Regulatory Class - Nov 14 Flashcards
Reasons for FDA inspections
Directed inspections for specific reason (received notice of complaint about a product)
Routine audit to ensure company compliance with GLPs, GCPs, cGMPs or QSRs
Reinspection following warning letter
Recall effectiveness check
Preapproval inspection (PAI)
What does FDA inspect?
Any product or activity required to comply with specific FDA regulations
Factory, warehouse, establishment in which regulated products are manufactured, processed, packed or stored
Nonclinical studies
Clinical trials
Safety reporting
FDA also inspects foreign manufacturers and clinical investigators if the products are distributed in the US; usually need their governmental approval first; if not inspected, product can be held at the border
What may FDA not inspect?
Financial data – except for Financial Disclosure related documents
Personnel data – other than information regarding qualifications of personnel performing FDA-related functions
Sales data – other than shipment information
Research data – other than information subject to reporting to and inspection by FDA
Quality Assurance audit reports
Unclear the rules about taking pictures
FDA Inspection Procedure
Primary contact reviews inspector’s credentials and FDA Form 482 – Notice of Inspection
Notify everyone that FDA is inspecting
Escort inspector to conference room and Always accompany inspector
Assemble inspection team (based on scope of inspection)
All questions should be directed to primary contact
FDA inspector may request documentation for review (only give specific documents)
Inspector may request copies (mark confidential and make copy for sponsor)
FDA inspector may request product samples (sponsor can charge for that sample)
End of FDA Inspection
At conclusion of inspection inspector holds exit interview
Inspector reviews and explains observations
Documented on Form 483
Cites appropriate regulation for each deficiency
Company can respond and identify perceived errors
Once Form 483 issued and inspector leaves facility, no changes can be made
Response to FDA Form 483
Should respond within 15 days of inspection and effective response can prevent warning letter
Contents:
An evaluation of the extent of the problem (how often does it happen)
Assessment of the root cause of the problem (insufficient training)
Corrective actions (want to see actions happen)
Preventive actions
Timeframe for training
Supporting documentation
Establishment Inspection Report (EIR)
Narrative report prepared by inspector after inspection
Describes inspectional findings – each observation included on Form 483 plus other lesser observations
Includes:
Reason for inspection
Dates
Classification and findings of previous inspection
Scope of inspection
Type of inspection
Brief description of products, processes or systems included
Would mention not follow guidance documents, because those can’t be written in the Form 483
cGMP Inspections
Comprehensive – covers all aspects of facility’s FDA- regulated products and processes (All major areas of quality system - every 2 years)
Abbreviated – performed on a specific area (May include one product or one specific aspect of company’s operations - due to new product or change)
Directed – in response to product failure or contamination (Focuses on conditions that led to violation, or complaint; comes from the FDA center)
Two classifications of inspections:
Routine Inspections (Scheduled biannually; Verify general compliance with GMPs)
Preapproval Inspections (PAI) - Prior to approval of NDA or PMA
PAI Inspections
Cover all facilities associated with a submission, including drug component manufacturing (drug substances), finished drug product manufacturing, device manufacturing, and control testing laboratories
Risk-based decision criteria to determine which facilities to inspect and scope of inspection
Must do it at a reasonable time - which means during normal business hours
Scheduled to ensure no delay in meeting approval timelines
PAI Inspections Objectives
Ensure information contained in the submission (e.g. CMC information) is consistent with on-site information (can the company do what they say they will do)
Ensure company can manufacture the product in accordance with information submitted
Readiness for commercial marketing
Quality system is designed to achieve sufficient control over
the facility and commercial manufacturing operations
Ensure data integrity
Audit raw data and verify all relevant data was submitted
PAI Inspections:Typical Form 483 observations
Lack of an adequate proposed commercial batch record to provide for a reproducible manufacturing operation
Missing data related to the data filed in the CMC section
Insufficiency, discrepancy, or failing of an analytical method validation program
Lack of suitability of the facility, equipment or manufacturing operations intended for making the commercial API or finished product
Bioresearch Monitoring (BIMO)
Protect the rights, safety and welfare of subjects involved in FDA-regulated clinical trials
Verify accuracy and reliability of clinical trial data
Assess compliance with statutory requirements and FDA’s regulations
Inspect everything related to clinical trials
Nonclinical Laboratory Inspections
Verify quality and integrity of data submitted in research or marketing application
Inspect nonclinical laboratories conducting safety studies intended to support research or marketing applications (Approximately every 2 years and usually without prior notification)
Two classifications of inspections:
Surveillance Inspections
Directed Inspections
Nonclinical Laboratory Inspections: Surveillance Inspections
Periodic, routine determination of compliance with GLP regulations
Facility inspections
Audits of ongoing or recently completed studies
Inspector will probably look at multiple studies
Nonclinical Laboratory Inspections: Directed Inspections
Verifying the reliability, integrity, and compliance of critical safety studies supporting pending submissions
Investigating issues brought to FDA’s attention
Reinspecting laboratories previously classified OAI (Generally within 6 months after firm responds to warning letter)
Verifying results from third-party or sponsor audits submitted to FDA
Nonclinical Laboratory Inspections Procedures
Interview personnel
Tour facility
Review SOPs
Review at least one completed study
Nonclinical Laboratory Inspections: Criteria for determining studies to inspect
Safety studies conducted on FDA-regulated products that have been initiated or completed since the last GLP inspection
Safety studies that encompass the full scope of laboratory operations
Studies that are significant to safety assessment, e.g. carcinogenicity, reproductive toxicity, chronic toxicity studies
Studies in several species of animals
Clinical Investigator Inspections
Protect the rights, safety and welfare of subjects
Assess compliance
Verify accuracy and reliability of clinical data submitted to FDA
Investigator is responsible for the overall conduct of the clinical study
Inspections may be announced or unannounced
Usually investigating sites contributing the most data for a marketing application (or high-enrolling)
Will do real-time clinical site inspections but cannot do data verifications
Types of Clinical Investigator Inspections
Study-oriented inspections
Investigator-oriented inspections
Bioequivalence study inspections
Clinical Investigator Inspections: Study-oriented inspections
Conducted by field office personnel
Typically 2-4 days
Assigned by FDA headquarters based on pending marketing submission
Sites generally selected based on amount of data contributed (e.g. highest enrolling sites)
Majority of inspections
Clinical Investigator Inspections: Investigator-oriented inspections
Verify accuracy and reliability of submitted data
Investigator’s data is crucial to product’s approval
Unusual findings or trends in submitted data
Investigator has participated in many studies
Investigator conducted study outside their specialty
Targeted “for-cause” based on complaint
Sponsor concerns
Termination of clinical site
During on-going study for real-time assessment
Request of FDA review division
Class of products identified by FDA as products of special interest (i.e. targeted based on public health concerns)
Clinical Investigator Inspections: Bioequivalence study inspections
Conducted for pending NDA or ANDA including bioequivalence data that is critical to product approval
Common for ANDA submissions
Clinical Investigator Inspections Procedure
Field office contacts investigator to schedule inspection (wants it in 10 days of initial contact)
FDA inspector presents credentials and FDA Form 482 (Notice of Inspection)
Interviews investigator, study coordinator, or responsible person at site
Inspection process includes review of: Delegation of authority IRB approval of study documents Protocol compliance Informed consent Financial disclosure Drug/device accountability Monitoring oversight Study data
Conclusion of Clinical Investigator Inspections
Exit interview with investigator
Findings discussed and clarified
Issue Form 483 “Inspectional Observations” to clinical investigator
Common Form 483 observations: Failure to follow protocol Failure to conduct or supervise study Protocol deviations Inadequate recordkeeping Investigational product accountability Informed consent issues
Sponsor Inspections
Inspection of sponsor and/or CRO:
Generally unannounced but not always
Assess how sponsor assures the validity of data submitted to them by clinical investigators
Verify compliance with applicable regulations
2 types of inspections: Routine/Surveillance For cause
What FDA inspects during Sponsor Inspections
Protocol (original & revisions) Investigator agreements & financial disclosures Organizational charts Correspondence CRO or vendor agreements Product accountability records Monitoring plan & reports Qualification records for Monitors and Clinical Investigators Training records Study subject records (CRFs, diaries, etc.) Adverse event reports Clinical Databases/Data line listings SOPs for conduct of study
Sponsor Inspections: Common inspection observations
Inadequate monitoring
Failure to secure investigator compliance
Failure to submit Progress Reports
Inadequate adverse event analysis and reporting
Failure to notify FDA, investigators or IRBs
Inadequate product accountability
Failure to obtain signed Investigator Agreement/1572 Failure to obtain FDA or IRB approval
Inspection Results Classification
No Action Indicated (NAI)
No substantive noncompliances
Voluntary Action Indicated (VAI)
Substantive noncompliances but no further regulatory action
required
May or may not require response
Official Action Indicated (OAI)
Serious deviations from regulations requiring prompt
correction
Administrative and/or judicial regulatory actions required
Adulteration
Adulteration – quality-related deficiencies
Produced under unsanitary conditions or containing
filthy, putrid or decomposed substance
Not manufactured in compliance with GMPs
Strength, quality or purity differs from how it is represented
Class III medical device without approved PMA (or not exempt)
Banned device
Misbranding
Misbranding – false or misleading labeling or other information
Label fails to include the manufacturer name/address
Label includes an inaccurate statement regarding quantity
Label does not include established name of the drug
Label does not contain adequate directions for use and warnings necessary to protect users
Dangerous to health when used in dosage or manner recommended by labeling
FDA Administrative Actions
Untitled letter
Warning letter
Reinspection to verify corrective actions
Regulatory meeting
Clinical hold on study
Withdrawal of approval
Rejection of data
FDA-initiated product recall
Initiation of Disqualification Proceedings
Deferral of substantive review of submissions
Warning Letter
Usually issued following Form 483
Repeated noncompliances
Company does not correct/resolve issues
Serious noncompliances
Issues are basic to quality control and require immediate correction
Respond within 15 days
Recall
Actions taken by manufacturer to remove from the market products that are in violation of FDA regulations
May be: Voluntary In response to FDA request By FDA order
3 classes of recall
Class I recall – reasonable probability that use of or exposure to suspected product will cause serious adverse health consequences or death
Class II recall – use of or exposure to suspected product may cause temporary or medically reversible adverse health consequences; or probability of serious adverse health consequences is remote (most are Class II)
Class III recall – use of or exposure to suspected product is not likely to cause adverse health consequences
Disqualification of Clinical Investigators
Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE)
Process to disqualify clinical investigator from receiving investigational products
Investigator has repeatedly or deliberately failed to comply with regulatory requirements
Investigator has deliberately or repeatedly submitted false information to sponsor or FDA
FDA Judicial Actions
Injunction
Seizure
Civil money penalties
Referral to FDA’s Office of Criminal Investigations and Prosecution
Injunction
Used where there is a likelihood that violations will continue or recur
FDA seeks injunctions when:
Chronic violations and efforts by FDA to obtain voluntary compliance have been unsuccessful
Immediate court intervention is needed to address an imminent public health hazard
Forcing an action or prohibition of an action - this is an action against the products
Seizure
Civil action providing for government “arrest” of the goods
Initiated by FDA through the Department of Justice (DOJ)
US Attorney files Complaint for Forfeiture, judge signs order for arrest of good, US Marshalls Service executes the warrant
Indicated when company refuses to undertake recall requested by FDA or FDA has reason to believe a recall would not be effective or discovers a violation is continuing
Response to FDA:
Propose that goods be reconditioned to bring into compliance
Deny FDA’s allegation of adulteration or misbranding (go to trial)
*if not claimed, they are destroyed
Types of Seizure
Based on size
Lot - One or more lots of product in one location that is adulterated or misbranded
Multiple - More than one action to arrest goods located in different jurisdictions where goods are adulterated or lack required approval
Mass - Warehouse full of products deemed adulterated or misbranded
Criminal Prosecution
FDA Office of Criminal Investigations
Obtains and executes search warrants and arrest warrants
Conducts physical surveillance
Obtains and serves grand jury subpoenas
Obtains and reviews materials and documents to support case against an individual or company
Department of Justice (not FDA) must bring criminal case to court
FDA recommends criminal prosecution in cases where:
There are gross violations that are evidence of management’s disregard for compliance with FD&C Act
Obvious and continuing violations where management has not exercised appropriate care
Life-threatening violations or where injuries have already occurred
Deliberate attempts to circumvent the law
