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GOOD MANUFACTURING PRACTICES

IN A QUALITY WORLD

Gordon Harnack

President, Oracle Consulting Group

Tucson, AZ

www.fdamaze.com

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The Discussion Plan

Definitions General Discussion

Drugs Devices In Vitro Diagnostics Food Cosmetics

GMP Specifics – Device GMPs

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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

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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

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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!

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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.

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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”

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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.

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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

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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.

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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”

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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

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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.”

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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

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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

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What Types of Firms are Exempted from Device GMPs?

Component manufacturersNote: 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).

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In Vitro Devices GMPs

21 CFR 809 – In vitro diagnostic products for human use - approximately 25 “shalls”

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Cosmetic GMPs – No Specific GMP Regulations

Regulated under the FFDC Act for: Labeling Ingredients Contaminants Processing Packaging, or Shipping and handling

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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

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Now a Close Examination of Medical Device GMPs

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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

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Medical Device GMP20 Elements

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

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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…

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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…

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Quality System Controls

Establish procedures for quality audits … Sufficient personnel with necessary education,

background, training & experience to…

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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…

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Design Controls

Planning Requirements Specifications Verification Validation

Change Control Review Transfer Design History File

(DHF)

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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

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Document & Data Controls

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

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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

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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…

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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…

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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

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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…

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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

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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

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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

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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…

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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

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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

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Label, Labeling & Packaging EMP to control labeling activities,

including label: Integrity Inspection Storage Operations Control number

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Packaging

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

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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

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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..

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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

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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

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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

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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

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Handling, Storage, Preservation& Delivery Controls

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

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Delivery Controls

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 Name & address of initial consignee Date, ID & quantity of devices shipped Any control numbers used

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Quality Record Controls 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

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Quality Records – Quality System Records (QSR)

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: SOP creation & numbering SOPs Training SOPs and records Purchasing SOPs and records Supplier assessment SOPs and records

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Quality Records – Device Master Record (DMR)

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

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Quality Records – Device History Record (DHR)

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

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Installation & Servicing Controls

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

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Installation & Servicing Controls

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

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Servicing Controls 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

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Complaint Handling Controls

EMP for: 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

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Complaint Handling Controls (continued)

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

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Complaint Handling Controls (continued)

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: 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

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Complaint Handling Controls (continued)

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

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Statistical Technique Controls

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…

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Useful Tools in Understanding GMPs

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

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One Final Note 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.

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One Final Note (continued)

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

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One Final Note (continued)

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.”

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One Final Note (continued)

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.”

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One Final Note (continued)

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.”

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One Final Note (continued)

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.”

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One Final Note (continued)

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 all 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

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One Final Note ( continued)

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).

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Questions

?

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Abbreviations Used

§ - ParagraphAPIs - Active pharmaceutical ingredientsCAPA – Corrective Action & Preventive ActionCBER – Center for Biologics Research &

DevelopmentCDER – Center for Drug Evaluation & ResearchCDRH – Center for Devices & Radiologic HealthCVM – Center for Veterinary MedicineCFR – Code of Federal RegulationscGMP – Current Good Manufacturing PracticeCPGs – Compliance Policy GuidesCPGM – Compliance Program Guidance ManualDHF – Design History FileDHR – Device History RecordDMR – Device Master RecordFDA – Food & Drug Administration

FDA – Food & Drug AdministrationFFDC or FFD&C – Federal Food Drug &

Compliance (Act)FMEA – Failure Mode & Effects AnalysisEMP – Establish & maintain proceduresGMP – Good Manufacturing PracticeID - IdentificationISO – Acronym for International Standards

OrganizationOTC – Over the CounterNCP – Nonconforming ProductQA – Quality AssuranceQS – Quality SystemQSR – Quality System RegulationSOP – Standard Operating ProcedureUTMD – Utah Medical Device