# Presentation: 132814

## GHTF.SG3.N15-R8: Implementation of Risk Management Principles and Activities Within a Quality Management System

**Presented by Carolyn Albertson**
**Gunter Frey**
**Member, SG3**
**NEMA**

## Medical device manufacturers are generally required to have a quality management system as well as processes for addressing device related risks. 
These processes have become stand alone management systems.  

**These processes have become stand alone management systems.  **

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## While manufacturers may choose to maintain these two management systems separately, it may be advantageous to integrate them as it could reduce costs, eliminate redundancies, and lead to a more effective management system.

- September 11, 2001

## This document is intended to assist medical device manufacturers with the integration  of a risk management system or the risk management principles and activities into their existing quality management system by providing practical explanations and examples

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## The document is based on general principles of a quality management system and general principles of a risk management system and not on any particular standard or regulatory requirement. 

- September 11, 2001

## An effective quality management system is essential for ensuring the safety and performance of medical devices.  
It includes safety considerations in specific areas.  
Given the importance of safety, it is useful to identify some key activities that specifically address safety issues and ensure appropriate input and feedback from these activities into the quality management system.

**It includes safety considerations in specific areas.  **
**Given the importance of safety, it is useful to identify some ****key activities**** that specifically address safety issues and ensure appropriate input and feedback from these activities into the quality management system.**

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## The degree to which safety considerations are addressed should be commensurate with the degree of the risk,  the nature of the device and the benefit to the patient.
Some devices present relatively low risk or have well-understood risks with established methods of risk control. 

**Some devices present relatively low risk or have well-understood risks with established methods of risk control. **

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## In general, risk management is characterized by four phases of activities:
Determination of acceptable levels of risk 
Risk analysis
Determination of risk reduction measures
Risk control and monitoring activities

**Determination of acceptable levels of risk **
**Risk analysis**
**Determination of risk reduction measures**
**Risk control and monitoring activities**

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## Determination of acceptable levels of risk:
Risk acceptability criteria should be defined.  
These criteria may come from:
an analysis of the manufacturer’s experience with similar medical devices
currently accepted risk levels by regulators, users, or patients, given the benefits from diagnosis or treatment with the device.  
The criteria should be reflective of state-of-the-art in controlling risks.

**Risk acceptability criteria should be defined.  **
**These criteria may come from:**
**an analysis of the manufacturer’s experience with similar medical devices**
**currently accepted risk levels by regulators, users, or patients, given the benefits from diagnosis or treatment with the device.  **
**The criteria should be reflective of state-of-the-art in controlling risks.**

- September 11, 2001

## Risk analysis:
This phase starts with identifying hazards that may occur due to characteristics or properties of the device during normal use or foreseeable misuse.
After hazards are identified, risks are estimated for each of the identified hazards, using available information.

**This phase starts with identifying hazards that may occur due to characteristics or properties of the device during normal use or foreseeable misuse.**
**After hazards are identified, risks are estimated for each of the identified hazards, using available information.**

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## Determination of risk reduction measures:
In this phase, the estimated risks are compared to the risk acceptability criteria.  
This comparison will determine an appropriate level of risk reduction.  This is called risk evaluation.  
The combination of risk analysis and risk evaluation is called risk assessment.

**In this phase, the estimated risks are compared to the risk acceptability criteria.  **
**This comparison will determine an appropriate level of risk reduction.  This is called risk evaluation.  **
**The combination of risk analysis and risk evaluation is called risk assessment.**

- September 11, 2001

## Risk control and monitoring activities:
Actions intended to eliminate or reduce each risk to meet the previously determined risk acceptability criteria. 
One or more risk control measures may be incorporated.  
Risk controls may begin as early as design input and continue over the medical device life time. 

**Actions intended to eliminate or reduce each risk to meet the previously determined risk acceptability criteria. **
**One or more risk control measures may be incorporated.  **
**Risk controls may begin as early as design input and continue over the medical device life time. **

- September 11, 2001

## Risk control and monitoring activities:
Some regulatory schemes prescribe a fixed hierarchy of risk controls that should be examined in the following order:
Inherent safety by design
Protective measures in the device or its manufacture
Information for safety, such as warnings, maintenance schedules, etc.

**Some regulatory schemes prescribe a fixed hierarchy of risk controls that should be examined in the following order:**
**Inherent safety by design**
**Protective measures in the device or its manufacture**
**Information for safety, such as warnings, maintenance schedules, etc.**

- September 11, 2001

## Risk control and monitoring activities:
Throughout the life-cycle of the device the manufacturer monitors whether the risks continue to remain acceptable and whether any new hazards or risks are discovered.
An effective and well defined Quality Management System is key!

**Throughout the life-cycle of the device**** the manufacturer monitors ****whether the risks continue to remain acceptable**** and whether any new hazards or risks are discovered.**
**An effective and well defined Quality Management System is key!**

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## Risk control and monitoring activities:
Information typically obtained from the quality management system, for example, production, complaints, customer feedback, should be used as part of this monitoring.

Let’s examine this a little closer ...

**Information typically obtained from the quality management system, for example, production, complaints, customer feedback, should be used as part of this monitoring.**
**Let’s examine this a little closer ...**

- September 11, 2001

## Key Quality Data Points

**Key Quality Data Points**

**Service Reports**

**Product**
**Complaints**

**Complaints entered**
**into **
**Complaint Handling System**

**CAPA Process**
**(i.e. Investigate**
**Cause, document rationale for no investigation, etc.)**

**Manufacturing**
**Non-conformities/**
**Defects**

**Engineering**
**Non-conformities/**
**Defects**

**Quality System**
**Non-conformities/Defects**

_**Possible CAPA Actions**_
** ****Product Change**
** ****Process Change**
** ****Supplier Change Notice**
** ****Field Upgrade to installed base**
** ****Input for New Products**
**Input to RM process start**

**Supplier**
**Audits**

**Internal and external**
**Audits**

**Purchased**
**Part **
**Non-conformities**

**Production**
**Non- conformities**

**Complaint?**

**Yes**

**No**

**Known **
**Problem?**

**Yes**

**No**

**Data analysis/trending**

**Action required?**

**No**

**Continue Monitoring**

**Yes**

**Risk Management**
**Process**

**Other Management**
**Data Points ****(1)**

**Such as Finished Goods Returned, Credit restock**
**The relationship will depend upon the output of the investigation. This process can be iterative**

**(2)**

**Action required?**

**Data analysis/trending**

**Yes**

**No**

- September 11, 2001

## Risk control and monitoring activities:
If, at any time, a risk is determined to be unacceptable, part or all of the existing risk analysis should be re-examined and appropriate action taken to meet the established risk acceptability criteria.  
If a new hazard is identified, all four phases of risk management should be performed. 

**If, at any time, a risk is determined to be unacceptable, ****part or all of the existing risk analysis should be re-examined and appropriate action taken**** to meet the established risk acceptability criteria.  **
**If a new hazard is identified, all four phases of risk management should be performed****. **

- September 11, 2001

## Risk Management In Design Controls

**Identify hazards****, develop a hazards list**
**Determine the ****source of the hazard**** (any combination of  product design, manufacturing, user)**
**Analyze the hazard using appropriate tools (FTA, FMEA, HACCP, Human Factors Analysis, etc.)**

- September 11, 2001

## Risk Management In Design Controls

**Minimize risks**** (redesign, process validation or process variability reduction, labeling, user education, etc.)**
**Determine**** the overall or total ****risk from all sources**
**Determine risk acceptability**** as a part of the completed design validation**

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## Slide 20

- September 11, 2001

## Risk Management In The Quality System

- Risk Management decisions and documentation from design and development becomes a living and ever changing  design input as experience and post market feedback occurs!

- September 11, 2001

## Risk Management In The Quality System

- Risk Management needs to be procedurally tied into:
- Design Controls
- Purchasing procedures and criteria
- Acceptance Activity procedures and criteria
- Manufacturing activities
- Process validations
- Rework procedures and decisions
- Corrective and preventive actions

- September 11, 2001

## Risk Management Principles and Activities Within a Quality Management SystemCase Study

## Temporomandibular Joint (TMJ) Implants

- September 11, 2001

## TemporomandibularJoint (TMJ)

**The TMJ is comparable to a ball-in-socket joint. **
**The ball (condyle) is a part of the lower jaw (mandible). **
**The socket (fossa) is part of the skull. **
**These two parts come together to form the moveable joint, which can be felt when placing fingers over the skin in front of the ears while opening and closing the mouth. **

- September 11, 2001

## TMJ Implants

**In March 1983, a company began marketing a Interpositional Implant (IPI) to treat TMJ problems. The firm claimed substantial equivalence to an existing product, silicone sheeting, which was also used as a TMJ implant. **
**Both products included Teflon as key components.**

- September 11, 2001

## TMJ Implants

**Warnings against the use of Teflon in these type of applications date back to 1963 and 1974**
**Study published in 1984 concludes Proplast coating (consisting of Teflon) has insufficient strength.**
**Subsequent studies published in 1986 raise further concerns regarding the use of teflon in these applications. **

- September 11, 2001

## TMJ Implants

**Patients and physicians began reporting problems, including:**
**severe pain around the ear and in the jaw area**
**radiographic evidence of severe bone loss to the condyle and glenoid fossa**
**limited lower jaw movement**
**bone degeneration/soft tissue deterioration**
**joint noise in the jaw**
**nausea, dizziness or ringing in the ear**
**fragmentation and/or displacement of the implant**
**infection**
**vision and hearing problems**

- September 11, 2001

## TMJ Implants

**Complaints in conjunction with data published earlier led to these implants being taken off the market.**

- September 11, 2001

## TMJ Implants

**Could this have been avoided or prevented under current approach to Risk Management?**

- September 11, 2001

## As discussed in previous slides....

The degree to which safety considerations are addressed should be commensurate with the degree of the risk,  the nature of the device and the benefit to the patient.

Use of teflon in joint replacement was known to be problematic as early as 1963 – further research appears to have been indicated before starting production or placing on the market. 

**The degree to which safety considerations are addressed should be **_***commensurate with the degree of the risk***_**,  **_***the nature of the device***_** and **_***the benefit to the patient***_**.**
**Use of teflon in joint replacement was known to be problematic as early as 1963 – further research appears to have been indicated before starting production or placing on the market. **

- September 11, 2001

## Determination of acceptable levels of risk:
Known issues and published concerns regarding the use of teflon based materials in implants were not properly recognized during the development period. 

**Known issues and published concerns regarding the use of teflon based materials in implants were not properly recognized during the development period. **

- September 11, 2001

## Risk analysis
Known and published general hazards were not properly recognized

Intense “foreign body” reactions
Insufficient strength to withstand normal weight-bearing loads
Deterioration of bone and tissue
Intended as a long-term implant?

**Known and published general hazards were not properly recognized**
**Intense “foreign body” reactions**
**Insufficient strength to withstand normal weight-bearing loads**
**Deterioration of bone and tissue**
**Intended as a long-term implant?**

- September 11, 2001

## Risk estimation 
Overall activity appears to have been incomplete! 
Certain aspects not included in the Risk Analysis may have easily been .... 

For example:
Adverse tissue reactions caused by wear debris (concern published in 1963)
silicone rubber and Teflon-Proplast are not biologically acceptable implant materials in the functional TMJ (study published 1989)
Results of laboratory tests on IPIs (published in 1992) showed a service life of about three years. Intermediate and long-term survival of implant was uncertain.

**Overall activity appears to have been incomplete! **
**Certain aspects not included in the Risk Analysis may have easily been .... **
**For example:**
**Adverse tissue reactions caused by **_***wear debris***_** (concern published in 1963)**
**silicone rubber and Teflon-Proplast are not biologically acceptable implant materials in the functional TMJ (study published 1989)**
**Results of laboratory tests on IPIs (published in 1992) showed a service life of about three years. Intermediate and long-term survival of implant was uncertain.**

- September 11, 2001

## Determination of risk reduction measures:

Since not all risks were properly identified, risk reduction measures were not identified for key aspects!
Package insert states “Prognosis for the implant’s success beyond 3 years was unknown”

**Since not all risks were properly identified, risk reduction measures were not identified for key aspects!**
**Package insert states “Prognosis for the implant’s success beyond 3 years was unknown”**

- September 11, 2001

## Risk control and monitoring activities
Risk control measures taken by the firm as a result of post market information were limited to:
1988 – product distribution suspended
1990 – Company issues advisory letter to physicians

**Risk control measures taken by the firm as a result of post market information were limited to:**
**1988 – product distribution suspended**
**1990 – Company issues advisory letter to physicians**

- September 11, 2001

## This is a case where risk management:

**This is a case where risk management:**
**might have helped determine that teflon was not an appropriate material for TMJ implants. **
**might have helped the company recognize the problem with the product sooner, before thousands of patients received the implants. **

- September 11, 2001

## Thank you  on behalf of Study Group 3 and the GHTF for your time and attention.

Questions?

**Questions?**

- September 11, 2001

## APPENDIX

## Definitions

**Harm**
- physical injury or damage to the health of people, or damage to property or the environment [ISO/IEC Guide 51:1999, definition 3.1]
**Hazard**
- - potential source of harm [ISO/IEC Guide 51:1999, definition 3.5]
**Residual Risk**
- risk remaining after protective measures have been taken [ISO/IEC Guide 51:1999, definition 3.9]
**Risk**
- combination of the probability of occurrence of harm and the severity of that harm [ISO/IEC Guide 51:1999, definition 3.2]

- September 11, 2001

## Definitions

**Risk Analysis**
- systematic use of available information to identify hazards and to estimate the risk [ISO/IEC Guide 51:1999, definition 3.10]
**Risk Assessment**
- - overall process comprising a risk analysis and a risk evaluation [ISO/IEC Guide 51:1999, definition 3.12]
**Risk Control**
- process through which decisions are reached and protective measures are implemented for reducing risks to, or maintaining risks within, specified levels [ISO 14971:2000, definition 2.16]

- September 11, 2001

## Definitions

**Risk Evaluation**
- judgment, on the basis of risk analysis, of whether a risk which is acceptable has been achieved in a given context based on the current values of society [NOTE Based on ISO/IEC Guide 51: 1999, definitions 3.11 and 3.7]
**Risk Management**
- systematic application of management policies, procedures and practices to the tasks of analyzing, evaluating and controlling risk [ISO 14971:2000, definition 2.18]

- September 11, 2001

## Regulatory Links &Sources of Standards

- September 11, 2001

## Additional information

**European Medical Device Directive 93/42/EEC:**
- _[http://3.70.4.1/~qualsys/regulatory/MDD/1993L0042_consolid.](http://3.70.4.1/~qualsys/regulatory/MDD/1993L0042_consolid.pdf)__[pdf](http://3.70.4.1/~qualsys/regulatory/MDD/1993L0042_consolid.pdf)_
**European Medical Device Directive Guidance documents:**
- _[http://www.meddev.info](http://www.meddev.info/)_
**Canadian Medical Devices Regulations:**
- _[http://laws.justice.gc.ca/en/f-27/sor-98-282/126598.html](http://laws.justice.gc.ca/en/f-27/sor-98-282/126598.html)_
**Australian Medical Devices Regulations:**
- _[http://scaleplus.law.gov.au/html/pastereg/3/1762/top.htm](http://scaleplus.law.gov.au/html/pastereg/3/1762/top.htm)_
**Global Harmonization Task Force:**
- _[http://www.ghtf.org](http://www.ghtf.org/)_
**Japan MHLW:                                              **
- _[http://www.mhlw.go.jp/english/index.html](http://www.mhlw.go.jp/english/index.html)_
**China:**
**       ****CNCA: **  _[http://www.cnca.gov.cn/index.htm](http://www.cnca.gov.cn/index.htm)_ or _[http://www.cnca.gov.cn/download/english.html](http://www.cnca.gov.cn/download/english.html)_
**       ****SFDA:    **_**[http://www.sfda.gov.cn/eng/](http://www.sfda.gov.cn/eng/)**_

- September 11, 2001

## Additional information (cont.): 

**FDA:**
**General:**
- _[http://www.fda.gov](http://www.fda.gov/)_
**FDA site searchable for QSR and Electronic Records & Signature (21 CFR Parts 820 and 11)** :
- _[http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm)__[cfm](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm)_
**FDA Guidance documents**
- _[http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfGGP/Search.cfm](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfGGP/Search.cfm)_
**GEHC Internal sites:**
- Americas:	_[http://supportcentral.ge.com/products/sup_products.asp?prod_id=23217](http://supportcentral.ge.com/products/sup_products.asp?prod_id=23217)_
- Europe:   	_[http://gein.euro.med.ge.com/engineering/](http://gein.euro.med.ge.com/engineering/qualsys/)__[qualsys](http://gein.euro.med.ge.com/engineering/qualsys/)__[/](http://gein.euro.med.ge.com/engineering/qualsys/)_
- Asia:	_[http://3.28.123.6/free/qmc/qasr/newQASRasia/](http://3.28.123.6/free/qmc/qasr/newQASRasia/)_

- September 11, 2001

## Additional information (cont.)

**Council Directive 93/42/EEC** of 14 June 1993 concerning medical devices Official Journal L169, 12/07/1993 P. 0001 - 0043 can be found at:
- _[http://3.70.4.1/~qualsys/regulatory/MDD/1993L0042_consolid.](http://3.70.4.1/~qualsys/regulatory/MDD/1993L0042_consolid.pdf)__[pdf](http://3.70.4.1/~qualsys/regulatory/MDD/1993L0042_consolid.pdf)_
- Note: While Directives amending 93/42/EEC have been published (specifically Directive 98/79/EC
- Directive 2000/70/EEC, and Directive 2001/104/EEC), GE Healthcare Technologies does not currently manufacture products governed by these directives – GE Healthcare BioSciences might.
**Guidance on Technical Files** developed by the Co-ordination of Notified Bodies - Medical Devices (NB-MED) can be found at:
- _[http://www.meddev.info/_documents/R2_5_1-5_rev4.pdf](http://www.meddev.info/_documents/R2_5_1-5_rev4.pdf)_
**Guidance on “Essential Principles of Safety and Performance of Medical Devices**
**on a Global Basis“ **developed by Study Group 1 of the Global Harmonization Task Force** **can be found at:
- _[http://www.ghtf.org/sg1/inventorysg1/sg1-n20r5.pdf](http://www.ghtf.org/sg1/inventorysg1/sg1-n20r5.pdf)_

- September 11, 2001

## The International Electrotechnical Commission (IEC) is the leading global organization that prepares and publishes international standards for all electrical, electronic and related technologies. 
International Electromedical Commission (IEC)
Central Office of the IEC
3, rue de Varembe
P.O. Box 131
CH-1211 Geneva 20
Switzerland
Telephone:	(+41) 22 919 02 11
Fax:		(+41) 22 919 03 00
Web Site:	http://www.iec.ch

- International Electromedical Commission (IEC)
- Central Office of the IEC
- 3, rue de Varembe
- P.O. Box 131
- CH-1211 Geneva 20
- Switzerland
- Telephone:	(+41) 22 919 02 11
- Fax:		(+41) 22 919 03 00
- Web Site:	_[http://www.iec.ch](http://www.iec.ch/)_

- Sources of Standards - IEC

- September 11, 2001

## ISO is a non-governmental organization, consisting of a network of the national standards institutes of 148 countries, on the basis of one member per country, with a Central Secretariat in Geneva, Switzerland, that coordinates the system
International Organization for Standardization (ISO)
1, rue de Varembe
Case postale 56
CH-1211 Geneve 20
Switzerland
Telephone:	(+41) 22 749 01 11
Fax:		(+41) 22 733 34 30
e-mail:		central@iso.ch
Web Site:	http://www.iso.ch

- International Organization for Standardization (ISO)
- 1, rue de Varembe
- Case postale 56
- CH-1211 Geneve 20
- Switzerland
- Telephone:	(+41) 22 749 01 11
- Fax:		(+41) 22 733 34 30
- e-mail:		_[central@iso.ch](mailto:central@iso.ch)_
- Web Site:	_[http://www.iso.](http://www.iso.ch/)__[ch](http://www.iso.ch/)_

- Sources of Standards - ISO

- September 11, 2001

## CEN, the European Committee for Standardization, develops voluntary technical standards which promote free trade, the safety of workers and consumers, interoperability of networks, environmental protection, exploitation of research and development programs, and public procurement.
European Committee for Standardization (CEN)
Rue de Stassart, 36
B-1050 Brussels
Belgium
Telephone:	(+32) 2 550 08 11
Fax:		(+32) 2 550 08 19 
E-Mail:		infodesk@cenorm.be
Web Site:	http://www.cenorm.be/cenorm/index.htm

- European Committee for Standardization (CEN)
- Rue de Stassart, 36
- B-1050 Brussels
- Belgium
- Telephone:	(+32) 2 550 08 11
- Fax:		(+32) 2 550 08 19
- E-Mail:		_[infodesk](mailto:infodesk@cenorm.be)__[@cenorm.be](mailto:infodesk@cenorm.be)_
- Web Site:	_[http://www.cenorm.be/cenorm/index.htm](http://www.cenorm.be/cenorm/index.htm)_

- Sources of Standards - CEN

- September 11, 2001

## CENELEC is a non-profit technical organization set up under Belgian law and composed of the National Electrotechnical Committees of 28 European countries. CENELEC prepares voluntary electrotechnical standards. 

Comite Europeene de Normalisation Electrotechnique (CENELEC)
Rue de Stassart, 35
B-1050 Brussels
Belgium
Telephone:	(+32) 2 519 68 71
Fax:		(+32) 2 519 69 19
E-Mail:		info@cenelec.org
Web Site:	http://www.cenelec.org

- Comite Europeene de Normalisation Electrotechnique (CENELEC)
- Rue de Stassart, 35
- B-1050 Brussels
- Belgium
- Telephone:	(+32) 2 519 68 71
- Fax:		(+32) 2 519 69 19
- E-Mail:		_[info@cenelec.org](mailto:info@cenelec.org)_
- Web Site:	_[http://www.cenelec.org](http://www.cenelec.org/)_

- Sources of Standards - CENELEC

- September 11, 2001

## ASTM International develops voluntary technical standards for materials, products, systems, and services. 

American Society for Testing and Materials (ASTM)
100 Barr Harbor Drive
West Conshohocken, PA, 19428-2959 
USA
Telephone:	(610) 832-9500
Fax:		 (610) 832-9555
Web Site:	http://www.astm.org

- American Society for Testing and Materials (ASTM)
- 100 Barr Harbor Drive
- West Conshohocken, PA, 19428-2959
- USA
- Telephone:	(610) 832-9500
- Fax:		 (610) 832-9555
- Web Site:	_[http://www.astm.org](http://www.astm.org/)_

- Sources of Standards - ASTM

- September 11, 2001

## The American National Standards Institute (ANSI) is a private, non-profit organization (501(c)3) that administers and coordinates the U.S. voluntary standardization and conformity assessment system.

American National Standards Institute (ANSI)
1819 L Street, NW, Suite 600
Washington, DC 20036
USA
Telephone:	(202) 293-8020 
Fax:		(202) 293-9287 
Web Site:	http://www.ansi.org

- American National Standards Institute (ANSI)
- 1819 L Street, NW, Suite 600
- Washington, DC 20036
- USA
- Telephone:	(202) 293-8020
- Fax:		(202) 293-9287
- Web Site:	_[http://www.ansi.org](http://www.ansi.org/)_

- Sources of Standards - ANSI

- September 11, 2001

## The AAMI standards program consists of over 100 technical committees and working groups that produce Standards, Recommended Practices, and Technical Information Reports for medical devices.

Association for the Advancement of Medical Instrumentation (AAMI)
1110 North Glebe Road, Suite 220
Arlington, VA 22201-4795 
USA
Telephone:	(703) 525-4890 
Fax:		(703) 276-0793
Web Site:	http://www.aami.org

- Association for the Advancement of Medical Instrumentation (AAMI)
- 1110 North Glebe Road, Suite 220
- Arlington, VA 22201-4795
- USA
- Telephone:	(703) 525-4890
- Fax:		(703) 276-0793
- Web Site:	_[http://www.aami.org](http://www.aami.org/)_

- Sources of Standards - AAMI

- September 11, 2001

## NEMA provides a forum for the standardization of electrical equipment and develops technical standards.

National Electrical Manufacturers Association (NEMA)
1300 N. 17th Street, Suite 1847
Rosslyn, VA, 22209
USA
Telephone:	(703) 841-3200
Fax:		(703) 841-5900
E-Mail:		webmaster@nema.org
Web Site:	http://www.nema.org

- National Electrical Manufacturers Association (NEMA)
- 1300 N. 17th Street, Suite 1847
- Rosslyn, VA, 22209
- USA
- Telephone:	(703) 841-3200
- Fax:		(703) 841-5900
- E-Mail:		_[webmaster@nema.org](mailto:webmaster@nema.org)_
- Web Site:	_[http://www.nema.org](http://www.nema.org/)_

- Sources of Standards - NEMA

- September 11, 2001

## Underwriters Laboratories Inc. (UL) is an independent, not-for-profit product-safety testing and certification organization, as well as a developer of safety standards

Underwriters Laboratories, Inc.
333 Pfingsten Road
Northbrook, IL 60062-2096
USA
Telephone:	(847) 272-8800
Fax: 		(847) 272-8129
E-mail: 		northbrook@us.ul.com
Web Site:	http://www.ul.com

- Underwriters Laboratories, Inc.
- 333 Pfingsten Road
- Northbrook, IL 60062-2096
- USA
- Telephone:	(847) 272-8800
- Fax: 		(847) 272-8129
- E-mail: 		_[northbrook](mailto:northbrook@us.ul.com)__[@us.ul.com](mailto:northbrook@us.ul.com)_
- Web Site:	_[http://www.ul.com](http://www.ul.com/)_

- Sources of Standards - UL

- September 11, 2001

## Certification Accreditation Administration Of The People's Republic Of China (CNCA)
9A Madian Street
Haidian District
Beijing 100088 
China
Telephone:	(+86) 10 - 82260766 or 82262775
Fax:		(+86) 10 - 82260767
E-Mail:		webmaster@cnca.gov.cn
Web Site:	http://www.cnca.gov.cn

- 9A Madian Street
- Haidian District
- Beijing 100088
- China
- Telephone:	(+86) 10 - 82260766 or 82262775
- Fax:		(+86) 10 - 82260767
- E-Mail:		_[webmaster@cnca.gov.cn](mailto:webmaster@cnca.gov.cn)_
- Web Site:	_[http://www.cnca.gov.](http://www.cnca.gov.cn/)__[cn](http://www.cnca.gov.cn/)_

- Sources of Standards - CNCA

- September 11, 2001

## JISC consists of many national committees and plays a central role in standardization activities in Japan. 

Japanese Industrial Standards Committee (JISC)
1-3-1 Kasumigaseki
Chiyoda-ku
Tokyo 100-8901
Japan
Telephone:	not available at time of this writing
Fax:		not available at time of this writing
E-Mail:		jisc@meti.go.jp
Web Site:	http://www.jisc.go.jp/eng/

- Japanese Industrial Standards Committee (JISC)
- 1-3-1 Kasumigaseki
- Chiyoda-ku
- Tokyo 100-8901
- Japan
- Telephone:	not available at time of this writing
- Fax:		not available at time of this writing
- E-Mail:		_[jisc](mailto:jisc@meti.go.jp)__[@meti.go.jp](mailto:jisc@meti.go.jp)_
- Web Site:	_[http://www.jisc.go.jp/eng/](http://www.jisc.go.jp/eng/)_

- Sources of Standards - JISC

- September 11, 2001

## Quality Management Systems:History and Evolution

- Presented by Jan Welch
- U.S. Food and Drug Administration
- Center for Devices and Radiological Health

## Introduction

- Why comply with quality management system standard
- What is a quality management system?
- Evolution of quality practices

- September 11, 2001

## Why should a manufacturer comply with a quality management system standard?

- Provides high degree of assurance that manufacturer will consistently produce medical devices that:
- Are safe
- Perform as intended
- Comply with customer requirements
- Comply with regulatory requirements
- Have the appropriate degree of quality

- September 11, 2001

## What is a quality management system for medical devices?

- Based on ISO 9001, and contains additional requirements
- “Full” quality management system includes design and development (mandatory for highest risk devices)
- “Production” quality management covers all activities except design and development

- September 11, 2001

## Evolution of Quality – No Quality Efforts

- Design **** manufacture **** distribute **** Result: product may fail **** customer complains

- September 11, 2001

## Evolution of Quality – Quality Control

- Design **** manufacture **** test **** discard rejects **** distribute accepted product **** Results: Fewer failing product are distributed, but design problems may arise **** Customer complains. Manufacturer is unhappy about rejects and waste

- September 11, 2001

## Evolution of Quality – Quality Assurance & Good Manufacturing Practice (GMP)

- Design **** build quality into manufacturing steps **** control manufacture **** test **** discard rejects **** distribute accepted product **** Result: Fewer product rejects due to manufacturing. Manufacturer is happier, but design problems may still arise. Customer complains.

- September 11, 2001

## Evolution of Quality – Quality System

- Build quality into design **** build quality into manufacturing **** control manufacture **** Test **** Discard rejects **** Distribute accepted product **** Results: Better-designed products satisfy customers. Manufacturer is happy with fewer rejects and fewer customer complaints

- September 11, 2001

## Evolution of Quality – Quality Management Systems

- Management has greater commitment to and responsibility for:
- establishing effective quality system,
- providing adequate resources
- periodically evaluating quality system
- making changes and adjustments

- September 11, 2001

## Summary

- Why comply with a quality management system standard?
- What is a quality management system?
- Evolution of quality practices

- September 11, 2001

##  ISO13485:2003- An Overview -

**Gunter Frey**
**Member, SG3**
**NEMA**

## This presentation is based on

**ISO13485:2003, *****Medical devices - Quality management systems - Requirements for regulatory purposes***** **
**ISO/TR 14969, *****Medical devices - Quality management systems - Guidance on the application of ISO13485:2003***

- September 11, 2001

## This presentation focuses on the key sections of  ISO13485:2003:

- Section 4.0 - Quality Management System Requirements
- Section 5.0 - Management Responsibility
- Section 6.0 - Resource Management
- Section 7.0 - Product Realization
- Section 8.0 - Measurement, Analysis, and Improvement

- September 11, 2001

## Maintain Effectiveness of the Quality Management System (QMS)

***Measurement Analysis****** and****** Improvement***

***Resource******Management***

**Input**

**Output**

***Product***

- Feedback from Customers& RegulatoryAuthorities

***Management Responsibility***

- Process-oriented structure

- ISO 13485:2003 promotes a process approach when developing, implementing, and improving a QMS

**Requirements from Customers & Regulatory Authorities**

**Value-added activities**

**Information Flow**

- September 11, 2001

## 4. Quality Management System

- 4.1 - General requirements
- Implementation and maintenance of an effective QMS to provide medical devices meeting customer and regulatory requirements.
**Activities include:**
- internal audits, management review, corrective and preventive actions, independent external assessments, etc.
**Enables:**
- Response to external factors (regulatory requirements, customer feedback) and internal factors (personnel, facilities, processes, etc.)

- September 11, 2001

## 4. Quality Management System

- 4.2 - Documentation requirements
- what is to be done and by whom,
- when, where, and how it is to be done,
- what materials, equipment and documents are to be used,
- how an activity is to be monitored and measured, and
- records and files (such as Design History File, Technical File, Complaint File, device records, etc.)
- all the above documents MUST be controlled and retention periods defined!
**Examples:** Quality Manual, procedures, work instructions, flow charts, forms, templates, specifications, etc.

- September 11, 2001

## Applied QMS

**Any exclusions?**
**(Section 7 only!)***

**QMS**
**Manual**

**Quality System Procedures**

**Detailed Quality **
**Procedures / Work  **
**Instructions / Forms / Records**

**Quality**
**Policy**

**Procedures with Master List, etc.**

**Applied QMS**

***see next slides**

- September 11, 2001

## Product Realization - Exclusions

**Exclusions of design and development (7.3) from the QMS is allowed only if allowed by regulation. **
**See NOTE 2 of 7.1: **The organization** **_***MAY***_** **also apply the requirements given in 7.3 to the development of product realization processes.
- Organizations whose quality management systems** **exclude design and development control** **(7.3 of ISO 13485),** **are still** **_***required to comply with the product verification and validation requirements as specified in 7.1 of ISO 13485 dealing with product realization***_**. **In such organizations, the _***controls included in 7.3 should be considered for all changes made to the product***_. Such changes will require objective evidence (e.g., product verifications and validations, inspection and test specifications, revised procedures, etc.) of the results of the activities described in 7.3 of ISO 13485.

- September 11, 2001

## Product Realization - Non-applicability

**“****Non-inclusion” of product realization requirements is allowed if those functions are not required by the nature of the medical device being provided by the organization.**
- For example, an organization providing single-use, sterile medical devices may not need to include within its quality management system elements related to installation and servicing.

- September 11, 2001

## 5. Management Responsibility

- 5.1 Management commitment
- Is demonstrated by actions ensuring processes operate as an effective network of interrelated processes
**Accomplished by:**
- ensuring sequence & interaction of processes effectively achieve planned results,
- clear definition & control of process inputs, activities & outputs,
- monitoring inputs and outputs to verify processes are linked and operate effectively,

- September 11, 2001

## 5. Management Responsibility

- 5.1 Management commitment (cont.)
**Accomplished by:**
- identifying hazards and managing risks,
- data analysis to facilitate improvement of processes,
- identifying process owners with responsibility & authority, and
- managing each process to achieve the process objectives.

- September 11, 2001

## 5. Management Responsibility

- 5.2 Customer focus
- ensure customer requirements are understood
- availability of necessary resources to meet requirements
- (See also clauses 7.2.1 and 8.2.1 of ISO 13485)

- September 11, 2001

## 5. Management Responsibility

- 5.3 Quality policy
**Establishes commitment to:**
- quality
- continuing effectiveness of the quality management system
- meeting customer and regulatory requirements,
**Defines:**
- clear quality objectives for the business
- the relationship of these objectives to customers’ requirements.
**Should be reviewed periodically for continued applicability**

- September 11, 2001

## Case Study: Quality Policy

- The policy of Superior Devices, Inc., is to strive to sell products that satisfy our customers, comply with applicable standards and regulations, and reward employees who contribute substantially to our financial success with a share of our profits.
- Is this a good quality policy? Why or why not?

- September 11, 2001

## 5. Management Responsibility

- 5.4 Planning
**Includes:**
- setting quality objectives & associated targets for the _***quality management system***_ AND for _***medical devices & related services***_ (see 7.1 a)
- defining timeframes for achieving targets
- An organization's QMS is influenced by _***varying needs***_, _***particular objectives***_, the _***products provided***_, the _***processes***_ employed, the _***size & structure***_ of the organization, etc.

- September 11, 2001

## Important

- 5.4 Planning
**Important**
- ISO13485 does _**NOT**_ imply uniformity in the structure of quality management systems or uniformity of documentation!

- September 11, 2001

## 5. Management Responsibility

- 5.5 Responsibility, authority and communication
- Examples demonstrating Responsibility & Authority:
- documented position descriptions, including responsibilities and authorities
- organization charts
- can be included in documented procedures or flowcharts.
- Independence must be demonstrated for certain activities (e.g. internal audits, one design review participant; management representative)
- Above documents must be controlled (see 4.2.3).

- September 11, 2001

## 5. Management Responsibility

- 5.5 Responsibility, authority and communication
- One management representative - designated by top management!
- Functions can be entirely related to quality management system activities or in conjunction with other functions and responsibilities within the organization.
- If responsibility for other functions, ensure no conflict of interest between the responsibilities!

- September 11, 2001

## 5. Management Responsibility

- 5.5 Responsibility, authority and communication
- Within an effective quality management system communications must be:
- encouraged
- clear and understandable
- bi-directional
- at all levels of the organization
- open and active
**Examples:** Internal audits, external assessments, management reviews, bulletin boards, all employee meetings, suggestion boxes, etc.

- September 11, 2001

## 5. Management Responsibility

- 5.6 Management Review
- Periodic assessment of the QMS for continued suitability, adequacy and effectiveness. **Inputs include:**
- a) results of audits,
- b) customer feedback,
- c) process performance and product conformity,
- d) status of preventive and corrective actions,
- e) follow-up actions from previous management reviews,
- f) changes that could affect the quality management system,
- g) recommendations for improvement, and
- h) new or revised regulatory requirements.

- September 11, 2001

## 5. Management Responsibility

- 5.6 Management Review
**Outputs include:**
- agenda
- attendance record
- presentation materials
- improvements needed to maintain the effectiveness of the quality management system and its processes
- b) improvement of product related to customer requirements
- c) resource needs
- d) statement of conclusion the effectiveness of the quality management system

- September 11, 2001

## Case Study: Management Reviews  Part 1

- Perfect Devices, Inc., (PD) established their quality system 5 years ago, and things have been running smoothly. They have been producing the same devices for the past 5 years. The FDA inspection 6 months ago was NAI. PD performs management reviews annually.
- Is an annual management review sufficient?

- September 11, 2001

## Case Study: Management Reviews Part 2

- Superior Medical, Inc., (SM) established their quality system 5 years ago. This year’s production was double that of 5 years ago. Six months ago SM installed an ethylene oxide sterilization chamber and started distributing sterile devices. Several sterilization lots have failed. SM performs management reviews annually.
- Is an annual management review sufficient?

- September 11, 2001

## 6. Resource Management

- 6.1 Provision of resources
**Resources can be:**
- people
- infrastructure
- work environment
- information
- suppliers and partners
- natural resources
- financial resources
**Adequate resources are prerequisite to an effective QMS**

- September 11, 2001

## 6. Resource Management

- 6.2 Human Resources
- Personnel performing work affecting product quality and device safety and effectiveness must be competent ....
-    Qualifications include:
- Education
- Experience
- Skills
- _EFFECTIVE_ Training (initial and refresher)
- Formal certification (e.g. welding, soldering)
-    Organization must be able to demonstrate this!

- September 11, 2001

## 6. Resource Management

- 6.3 Infrastructure
**Includes:**
- Buildings
- Work space
- Utilities (water, electricity, waste management, etc.)
- Process equipment (software and hardware)
- Equipment maintenance activities & frequency
- Supporting services (cleaning, etc.)
- If not considered and appropriately defined, the above examples can potentially affect conformance with product requirements!

- September 11, 2001

## Case Study: Facilities

- Oops! An existing piece of equipment was moved to make room for some new equipment. When scheduled maintenance was due on the first piece of equipment, the maintenance man was unable to perform these tasks, as the equipment was too close to the wall. He got creative and suggested installing doors in the wall to allow access to that side of the equipment. This is an outside wall!
- Is this an acceptable solution? Why or why not?

- September 11, 2001

## 6. Resource Management

- 6.4 Work Environment
- The most significant factors within the work environment that can affect product quality are:
- process equipment,
- established work environment (controlled environments, clean rooms, etc.)
- personnel – internal _and __***external***_! (health, cleanliness, protective equipment/gear, i.e. static dissipating wrist bands, hoods & gowning, etc.)
- “Established” means defined, documented, implemented and maintained!

- September 11, 2001

## Case Study: Clean Rooms

- An electrical outlet in the clean room is not working, and an electrician has been called to replace it. SOPs (procedures) require employees who work in the clean room to wear a hair cover, face mask, shoe covers, lab coat and gloves.
- Should the electrician follow the same gowning procedures? Why or why not?

- September 11, 2001

## 7. Product Realization

- 7.1 Planning of product realization
- “Product realization” describes the processes starting with
- planning
- determination of customer requirements
- customer communication
- design and development (7.3),
- purchasing (7.4),
- production and servicing (7.5),
- control of monitoring and measuring devices (7.6)
- delivery of the medical device
- record keeping requirements

- September 11, 2001

## 7. Product Realization

- 7.1 Planning of product realization
- This includes:
- product quality objectives & requirements
- definition of medical device lifetime (record retention!)
- establishing processes & documents
- resource needs
- design and development (7.3),
- verification & validation
- monitoring and inspection
- test activities and product acceptance criteria
- RISK MANAGEMENT
- RECORDS

- September 11, 2001

## 7. Product Realization

- 7.2 Customer-related processes
- Focus is on product and services to be supplied. This includes requirements related to the product:
- design input/output for new product development,
- customer delivery expectations vs. delivery schedules
- customer feedback & communications relative to orders placed or product delivered
- regulatory or legal requirements
- design related factors included in customer orders
- unspecified customer expectations.

- September 11, 2001

## 7. Product Realization

- 7.2 Customer-related processes
- Review of product requirements prior to committing to supply:
- product requirements defined & documented
- resolution of contract/order discrepancies
- ensure ability to meet defined requirements
- Review of post-marketing product performance
- additional product information (e.g. service, additional applications, maintenance, upgrades)
- customer complaints
- advisory notices
- Again, records are key!

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
- Established procedures describing design processes and ALL design activities
- goals and objectives of the design and development program (i.e. what is to be developed, timeline, etc.)
- the markets intended
- identification of organizational responsibilities with respect to assuring quality during the design and development phase, to include interface with any suppliers
- identification of the major tasks by phases of the design
- expected outputs (deliverables and records) from each phase

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
- Established procedures describing design processes and ALL design activities (cont.)
- identification of appropriate existing and anticipated measurement & monitoring devices for development of product specifications, verification, validation and production related activities
- the selection of reviewers & composition of review teams
- planning transfer to production
- risk management activities
- supplier selection

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
**Design inputs** include:
- intended use of the device,
- Indications and contra-indications for use of the device,
- performance claims and performance requirements (including normal use, storage, handling and maintenance),
- user and patient requirements,
- physical characteristics,
- human factors/usability requirements,
- safety and reliability requirements,
- toxicity and biocompatibility requirements,

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
**Design inputs** (cont.):
- electromagnetic compatibility requirements,
- limits/tolerances,
- measurement and monitoring instruments,
- risk management or risk reduction methods
- reportable adverse events, complaints, failures for previous products,
- other historical data,
- documentation for previous designs,
- compatibility requirements with respect to accessories and auxiliary devices,

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
**Design inputs** (cont.):
- compatibility requirements with respect to the environment of intended use,
- packaging and labeling (including considerations to deter foreseeable misuse),
- customer/user training requirements,
- regulatory and statutory requirements of intended markets,
- relevant voluntary standards (including industry standards, national, regional or international standards, “harmonized” and other consensus standards),

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
**Design inputs** (cont.):
- manufacturing processes,
- sterility requirements,
- economic and cost aspects,
- lifetime of the medical device requirements, and
- need for servicing.

- September 11, 2001

## Case Study: Hospital vs. Home Use

- For several years Advanced Devices has been selling a patient monitor for use in the hospitals. Recently one of their salespeople suggested marketing the patient monitor for home use since patients are spending less and less time in the hospital.
- Will home use change the design input? Why or why not?

- September 11, 2001

## Case Study: Hospital vs. Home Use

- Considerations:
- User less skilled, no medical training
- Users impaired? Poor vision, poor manual dexterity?
- User environment different; electromagnetic interference from TV, cell phones, etc.
- Multiple users, etc.

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
**Design outputs** may include:
- specifications for raw materials, component parts and sub-assemblies,
- drawings and parts list,
- customer training materials,
- process and materials specifications,
- finished medical devices,
- product and process software,
- quality assurance procedures (including acceptance criteria),
- manufacturing and inspection procedures,

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
**Design outputs** (cont):
- work environment requirements needed for the device,
- packaging and labeling specifications,
- identification and traceability requirements (including procedures, if necessary),
- installation and servicing procedures and materials,
- documentation for submission to the regulatory authorities where the medical devices will be marketed, if appropriate, and
- a record/file to demonstrate that each design was developed and verified in accordance with the design and development planning

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
**Design reviews** may address the following questions:
- Do designs satisfy specified requirements for the product?
- Is the input adequate to perform the design and development tasks?
- Are product design and processing capabilities compatible?
- Have safety considerations been addressed?
- What is the potential impact of the product on the environment?
- Do designs meet functional and operational requirements, for example, performance and dependability objectives?

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
**Design reviews** (cont.):
- Have appropriate materials been selected?
- Have appropriate facilities been selected?
- Is there adequate compatibility of materials, components and/or service elements?
- Is the design satisfactory for all anticipated environmental and load conditions?
- Are components or service elements standardized and do they provide for reliability, availability and maintainability?
- Is there a provision in tolerances, and/or configuration, for interchangeability and replacement?

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
**Design reviews** (cont.):
- Are plans for implementing the design technically feasible (e.g. purchasing, production, installation, inspection and testing)?
- If computer software has been used in design computations, modeling or analyses, has the software been validated, authorized, verified and placed under configuration control?
- Have the inputs to such software, and the outputs, been appropriately verified and documented?
- Are the assumptions made during the design processes valid?

- September 11, 2001

## Case Study: Design Review

- Can a formal design review be conducted without holding a meeting?
- Would circulating design review issues and approving outcomes by e-mail or on paper be an acceptable alternative to holding a meeting?

- September 11, 2001

## Case Study: Design Review

- Nowhere in the standard or the guidance is it stated that a design review must be conducted by holding a meeting!
- If all design review requirements of the standard are met, the design review could take place by e-mail or review of paper summary.
- Design reviews conducted by e-mail or paper probably are best used for relatively simple reviews.

- September 11, 2001

## Case Study: Design Review

- Please keep in mind that additional requirements may exist for electronic records, as well as electronic signatures.
- If design reviews are conducted via e-mail or paper copy circulation, results of the review will still need to be documented. Documentation typically includes identifying attendees, which is best done by signatures next to printed name. Print a signature page from the e-mail, sign and scan it and retain in the Design History File.

- September 11, 2001

## Case Study: Design Review

- Persons making authorized entries on records or verifying such entries should do so in clear legible writing, and should confirm the entry by adding their initials, signature or equivalent, and the date (14969 guidance).

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
**Design verification** is necessary to ensure that the design outputs conform to specified requirements (design inputs).
- tests (bench tests, lab tests, chemical analysis, etc.)
- alternative calculations,
- comparison with proven design,
- inspections, and
- document reviews (e.g. specifications, drawings, plans, reports).

- September 11, 2001

## 7. Product Realization

- 7.3 - Design and development
**Design validation** goes beyond the technical issues of verifying output met input. It is intended to ensure that the medical device meets user requirements and the intended use.
- actual or simulated conditions
- consider capability and knowledge of user
- operating instructions
- compatibility with other systems
- the environment in which it will be used
- any restriction on the use of the product
- performed on production or production equivalent unit(s)
- If production equivalent – need to document why it is equivalent!

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
- Control of design and development changes
-    Product design may require change or modification for
-       many reasons.
-    Change can happen during or after the design phase
-    Changes may result from:
- design review
- design verification or validation
- omissions or errors during the design phase which have been identified afterwards

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
-    Changes may result from:
- difficulties in manufacturing, installation and/or servicing
- risk management activities,
- requests from the customer or supplier,
- changes required for corrective or preventive action
- changes needed to address safety, regulatory, or other requirements
- improvements to function or performance

- September 11, 2001

## 7. Product Realization

- 7.3 Design and development
-    When changes are necessary, evaluate effects on:
- product requirements and specifications
- intended use
- current risk assessment
- different components of the product or system
- manufacture, installation or use
- Verification and validation
- the regulatory status of the product

- September 11, 2001

## 7. Product Realization

- Supplier selection and control consists of:
- establishing criteria (product, parts, quality system, process controls, metrology, etc.)
- evaluating against those predetermined criteria
- selecting
- ongoing monitoring
- The extent depends on the nature and risk associated with the product or service, and includes outsourced processes.
- Purchasing should only occur from list of approved suppliers!

- September 11, 2001

## Case Study: Purchasing Controls

- Perfect Devices, Inc. is evaluating potential suppliers of a plastic resin for injection molded parts. Perfect contacted several potential suppliers to schedule audits to evaluate them, but two large firms have declined to be audited.
- What should Perfect Devices, Inc. do?
- Buy only from firms allowing audits?
- Find another way to evaluate large firms?
- Other alternatives?

- September 11, 2001

## 7. Product Realization

**Purchasing information d**escribes the product to be purchased in sufficient detail, such as:
- technical information and specifications,
- test and acceptance requirements,
- quality requirements for products, services, and outsourced processes,
- environmental requirements (in manufacturing, storage, transportation, etc.)
- regulatory requirements,
- certification requirements

- September 11, 2001

## Case Study: Incoming Acceptance - 1

- Perfect Devices, Inc. recently selected three new suppliers based on the following information:
- Aim To Please, Inc.: Supplier audit documented an excellent quality system.
- A-1 Plastics: Refused audit, highly recommended by other device manufacturers.
- OK Parts, Inc.: Sole source of component! Supplier audit: No quality system!
- Which approach to acceptance of incoming components would you recommend for each supplier?

- September 11, 2001

## Case Study: Incoming Acceptance - 2

- Aim to Please, Inc. - A-1 Plastics - OK Parts, Inc.
- From ANSI.ASQ Z1.4:
- “Tightened Inspection followed by normal inspection when 5 consecutive lots are acceptable
- “Normal Inspection” followed by reduced inspection and 10 consecutive lots are accepted and additional criteria in 8.3.3.b are met.

- September 11, 2001

## 7. Product Realization

**Purchasing information** (cont.):
- May also include:
- requirements for product approval and subsequent changes
- procedures, processes & equipment
- qualification of personnel
- QMS requirements
- method of communication
- responsibilities (special instructions, traceability & test records, record retention & retrievability, etc.)
- conditions for review & changes to purchasing agreement
**SUPPLIER RECORDS** and the **ORGANIZATION’S RECORDS**

- September 11, 2001

## 7. Product Realization

**Verification of purchased product **to ensure specified requirements are met:
- receiving Inspection (shipments are complete, properly identified, undamaged)
- product incoming inspection (100%, sampling, skip lot, etc.)
- certification of suppliers
- certificates of conformance or acceptance test reports from supplier
- Must be procedurally defined within the organization's QMS, ***including actions when requirements are not met***!
**Applies to *****ALL product received from ***
***outside the organization’s QMS***!

- September 11, 2001

## Records are key!

**Control of production and service** requires ***controlled conditions*** and includes many aspects:
- infrastructure (see 6.3)
- documentation and records (procedures, specifications, work instructions, test results, etc.)
- defined by _*impact on quality*_* & *_*regulatory requirements*_ as well as _*output from risk management activities*_
- suitable equipment (process, measurement, monitoring)
- activities for release, delivery, and post delivery, including traceability

- 7. Product Realization

- September 11, 2001

## Case Study: Installation Instructions

- Zap Em, Inc. manufactures linear accelerators for radiation therapy for cancer. Zap Em installs the equipment for a significant fee. Hospitals have requested installation instructions for self-installation. Zap Em says they would be glad to provide instructions and equipment if the hospital employees attend Zap Em’s 2 day installer training for $9,500.
- Is Zap Em entitled to withholding instructions from 3rd party installers unless they attend a training course?

- September 11, 2001

## 7. Product Realization

**Validation of processes for production & service** is required where the resulting output cannot be verified!
- defined criteria for review and approval of processes
- approval of equipment and ***personnel qualification***
- use of specific methods and procedures
- criteria for revalidation
- software used in automated processes **MUST **be validated

- September 11, 2001

## 7. Product Realization

**Validation of processes for production & service** (cont.)
- Process validation activities can be described in phases:
- definition, review and approval of equipment specifications
- installation qualification (IQ)
- operational qualification (OQ)
- performance qualification (PQ)
- Validation is a complex activity – SG 3 has developed specific guidance on this topic (GHTF/SG3/N99-10:2004).
- A  separate presentation “Process Validation Guidance” addresses this in greater detail.

- September 11, 2001

## 7. Product Realization

**Identification** is required throughout the product realization process. It includes:
- raw materials
- components
- finished medical devices
- This facilitates fault diagnosis in the event of quality problems and is a pre-requisites for traceability!
- Provisions for identifying & segregating returned medical devices from conforming product must also be established!

- September 11, 2001

## 7. Product Realization

**Traceability** means the ability to trace the history or location of a product or activity by recorded identification:
- forward to customers (also known as “device tracking”)
- backward to raw materials, components, processes used in manufacturing, calibration, etc.
- Example: trace a nonconformity back to it’s source and determine location of the remainder of the affected batch/series.
-    Particular requirements are defined for implantable devices!

- September 11, 2001

## 7. Product Realization

**Customer property** within the context of the standard is defined as property or assets owned by the customer and under control of the organization.
- Examples of such property are
- raw materials or components supplied for inclusion in product (including packaging materials),
- product supplied for repair, maintenance or upgrading,
- product supplied for further processing (e.g., packaging, sterilization or testing),
- customer intellectual property
- These must be properly identified, safeguarded, maintained, etc.

- September 11, 2001

## 7. Product Realization

**Preservation of product **applies throughout the product realization processes and includes storage, handling, transportation and delivery (may include installation).
- gloves, static-dissipative measure, gowning,
- temperature, humidity, dust (particle count),
- packaging
- method of transportation (air, sea, ground, environmentally controlled, etc.)
- To avoid damage, deterioration or contamination during handling, storage, distribution.

- September 11, 2001

## 7. Product Realization

- The standard explicitly refers to monitoring and measuring devices, **including software**. To ensure valid results, instruments shall be
- calibrated or verified at specified intervals (traceable to standard!)
- uniquely identified (traceability to products!)
- protected from damage/deterioration or inadvertent adjustment during storage and use
- Software used in the monitoring or measurement process must be validated!
- Exempt from  calibration may be: instruments used for indication only (not quantitative!), volumetric measurement glassware, etc.

- September 11, 2001

## 8. Measurement, analysis and improvement

- 8.1 General
- Monitoring and measurement processes are required to:
- ensure product conformance
- ensure conformance of the QMS
- maintain effectiveness of the QMS
- These processes include measurement and analysis of products AND processes.

- September 11, 2001

## 8. Measurement, analysis and improvement

- 8.2 Monitoring and Measurement
**Feedback** as key performance indicators of the QMS include:
- customer related information, post-market surveillance, etc.)
- internal & external audit results
- monitoring and measurement of processes (not limited to production processes but also QMS processes!)
- monitoring and measurement of product (may extend to point of installation!)

- September 11, 2001

## 8. Measurement, analysis and improvement

- 8.3 Control of nonconforming product
- This includes nonconforming product occurring in the organization’s own facilities as well as to nonconforming product **received** or **delivered** by the organization.
- determine product(s) affected
- identify the nonconforming product (at supplier, in house, in transit, at customer)
- document the existence and root cause of the nonconformity
- evaluate the nature of the nonconformity

- September 11, 2001

## 8. Measurement, analysis and improvement

- 8.3 Control of nonconforming product** **(cont.)
- determine and record disposition to be made,
- control (e.g. by physical segregation) the subsequent processing of the nonconforming product consistent with the disposition decision
- notify others as appropriate (regulatory authorities, customer, supplier, alternate manufacturing facilities, etc.)
- define and implement **corrective** and **preventive** actions
- assess the effectiveness of corrective and preventive actions

- September 11, 2001

## 8. Measurement, analysis and improvement

- 8.4 Analysis of data** **
- This includes determination, collection, and analysis of appropriate data to demonstrate the
- suitability and effectiveness of the QMS and
- to evaluate if improvement of the QMS effectiveness can be made.
- This encompasses supplier performance, product conformance, trends of processes & products, feedback, etc.
- The results of these activities should feed into management reviews as well considered for risk management activities.
- They also serve to identify opportunities for preventive actions.

- September 11, 2001

## Case Study: Data Analysis

- Which items below would be appropriate data sources to analyze to identify non-conforming product and quality problems?

- Incoming Acceptance
- 	Records
- Complaints
- Service Records
- Sales Figures
- Internal Audits
- Records of Installation

- Customer Lists
- Reports of external audits
- Personnel Records
- Lawsuits
- Finished device Acceptance
- 	Records
- In process Acceptance
- 	Records

- September 11, 2001

## Case Study: Data Analysis

- Which items below would be appropriate data sources to analyze to identify non-conforming product and quality problems?

**Incoming Acceptance **
**	****Records**
**Complaints**
**Service Records**
- Sales Figures
**Internal Audits**
**Records of Installation**

- Customer Lists
**Reports of external audits**
- Personnel Records
**Lawsuits**
**Finished device Acceptance **
**	****Records**
**In process Acceptance **
**	****Records**

- September 11, 2001

## 8. Measurement, analysis and improvement

- 8.5 Improvement
- This again covers a broad scope:
- continued suitability and effectiveness of the QMS
- documented complaint investigations and resulting actions
- product  advisory notices (field corrective actions, etc.) communicated to customers and (where applicable) to regulatory authorities

- September 11, 2001

## 8. Measurement, analysis and improvement

- 8.5 Improvement
**Corrective action **is intended to eliminate nonconformities with the intent to prevent recurrence. Nonconformities may be identified
- in the QMS
- on the product
- in manufacturing processes
- in metrology
- with training
- environmental conditions
- control of equipment
- with suppliers, etc.

- September 11, 2001

## 8. Measurement, analysis and improvement

- 8.5 Improvement
_***Effective***_ **corrective action** includes the following:
- clear and accurate identification of the nonconformity
- affected process(es) or procedure(s)
- identification of affected device(s) and recipient(s)
- identification of the root cause of the nonconformity,
- action required to prevent recurrence
- required approvals prior to taking action
- records that corrective action was taken as identified
- Effectiveness checks (likely to prevent recurrence, no new risks introduced by the corrective action, etc.)

- September 11, 2001

## 8. Measurement, analysis and improvement

- 8.5 Improvement
**Preventive action **is initiated to address _***potential***_ nonconformities. Sources to consider include information & data from:
- receiving and incoming inspection
- products requiring rework, reject or yield data
- customer feedback and warranty claims,
- process measurements,
- identification of results that are out-of-trend but not out-of-specification,
- suppliers performance
- service reports, and,
- concessions/deviations.

- September 11, 2001

## While the information covered during this session is based on ISO13485:2003 and ISO/TR14969, 
it essentially describes 
GOOD BUSINESS PRACTICES.

**it essentially describes **
**GOOD BUSINESS PRACTICES.**

- September 11, 2001

## If successfully implemented, the organization’s quality system will meet the requirements of the European Medical Device Directive (MDD 93/42/EEC).

- September 11, 2001

## For further guidance, please refer to 
ISO/TR 14969

Thank you  on behalf of Study Group 3 and the GHTF for your time and attention.

Questions?

**ISO/TR 14969**
**Thank you  on behalf of Study Group 3 and the GHTF for your time and attention.**
**Questions?**

- September 11, 2001

## APPENDIX

## Examples of Key Records				 

- Management Review (5.6.1)
- Education, training, skills and experience (6.2.2.e)
- Product realization processes (7.1.d)
- Product requirements review and action (7.2.2)
- Product requirements inputs (7.3.2)
- Design reviews and actions (7.3.4)
- Design verification and actions (7.3.5)
- Design validation and actions (7.3.6)
- Design changes (7.3.7)
- Design change reviews (7.3.7)

- September 11, 2001

## Examples of Key Records (cont.)				 

- Supplier evaluation and actions (7.4.1)
- Process validation (7.5.2)
- Traceability (7.5.3)
- Customer notification regarding damage to customer property (7.5.4)
- Production or service delivery, as determined to be necessary for special processes (7.5.2)
- Review of previous measuring results when measuring equipment is found not to conform to requirements (7.6)
- Calibration or verification (7.6)

- September 11, 2001

## Examples of Key Records (cont.)				 

- Product release authorization (8.2.4)
- Nonconformities and actions taken (8.3)
- Corrective actions taken (8.5.2 e)
- Preventive actions taken (8.5.3 d)

- Examples of Key Records (cont.)

- September 11, 2001

## Process Validation GuidanceGHTF/SG3/N99-10:2004Study Group 3

- Presented by Jan Welch
- U.S. Food and Drug Administration
- Center for Devices and Radiological Health

## Introduction

- Definitions
- How are processes validated?
- What processes must be validated?
- How to maintain state of validation
- Revalidation

- September 11, 2001

## 1.1  Purpose of Guideline

- To assist manufacturers in understanding quality management system requirements concerning process validation

- September 11, 2001

**Notes:**
Guidance contains general suggestions for carrying out process validation
The actual methods of process validation will vary depending on the type of manufacturing process.

## 1.2  Scope of Guideline

- Applicable to manufacturing, servicing and installation processes for medical devices
- Does not cover verification of design output or design validation

- September 11, 2001

## What is Process Validation?

- September 11, 2001

## Three Elements of Process Validation

- Verify that equipment is installed and operating properly   *(Installation Qualification) *
- Develop process that can produce product or result that meets all specifications *(Operational Qualification)*
- Verify that process can produce product or result that meets all specifications consistently over time   *(Performance Qualification)*

- September 11, 2001

## Steps in Validating a Process

- Develop validation protocol
- Conduct installation qualification
- Conduct operational qualification
- Conduct performance qualification
- Analyze results and reach conclusions

- September 11, 2001

## 2. Definitions

- September 11, 2001

## 2.4  Process Validation

- Establishing by *objective evidence* that a process *consistently* produces a result or product meeting its *predetermined requirements*.

- September 11, 2001

**Notes:**
Note that the definition talks about producing a result or product. 
A product can be a component or an assembly as well as a finished device
What do you think a result is?  (sterility, cleanliness of product or mfg. equip.)
This definition conveys several important concepts or ideas.
First, it calls for objective evidence. What do you do to get objective evidence that a product meets requirements? (test or inspect)
Second, it talks about meeting predetermined requirements. What do you think “predetermined requirements” means? [determined before you started the process validation study]
Meeting predetermined requirements also means the process is “capable.”
3rd, the definition says “consistently” . This means the process has long term stability.

## 2.6  Verification

- Confirmation by examination and provision of *objective evidence* that the specified requirements have been fulfilled.

- September 11, 2001

**Notes:**
Note that the definition does not include the term “consistently.”
It does include “Objective evidence” so what does that mean?
The definition talks about specified requirements being fulfilled. So we have some requirements or specifications for the outcome of the verification.
It looks like verification could give us an indication of the capability of a process but not the ------??? Long term stability of the process

## 2.5  Process validation protocol

- A document stating how validation will be conducted, including test parameters, product characteristics, manufacturing equipment, and decision points on what constitutes acceptable test results.

- September 11, 2001

## 2.1  Installation Qualification (IQ)

- Establishing by objective evidence that all key aspects of the process equipment and ancillary system installation adhere to the manufacturer’s approved specification and that the recommendations of the supplier of the equipment are suitably considered.

- September 11, 2001

**Notes:**
an initial qualification of the equipment used and provision of necessary services 

## Some IQ Considerations

- Equipment manufacturer’s recommendations
- Electricity: supply, reliability
- Water: supply, pressure, quality
- Air: pressure, quality
- Calibration: schedule, documentation
- Maintenance: schedule, procedures, documentation, spare parts

- September 11, 2001

## 2.2  Operational Qualification (OQ)

- Establishing by *objective evidence* process control limits and *action levels* which result in product that meets _*all *_predetermined requirements.

- September 11, 2001

**Notes:**
a demonstration that the process will produce acceptable results and establishment of limits (worst case) of the process parameters 

## Some OQ Considerations

- Establish:
- Procedure
- Process control limits
- Output specifications
- Alert levels and action levels
- Specifications for components, manufacturing materials

- September 11, 2001

**Notes:**
Explain difference between components and Mfg materials

## Some OQ Considerations

- Some environmental conditions that may affect process stability
- Temperature
- Humidity
- Light
- Particle count, contamination
- Other

- September 11, 2001

## 2.3  Performance Qualification (PQ)

- Establishing by objective evidence that the process, under *anticipated conditions*, *consistently* produces a product which meets _*all*_ predetermined requirements

- September 11, 2001

**Notes:**
establishment of long term process stability 

## Normal curve applied to histogram

- September 11, 2001

## Slide 175

- September 11, 2001

**Notes:**
1 characteristic measured for 7 runs or lots

## Slide 176

- September 11, 2001

**Notes:**
1 characteristic measured for 7 runs or lots

## Maintaining a State of Validation

- September 11, 2001

## 6.1 Monitor and control process

- Purpose: to ensure process remains within established parameters under anticipated conditions
- Investigate deviations from established parameters
- Take corrective action
- Consider whether revalidation is necessary

- September 11, 2001

## 6.2 Changes in process or product

- Evaluate changes in process, product, procedures, equipment, personnel, environment, etc. to determine effect of change
- Is revalidation necessary?
- How much revalidation is necessary to assure process is capable and stable?

- September 11, 2001

**Notes:**
Example: major repair to equipment, change key component of manufacturing equipment. 
Operate equipment; compare operation after repair with before repair

## Periodic revalidation

- Consider periodic revalidation where *cumulative* minor changes to process and raw materials may eventually affect process
- Sterilization processes typically are revalidated periodically (once a year) as specified in voluntary standards

- September 11, 2001

## Some reasons for revalidation

- Change in process that may affect quality or validation status
- Negative trend in quality indicators
- Change in the product design that affects the process
- Process is moved within facility or transferred from one facility to another
- Change in the application of the process

- September 11, 2001

## Using historical data for validation

- batch or lot records
- manufacturing log books
- test and inspection results
- control charts

- customer feedback
- field failure reports
- service reports
- audit reports
- generic feedback

-  Validation can be partially based on
-   accumulated historical manufacturing,
-   testing, control and other data
-  Sources of historical data:

- September 11, 2001

## Using historical data for validation

- All appropriate data must have been collected AND collected in a manner that allows adequate analysis
- Historical pass/fail manufacturing data usually is not adequate

- September 11, 2001

## Summary

- Definitions
- How are processes validated?
- What processes must be validated?
- How to maintain state of validation
- Revalidation

- September 11, 2001

## Process Validation GuidanceGHTF/SG3/N99-10:2004Study Group 3

- Presented by Jan Welch
- U.S. Food and Drug Administration
- Center for Devices and Radiological Health

## Introduction

- Definitions
- How are processes validated?
- What processes must be validated?
- How to maintain state of validation
- Revalidation

- September 11, 2001

## 1.1  Purpose of Guideline

- To assist manufacturers in understanding quality management system requirements concerning process validation

- September 11, 2001

**Notes:**
Guidance contains general suggestions for carrying out process validation
The actual methods of process validation will vary depending on the type of manufacturing process.

## 1.2  Scope of Guideline

- Applicable to manufacturing, servicing and installation processes for medical devices
- Does not cover verification of design output or design validation

- September 11, 2001

## What is Process Validation?

- September 11, 2001

## Three Elements of Process Validation

- Verify that equipment is installed and operating properly   *(Installation Qualification) *
- Develop process that can produce product or result that meets all specifications *(Operational Qualification)*
- Verify that process can produce product or result that meets all specifications consistently over time   *(Performance Qualification)*

- September 11, 2001

## Steps in Validating a Process

- Develop validation protocol
- Conduct installation qualification
- Conduct operational qualification
- Conduct performance qualification
- Analyze results and reach conclusions

- September 11, 2001

## 2. Definitions

- September 11, 2001

## 2.4  Process Validation

- Establishing by *objective evidence* that a process *consistently* produces a result or product meeting its *predetermined requirements*.

- September 11, 2001

**Notes:**
Note that the definition talks about producing a result or product. 
A product can be a component or an assembly as well as a finished device
What do you think a result is?  (sterility, cleanliness of product or mfg. equip.)
This definition conveys several important concepts or ideas.
First, it calls for objective evidence. What do you do to get objective evidence that a product meets requirements? (test or inspect)
Second, it talks about meeting predetermined requirements. What do you think “predetermined requirements” means? [determined before you started the process validation study]
Meeting predetermined requirements also means the process is “capable.”
3rd, the definition says “consistently” . This means the process has long term stability.

## 2.6  Verification

- Confirmation by examination and provision of *objective evidence* that the specified requirements have been fulfilled.

- September 11, 2001

**Notes:**
Note that the definition does not include the term “consistently.”
It does include “Objective evidence” so what does that mean?
The definition talks about specified requirements being fulfilled. So we have some requirements or specifications for the outcome of the verification.
It looks like verification could give us an indication of the capability of a process but not the ------??? Long term stability of the process

## 2.5  Process validation protocol

- A document stating how validation will be conducted, including test parameters, product characteristics, manufacturing equipment, and decision points on what constitutes acceptable test results.

- September 11, 2001

## 2.1  Installation Qualification (IQ)

- Establishing by objective evidence that all key aspects of the process equipment and ancillary system installation adhere to the manufacturer’s approved specification and that the recommendations of the supplier of the equipment are suitably considered.

- September 11, 2001

**Notes:**
an initial qualification of the equipment used and provision of necessary services 

## Some IQ Considerations

- Equipment manufacturer’s recommendations
- Electricity: supply, reliability
- Water: supply, pressure, quality
- Air: pressure, quality
- Calibration: schedule, documentation
- Maintenance: schedule, procedures, documentation, spare parts

- September 11, 2001

## 2.2  Operational Qualification (OQ)

- Establishing by *objective evidence* process control limits and *action levels* which result in product that meets _*all *_predetermined requirements.

- September 11, 2001

**Notes:**
a demonstration that the process will produce acceptable results and establishment of limits (worst case) of the process parameters 

## Some OQ Considerations

- Establish:
- Procedure
- Process control limits
- Output specifications
- Alert levels and action levels
- Specifications for components, manufacturing materials

- September 11, 2001

**Notes:**
Explain difference between components and Mfg materials

## Some OQ Considerations

- Some environmental conditions that may affect process stability
- Temperature
- Humidity
- Light
- Particle count, contamination
- Other

- September 11, 2001

## 2.3  Performance Qualification (PQ)

- Establishing by objective evidence that the process, under *anticipated conditions*, *consistently* produces a product which meets _*all*_ predetermined requirements

- September 11, 2001

**Notes:**
establishment of long term process stability 

## Normal curve applied to histogram

- September 11, 2001

## Slide 203

- September 11, 2001

**Notes:**
1 characteristic measured for 7 runs or lots

## Slide 204

- September 11, 2001

**Notes:**
1 characteristic measured for 7 runs or lots

## Maintaining a State of Validation

- September 11, 2001

## 6.1 Monitor and control process

- Purpose: to ensure process remains within established parameters under anticipated conditions
- Investigate deviations from established parameters
- Take corrective action
- Consider whether revalidation is necessary

- September 11, 2001

## 6.2 Changes in process or product

- Evaluate changes in process, product, procedures, equipment, personnel, environment, etc. to determine effect of change
- Is revalidation necessary?
- How much revalidation is necessary to assure process is capable and stable?

- September 11, 2001

**Notes:**
Example: major repair to equipment, change key component of manufacturing equipment. 
Operate equipment; compare operation after repair with before repair

## Periodic revalidation

- Consider periodic revalidation where *cumulative* minor changes to process and raw materials may eventually affect process
- Sterilization processes typically are revalidated periodically (once a year) as specified in voluntary standards

- September 11, 2001

## Some reasons for revalidation

- Change in process that may affect quality or validation status
- Negative trend in quality indicators
- Change in the product design that affects the process
- Process is moved within facility or transferred from one facility to another
- Change in the application of the process

- September 11, 2001

## Using historical data for validation

- batch or lot records
- manufacturing log books
- test and inspection results
- control charts

- customer feedback
- field failure reports
- service reports
- audit reports
- generic feedback

-  Validation can be partially based on
-   accumulated historical manufacturing,
-   testing, control and other data
-  Sources of historical data:

- September 11, 2001

## Using historical data for validation

- All appropriate data must have been collected AND collected in a manner that allows adequate analysis
- Historical pass/fail manufacturing data usually is not adequate

- September 11, 2001

## Summary

- Definitions
- How are processes validated?
- What processes must be validated?
- How to maintain state of validation
- Revalidation

- September 11, 2001

## GHTF SG3 Session Overview 

**GHTF SG3 Session Overview**** **

- September 11, 2001