOPs that require servicing meets specified requirements Service reports are analyzed with appropriate statistical methods 58

Servicing Controls n n Service reports that represent an event that must be reported Servicing Controls n n Service reports that represent an event that must be reported to FDA under MDR regulations shall automatically be considered a complaint & handled in accordance with FDA complaint handling regulations Reports shall include: ¡ ¡ ¡ Name, date, ID & any control # of devices serviced Individual performing service & service performed Any test & inspection data 59

Complaint Handling Controls n EMP for: ¡ n Receiving, reviewing & evaluating complaints by Complaint Handling Controls n EMP for: ¡ n Receiving, reviewing & evaluating complaints by a FORMALLY DESIGNATED UNIT Complaints shall be ¡ ¡ ¡ Processed in a uniform & timely manner Oral (complaints) documented upon receipt Evaluated to determine if complaint represents an MDR event requiring reporting 60

Complaint Handling Controls (continued) n Manufacturers shall: ¡ ¡ Review & evaluate all complaints Complaint Handling Controls (continued) n Manufacturers shall: ¡ ¡ Review & evaluate all complaints to determine if an investigation is necessary If a determination is made that no investigation is required, a record of shall be made that IDs the reason & the individual making the decision 61

Complaint Handling Controls (continued) n Complaints involving device failures to meet ANY specification shall Complaint Handling Controls (continued) n Complaints involving device failures to meet ANY specification shall be: ¡ ¡ Reviewed, evaluated & investigated – unless such investigation has already been performed for a similar complaint & another investigation is unnecessary Documented to show a determination of: n n n Whether the device failed to meet specifications Whether the device was being used for treatment or diagnosis Any relationship to any device to any reported incident or adverse event 62

Complaint Handling Controls (continued) n Complaint investigation records shall include: ¡ ¡ ¡ ¡ Complaint Handling Controls (continued) n Complaint investigation records shall include: ¡ ¡ ¡ ¡ Device name & date complaint received Device ID & control #s used Name, address & phone # of complainant Nature & details of complaint Dates & results of investigation Any corrective action taken Any reply to complainant 63

Statistical Technique Controls n Where appropriate, EMP for: ¡ ¡ ¡ Identifying valid statistical Statistical Technique Controls n Where appropriate, EMP for: ¡ ¡ ¡ Identifying valid statistical techniques required for establishing, controlling & verifying the acceptability of process capability and product characteristics Sampling plans, when used, shall be written & based on valid rationale Ensuring sampling methods are adequate for their intended use… 64

Useful Tools in Understanding GMPs n n n n n Warning Letters & Recall Useful Tools in Understanding GMPs n n n n n Warning Letters & Recall postings Guidance Documents Compliance Policy Guides (CPGs) Compliance Program Guidance Manual (CPGM) Guidance Documents for Regulated Industry Regulatory Procedures Manual (RPM) Investigations Operations Manual Laboratory Information Bulletins Laboratory Procedures Manual 65

One Final Note n n FDA is NOT ALWAYS RIGHT! The Agency is made One Final Note n n FDA is NOT ALWAYS RIGHT! The Agency is made up of PEOPLE, people with strong convictions & egos The Agency is a bureaucracy & bureaucracies over-reach, over-state, over-react & almost NEVER admit they are wrong The following is an example of a bureaucratic mis-step. 66

One Final Note (continued) n n n Between 2001 – 2004 Utah Medical was One Final Note (continued) n n n Between 2001 – 2004 Utah Medical was cited by FDA for a number of GMP violations August 2004 FDA sought a Permanent Injunction to stop the firm from manufacturing & distributing medical devices UNTIL the firm DEMONSTRATED corrections in deviations from GMPs "FDA will not tolerate manufacturing practices that can potentially put patients at risk, " said FDA Acting Commissioner Dr. Lester M. Crawford 67

One Final Note (continued) n n FDA’s injunction followed three years of FDA inspections One Final Note (continued) n n FDA’s injunction followed three years of FDA inspections that FDA claimed “revealed a pattern of significant deviations from the Quality System regulation at Utah Medical's Midvale facility. ” FDA claimed “Utah Medical has consistently failed to ensure that its products are manufactured in accordance with the Quality System regulation. ” 68

One Final Note (continued) n On Oct 21, 2005 Federal Judge Bruce Jenkins found One Final Note (continued) n On Oct 21, 2005 Federal Judge Bruce Jenkins found & stated “This is an unusual case. The safety of the products manufactured by Utah Medical has never been at issue. ” 69

One Final Note (continued) n The judge noted that “Even though product safety is One Final Note (continued) n The judge noted that “Even though product safety is a non-issue, the relief originally sought by the United States was to stop Utah Medical’s products from entering commerce because of alleged persistent deficiencies of Utah Medical in complying with the applicable quality system regulations (21 CFR § 820), and asserting that a failure to comply by definition produced an adulterated product and subjected the product and the persons responsible for the product to regulatory action. ” 70

One Final Note (continued) n n Judge Jenkins went on to state “In short, One Final Note (continued) n n Judge Jenkins went on to state “In short, the United States asked that Utah Medical be ordered to stop the sale of product until Utah Medical complies with the regulation 21 CFR § 820 and in a manner that has been found acceptable to FDA. ” Further he stated “The court has been impressed as well by Utah Medical’s design of product, its record-keeping of each step along the way, the acceptance in the market of its products, the Company’s uniform processing of complaints, and the manner in which change is made in practice and procedure as a result of complaint handling. ” 71

One Final Note (continued) n n Judge Jenkins concluded “It makes no sense for One Final Note (continued) n n Judge Jenkins concluded “It makes no sense for the court to order Utah Medical to do something they are already doing. ” The Court disagreed with allegations by the FDA, and dismissed the lawsuit filed in August 2004 that sought to shut down UTMD, without any evidence of unsafe, ineffective, or defective products or products causing any patient harm, until UTMD complied with the FDA’s interpretation of the QSR, an interpretation that was never provided to UTMD until after the lawsuit was filed 72

One Final Note ( continued) n The U. S. Federal District Court in Salt One Final Note ( continued) n The U. S. Federal District Court in Salt Lake City confirmed that UTMD is operating in compliance with 21 CFR § 820, the U. S. Food & Drug Administration (FDA) Quality System Regulation (QSR). 73

Questions ? 74 Questions ? 74

Abbreviations Used § - Paragraph APIs - Active pharmaceutical ingredients CAPA – Corrective Action Abbreviations Used § - Paragraph APIs - Active pharmaceutical ingredients CAPA – Corrective Action & Preventive Action CBER – Center for Biologics Research & Development CDER – Center for Drug Evaluation & Research CDRH – Center for Devices & Radiologic Health CVM – Center for Veterinary Medicine CFR – Code of Federal Regulations c. GMP – Current Good Manufacturing Practice CPGs – Compliance Policy Guides CPGM – Compliance Program Guidance Manual DHF – Design History File DHR – Device History Record DMR – Device Master Record FDA – Food & Drug Administration FFDC or FFD&C – Federal Food Drug & Compliance (Act) FMEA – Failure Mode & Effects Analysis EMP – Establish & maintain procedures GMP – Good Manufacturing Practice ID - Identification ISO – Acronym for International Standards Organization IQ – Installation Qualification OC – Operational Qualification OTC – Over the Counter NCP – Nonconforming Product PQ – Performance Qualification QA – Quality Assurance QS – Quality System QSR – Quality System Regulation SOP – Standard Operating Procedure UTMD – Utah Medical Device 75