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Regulatory Overview, Human

Resources & Leadership Regulatory

Considerations

Presented by: Rosario Bermúdez, B.Sc., RQAP-GLP

March 26, 2010



2

Section Outline

Overview of the Phases of Drug Development

Importance of Regulations and the Cost of Non-compliance Brief History of Regulations

Overview of GLP, GCP & GMP

Organization and Personnel- a GLP regulatory perspective- Key roles in GLP, Definition & Responsibilities

Sponsor, Study Director, Quality Assurance Unit,Personnel

Testing Facility Management Responsibilities

Compliance, Technical, Managerial & Administrative

Testing Facility Management Soft Skills



3

Section Objectives

Recognize the need for federal regulations and guidance

Understand the regulatory requirements at each phase of the drug development

Identify the principles of the regulations

Understand the role of laboratory managers from aregulatory perspective



4

Overview of Phases of Drug Development

Pre-Clinical Process

5 to 10 years

Discovery

Research

Clinical Studies

Up to 6 years

Under sponsor control

Approval Process

6 to 10 months

Under FDA review

control



5

Phases of Clinical Trials

Phase IEmphasis ondrug safety

Metabolism and

excretion of the

Drug

Side effects

Possible toxicity

Healthy

Volunteers

Typically consists of

10 to 80 healthy volunteers

Phase IIEmphasis onEffectiveness

Studied in

Disease

Population

Use of placebo

Safety

continued to beStudied

Typically---12to 300 patients

Phase IIIEmphasis on ContinuedSafety and Effectiveness

Use in different

populations

Use of different dosagesCombination with other

drugs

Indications for labeling

Typically 100 to 3000patients

Multi-centeredRandomized, blinded,

placebo-controlled

Phase IV Any study aftermarketing approval

New indications

New dosing strategies

New diseases/

populations

Pharmacoeconomicquality of life



6

Regulatory Requirements

Preclinical

Good Laboratory Practices

(GLP)

Animal Welfare Regulations

and Guidelines: AAALAC in US

CCAC in Canada

Clinical

Good Manufacturing Practices

(GMP)

Good Clinical Practices (GCP)

Good Laboratory Practices(GLP)



7

Why Regulations?

Ensure the safety and effectiveness of drug, biological andmedical devices drug products

Ensure that product packaging/labeling is truthful,informative and not deceptive

Regulate the process through which evidence of safety andefficacy are developed

Protect the safety and health of subjects undergoing

clinical trials and patients

Enforce the food, drug and cosmetic act & regulations



8

Drug Approval Key Points

Based on substantial evidence of effectiveness and safety

Drug development process relies on rules and regulationsenforced by regulatory agencies

Products that make it through all pre-clinical testing and studiesin humans have a chance in becoming a leading drug on themarket

Individuals can rely on the FDA & other regulatory agencies to

ensure safety in humans because of strict regulations and

guidelines essential for all types of research We can guarantee to society, in the prevention and treatments of

diseases, superior quality of life for everyone



9

The Cost of Non-Compliance

Repeat testing or additional studies: Delays and IncreasedCosts

Delays in approval process: Increased cost of delayed sales

revenue Legal issues & disqualification of Facilities

Economic advantages of understanding the regulations andmanaging the laboratories so that the regulations may befollowed are enormous

Compliance to regulations makes Good Business Sense!



10

Brief History of GLP Regulations

1976, IBT inspection-´The Swampµ

Issues with animal care

Scientific misconduct: fabrication of data, removal of health effect findings from

reports, data and reports manipulation to make it look more favorable

1975, G.D. Searle & Company (Searle) Produced several major pharmaceutical products

Discrepancies between individual and summary data

Findings categorized in: Lack of personnel training, deviations from study protocols,lack of quality control of reported data, lack of QA procedures and test article

characterization, etc.

Th e discovery of t h e lack of companies· ad h erence to t h ese principles led to t h e development of t h e GLP

regulations, t h e driving force be h ind t h e quality of non-clinical laboratory studies..



11

Brief History-GCP Regulations Evolution

Early 1900s Drug industry unregulated

Little or no oversight

Free to claim cures for anything

1947

Nuremberg Code: Important document in the history of the ethics of medical research

and the first of its kind to ensure the rights of subjects 1964

Declaration of Helsinki

Cornerstone of research ethics and ground root of ICH

Major focus is on study subject protection

1979

Belmont Report

Three basic principles: Respect of persons, Beneficence, Justice

R egulations often result in response to abuse of h uman researc h subjects and concerns about t h e validity of data and

conclusions from clinical trials



12

GLP, GCP & GMP Regulations Overview

Scope

GLP GCP GMP

Conduct of Non clinical

Laboratory Studies In vivo or in vitro lab

experiments designed to

prospectively determine thesafety of test materials in

test systems Does not include human or

field animal trials

Does not include basic

exploratory studies:Efficacy studies, Proof of concept, Animal modeling,

Method development

Conduct of Human

Clinical Studies

Methods and Practice,

Facilities and Controls to be

used for the manufacturing,

processing or packing of a

drug



13

GLP, GCP & GMP Regulations Overview

Definition & Objectives

GLP GCP GMP

́A Quality system

concerned with theorganizational process

and the conditions,

under which non clinical

health and

environmental safety

studies are planned,

performed, monitored,

recorded, archived and

reported.µ OECD 1997.

́A standard for the design,

conduct, performance,monitoring, auditing,

recording, analyses and

reporting of clinical trials

that provides assurance that

the data and reported results

are credible and accurate,

and that the rights,

integrity and

confidentiality of trial

subjects are protected.µ

(ICH 1.24)

Good clinical Practices

(GCP) are an international

ethical and scientific quality

standard

Set of standards defined by

regulatory agencies to ensureproducts are manufactured under

controlled and consistent

conditions

Provides the basis of all quality

systems for companies involved with

manufacturing, packaging, labeling,

importing, distributing, and/or

testing of pharmaceutical

products within the

pharmaceutical industry



14

GLP & GMP in United States and Canada

UNITED STATES CANADA

GLP 21 Code of Federal

Regulations Part 58

Monitoring authority:

FDA

OECD (Organization for Economic

Cooperation and Development)Principles of GLP

Monitoring authority:Health Canada through a MOU

signed with the SCC(Standards Council of Canada) in

2009

GMP cGMP: 21 Food and Drugs

Parts 210 & 211


FDA

GMP Guidelines


Health and Food Branch

Inspectorate (HFBI)



15

Organization and Personnel

A GLP Regulatory Perspective

Definition of Key Roles and Responsibilities



16

Organization and Personnel-A GLP Regulatory Perspective-

Sponsor A person who initiates and supports, by

provision of financial or other resources, anonclinical laboratory study

A person who submits a nonclinical study tothe FDA in support of an application for aresearch or marketing permit; or

A testing facility, if it both initiates and actually conducts the study.



17


Study DirectorStudy director is the individual responsible for the overall

conduct of a non clinical laboratory study.

For each non clinical laboratory study A scientist or other professional of appropriate education,

training and experience

Overall responsibility for the technical conduct of the study

Interpretation, analysis, documentation and reporting of results

Represents the single point of study control



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Quality Assurance Unit Person or organizational element, except the study director,

designated by Testing Facility Management to perform the duties

relating to quality assurance of non-clinical laboratory studies

Monitoring each study to assure Management that the facilities,equipment, personnel, methods, practices, records, and controls are in

conformance with the regulations in this part.

Entirely separate from and independent of the personnel engaged inthe direction and conduct of that study



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Quality Assurance Unit Inspect each non clinical laboratory study at intervals

adequate to assure the integrity of the study

Maintain written and properly signed records of each

inspection Any problems found during the course of an inspection

which are likely to affect study integrity shall be brought tothe attention of the study director and managementimmediately.

Periodically submit to Management and the study director written status reports on each study, noting any problems andthe corrective actions taken.



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Personnel

Education, training, and experience, or combinationthereof, to perform the assigned functions.

Maintain a current summary of training, experienceand job description

Sufficient number of personnel for the timely andproper conduct of the study according to the

protocol



21

Testing Facility Management

Compliance Responsibilities

Designate and replace the study director

Assure that there is a Quality Assurance Unit

Assure that the test article or mixtures have been appropriately testedfor identity, strength, purity, stability, and uniformity, as applicable.

Assure that personnel, resources, facilities, equipment, materials

and methodologies are available as scheduled

Assure that personnel clearly understands the functions they are toperform

Assure that any deviations from these regulations reported by thequality assurance unit are communicated to the study director and

corrective actions are taken and documented



22


Technical Responsibilities

E valuate knowledge assets

Understand regulations, risk management & quality

management

Understand the science behind the business Speak the regulatory and scientific language

Understand and keep updated in the latest technology &regulations

Technical problem solving skills Review and approval of documents, including QA reports



23


Managerial Responsibilities

Manage some or all aspects of business

Allocate resources where and when needed-Effectively-

Ensure that facilities are adequate for the work to beperformed

Ensure that appropriate equipment, materials andmethodologies are available

Ensure efficient workflow

Assure that personnel clearly understands thefunctions they are to perform



24


Administrative Responsibilities

Supervise and coordinate all resources

Improve procedures and processes

Reduce errors and inefficiencies Adhere to budget and schedule

Develop new/cultivate existing relationships



25


Soft Skills

Leadership

Planning and organization

Effective communication

Relationship building

Training & Mentoring

Delegation



26

Regulatory References

21 CFR Part 58 ´Good Laboratory Practices for Non Clinical Laboratory Studiesµ

21 CFR Part 210 & 211 Current Good Manufacturing Practices

21 CFR Part 50 Protection of Human Subjects

21 CFR Part 11 Electronic Records and Electronic Signatures

ICH (International Conference on Harmonization): Guideline for GoodClinical Practice

OECD (Organization for Economic Cooperation and Development)Principles of GLP

Health Canada Good Manufacturing Practices Guidelines

United States Pharmacopoeia (USP)



27

Quality Assurance & Regulatory

Inspections



28

Section Outline

Facilities

Equipment

Standard Operating Procedures

Test Article Handling & Test system

Study protocol, Study conduct, Records & Reporting

Records retention

21 CFR Part 11, Electronic Records and Electronic Signatures

FDA Inspections

Quality Beyond Compliance



29

Section Objectives

Understand the regulatory requirements for facilities andequipment

Identify the importance of Standard Operating Procedures

(SOPs) in a regulated laboratory Understand the principles of electronic records and electronic

signatures regulations

Recognize the importance of Quality Systems and Quality Management in addition to compliance to regulations



30

Facilities-Housing of Test System

Suitable size and construction

Degree of separation to prevent any function or activity to have anadverse effect on the study

Sufficient number of animal rooms or areas as needed to assureproper:

Separation of species

Isolation of individual projects Quarantine of animals, Routine or specialized housing of animals

Separate areas for the diagnosis, treatment, and control of laboratory animal diseases

Collection and disposal of all animal waste or for safe sanitary

storage of waste before removal from the animal facility. Storage areas for feed, bedding, supplies, and equipment.

Separate from areas housing the test systems and protectedagainst infestation or contamination



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Facilities-Housing of Test Article

Necessary to prevent contamination or mix ups for thereceipt, storage and mixing of the test article

Separate from the housing of test systems

Adequate to preserve:

the identity

strength

purity

stability of the test articles and mixtures



32

Facilities

Lab Operations

Separate lab space as needed for the performance of theroutine and specialized procedures required by nonclinicallab studies

Specimens & Data Storage

Controlled access

Preserve the integrity of the specimen and records Secure and contents properly indexed



33

Equipment- Design, Maintenance &

Calibration

Design and capacity adequate to function according to the protocol

Equipment used for environmental controls

Suitably located for operation, inspection, cleaning, and maintenance

Operated, clean and maintained in a manner that prevents

contamination SOPs for equipment cleaning, maintenance, testing, calibration

SOP should include the person responsible for the performance of each operation: In house or outsourcing

Frequency of calibration to be consulted with manufacturer

Witten records maintained for all inspections, maintenance, testing,calibration



34

Standard Operating Procedures

Control day-to-day operations of the facility and the performance of experiments

When properly written and designed, their dedicated observance willguarantee overall compliance

SOPs must contain methods that management is satisfied will ensure the

quality and integrity of the data generated in the course of a study Significant changes in an SOP must be properly authorized in writing by the

SD and Management

Writing of clear, easily followed SOPs is an art which must be acquired by those responsible for this task

A list of minimum set of SOPs needed in the lab is given in the GLP regs.

First SOP should be on How to Prepare, Control, Issue SOPs



35

Test Article Handling

Test Article Definition Drug, biological product, food additive, color additive, medical device for human

use being investigated to be approved

Test Article Characterization

Identity, strength, purity, and composition determined for each batch and shouldbe documented

Methods of synthesis, fabrication or derivation documented by the Sponsor or the

testing facility

Stability: Before initiation of the study or in parallel in adherence to SOPs

Mixtures of Test Articles with Vehicles

Concentration verification, homogeneity, and stability, solubility

Storage conditions tested and appropriate



36

Test System

Test System Definition

Any animal, plant, microorganism, or subparts thereof to whichthe test article is added or administered for study

Animal Care and Procedures

AALAC and CCAC guidelines for working with laboratory animals

SOPs for housing, feeding, handling and care

Isolated and health status evaluation

Treatments should not interfere with the study

Proper identification Separated per study to prevent inadvertent exposure to other test

articles or animal mix ups



37

Study Protocol Outlines the objectives and methods

Identifies the test articles and make reference to the characterization

Sponsor and key personnel

Test system and characteristics: Species, strain, sex, age, etc.

Describes the experimental design

Describes and identifies the diet used Indicates the dosage levels to be administered

Method and frequency of administration of the test article to the testsystem

Type and frequency of tests, analysis and measurements

Records to be maintained Date of approval of the protocol by sponsor and the dated signature of the

Study Director

Study initiation: Study Protocol, Study Start Meetings, Study Planning P h ase



38

Study Conduct

In accordance with the Study Protocol In accordance with SOPs

Test systems monitored and in accordance with the protocol

Samples analysis with proven stability

Procedures and records inspected promptly and per protocol

Issues, deviations and changes promptly documented and justified

Specimens are identified by test system, study, nature, and date of

collection

Records of gross findings for a specimen from post mortem

observations should be available to a pathologist when examining histopathologically



39

Records

Data Integrity

Recorded directly, promptly, and legibly in ink

All data entries shall be dated on the date of entry

Signed or initialed by the person entering the data

Entries made do not obscure the original entry

Changes made indicate the reason for such change

The above apply to automated data collection systems as well

T raceable, Accurate, Complete, Legible, Contemporary, Attributable, Clear, Unambiguous



40

I f I t Was Not Documented«

I t I s a R umor!



41

Reports Names and address of the facility, study initiation and completion dates

Statistical methods, test and control articles characteristics including stability Methods used, test system, number of animals, sex, body range, species,

strain, age and procedures used for identification Description of the dosage, dosage regimen, route of administration Circumstances that may have affected the quality or integrity of the data Name of the Study Director, scientists or professionals, and all supervisory

personnel Transformations, calculations or operations performed on the data Summary and analysis of the data, conclusions drawn from the analysis Locations where all specimens, raw data and the final report are to be stored Quality Assurance Statement

The Rule of One·s

One Study Protocol, One Study R eport, One Study Director



42

Records Retention & Storage

All raw data, documentation, protocols, final reports« generated as a result

of a nonclinical laboratory study shall be retained Archives for orderly storage and expedient retrieval

Conditions of storage shall minimize deterioration

An individual identified as responsible for the archives

Controlled access

Material retained indexed to permit expedient retrieval

21 CFR Part 58.195 Retention of records

(c) «retained in the archives for whichever of the following periods is theshortest:

(1) A period of at least 2 years following the date on which an application« isapproved..

(2) A period of at least 5 years following the date on which the results aresubmitted to the FDA in support of an application



43

21 CFR Part 11

Electronic Records & Electronic Signatures

Definition

Defines the criteria under which electronic records and

electronic signatures are considered to be trustworthy, reliableand equivalent to paper records.

Part 11 requires FDA-regulated industries to implementcontrols, including audits, validation systems, anddocumentation for software and computer systems involved in

processing data.

Sets the minimum requirements to demonstrate that a record istrustworthy and reliable



44

21 CFR Part 11


Scope

FDA-required records when maintained in electronic form

Electronic signatures and handwritten signatures executed toelectronic records, whether or not the signatures are required

E

lectronic records submitted to FDA Records in electronic form under any records requirement set

forth in agency regulations

Electronic signatures and their associated records will beconsidered equivalent to paper

E

lectronic records may be used in lieu of paper Computer systems, controls, and attendant documentation will

be available for FDA inspection



45

21 CFR Part 11


Regulatory Expectations

The proper system is used to achieve the task

The system consistently performs as intended

The records comply with the predicate rule: Data integrity and recordsretention requirements

Able to demonstrate that the records are ´trustworthy and reliableµ Records will be readily available for inspection

Electronic records and signatures are considered the legal equivalents of paper records and handwritten signatures executed on paper, respectively, when they comply with 21 CFR Part 11.

Alt h oug h h onesty cannot be ensured, t h e presence of strong accountability and responsibility policies are necessary to ensure t h at employees understand t h e importance of maintaining t h e

integrity of electronic records and signatures



46

21 CFR Part 11


Regulatory Expectations

Data Security and Integrity

One of the greatest concerns of the FDA

Imperative to demonstrate that the records are ´trustworthy and reliableµ

Access

Audit Trails

Backup and Recovery

Disaster Recovery

Archiving

Long term retention of electronic records Able to access for review & able to provide electronic copies

Retention for period required by predicate rule and defined in SOP

Data Migration & time Capsule



47

FDA Inspections

Types of Establishment Inspections

cGMP, GLP, GCP

IND, Animal Study, IDE

Pre-Approval

For Cause Adverse E vents

Complaints

Field Survey



48

FDA Inspections

The Investigator is in the Plant Investigator go to reception areas

Show credentials

Issue Notice of Inspection (FDA-482) to a company official

Introductions

General session/opening meeting

FDA/company personnel

Inspection purpose

Discuss inspection agenda



49

FDA Inspections

Inspection Conduct

Records Review

Change control, Amendments& Deviation, Reanalysis, OOS, SOPs andRecords

Training SOP and Records

Equipment & Instrument Validation Protocols, Data, Records

Part 11 Program

Trade secrets & Confidential information:

Authorized access to virtually all drug product related records. But notfinancial or personnel records (except for training)

Any refusal is listed on the 483 and in the EIR ( Establishment

Inspection Report) Investigators must abide by the rules of confidentiality

Record document review -Spent majority of the time-



50

FDA Inspections

Inspection Conduct

Facility Tour

Investigators will usually point out conditions they view as notmeeting FDA·s expectations

Observations can be listed on the FDA-483

Company Escorts should take copious notes and clarify issuesduring daily briefings

E valuation of accuracy and authenticity

Looking for´Data Integrityµ



51

FDA Inspections

Closing Meeting & FDA-483

FDA-483 List of Observations- Factual listing of objectionable conditions

Presented at the end of the inspection

Discussed with Management: Upper Management in the room

shows interest and commitment Corrective actions acknowledge

Disputed observations/technical issues noted

The 483 is not required to be issued, not a requirement in theregulations or law

It is done as part of FDA·s mode of communication The FDA-483 becomes a Public Document after it is approved at

the district office



52

FDA Inspections

Closing Meeting & FDA-483

Exit Meeting

If a FDA 483 is issued the company should assureunderstanding of all listed items

Report completed or planned corrections Document inaccuracies but do not argue

FDA-483 list may and can be revised

If no FDA-483 is issued, the company should listen to and

discuss any investigators· comments



53

FDA Inspections

Establishment Inspection Report (EIR)

Establishment Inspection Report (EIR) An extended version of the actual inspection

Prepared by the investigator or members of the inspection team

Discusses the actual inspection in detail

Provides detailed presentation of FDA 483 findings

List any promised corrections, etc. Becomes a Public Document

Processing Inspection Reports

Review Chain: District compliance branch, FDA center compliance divisions

Consider administrative actions, if necessary

Warning letters

Withhold approvals

Additional reviews for legal actions



54

FDA Inspections

After the Inspection

After the Inspection

Conduct a debriefing meeting

Focus on addressing any observations in the FDA-483-

Further regulatory enforcement-Warning letters Focus on establishing a good relationship with the FDA

Critique the company participation in the inspection & makechanges as needed-Learn from the mistakes!

Begin preparations for the next inspection³BE PR EPAR ED



55

Successful inspections can result in:

Product approvals

Business reputation

Contracting, Customers

Stockholder/Market Freedom from Legal Problems

Assuring customer safety (#1 Goal) & Product quality

Non-Successful inspections can result in:

Product not approved or delays on approval Losing business & money

Legal issues-Jail

FDA Inspections

Impact on Business



56


Principles of Quality Leadership

Demings· TQM Principle on Leadership

Leadership is a key issue in the Deming Management method

The job of management is not supervision, but leadership

Management·s role is to focus on sources of improvement, theintent of quality, and the translation of that intent into thedesign[1]

Flaws of QA to keep management informed about the amountof defect: Regulated industry mindset is progressing towardsbuild quality into a system

Not All Managers Are Leaders- Not All Leaders Are Managers

[1] Deming, W. Edwards., Out of the Crisis, MIT Press Edition, 2000, p.54



57


Quality Management

´Leadership is essential to establish and maintain a company-widecommitment to quality and for the performance of the pharmaceutical

quality systemµ[1]

Pharmaceutical Quality System Elements

Process Performance and Product Quality Monitoring System Quality risk management, data management and statistical tools,

identify sources of variation affecting process performance andproduct quality, feedback on product quality from internal and externalsources

Corrective Action and Preventive Action (CAPA) System

Change Management System Management Review of Process Performance & Product Quality

[1] Q10 Pharmaceutical Quality System, FDA Guidance for Industry



58


Quality A Life Style!

Management

Takes responsibility for Quality and compliance, not just afunction of the QA/QC group

Views quality issues equal to production issues

Balances business needs with quality requirements

Regulations are viewed as Good Business Practice

Quality and compliance seen as an opportunity, not anobligation, and is owned by everyone in the organization

Address tough issues and are not afraid to make

uncomfortable decisions if they are the right thing to do



59



Proactively anticipate changing standards

Acknowledge other perspectives

Effectively use a Corrective and Preventive Action system

Use statistical tools and techniques to prevent problems

Training is viewed as an investment, not a cost

People are trained in their job skills

Internal audits are performed and viewed as a process foridentifying gaps in the operating systems and processes





People use the words ́weµ and ´ourµ more than they use the words ´theyµ and ´theirµ

Managers are visible and ask open-ended questions. And thenlisten to the answers

People care about the work they do. People take ownership of their work

Performance metrics are clear, visible, and understood by everyone in the organization

There is a sense of pride throughout the organization

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