# Presentation: 257771

## Latin America APEC Funded Medical Device Regulatory Seminar

## Overview of the Global Harmonization Task Force (GHTF)

## Trainers

- Center for Devices & Radiological Health
- U.S. Food and Drug Administration
- Tim Missios
- Canadian Industry (MEDEC) Representative
- Boston Scientific Corporation
- Bob Turocy
- NEMA – US Industry Representative
- Philips Medical Systems (Cleveland), Inc.

**Trainers**

## Introduction

- Brief History/Goal
- Steering Committee
- FIVE (5) STUDY GROUPS (SGs)
- SG4 Auditing

## Brief History/Goal

- Established 1992
- USA, EC, JA, AU, & CA
- International Partnership
- Harmonize Regulatory Practices

## GHTF Goals

- “The purpose of the GHTF is to encourage convergence in regulatory practices related to ensuring the safety, effectiveness / performance and quality of medical devices, promoting technological innovation and facilitating international trade, and the primary way in which this is accomplished is via the publication and dissemination of harmonized guidance documents on basic regulatory practices. These documents, which are developed by five (5) different GHTF Study Groups, can then be adopted/implemented by member national regulatory authorities.”

**Notes:**
 GHTF was founded in the early ‘90s for the purpose of harmonizing the way member countries regulate medical devices
 The guidance documents developed to promote this harmonizing among member countries are also useful to other countries that wish to regulate medical devices.

## Benefits of GHTF

**Benefits of GHTF**

## GHTF MEMBERSHIP Represents: 

**GHTF MEMBERSHIP Represents:**** **
**Regulatory authorities **
**Industry**

- From the five founding countries
- Australia - Canada
- European Union  - Japan
- United States of America

## GHTF Structure

- Steering Committee:
- regulatory and industry members from each founding _geographic area_
- Study Groups
- 5 study groups

## Steering Committee

- Provides Policy Direction
- Strategic Planning
- Assign & Provide Oversight  Of Technical Work Initiatives
- Decision on SG Actions

## Study Group 1

- Study Group 2

- Study Group 3

- Study Group 4

**Focus: Regulatory Requirements for Premarket Review**
**Chair: ****Ginette Michaud, M.D.**

**Focus: Medical Device Vigilance/ Post-Market Surveillance**
**Chair: ****Jorge Garcia - Australia**

**Focus: Quality System Requirements and Guidance**
**Chair: ****Alain Prat****European and International Affairs**

**Focus: Regulatory Auditing of Medical Device Manufacturers**
**Chair: Dr. Horst Frankenburger – Europe**

- Steering Committee

**Focus: Clinical Safety & Performance**
**Chair: Dr Graeme Harris-Australia**

- Study Group 5

## GHTF

- GHTF welcomes observers from  other countries!

**Notes:**
 Other countries are welcome to participate in Global Harmonization Activities.
 The study group I belonged to had visitors from Israel, China, Korea, Switzerland, Brazil and Taiwan, 

## How to Participate in GHTF

- Check GHTF web site for new guidance documents
- Comment on proposed guidance
- Adopt final guidance documents as appropriate
- Attend GHTF conferences

## Additional Information - GHTF 

- Visit the GHTF web site at:  www.ghtf.org
- Website includes:
- Steering Committee & procedures documents
- Study group guidance documents & membership
- Discussions from past GHTF conferences
- Upcoming Meetings and strategic plan 2005-2007

## GHTF SG4 

- APEC 2006

**AUDITING **
- May 9- 12, 2006

## Agenda

- Goals of SG 4 – Auditing
- SG 4 Membership
- Definitions of terms
- Summary of guidance documents

## GHTF SG 4 “Auditing” -  Purpose

**Purpose of Study Group SG4 **
**Guidance to Regulatory Audit Organizations, ****Auditors and Manufacturers of Medical Devices**
-   „SG4 has been charged with the task of examining quality system auditing practices (initially among the founding members of the GHTF) and developing guidance documents laying harmonized principles for the medical device auditing process“

## Goals of GHTF SG 4

- Provide guidance for regulatory auditing of medical device manufacturers’ quality systems
- Improve the effectiveness of regulatory audits
- Promote greater uniformity in the way regulatory bodies throughout the world conduct audits

## SG 4 Current Membership

- U.S. (3)
- Regulatory (2)
- Industry (1)
- Canada (2)
- Regulatory (1)
- Industry (1)
- Australia (1)
- Regulatory (1)

- Europe (6)
- Regulatory (1 )
- Industry (3 – **SG4 Chair & Secretary**)
- EU Notified Bodies (2)
- Japan (4)
- Regulatory (2)
- Industry (2)

**Notes:**
Total Regulatory: 7
Total industry: 7
EU Notified Bodies: 2

## Guidelines for
Regulatory Auditing
of Quality Management Systems of Medical Device Manufacturers - Part 1- General Requirements
 Four Supplements to document
GHTF.SG4.(99)28

**Regulatory Auditing**
**of Quality Management Systems of Medical Device Manufacturers - Part 1- General Requirements**
** ****Four Supplements to document**
**GHTF.SG4.(99)28**

**SG 4 – Five Final Guidance Documents**

## 
SG4(99)28, Guidelines for Regulatory Auditing
of Quality Systems of Medical Device Manufacturers
 Part 1: General Requirements

SG4(99)14, Supplement 1:
    Audit Language Requirements

SG4(00)3, Supplement 3:
    Training Requirements for Auditors

SG4-N(99) 24 R3, Supplement 4:
    Compilation of Audit Documentation

SG4 N26 R1,Supplement No. 6 
Observed Audits of Conformity Assessment Bodies

- SG4(99)28, Guidelines for Regulatory Auditing
- of Quality Systems of Medical Device Manufacturers
-  Part 1: General Requirements
- SG4(99)14, Supplement 1:
-     Audit Language Requirements
- SG4(00)3, Supplement 3:
-     Training Requirements for Auditors
- SG4-N(99) 24 R3, Supplement 4:
-     Compilation of Audit Documentation
- SG4 N26 R1,Supplement No. 6
- Observed Audits of Conformity Assessment Bodies

**SG 4 – Five Final Guidance Documents**

## SG 4 – One Proposed Guidance Document

- SG4/N30 R 18:
- Guidelines for
- Regulatory Auditing
- of Quality Management Systems of
- Medical Device Manufacturers
- Part 2: Regulatory Auditing Strategy

## SG 4 – Guidance Documents Under Development

- SG4/N33: Part 3: Audit Reports

## SG 4 Final Guidance GHTF SG4 (99)28: Guidelines forRegulatory Auditingof Quality Management Systems of Medical Device Manufacturers Part 1- General Requirements 

## SG 4 – Main Guidance Document

- Guidelines for Regulatory Auditing of Quality Systems of Medical Device Manufacturers: General Requirements
- Contains general principles and guidance for managing and conducting regulatory audits
- Other guidance documents supplement it

## Part 1: General Requirements

- Scope:
- Guidelines for auditing organisations
- Competence criteria for the *audit* team
- Requirements for the *audit* report and follow-up on corrective actions

## General Requirements: Definitions

## Audit

- A systematic and independent examination to determine whether quality activities and related results comply with planned arrangements and whether these arrangements are implemented effectively and are suitable to achieve objectives       [ISO 8402]  			*More . . .*

## For the purpose of these guidelines, "audit" means audit of the auditee’s quality system to determine compliance with the relevant regulatory requirements

**Audit cont’d**

## Any organisation whose quality systems are to be audited for compliance with the relevant medical device regulatory requirements
Note.  This can be the manufacturer and/or their subcontractor(s)

*Note.  This can be the manufacturer and/or their subcontractor(s)*

**Auditee**

## Auditing Organization

- A body designated, on the basis of specific regulations, to carry out *audits* according to assigned tasks

## Auditor

- A person with relevant qualifications and competence to perform *audits* or specified parts of such *audits* and who belongs to, or is authorised by, the *auditing organisation*

## Manufacturer

- The legal entity subject by regulation to *quality system* requirements
*Note 8.  In several international standards the term 'supplier' is substituted for the term 'manufacturer'*

## Nonconformity

- The non-fulfilment of specified requirements within the planned arrangements
- Other terms with the same meaning as *nonconformity *are “non‐compliance” and “deficiency”

## Quality System

- The organisational structure, responsibilities, procedures, processes and resources for implementing quality management 	    [ISO 8402].
- For the purpose of these guidelines 'implementing quality management' is taken to include both the establishment and maintenance of the system

## Regulatory Requirements

- For the purpose of these Guidelines any part of a law, ordinance, decree or other regulation which applies to *quality systems* of medical device manufacturers

**Notes:**
Note 11.   Guidelines, notes, draft documents, or the like should not be used as regulatory documents and are not to be construed as such unless formally promulgated

## General Requirements:Important Principles for Regulatory Auditing

## Independence of Auditors

*Auditing organisations* and *auditors* shall be impartial and free from engagements and influences which could affect their objectivity

## Independence of Auditors

*Auditing organisations* and *auditors* shall _not_ be:
- Involved in design, construction, marketing, installation, servicing or  supply of devices being audited
- Involved in design, construction, implementation or maintenance of *quality system* being audited
- An authorised representative of the *manufacturer*

## Responsibility for Quality System

*Audits* _do not_ result in a transfer of the responsibility for implementing an effective *quality system* from the *manufacturer* to the *auditing organisation**	**	**	**	**	**	**	**	**More . . .*

## Responsibility for Quality System

- The *manufacturer* is ultimately responsible for implementing and maintaining an effective *quality system* and taking necessary corrective and preventive actions

## General Requirements: Other Elements of Managing the Audit Process

## Audit Objectives and Scope

- Should be:
- Clearly defined and documented by the *auditing organisation* and the *audit* team
- Agreed to by the *manufacturer,* as permitted by *regulatory requirements*
- May be modified, based on the quality *audit *observations

## Types of Audits

- Initial *audit*
- Surveillance *audit*
- Special *audit*
- Unannounced *audit*

## Initial Audit

- First *audit* of *manufacturer*
- All elements of *quality system* should be audited

## Surveillance Audit

*Manufacturer* has been audited previously
*Audit* may cover complete *quality system* or only part of it

## Surveillance Audit

- Interval between surveillance audits is determined by:
- Risk associated with intended use of the medical devices
- Number of *quality system* elements to be examined
- Nature of *quality system* elements to be examined
- Scope and results of previous *audits*
- Any post market surveillance data indicating a possible deficiency in *quality system*

## Special audit

- An *audit* conducted when:
- Post-market surveillance data indicate a possible significant deficiency in the *quality system*
- Significant safety related information is obtained from another source
- Significant changes occur to a *manufacturer*, which could affect the decision on the *manufacturer*'s state of compliance with the *regulatory requirements*

## Unannounced Audit

- An unannounced *audit* may be conducted when the* auditing organization* has justifiable concerns about the *manufacturer’s *implementation of corrective actions or compliance with *regulatory requirements*

## SG 4 Final Guidance  SG4(99)14, Supplement 1:Audit Language Requirements 

## Audit Language Requirements 

**Purpose:** To assure that *auditors* and the *auditee *are able to communicate clearly during an audit
- Before the audit, determine if *auditors *and *auditee* have a common language
- Arrange for an interpreter if there is no common language

## SG 4 Final Guidance SG4(00)3, Supplement 3:Training Requirements for Auditors

## Training Requirements for Auditors 

**Scope:** The document describes training elements required to:
- Prepare an individual to be an auditor
- Qualify auditors to conduct regulatory audits of medical device manufacturers’ quality systems
- Maintain auditor qualifications

## Training Topics to Prepare an Individual to Be an Auditor

- Principles and applications of quality systems and auditing
- Interviewing people
- Collecting, documenting and reporting quality audit observations and non-conformities
- Auditing organization’s policies and procedures

## Training Topics to Qualify Auditors to Conduct Regulatory Audits 

- Understanding, applying and enforcing laws and *regulatory requirements*
- The role of the *auditing organization*
- Principles and applications of *quality systems* and auditing for medical device *manufacturers    *

## Training Topics to Qualify Auditors to Conduct Regulatory Audits

- Overview of medical devices, their intended uses, safety and risks
- Overview of processes commonly used to design and manufacture medical devices

## Training Topics to Qualify Auditors to Conduct Regulatory Audits

- Special training on specific topics such as sterilization processes and in–vitro diagnostics
- On–the-job or practical training in conducting *audit*s

## Training to maintain auditor qualifications

- Training courses
- Scientific meetings
- Independent study

**Notes:**
Purpose: to ensure timely awareness of new or modified regulatory requirements, policies, procedures, etc., as well as emerging technologies

## Assuring that Auditors are Qualified

- Experienced *auditor *should observe and evaluate *auditor-*in-training conducting one or more audits
*Auditors* should be judged competent to conduct *audits* before they are allowed to work without supervision
*Auditors *should be judged competent to *audit *highly specialised technologies before they are allowed to work without supervision

## SG 4 Final Guidance  SG4-N(99) 24 R3, Supplement 4:Compilation of Audit Documentation

## Compilation of Audit Documentation

**Purpose/Scope:** Provides guidelines for compiling audit documentation within auditing organization for internal use
- This document does not address the exchange of audit documentation between auditing organizations

## SG 4 Final Guidance SG4 N26 R1,Supplement No. 6 Observed Audits of Conformity Assessment Bodies

## Observed Audits of Conformity Assessment Bodies 

**Purpose:** Sets out guidance for observing audits conducted by Conformity Assessment Bodies (CABs).
- Observing audits enables a regulatory authority to evaluate the adequacy of the CAB’s audits

## Remember:

 To audit = to listen    > need to understand language!
 Only trained auditors will do a good job!
 No job is finished until the paperwork is   done!

-  To audit = to listen    > need to understand language!
-  Only trained auditors will do a good job!
-  No job is finished until the paperwork is   done!

## Common understanding how to audit manufacturer <> auditing organisation
Alignment of procedures between auditing organisations 
Improvement of audit quality

- stated in document GHTF.SG4.(99)28**  **

- Common understanding how to audit manufacturer <> auditing organisation
- Alignment of procedures between auditing organisations
- Improvement of audit quality

## SG 4 Proposed Guidance  SG4/N30 R 18: Guidelines forRegulatory Auditingof Quality Management Systems of Medical Device Manufacturers Part 2: Regulatory Auditing Strategy Proposed Final Document to Steering Committee: June 2006

## Regulatory Auditing: 

**Regulatory Auditing: **
**ISO13485:2003 & 21CFR 820**

## Auditing Strategy

**Purpose:** to provide guidance on how to audit quality systems for conformance with regulatory requirements
- Having a consistent approach for auditing that GHTF members agree upon can encourage members to rely on one another’s audits
- Promote audit consistency – a necessity for harmonization and mutual recognition of audit results.

## Auditing Strategy

- Introduction, Scope, References, & Definitions
- General Remarks
- Auditing Sub-systems
- Appendices

## Scope

- ISO 13485:2003 & 21 CFR 820
- Risk Management
- Software, Human Factors
- Additional Regulatory Requirements
- Initial & Surveillance Audits

## References

- GHTF/SG4/N28R2
- GHTF/SG1/011R16
- 21 CFR 820
- QSIT
- 21 CFR 803, 806, & 821
- ISO 13485:2003
- ISO 19011:2002
- ISO/TC 210/WG1 N62

- ISO/IEC GUIDE 62:1996 & APPLIC.
- ISO 14971:2000
- GHTF SG3/N99-8
- GHTF SG3/N99-9
- GHTF SG3/N99-10
- GHTF SG3/N15 R6

## Definitions

- Audit
- Regulatory Audit
- Audit Criteria
- Audit Evidence
- Technical Files

- Medical Device
- Process
- Regulatory Requirements
- Establish
- Risk Mgt

## General Remarks

- Objectives
- Systems & Sub-systems
- Audit Approaches
- Process Based Auditing
- Sampling
- Planning - Audit Frequency and Duration
- Logistics
- Linkages

## Objectives of a Regulatory Audit

-  	Process-orientation of the audit – according to 	ISO 13485:2003
-  	Audit with a focus on key processes
-  	Transparency of the audit to the auditee
-  	Similiarity of the audit process and results – 	regardless of which audit organization and 	individual auditors conduct the audit

**Objectives of a Regulatory Audit**

## Auditing Sub-systems

- Subsystems have been identified – associated with clauses of ISO 13485:2003 and sections of 21 CFR Part 820
- Subsystems based in part on the **Q**uality **S**ystem **I**nspection **T**echnique (QSIT): Management, Design and Development, Production Processes Controls, Corrective and Preventive Actions
- GHTF SG4 has identified additional subsystems: Product Design Documentation, Purchasing Controls, Documentation and Records, Customer requirements

## Auditing sub-systems

- Management
- Design and Development
- Production Design Documentation
- Production & Processes Controls
- Corrective and Preventive Actions
- Purchasing Controls
- Documentation and Records
- Customer Requirements

## Auditing sub-systems (cont’d)  

**	****GOAL:** The purpose of the management subsystem audit is to evaluate whether top management ensures that an adequate and effective quality system has been established and maintained.

**Auditing sub-systems (cont’d)  **

## Auditing sub-systems (cont’d)

**Design and Development**
**	****GOAL:** The purpose of auditing the design and development subsystem is to determine whether the design process is controlled to ensure that devices meet user needs, intended uses and specified requirements.

## Auditing sub-systems (cont’d)  

-     Production Design Documentationis to confirm that the manufacturer has taken the necessary steps to ensure that products will be safe and effective.

**Auditing sub-systems (cont’d)  **

## Auditing sub-systems (cont’d)  

**Auditing sub-systems (cont’d)****  **

## Auditing sub-systems (cont’d)  

**Auditing sub-systems (cont’d)****  **

## Auditing sub-systems (cont’d)  

**	****GOAL:** The purpose of auditing the purchasing control activities is to ensure that products, components, materials and services supplied by suppliers, (including contractors and consultants) are in conformity. This is particularly important when the finished product or service cannot be verified by inspection (e.g. sterilisation services).This subsystem should be considered a main subsystem for “virtual manufacturers”.

**Auditing sub-systems (cont’d)****  **

## Auditing sub-systems (cont’d)  

**Auditing sub-systems (cont’d)****  **

## Auditing sub-systems (cont’d)  

**Auditing sub-systems (cont’d)****  **

## Audit Approaches

- Top-down approach
- Bottom-up approach
- Combination of these two approaches
- Horizontal Approach

## Process Based Auditing

- Check if all subsystems and processes of the quality management system are structured as a self-regulating control process – for example according to Deming‘s PDCA cycle: **P**lan, **D**o, **C**heck, **A**ct

**Process Based Auditing****  **

## Process Based Auditing  

**OUTPUT**

**MEASURE, MONITOR, ANALYZE, CAPA**

**TRANSFORM**

**Process Based Auditing****  **

## Plan, Do, Check, Act

- Has the manufacturer established the objectives and processes to enable the quality system to deliver the results in accordance with the regulatory requirements?
- Has the manufacturer implemented the quality system and the processes?
- Has the manufacturer checked process monitoring and measurement results against the objectives and the regulatory requirements? Does the manufacturer evaluate the effectiveness of the quality system periodically through internal audits and management reviews?
- Has the manufacturer implemented effective corrective and preventive actions? Confirm that the company is committed to providing high quality safe and effective medical devices, and that the company is conforming with applicable laws and regulations.

## 	Deming - PDCA - Cycle

**D****O**
**PROCESS****PARAMETER**

**C****HECK****OUTPUT****PARAMETER**

**A****CT/CORRECT****CONTROL****PARAMETER**

**P****LAN****INPUT****PARAMETER**

** ****OBJECTIVES**

**FULFILMENT**

## Regulatory Audit of the Quality System                               

**Regulatory Audit of the Quality System****                               **

**Start - Management controls - Stop**

**Process management**

- Design controls

- Production and process controls

- Records, documents,
- change controls

**CAPA**

- Material controls

**ACT**

**PLAN**

**DO**

**CHECK**

## QSIT QUALITY AUDIT

**QSIT QUALITY AUDIT**

- DESIGN CONTROLS

- PLAN

- DO

- CHECK

- ACT CAPA

- PLAN

- DO

- CHECK

- ACT CAPA

- PLAN

- DO

- CHECK

- ACT CAPA

- MANAGEMENT CONTROLS

- CORRECTIVE & PREVENTIVE ACTIONS CAPA

- MEDICAL DEVICE REPORTING

- REPORTS OF CORRECTIONS & REMOVALS

- MEDICAL DEVICE TRACKING

## Appendix 1 - Sampling

- Binomial Sampling Plans
- CONFIDENCE LIMIT 95% Or 99%

## TABLE 1BINOMINAL STAGED SAMPLING PLANSBINOMAL CONFIDENCE LEVELS*ucl = Upper Confidence Level

**Confidence Limits .95<**

**0 out of:**

**1 out of****:**

**2 out of:**

**A**

**B**

**C**

**D**

**E**

**TABLE 1****BINOMINAL STAGED SAMPLING PLANS****BINOMAL CONFIDENCE LEVELS*****ucl = Upper Confidence Level**

**F**

**.****30**** ****ucl***

**.25 ucl**

**.20 ucl**

**.****15**** ****ucl**

**.10 ucl**

**.****05**** ****ucl**

**11**

**13**

**17**

**23**

**35**

**72**

**17**

**20**

**26**

**35**

**52**

**115**

**22**

**27**

**34**

**46**

**72**

**157**

## TABLE 2BINOMINAL STAGED SAMPLING PLANSBINOMAL CONFIDENCE LEVELS*ucl = Upper Confidence Level

**Confidence Limits .99<**

**0 out of:**

**1 out of****:**

**2 out of:**

**A**

**B**

**C**

**D**

**E**

**TABLE 2****BINOMINAL STAGED SAMPLING PLANS****BINOMAL CONFIDENCE LEVELS*****ucl = Upper Confidence Level**

**F**

**.****30**** ****ucl***

**.25 ucl**

**.20 ucl**

**.****15**** ****ucl**

**.10 ucl**

**.****05**** ****ucl**

**15**

**19**

**24**

**35**

**51**

**107**

**22**

**27**

**34**

**47**

**73**

**161**

**27**

**34**

**43**

**59**

**90**

**190**

## Appendix 2 -Audit Duration

- Increase
- Reduce
- Multi-Site
- Other

## Appendix 3 - Sterilization

- Processes Planned, Monitored & Controlled
- Selection of Process
- Validation
- Biological Indicators
- Limits
- SW
- Equipment Status
- Personnel Training

## SG 4 Documents Under Development

- SG4/N33:
- Part 3
- Audit Reports

## Audit Reports

- Will provide harmonized content for reporting results of regulatory audits of quality systems
- Purpose is to facilitate the exchange of regulatory audit reports among regulatory authorities

## Audit Reports – First Steps 		Reporting requirements in different  	GHTF-regions are identified  	Administrative data 			Contents of the audit report

## Case Study

**AUDITING **

## ?

## Latin America APEC Funded Medical Device Regulatory Seminar

## STUDY GROUP 4 

**PLAN-DO-CHECK-ACT ****CASE STUDY**

## PHASE “P”

**Help me understand: **
**How do you know what to do? Or What needs to be done at this station?**
***  “******This is my plan, procedure, method, work instruction, flowcharts, pictures, etc. that establishes what I need to accomplish”***

## PHASE “D”

**You are doing a great job.**
**Please show me what you do. **
**Demonstrate that you are following the plan, procedure, method, work instruction, etc.**
***“******I would be happy to show you what happens at this station. - - - ”***

## PHASE “C”

**How do you know what you are doing is adequate?**
**How do you know if the output is correct?**
**Explain what you measure and monitor.**
**What do you do with results? **

## PHASE “A”

**If the output is Not Correct, what do You Do?**
** **
**How do you resolve the issue?**
**Do you use statistical tools to analyze the data & which ones? **
**Please show some data and decisions?**