acceptable)prac,ces)for)compliance) with)pet)gmp)regulaons) · pdf...

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


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

2


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

3


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

4


How Is Informa,on Collected?

•  Drug Marke,ng Applica,ons and Reports •  Product Complaints and Adverse Events •  FDA Compliance Inspec,on Program

5


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

6


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

7


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

8


How Many Prac,ces Are there? About 158 Unevenly Distributed

6

5

12

11

22

26

22

26

5

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

9


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”

10


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

11


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

12


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

13


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

14


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

15


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

16


What Observa,ons Are Found? Uneven DistribuBon

17

0

6

25

18

25

51

28

41

0

0

2

0

0 10 20 30 40 50 60

General Provisions


Quality Assurance

Facili?es and Equipment

Components

Produc?on and Process

Laboratory



Distribu?on

Complaints

Records


Impact Of Uneven Distribu,on? Requirements -‐ Problems

18

0

10

20

30 General Provisions


Quality Assurance

FaciliBes and Equipment

Components

ProducBon and Process

Laboratory



DistribuBon

Complaints

Records

21 CFR 212 Subpart

0

20

40

60

General Provisions


Quality Assurance

FaciliBes and Equipment

Components

ProducBon and Process

Laboratory



DistribuBon

Complaints

Records

FDA Form 483 Observa?ons


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

19



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

20



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

21



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

22


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”

23


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”

24


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”

25


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”

26


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”

27


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”

28


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

29


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

30


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

31



•  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

32



•  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

33


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

34


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

35


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

36


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

37


Acceptable Prac,ces for Compliance with PET GMP Regula,ons

acceptable)prac,ces)for)compliance) with)pet)gmp)regulaons) · pdf...

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