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Regulatory Overview, Human
Resources & Leadership Regulatory
Considerations
Presented by: Rosario Bermúdez, B.Sc., RQAP-GLP
March 26, 2010
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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
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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
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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
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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
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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)
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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
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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
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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!
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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..
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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
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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
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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
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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
Monitoring authority:
FDA
GMP Guidelines
Monitoring authority:
Health and Food Branch
Inspectorate (HFBI)
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Organization and Personnel
A GLP Regulatory Perspective
Definition of Key Roles and Responsibilities
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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.
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Organization and Personnel-A GLP Regulatory Perspective-
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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Organization and Personnel-A GLP Regulatory Perspective-
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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Organization and Personnel-A GLP Regulatory Perspective-
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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Organization and Personnel-A GLP Regulatory Perspective-
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
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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
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Testing Facility Management
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 ®ulations
Technical problem solving skills Review and approval of documents, including QA reports
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Testing Facility Management
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
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Testing Facility Management
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
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Testing Facility Management
Soft Skills
Leadership
Planning and organization
Effective communication
Relationship building
Training & Mentoring
Delegation
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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)
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Quality Assurance & Regulatory
Inspections
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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I f I t Was Not Documented«
I t I s a R umor!
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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
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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
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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
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21 CFR Part 11
Electronic Records & Electronic Signatures
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
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21 CFR Part 11
Electronic Records & Electronic Signatures
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
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21 CFR Part 11
Electronic Records & Electronic Signatures
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
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FDA Inspections
Types of Establishment Inspections
cGMP, GLP, GCP
IND, Animal Study, IDE
Pre-Approval
For Cause Adverse E vents
Complaints
Field Survey
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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
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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-
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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
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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
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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
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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
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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
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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
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Quality Beyond Compliance
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
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Quality Beyond Compliance
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
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Quality Beyond Compliance
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
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Quality Beyond Compliance
Quality A Life Style!
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
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Quality Beyond Compliance
Quality A Life Style!
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