Coalition for PET Drug Approval
Acceptable Prac,ces for Compliance with PET GMP Regula,ons
SNMMI Summer Mee,ng -‐ June 9, 2014
Steve Ehrhardt Vice President Biomarker Research and QA
Certus Interna,onal
Coalition for PET Drug Approval
Session Objec,ves
• Re-‐Affirm Why We Have GMP • Review Implica,ons of Non-‐Compliance • Contrast Types of GMP Requirements • Examine Types of Unacceptable Prac,ces • Discuss Inspec,on Management
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Coalition for PET Drug Approval
Perils of Technology
• Dependence on Goods and Services – Safety, Health, Well Being – We Demand Protec,on
• We Live Behind “Dikes*” of Quality Assurance • PET Drugs GMP – Meet Quality, Purity and Strength – Are Covered by a Marke,ng Authoriza,on – Conform to the Requirements of the FD&C Act
*Juran 1969
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Coalition for PET Drug Approval
What Happens If We Don’t Follow GMP?
• Drugs Are in Viola,on of the Act • Obligates a Legal Remedy • Leads to Enforcement Ac,ons – No,ce of Observa,ons – Warning Lecer – Seizure – Civil Penal,es – Criminal Penal,es
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Coalition for PET Drug Approval
How Is Informa,on Collected?
• Drug Marke,ng Applica,ons and Reports • Product Complaints and Adverse Events • FDA Compliance Inspec,on Program
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Coalition for PET Drug Approval
How Is the GMP Structured?
• Implements the Concept of Prac,ces or Controls to be Followed – Personnel – Facili,es and Equipment – Materials, Components, Reagents – Produc,on and Process – Quality
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Coalition for PET Drug Approval
How Do GMPs Compare? Drugs PET Drugs
General Provisions General Provisions Organiza,on and Personnel Personnel and Resources
Quality Assurance Buildings and Facili,es Facili,es and Equipment Equipment Control of Components Control of Components Produc,on and Process Controls Produc,on and Process Controls Laboratory Controls Laboratory Controls
Finished Product Controls
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Coalition for PET Drug Approval
cGMP Comparison Drugs PET Drugs
Packaging and Labeling Packaging and Labeling Holding and Distribu,on Distribu,on
Complaint Handling Records and Reports Records Returned and Salvaged Product
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Coalition for PET Drug Approval
How Many Prac,ces Are there? About 158 Unevenly Distributed
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5
12
11
22
26
22
26
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8
11
4
0 5 10 15 20 25 30
General Provisions
Personnel and Resources
Quality Assurance
Facili?es and Equipment
Components
Produc?on and Process
Laboratory
Finished Drug Acceptance
Packaging and Labeling
Distribu?on
Complaints
Records
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Coalition for PET Drug Approval
How Do Requirements Compare?
• Hard GMP – Clearly Stated – Objec,ve “No Formal Process Valida,on Is Performed”
• Sog GMP – Subjec,ve – Interpre,ve “Process Valida,on Does Not Demonstrate Consistency”
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Coalition for PET Drug Approval
How to Recognize Hard vs. Sog? Key To Compliance
Hard GMP SoK GMP
Personnel Sufficient Numbers
Adequate Training
Quality Assurance Procedures
Oversee Opera,ons Examine and Approve Find Errors and Correct Problems Determine Need to Inves,gate
Facility and Equipment Provide Maintain Calibrate
Adequate Suitable Reasonable
Components and Materials Acceptance Procedures Establish Suppliers
Adequate Assess Reliability
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Coalition for PET Drug Approval
Hard/Sog Differences Hard GMP SoK GMP
ProducBon and Process Master Batch Records and Content Batch Produc,on Records and Content
Ensure Cleanliness and Suitability Adequate Controls Demonstrate Process Verifica,on
Laboratory Test Methods Content and Records Solu,ons Iden,fied Expira,on Date Samples Iden,fied
Ensure Conformance Methods Are Adequate Methods Are Suitable
Stability Test Program Document Results
Adequate Suitable Reliable
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Coalition for PET Drug Approval
Hard/Sog Differences Hard GMP SoK GMP
Finished Product Acceptance Establish Specifica,ons Establish Test Methods
Adequate Suitable Assess Conformance Inves,gate Out-‐Of-‐Specifica,on Results
Packaging and Labeling Bear A Label
Suitable
Complaint Handling Procedures Complaint File
Adequate Review Adequate Inves,ga,on
Records Available
Complete
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Coalition for PET Drug Approval
Where Do We Find Acceptable Prac,ces?
• Preamble – FR Vol. 74, No. 236, December 10, 2009, pg. 65409
• cGMP – 21 CFR Part 212
• PET Drugs GMP Guidance – December 2009
• Media Fills Guidance – April 2012
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Coalition for PET Drug Approval
Where Do We Find Acceptable Prac,ces?
• FDA Inspec,ons/Inves,ga,ons Program – CPGM Program 7356.002P, December 2011
• FDA PET Ques,ons and Answers – December 2012
• Post Marke,ng Expecta,ons (Michael N.) – 21 CFR 314
• PET Drug NDA/ANDA Guidance (Bob W.) – August 2011
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Coalition for PET Drug Approval
Where Do We Get Our Compliance Status?
• FDA Inspec,ons/Inves,ga,ons – FDA Form 483, Inspec,onal Observa,ons – Establishment Inspec,on Report – Warning Lecers
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Coalition for PET Drug Approval
What Observa,ons Are Found? Uneven DistribuBon
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0
6
25
18
25
51
28
41
0
0
2
0
0 10 20 30 40 50 60
General Provisions
Personnel and Resources
Quality Assurance
Facili?es and Equipment
Components
Produc?on and Process
Laboratory
Finished Drug Acceptance
Packaging and Labeling
Distribu?on
Complaints
Records
Coalition for PET Drug Approval
Impact Of Uneven Distribu,on? Requirements -‐ Problems
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0
10
20
30 General Provisions
Personnel and Resources
Quality Assurance
FaciliBes and Equipment
Components
ProducBon and Process
Laboratory
Finished Drug Acceptance
Packaging and Labeling
DistribuBon
Complaints
Records
21 CFR 212 Subpart
0
20
40
60
General Provisions
Personnel and Resources
Quality Assurance
FaciliBes and Equipment
Components
ProducBon and Process
Laboratory
Finished Drug Acceptance
Packaging and Labeling
DistribuBon
Complaints
Records
FDA Form 483 Observa?ons
Coalition for PET Drug Approval
What Observa,ons Do We See? cGMP Controls Summary Non-‐Compliance
Personnel and Resources Lack adequate resources No documenta,on of training and qualifica,on Training not adequate to verify job du,es Operator asep,c qualifica,on
Quality Assurance Did not establish or follow wricen procedures No oversight of produc,on opera,ons Did not ensure PET drug meets quality and purity specs No documenta,on of batch review and approval QC and Produc,on persons allowed to review own work
Facili,es and Equipment Incomplete Qualifica,on Not suitable for intended purpose Not adequate to prevent contamina,on Incomplete environmental monitoring Incomplete calibra,on and maintenance
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Coalition for PET Drug Approval
What Observa,ons Do We See? cGMP Controls Summary Non-‐Compliance
Components and Materials Inadequate control Expira,on da,ng Lack of procedures to determine conformance Lack of procedures to complete acceptance decisions Inadequate storage and handling procedures
Produc,on and Process Controls
Insufficient control to ensure consistent produc,on Insufficient control to ensure quality and purity Master Records contain incomplete instruc,ons Process parameters not controlled Incomplete equipment cleaning procedures Equipment checks Deficient process verifica,on or valida,on Incomplete media fill simula,on studies Poor control of microbiological contamina,on
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Coalition for PET Drug Approval
What Observa,ons Do We See? cGMP Controls Summary Non-‐Compliance
Laboratory Controls Inadequate tes,ng procedures Incomplete laboratory records Inadequate determina,on of quality and purity Sampling procedures lacking Test method valida,on (accurate, precise, specific) Inadequate tes,ng procedures
Finished Product Controls Ini,a,on of and conduct of inves,ga,ons Inadequate determina,on of quality, purity, strength Specifica,ons Release procedures Non-‐conforming results and OOS management Problem correc,on inadequate
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Coalition for PET Drug Approval
What Observa,ons Do We See? cGMP Controls Summary Non-‐Compliance
Packaging and Labeling Label content Informa,on not contained in batch record Mix-‐up procedures inadequate
Complaints Health Hazard evalua,ons inadequate Problem reports not inves,gated Procedures for receipt and handling
Records Records not located Reten,on periods
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Coalition for PET Drug Approval
How Does FDA Describe Non-‐Compliance? ProducBon and Process Control
• “You did not review records to determine whether errors had occurred”
• “Your firm lacks adequate produc,on and process controls”
• “You failed to adequately validate the produc,on process”
• “You did not implement procedures to ensure that process parameters are controlled”
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Coalition for PET Drug Approval
How Does FDA Describe Non-‐Compliance? Laboratory Control
• “You did not establish and document accuracy, sensi,vity, specificity and reproducibility”
• “Your reagents and solu,ons are not adequately controlled”
• “Your sampling procedures do not ensure materials conform to standards”
• “You did not follow your wricen test procedures”
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Coalition for PET Drug Approval
How Does FDA Describe Non-‐Compliance? Components Control
• “Wricen acceptance procedures are not used to release purchased goods”
• “You did not adequately separate goods under quaran,ne from goods that are accepted”
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Coalition for PET Drug Approval
How Does FDA Describe Non-‐Compliance? FaciliBes and Equipment Control
• “Your analy,cal balance is not calibrated over the full range required to prepare reagents”
• “The ac,on limit for microbial monitoring is to broad”
• “You did not adequately classify the laminar flow hood to meet ISO Class 5”
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Coalition for PET Drug Approval
How Does FDA Describe Non-‐Compliance? Finished Drug Acceptance
• “Specifically, the firm failed to determine the need for an inves,ga,on for the following errors”
• “Sterility tes,ng on a final release PET drug was not started with 30 hours ager comple,on of produc,on”
• “The stability test results were not used in determining appropriate expira,on dates”
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Coalition for PET Drug Approval
How Does FDA Describe Non-‐Compliance? Quality Assurance
• “Quality control and produc,on personnel are permiced to review their own microbiological results”
• “You did not oversee produc,on opera,ons” • “You did not establish and follow wricen quality assurance procedures”
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Coalition for PET Drug Approval
How Does FDA Report Compliance?
• FDA Form 483 InspecBonal ObservaBons • Prepared by the Inves,gator • Issued to Most Responsible Person • Provides a list of observa,ons
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Coalition for PET Drug Approval
How Is a FDA 483 Structured?
• Observa,on #1 – Example A
• Discussion (i) • Discussion (ii)
– Example B
• Observa,on #2 – Example A
• Observa,on #n
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Coalition for PET Drug Approval
How Should We Respond?
• Inspec,on Prepara,on and Readiness – Develop and Inspec,on Management SOP – Test Your Records Retrieval Accuracy – Prepare a Room to Host – Prac,ce Unannounced Site Contact
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Coalition for PET Drug Approval
How Should We Respond?
• Collect Poten,al Observa,ons – Listen During the Inspec,on – Ask for Daily Wrap-‐Up
• Challenge Observa,ons – Not cGMP Requirement – Not Valid Interpreta,on
• Clarify Findings During Close-‐Out Mee,ng – Understand Each Observa,on – Clarify an Acceptable Prac,ce
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Coalition for PET Drug Approval
How Should We Respond?
• Prepare a Wricen Response – Respond to Each Observa,on
• Specific Ac,ons • Discuss a Root Cause(s) • Include or Commit to Data • Include a Target Comple,on Date
– Leave Out Extenua,ng Circumstances – Provide Systemic Remedies – Response Goes to a Compliance Officer
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Coalition for PET Drug Approval
How Do I Follow-‐Up?
• Prepare Progress Reports – Generally Monthly
• Reference the Commitment • Provide Specific Progress • Include Data and Suppor,ng Informa,on • Meet Target Dates • Ra,onalize Changes in Targets if Appropriate
• Provide a Close-‐Out Lecer – Indicate Everything is Done
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Coalition for PET Drug Approval
How Do I follow-‐Up?
• Request the EIR – District FOI Office
• It May Come Without Asking • It Will Not Come if an Enforcement Ac,on Is Being Contemplated
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Coalition for PET Drug Approval
When Can We Expect Inspec,ons?
• Pre-‐Approval (Once) – A Component of the ANDA/NDA Review
• Surveillance (2-‐4 Years) – Applied to Registered Establishments
• Directed (Never?) – Reported Problem – Adverse Events
• Announced or Unannounced
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Coalition for PET Drug Approval
Summary
• Compliance With PET GMP Is Legally Based • About 150 Different Prac,ces • Inspec,ons Find Non-‐Compliances • Sog GMP Requirements Are Difficult • Use Guidelines and Inspec,on Results to Prepare
• Respond Well
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