QUALITY CONTROL AND QUALITY ASSURANCE

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WHY QA & QC To ensure clinical data accuracy and

integrity, it is necessary to thoroughly review these data, to assess the validity of data and to carefully document query identification and resolution throughout a study's duration.

Maintaining accuracy and quality throughout a clinical study is a continual, dynamic process

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Understanding “Quality”

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DEFINITIONS Conformance to the standards.

Achieving excellence in a product/service by meeting/exceeding the requirements of the customer.

A refined process in which products are assessed, improved, ensured, and confirmed.

Quality means producing a defect free product from both manufacturer and customer’s viewpoint.

"Quality is never an accident; it is always the result of high intention, sincere effort, intelligent direction and skillful execution; it represents the wise choice of many alternatives."   

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Good quality product

Identify the needs/

requirements/

expectations of the

customer

Keep the PROACTIVE

PLAN in place

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PROACTIVE PLAN

QCQA

Make the QUALITY happen 6

Understanding “Quality Control”

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QC(ICH sec 1.47) : Operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial related activities have been fulfilled.

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Understanding “Quality Assurance”

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QA(ICH sec 1.46) all those planned and systemic actions that are established to ensure that the trial is performed and data are generated, recorded and reported in compliance with GCP and regulatory requirements .

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QC vs QA

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QC QA

helps to identify

abnormalities/inconsistencies

helps to prevent

abnormalities/inconsistencies

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QC QA

verification process

preventive process

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QC QA

it is the responsibility of a scientist

it is the responsibility

of management

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QC QA

will not perform QA

activity.

will perform QC activities to validate

the system.

so also called “QA over QC”

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QUALITY

Tries to find out the defects

QC QA

Tries to prevent the

defects 16

BENEFITS OF QUALITY SYSTEMS

Quality improvement

Work culture improvement

Teamwork Improved

Less waste and reworks Increased productivity

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QUALITY AND STANDARDS

Quality can be defined as:1. A standard of excellence2. Having or showing excellence3. Superiority in performance4. Suitability of intended purpose

A more tangible definition would be ADHERENCE TO STANDARDS

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THE QUALITY PLAN

The quality plan describes how the quality control and quality assurance processes will be applied throughout the clinical trial

Operational QC QC plan for each key operational stage of the

study that defines standards against which QC will be conducted

E.g. acceptable quality levels E.g. appropriate methods to report and

distribute results.

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THE QUALITY PLAN

PROTOCOL REVIEW During the study design phase, QC personnel

provide an independent review of the approved proposed protocol.

CRF The QC plan includes comparison of the

study's CRF to the objectives set forth in the protocol to ensure that it is designed to collect all necessary data

CRF FILLING GUIDELINES A requirement to review CRF completion

guidelines is also an element of the QC plan.20

FOR OVERALL SITE MANAGEMENT, A COMPLETE QC PLAN ADDRESSES

FOLLOWING

Investigator selection and qualifications – experience in conducting clinical trials

– experience with the specific indication– not on the FDA's restricted or debarred lists– adequate staff and facilities– personal involvement

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STUDY CONDUCT (MONITORING)

– subject informed (signed informed consent form)– subject's eligibility (inclusion/exclusion)– protocol compliance– adverse events (AEs) and concomitant medication– drug accountability and storage

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SOURCE DOCUMENT VERIFICATION

– medical records– lab data– progress notes– diagnostic tests

query resolution completed data clarification forms compliance with regulations

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FIVE BASIC VARIABLES

1. Man2. Materials3. Methods4. Equipment5. Environment

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THE ROLE OF QA FUNCTION Confirm GCP compliance Act as a catalyst for quality

improvement Provide advice on GCP matters Provide help with training clinical

research staff To help establish a quality and

compliance based culture

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CLINICAL TRIALS – GCP ASPECTS

Design Conduct Performance

Good Clinical PracticeGood Clinical PracticeGCP StandardsGCP Standards

Reporting

Monitoring Analysis Recording Audits26

ASSURANCE BY GCP

Credibilityof data

Accuracyof data

ASSURANCEASSURANCE

Protection of Rights,Integrity & Confidentiality

of Trial Subjects27

CLINICAL TRIALS – GLP ASPECTS

LaboratoryRecords

BioanalyticalMethods

Controls

Assurance of Compliance to Assurance of Compliance to Regulations (GLP aspects)Regulations (GLP aspects)

Facilities(Laboratory)

Equipment &Instruments

Personnel(Analysts)

WorkPractices

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ROLE OF QUALITY ASSURANCE

COMPLIANCETO GCP

COMPLIANCETO GLP

COMPLIANCE TOSTUDY PROTOCOL

COMPLIANCE TOSOPs / WGs

COMPLIANCE TO OTHERAPPLICABLE REGULATORY

REQUIREMENT(S)

QUALITY ASSURANCE (QA)QUALITY ASSURANCE (QA)

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HOW IS IT ENSURED ?

Screening ofVolunteers

ClinicalChemistry

ClinicalResearch

Implementation ofImplementation ofQUALITY SYSTEMSQUALITY SYSTEMS

Bioanalytical

ProjectManagement

TechnologyServices

Pharmacokinetics& Biostatistics

QualityAssurance

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HOW IS IT MEASURED / ENSURED ?

In-processAudits

RetrospectiveAudits

Compliance to the RequirementsCompliance to the Requirements(GCP, GLP, SOPs, Protocol and others)(GCP, GLP, SOPs, Protocol and others)

System Audits &Other Internal

Audits

ManagementReview Meetings

Quality ControlExternal Auditsby Sponsors /

Regulatory Bodies31

CLINICAL AUDIT POLICY QA is independent to systems and

persons Agreement and commitment of all QA

persons. Applied on clinical trial process as well

as data Audits are done during as well as after

trial Applied to each part of clinical

development process 32

SYSTEMS AUDITS

Adverse event handling and reporting Staff training records Standard Operating Procedures Equipment records Facilities Procedural inspections Archiving

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ADVERSE EVENT HANDLING

All staff aware of reporting AE procedure

SOPs available for reporting AEs Documentation to demonstrate timely

and satisfactory handling of AEs Regulatory reporting requirements

fulfilled

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STAFF TRAINING Job description must be created for

each member of staff A CV Training records Organizational chart of the company Procedures and SOPs

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STANDARD OPERATING PROCEDURES

Ensure that they are consistent with:

Relevant international regulations Local requirements eg Thai FDA Guidelines such as ICH-GCP Company policies and procedures

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EQUIPMENT RECORDS An SOP describing the use of the

equipment The service and maintenance

requirements of the equipment Records to illustrate that the use,

service and maintenance of the equipment occurred in accordance with requirements

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FACILITIES

Certain in-house facilities, for example , for human volunteer studies, may need to comply with specific standards. QA need to verify for compliance.

Eg. ABPI guidelines on standards for the facilities in which studies on non-patient volunteers are conducted.

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ARCHIVING A dedicated facility An individual responsible An index of the archive contents Records of entry and data examined Data should be logged into the archive within

a resonable period of time Appropriate data protection measures SOPs

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MASTER SCHEDULE

Aware of planned studies and must have a copy

Plans audits necessary to support the study Maintains its own audit plans study by study

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RESPONSIBILITIES OF QA PERSONNEL Maintain all approved protocol and

SOP’s and have access to up-to-date master schedule

Verify Protocol Conduct audits – Study based, facility,

processed (record to be retained) Audit records and final reports Training organizational personnel in

regulatory requirements41

RESPONSIBILITIES OF QA PERSONNEL Report inspection report to

management/study director/ principal investigator

Prepare and sign a QA statement Acting as the laboratory contact point

for regulatory and other inspections Maintaining record of quality assurance

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REQUIREMENTS FOR FUNCTIONING Written SOPsRepresentative list Quality assurance units aims, scope and

organization Selection and training of QAU SOPs Conducting study phase inspection Conducting study data inspection Conducting process inspection Final report audit Preparing QA statement

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REQUIREMENTS FOR FUNCTIONING

Documented training program Encompassing all aspects of QA work Where ever possible include on-the-job

experience Training in communication techniques

and conflict handling(advisable) Training documented and evaluated

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QUALIFICATION OF QA PERSONNEL

Training, expertise and experience Familiar with test procedures, standards and

systems Understand the basic concepts underlying the

activities being monitored

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QUALITY SYSTEMS

Organizational Structure

– Well defined functional departments and organograms

– Clearly identified and written job responsibilities of employees

– Continuous training to the employees

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QUALITY SYSTEMS

Operational Procedures

– Quality manual of the Organization

– Study specific Protocols

– Department wise SOPs and Working Instructions for conduct of study related activities

– Review of SOPs & Working Instructions periodically

– Design of study specific Protocols

– Evaluation of technical changes through Change Control system

– SOPs / Protocol deviations handling procedure47

NEED FOR QA IN CHANGING CLINICAL TRIALLANDSCAPE

More studies, more sites, greater volume New players in the role (CROs)

New technologies (Electronic Records, Electronic CTD ofdossiers)

Stringent regulatory requirements(EC Directives – 2001/20/EC)

Increasing inspections by Regulatory Authorities(WHO, USFDA, MHRA-UK etc.)

More participation by vulnerable subjects

Global expansion48

Internal audits by Quality Assurance

– In-process Audits– Retrospective Audits of raw data generated during

study / reports / documents– System Audits– Pre-inspection audit– Follow up audit– For cause (Investigational)

QUALITY SYSTEMS

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WHAT DOES QA DO ?

QA Assures:

Readiness of site for any external audit

Internal processes are effectively implemented

Data generated is valid & verified

Study personnel are compliant

Avoid reworks !!50

QA POLICIES AND PROCEDURESQA SOPS Review of clinical study protocols Audit of clinical study reports Audit of clinical study data bases Investigator site audit Filing and archiving of QA records Training of QA staff Review of SOPs Inspection of clinical study files Review of data handling procedures Inspection of CROs Review of computer systems Handling of fraud Systems inspection

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THE ROLE OF QA IN COMPUTER SYSTEMSCHECK FOR MINIMUM DOCUMENTATION TO DEMONSTRATE:

System is clearly defined including objectives A formal validation policy and master plan

exists Systems and its functions are adequately

tested (test protocols, records of testing, lists of tests performed)

Procedures for making any changes Security of the system Electronic archiving of the data and related

SOPs Necessary documentation and SOPs exists in

the production area52

EFFECTIVE QUALITY MANAGEMENT1. Anticipate errors

- Look for all the ways a process could fail and then make improvements to ensure that it doesn’t

2. Procedures- Develop clear systems and procedures

3. Train- Ensure that staff are trained for the tasks they perform

4. ValidateAll operations must be validated

5 Avoid short-cuts- Follow SOPs

6. Control change- Uncontrolled change can cause non-compliance

7. Challenge what you do-Regularly check that systems meet applicable standards53

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