Educational Web Seminar

““Preparing for a FDA Inspection”Preparing for a FDA Inspection”

Thursday, August 11, 201112:00 Noon 12:00 Noon -- 1:15 PM ET1:15 PM ET

DescriptionDescriptionPresenters will outline their approaches to the area of Good Manufacturing Practice

specifically for facilities involved with products for cellular therapies. This web seminar will focus on preparing for a FDA inspection and understanding the parameters,

approaches, and concerns of FDA inspectors

--SpeakersSpeakers--Robert Lindblad, MDRobert Lindblad, MD

PACT Coordinating Center PI

Fran Rabe, MS, CQM (ASQ)Director of QA, University of Minnesota, MCT

Kip J. Hanks FDA Field Inspector

USFDA Division of Domestic Field Investigations

The presentation slides for this web seminar are available publicly on the main page at:www.pactgroup.netwww.pactgroup.net

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of AABB and PACT AABB is accredited by the ACCME to providePACT. AABB is accredited by the ACCME to provide

continuing medical education for physicians and clinical laboratory personnel. In accordance with the ACCME

Standards for Commercial Supportsm, all faculty for this event have signed a conflict of interest form in which they have disclosed any significant financial interests or other relationships with the industry relative to the topics they

will discuss during this program.

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Faculty Disclosure Nature of Relationship Manufacturer/Provider

Fran Rabe, MS, CQM (ASQ) None non-PACT member University of Minnesota

Kip J. Hanks None non-PACT member FDA

Robert Lindblad, MD None PACT member The EMMES Corporation

Lisa Davis None PACT member The EMMES Corporation

Karin Quinnan None PACT member The EMMES Corporation

David Styers None PACT member The EMMES Corporation

Debbie Wood None PACT member The EMMES Corporation

PACT UpdatesPACT Updates

Registration open. Visit www.pactgroup.net to register

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8/10/2011

FDA Inspections: FDA Inspections: An Overview An Overview

Robert Lindblad, MD The EMMES Corporation

August 11, 2011

researchcartoons.com

Why Inspections?

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8/10/2011

Why Inspections?

To evaluate compliance with regulations To establish that an entity exists To establish there are written procedures

T t bli h th itt d To establish the written procedures are followed

WHY NOT INSPECTIONS ?

Categories of Inspections6

Routine = Surveillance For Cause = Directed

a) product complaint/problem reported by the PI or other entityother entity

b) adverse events - too many or too few (as compared to other investigational sites)

c) patient complaintd) sponsor reports concerns about investigatore) too many research subjects enrolled (as compared to

other investigational sites)f) employee notification of “problems”

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8/10/2011

Types of FDA Inspections7

Compliance Audit – Unlicensed Product 361 product Manufacturer of devices (e.g. infectious disease test kits,

Isolex) Testing laboratory (e.g. donor screening, microbiological g y ( g g, g

cultures) licensed product

Bioresearch Monitoring (BIMO) Clinical trials - IND or IDE

Biologics License Application (BLA) pre-licensure review data used to support the application

7341.002 Compliance Program Objective

To assess whether all HCT/Ps intended for implantation, transplantation, infusion, or transfer are manufactured inaccordance with the applicable provisions of 21 CFR Partaccordance with the applicable provisions of 21 CFR Part

1271, to prevent the introduction, transmission, and spread of communicable disease

Compliance Program Manuals for Inspectors

7341.002 - Inspection of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) (HCT/Ps recovered on or after to 5-25-05)

7341.002A - Inspection of Tissue Establishments (HCT/Ps recovered prior to 5-25-05)

7345.848* - Inspection of biological drug products

*HCT/Ps that don't meet all the criteria will more than likely be inspected as biological drug products

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HCT/P Inspections Performed

FDA website 5/21/2011

Procedures for all steps performed in the testing, screening and/or determining of donor eligibility of HCT/Ps were not established, maintained, defined, documented, implemented, followed, reviewed and/or revised. [21 CFR 1271.47(a)]

Top 3 citations issued on 483s for HCT/Ps (2 refer to donor eligibility)

Procedures appropriate to meet core CGTP requirements for all steps that you perform in the manufacture of HCT/Ps were not established, maintained, defined, documented, implemented, followed, reviewed and/or revised. [21 CFR 1271.180(a)]

Donors were not screened by a review of relevant medical records for risk factors and/or clinical evidence of communicable disease agents and diseases. [21 CFR 1271.75(a)(1)]

The responsibilities and procedures applicable to the quality control unit are not in writing and/or fully followed. [21 CFR 211.22(d)]

Written production and process control procedures are not followed in the execution of production and process control

Top 3 citations issued on 483s for drugs (including biological drugs)

p pfunctions and/or documented at the time of performance. [21 CFR 211.100(b)]

Control procedures are not established which monitor the output and/or validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. [21 CFR 211.110(a)]

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What is BIMO? Investigational New Drug (IND) Regulations went into effect in 1963

FDA has exercised oversight of the conduct of clinical studies involving FDA regulated products

BackgroundBackground

The Bioresearch Monitoring (BIMO) Program was established in 1977 by a task force that included representatives from the drug, biologic, device, animal drug, and food areas

Compliance programs (CP) were developed to provide uniform guidance and specific instructions for inspections of Clinical Investigators , Sponsors , Institutional Review Boards , and Non-Clinical Laboratories

An investigation was not conducted in accordance with the signed statement of investigator and/or investigational plan. [21 CFR 312.60]

Failure to prepare or maintain adequate and/or accurate case h h b d d h

Top 3 BIMO citations issued on 483s (i.e. while product is still being investigated under protocol)

histories with respect to observations and data pertinent to the investigation and/or informed consent. [21 CFR 312.62(b)]

Investigational drug disposition records are not adequate with respect to dates, quantity and/or use by subjects. [21 CFR 312.62(a)]

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FDA Inspection/Facility FDA Inspection/Facility Notification Case StudiesNotification Case Studies

Fran Rabe, MSFran Rabe, MS

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Director of QADirector of QA

University of Minnesota, MCTUniversity of Minnesota, MCT

I Thought We Met FDA Requirements, I Thought We Met FDA Requirements, But …But …

Our Facility Received:Our Facility Received: A FDA Form 483A FDA Form 483 A FDA Untitled LetterA FDA Untitled Letter

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A FDA Warning LetterA FDA Warning Letter

All methods of notification are intended to All methods of notification are intended to notify facilities of practices that need to be notify facilities of practices that need to be amended.amended.

FDA 483s and Other FDA FDA 483s and Other FDA Notifications Contain Valuable Notifications Contain Valuable

InformationInformation

Use other organizations misfortunes to your Use other organizations misfortunes to your advantageadvantage

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Review the finding to ensure the same Review the finding to ensure the same problems don’t occur in your problems don’t occur in your facility/operationsfacility/operations

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Handling 483Handling 483

Response not “required”Response not “required”

-- But, lack of response is viewed as a lack of But, lack of response is viewed as a lack of concernconcern

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Immediately respond to reportImmediately respond to report

-- Response reviewed by FDA before Response reviewed by FDA before determining if a Warning Letter will be determining if a Warning Letter will be issued.issued.

FDA LETTERS – UNTITLED VERSUS WARNING

Untitled Warning

Expresses FDA’s stance (based on statue or rules) X X

Intended to induce voluntary compliance X

Next step may be enforcement action if not promptly and adequately corrected

X

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promptly and adequately corrected

Includes statement about potential enforcement X

Response required X

Serious stuff (call your lawyer) X

Warning LettersWarning Letters

Letter states requirement timeLetter states requirement time--line for line for response (usually 15 days)response (usually 15 days)

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Letter of closure issued after corrective Letter of closure issued after corrective actions have been satisfactorily addressedactions have been satisfactorily addressed

-- applicable to warning letters issued after applicable to warning letters issued after 9/1/20099/1/2009

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CSL Biotherapies Untitled LetterBrian McNameeChief Executive Officer (CEO)CSL Biotherapies45 Poplar RoadParkville, Victoria 3052Australia

[Example of Actual Untitled Letter]

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Dear Mr. McNamee:

The Food and Drug Administration (FDA) conducted an inspection of CSL Biotherapies, located at 45 Poplar Road, Parkville, Victoria 3052, Australia, between April 19 and April 28, 2010. During the inspection, FDA investigators documented deviations from current good manufacturing practice (CGMP) requirements in the manufacture of licensed biological vaccine products and monovalent influenza bulks.

We would like to meet with you and other senior management at CSL Biotherapies to further discuss the issues cited in this letter and how you will address them going forward..

FDA LettersFDA Letters

FDA posts warning letters on their web site:FDA posts warning letters on their web site:

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http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htmhttp://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm

FOIFOI The Freedom of Information Act (FOIA) and FDA's The Freedom of Information Act (FOIA) and FDA's

regulations governing disclosures require release regulations governing disclosures require release of inspection information to the publicof inspection information to the public-- List of inspectional observations (FDAList of inspectional observations (FDA--483)483)-- EIR (attachments and exhibits are excluded from EIR (attachments and exhibits are excluded from requirement)requirement)

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q )q )-- Warning letters communication with the Warning letters communication with the regulated establishment must be disclosed upon regulated establishment must be disclosed upon request by any member of the publicrequest by any member of the public

Mandate publicly accessible "electronic reading Mandate publicly accessible "electronic reading rooms" with electronic search and indexing rooms" with electronic search and indexing featuresfeatures

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FOIFOI-- RequestsRequests

Requests must be in writing (do not accept eRequests must be in writing (do not accept e--mail)mail) AA. Requestor's name, address, and telephone number.. Requestor's name, address, and telephone number. BB. A description of the records being sought. The records . A description of the records being sought. The records

should be identified as specifically as possible. A request should be identified as specifically as possible. A request for specific records that are releasable to the public can be for specific records that are releasable to the public can be processed much more quickly than a request for "all processed much more quickly than a request for "all information" on a particular subject Also fees for a moreinformation" on a particular subject Also fees for a more

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information on a particular subject. Also fees for a more information on a particular subject. Also fees for a more specific and limited request will generally be less.specific and limited request will generally be less.

CC. Separate requests should be submitted for each firm or . Separate requests should be submitted for each firm or product involved.product involved.

DD. A statement concerning willingness to pay fees, . A statement concerning willingness to pay fees, including any limitations.including any limitations.

FDA web:FDA web:http://www.fda.gov/RegulatoryInformation/FOI/HowtoMakeaFOIARequest/default.htmhttp://www.fda.gov/RegulatoryInformation/FOI/HowtoMakeaFOIARequest/default.htm

NAME AND TITLE OF WHOM REPORT ISSUED TOJane Doe, Vice President and General Manager

FIRM NAMEMedical Device UnlimitedThis document lists observations made by the FDA representative's) during the inspection ol your facility They are inspectional observations and do not represent

Dates of Inspection

FEI Number

District Address and Phone Number

Department of Health and Human Services

Food and Drug Administration

1111

inspection ol your facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance

OBSERVATION 1Complaint handling procedures have not been implemented to ensure that all complaints are processed in a uniform and timely manner.

Specifically, during a review of xx complaint files were reviewed that did not have complete investigation documentation, and/or deviated from your investigation procedure.The following are examples:

FORM FDA 483(04/03)Note: This is not intended to be an exact indication of a Form 483

Respond and CorrectRespond and Correct

When aware of FDA concerns via:When aware of FDA concerns via:–– Issued FDA Form 483Issued FDA Form 483

–– Untitled letterUntitled letter

–– Warning letterWarning letter

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Warning letter Warning letter

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Establishment Inspection ReportEstablishment Inspection Report(EIR)(EIR)

A detailed narrative of the inspection. Includes A detailed narrative of the inspection. Includes lists of all records reviewed, what aspect of lists of all records reviewed, what aspect of the facility was audited. A detailed summary the facility was audited. A detailed summary of the inspection. Includes identification of of the inspection. Includes identification of

ifi d i d id tifi ti fifi d i d id tifi ti f

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specific records reviewed, identification of specific records reviewed, identification of participating staff, staff commentsparticipating staff, staff comments Available to inspected establishment after Available to inspected establishment after

inspection process is inspection process is closedclosed Available to pubic through Available to pubic through Freedom of Freedom of

Information Act Information Act

Example EIRExample EIR

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Regenerative Sciences, IncJuly 25, 2008CERTIFIED MAILRETURN RECEIPT REQUESTEDChristopher J. Centeno, M.D.Medical DirectorRegenerative Sciences, Inc.11080 Circle Point RoadBuilding 2, Suite 140Westminster, Colorado 80020

Dear Dr. Centeno:

[Example of Actual Untitled Letter]

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The Food and Drug Administration (FDA) has reviewed your website at Internet address: http://www.regenexx.com and has determined that you are promoting your use of mesenchymal stem cells under conditions that cause these cells to be drugs under section 201(g) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 321(g)] and biological products, as defined in section 351(i) of the Public Health Service Act (PHS Act) [42 U.S.C. 262].

We request that you notify this office, in writing, of the steps you have taken or will take to address the violations noted above and to prevent their recurrence. Your response should be sent to me at the following address: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Suite 200 N, Rockville Maryland 20852-1448.

FDA NEWS RELEASEFor Immediate Release: August 6, 2010Media Inquiries: Shelly Burgess, 301-796-4651, shelly.burgess@fda.hhs.govConsumer Inquiries: 888-INFO-FDAFDA Seeks Injunction Against Colorado Manufacturer of Cultured Cell Product

The U.S. Food and Drug Administration is seeking an injunction in federal court against Regenerative Sciences LLC of

Example of Actual FDA News Release Regarding Action

1717uncements/ucm221656.htm

in federal court against Regenerative Sciences LLC, of Broomfield, Colo., citing violations of current good manufacturing practice (cGMP) that cause its cultured cell product to be adulterated. The product is also misbranded due to the lack of adequate directions for use and the failure to bear the “Rx only” symbol.

EnforcementEnforcement RecallsRecalls InjunctionInjunction

-- a civil action to prevent cease production and/or a civil action to prevent cease production and/or distributiondistribution

Seizure of final productSeizure of final product FinesFines Consent decreeConsent decree

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Consent decreeConsent decree-- an legal agreement to correct. Details exact an legal agreement to correct. Details exact requirements.requirements.

Criminal investigationsCriminal investigations-- allows FDA to hold employees legally liable for their allows FDA to hold employees legally liable for their actionsactions

http://www.fda.gov/Safety/Recalls/EnforcementReports/default.htmhttp://www.fda.gov/Safety/Recalls/EnforcementReports/default.htm

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*FDA Issue of an Order to Cease *FDA Issue of an Order to Cease Manufacturing Manufacturing

Vista Cord, LLCVista Cord, LLCSeptember 24, 2009September 24, 2009

Ongoing investigation of the cord blood bank has identified deviations from Ongoing investigation of the cord blood bank has identified deviations from requirements:requirements:

–– Donor eligibility screening and testingDonor eligibility screening and testing

–– Processing controlsProcessing controls

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gg

–– Environmental control and monitoringEnvironmental control and monitoring

–– Equipment and facilitiesEquipment and facilities

–– Supplies and reagentsSupplies and reagents

–– Process validationProcess validation

–– Labeling controlsLabeling controls

–– Receipt of productsReceipt of products

*http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm183756.htm*http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm183756.htm

Order to Cease Manufacturing of HCT/Ps Order to Cease Manufacturing of HCT/Ps

-- Vista Cord, LLCVista Cord, LLC FacilityFacility

Failure to provide plumbing, drainage, and access to sinks and toilets that are Failure to provide plumbing, drainage, and access to sinks and toilets that are adequate to prevent the introduction, transmission or spread of communicable adequate to prevent the introduction, transmission or spread of communicable disease. disease.

–– The restroom was not equipped with soap or paper towels.The restroom was not equipped with soap or paper towels.

Failure to utilize a suitable facility maintained in a good state of repairFailure to utilize a suitable facility maintained in a good state of repair–– There was a hole in a section of the processing area ceiling, which opens to the There was a hole in a section of the processing area ceiling, which opens to the

exteriorexterior

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exteriorexterior–– Several waterSeveral water--stained ceiling tiles located directly above storage shelves containing stained ceiling tiles located directly above storage shelves containing

processing supplies and in other parts of the facility. processing supplies and in other parts of the facility. –– Particles of dirt and dust were observed on …the top of an incubatorParticles of dirt and dust were observed on …the top of an incubator–– The lid was open on a large sharps receptacle containing used processing material. The lid was open on a large sharps receptacle containing used processing material.

This was located adjacent to the laminar flow hood.This was located adjacent to the laminar flow hood.–– You failed to document, and maintain records of, all cleaning and sanitationYou failed to document, and maintain records of, all cleaning and sanitation

Process validationProcess validation–– Failure to validate the two test methods for detection of bacterial/fungal Failure to validate the two test methods for detection of bacterial/fungal

contaminationcontamination

–– Red blood depletion of cord blood using hydroxyethyl starchRed blood depletion of cord blood using hydroxyethyl starch

483 Response Approach483 Response Approach

Root Cause Analysis Root Cause Analysis Exact CauseExact Cause

Prevent reoccurrence through application of Prevent reoccurrence through application of quality systems E G :quality systems E G :

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quality systems. E.G.:quality systems. E.G.:-- design controldesign control-- quality controlquality control-- quality review (trending, etc.)quality review (trending, etc.)-- early detection of problems (through audit)early detection of problems (through audit)

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483 Response483 Response FactualFactual

-- do not speculatedo not speculate Describe interim controlsDescribe interim controls Demonstrate evaluation of root cause and Demonstrate evaluation of root cause and

systems that may have contributed to problemsystems that may have contributed to problem Provide comprehensive description of corrected Provide comprehensive description of corrected

system controlssystem controls

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system controlssystem controls Address impact to past previously distribute Address impact to past previously distribute

productproduct Address impact to quarantine product inventoryAddress impact to quarantine product inventory Address prevention of future problemsAddress prevention of future problems Provide dates for completion of all corrective Provide dates for completion of all corrective

actionaction

483 Response483 ResponseEnsure safety of this product/lot # identified. Ensure safety of this product/lot # identified.

Determine dispositionDetermine disposition

Evaluate status of product collected and remaining in Evaluate status of product collected and remaining in establishment quarantine/released inventoryestablishment quarantine/released inventory

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Evaluate status of product (same type and/or lot #) Evaluate status of product (same type and/or lot #) that has been release and may be in (hospital) that has been release and may be in (hospital) inventoryinventory

Ensure future products are problem freeEnsure future products are problem free

Inaccurate Observation FindingsInaccurate Observation Findings

Demonstrate where finding is incorrectDemonstrate where finding is incorrect

-- provide documents and/or referencesprovide documents and/or references

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Dr. Cook Warning LetterDr. Cook Warning Letter

We acknowledge your July 2009 response and We acknowledge your July 2009 response and commitment to develop a commitment to develop a (b)(4)(b)(4). Please provide a . Please provide a copy of your copy of your (b)(4)(b)(4). . ΧΧ In addition, if not included in theIn addition, if not included in the (b)(4)(b)(4) provide corrective provide corrective actions to prevent similar deviations from recurring. actions to prevent similar deviations from recurring. ΧΧ Note that failure to have an adequate number of Note that failure to have an adequate number of qualified personnel is not justification to circumvent your qualified personnel is not justification to circumvent your adherence to CGMP requirements.adherence to CGMP requirements.

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adherence to CGMP requirements.adherence to CGMP requirements.

We acknowledge your July 2009 response that indicates We acknowledge your July 2009 response that indicates the the (b)(4)(b)(4) in the completion of your APRs and your in the completion of your APRs and your commitment to commitment to (b)(4)(b)(4) to complete APRs. to complete APRs. ΧΧ Please provide timeframes for the completion of the Please provide timeframes for the completion of the (b)(4)(b)(4). In addition, . In addition, ΧΧ please provide corrective actions to prevent similar please provide corrective actions to prevent similar deviations regarding your failure to follow your procedure. deviations regarding your failure to follow your procedure.

Dr. Cook Warning LetterDr. Cook Warning Letter

We acknowledge your July 2009 response and We acknowledge your July 2009 response and commitment to complete stability testing, commitment to complete stability testing, (b)(4)(b)(4) to ensure to ensure adherence to the stability procedure. adherence to the stability procedure. ΧΧ However, we believe your response does not provide However, we believe your response does not provide adequate preventive actions becauseadequate preventive actions because (b)(4)(b)(4) do not address do not address the failure of the QCD to ensure your procedures are the failure of the QCD to ensure your procedures are

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y py pfollowed and training is effective. Please provide corrective followed and training is effective. Please provide corrective action to prevent recurrence of similar deviations. For action to prevent recurrence of similar deviations. For example, you may develop a contingency plan to send example, you may develop a contingency plan to send your stability samples for testing to a qualified contract your stability samples for testing to a qualified contract laboratory, or you may reduce your product line to reduce laboratory, or you may reduce your product line to reduce the laboratory workload.the laboratory workload.

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XXX Laboratories XXX Laboratories -- Warning Letter ExpertsWarning Letter Experts

Your firm rejected 14 lots of product in 2008 due to Your firm rejected 14 lots of product in 2008 due to contamination and the corrective action was to retrain contamination and the corrective action was to retrain employees on aseptic technique.employees on aseptic technique.ΧΧ This corrective action was not effective. In 2009, your This corrective action was not effective. In 2009, your film received 23 complaints on contaminated product and film received 23 complaints on contaminated product and rejected 13 lots of product due to contamination. rejected 13 lots of product due to contamination. ΧΧ Additionally your firm's failure investigations intoAdditionally your firm's failure investigations into

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ΧΧ Additionally, your firm s failure investigations into Additionally, your firm s failure investigations into nonconforming products do not include reviewing the nonconforming products do not include reviewing the results of environmental testing of the fill room for the days results of environmental testing of the fill room for the days in which contaminated product has been produced. in which contaminated product has been produced.

ΧΧ You have failed to conduct a failure investigation You have failed to conduct a failure investigation that identifies the root cause of contaminationthat identifies the root cause of contaminationΧΧ You have not taken a corrective action that reduces You have not taken a corrective action that reduces the trend of contaminated product.the trend of contaminated product.

XY, Inc. XY, Inc. -- Warning Letter Experts Warning Letter Experts Broken glass was identified in filled 15 cc glass bottles of Broken glass was identified in filled 15 cc glass bottles of

TT--Gone Remedies on January 20, 2009, during product Gone Remedies on January 20, 2009, during product filling operations. This lot was rejected and destroyed on filling operations. This lot was rejected and destroyed on January 29, 2009. "Deviation Report," dated January 22, January 29, 2009. "Deviation Report," dated January 22, 2009, stated: "Broken glass was in the prepackaged and 2009, stated: "Broken glass was in the prepackaged and sealed bottles from the distributor. No risks were involved. sealed bottles from the distributor. No risks were involved. Product was pulled and destroyed on January 29,2009. Product was pulled and destroyed on January 29,2009. The broken glass inside the bottles accrued at the The broken glass inside the bottles accrued at the

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ggdistributor's operation. The drug product with the broken distributor's operation. The drug product with the broken glass was destroyed and all other products that were used glass was destroyed and all other products that were used with that component was rechecked and all were all were with that component was rechecked and all were all were clear." clear." ΧΧ The investigation failed to identify other related products and The investigation failed to identify other related products and lots manufactured with the implicated glass vials to assure no lots manufactured with the implicated glass vials to assure no additional broken glass was present. additional broken glass was present. ΧΧ Finally, the specific lot number of the problematic glass bottles Finally, the specific lot number of the problematic glass bottles (components) used to fill T(components) used to fill T--Gone Remedies on January 20, 2009 Gone Remedies on January 20, 2009 was not documented in the investigation.was not documented in the investigation.

Note: Information not an exact replication of the information

In A Nut ShellIn A Nut Shell

Information on FDA website and information Information on FDA website and information available by FOI can be used to your available by FOI can be used to your advantage to avoid the same pitfallsadvantage to avoid the same pitfalls

R d t 483 th hl t l dR d t 483 th hl t l d

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Respond to 483s thoroughly, accurately and Respond to 483s thoroughly, accurately and using evidenceusing evidence–– Consider impact of FDA finding across all Consider impact of FDA finding across all

systems and productssystems and products

Warning letters are a serious matterWarning letters are a serious matter

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8/10/2011

PREPARING FOR AN PREPARING FOR AN FDA INSPECTIONFDA INSPECTION

11

August 11, 2011August 11, 2011Kip J. Hanks, InvestigatorKip J. Hanks, InvestigatorBiologics National ExpertBiologics National Expert

FDA Division of Domestic Field InvestigationsFDA Division of Domestic Field Investigations

IS HE SPEAKING ENGLISH?IS HE SPEAKING ENGLISH?

•• cGMPcGMP: Current Good : Current Good Manufacturing PracticeManufacturing Practice

•• PHS ActPHS Act: Public Health Service Act: Public Health Service Act•• CFRCFR: Code of Federal Regulations: Code of Federal Regulations•• CPCP: Compliance Program: Compliance Program

•• EIEI: Establishment Inspection: Establishment Inspection•• EIREIR: EI Report: EI Report•• IOMIOM: Investigations Operations : Investigations Operations

ManualManual•• FD&C ActFD&C Act: Food, Drug & Cosmetic : Food, Drug & Cosmetic

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CPCP: Compliance Program: Compliance Program•• BLABLA: Biologics License Application: Biologics License Application•• HCT/P: HCT/P: Human Cells, Tissues and Human Cells, Tissues and

Cellular and TissueCellular and Tissue--Based ProductsBased Products•• BIMO: BIMO: BIoresearch MOnitoringBIoresearch MOnitoring

FD&C ActFD&C Act: Food, Drug & Cosmetic : Food, Drug & Cosmetic ActAct

•• INDIND: Investigational New Drug: Investigational New Drug•• MS: MS: MusculoSkeletalMusculoSkeletal•• HPC: HPC: Hematopoietic Hematopoietic

stem/Progenitor Cellstem/Progenitor Cell

WHAT ARE WE ATTEMPTING WHAT ARE WE ATTEMPTING TODAY?TODAY?

•• ME: Outline FDA’s approach to inspecting ME: Outline FDA’s approach to inspecting cGMPs specifically for facilities processing cGMPs specifically for facilities processing cellular therapy products. cellular therapy products.

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•• YOU: Learn how to prepare for an FDA YOU: Learn how to prepare for an FDA inspection and understand the parameters, inspection and understand the parameters, approaches and concerns of FDA investigators.approaches and concerns of FDA investigators.

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8/10/2011

WHAT AM I WHAT AM I NOTNOT ATTEMPTING ATTEMPTING TODAY?TODAY?

•• Give you the history of FDA’s regulation of Give you the history of FDA’s regulation of cellular therapy products.cellular therapy products.

•• Make you an expert on all things FDA.Make you an expert on all things FDA.

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y p gy p g

•• Provide you with any secrets or shortcuts on Provide you with any secrets or shortcuts on how to not receive an FDA 483, Inspectional how to not receive an FDA 483, Inspectional Observations.Observations.

DO I HAVE “361” OR “351” DO I HAVE “361” OR “351” HCT/Ps?HCT/Ps?

•• 361361–– PHS Act Section 361PHS Act Section 361–– 21 CFR 127121 CFR 1271–– Must meet all of criteria in 21 Must meet all of criteria in 21

CFR 1271.10(a)CFR 1271.10(a)

•• 351351–– PHS Act Section 351 & FD&C PHS Act Section 351 & FD&C

ActAct–– 21 CFR 1271, 210/211, 60021 CFR 1271, 210/211, 600--

680680Th HCT/P h d ’ Th HCT/P h d ’

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–– Premarket approval not Premarket approval not requiredrequired

–– Reproductive, MS, ocular and Reproductive, MS, ocular and heart tissue; hematopoietic heart tissue; hematopoietic stem cells; skin; arteries and stem cells; skin; arteries and veins; dura materveins; dura mater

–– CP 7341.002, Inspection of CP 7341.002, Inspection of HCT/PsHCT/Ps

–– Those HCT/Ps that don’t meet Those HCT/Ps that don’t meet 1271.10(a)1271.10(a)

–– Premarket approval may be Premarket approval may be requiredrequired

–– Vaccines; manipulated, Vaccines; manipulated, cultured or expanded cell cultured or expanded cell productsproducts

–– CP 7345.848, Inspection of CP 7345.848, Inspection of Biological Drug ProductsBiological Drug Products

HPCsHPCs

•• Regulatory framework for HPCs derived from Regulatory framework for HPCs derived from peripheral or cord blood is dependent upon whether peripheral or cord blood is dependent upon whether the product meets criteria in 21 CFR 1271.10(a) the product meets criteria in 21 CFR 1271.10(a) andandthe intended use:the intended use:

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–– If intended for unrelated allogeneic use, then they’re If intended for unrelated allogeneic use, then they’re regulated under PHS Act 351 as drugs, devices and/or regulated under PHS Act 351 as drugs, devices and/or biological products.biological products.

–– If intended for autologous use or allogeneic in 1If intended for autologous use or allogeneic in 1stst or 2or 2ndnd

degree blood relatives, and meet criteria in 1271.10(a), degree blood relatives, and meet criteria in 1271.10(a), then they’re regulated under PHS Act 361.then they’re regulated under PHS Act 361.

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8/10/2011

REMEMBER…REMEMBER…

•• Many HCT/P establishments that process HPCs Many HCT/P establishments that process HPCs derived from peripheral or cord blood derived from peripheral or cord blood manufacture the products for use in both (1) manufacture the products for use in both (1)

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unrelated allogeneic and (2) autologous or 1unrelated allogeneic and (2) autologous or 1stst

or 2or 2ndnd--degree blood relative allogeneic use, degree blood relative allogeneic use, i.e. it is common for manufacturers to produce i.e. it is common for manufacturers to produce both HPCs regulated solely under PHS Act 351 both HPCs regulated solely under PHS Act 351 and HPCs regulated under PHS Act 361.and HPCs regulated under PHS Act 361.

CORD BLOOD BANKSCORD BLOOD BANKS

•• Ellen F. Lazarus, MD’s presentation:Ellen F. Lazarus, MD’s presentation:–– www.fda.gov/downloads/BiologicsBloodVaccines/www.fda.gov/downloads/BiologicsBloodVaccines/

NewsEvents/WorkshopsMeetingsConferences/UCMNewsEvents/WorkshopsMeetingsConferences/UCM

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200358.ppt200358.ppt

BIOLOGICAL DRUG PRODUCTS, BIOLOGICAL DRUG PRODUCTS, WHO’S INSPECTING THEM?WHO’S INSPECTING THEM?

•• Team BiologicsTeam Biologics–– Expert investigators in the areas of antitoxins, vaccines, Expert investigators in the areas of antitoxins, vaccines,

plasmaplasma--derived products, in vivo diagnostics, allergenic derived products, in vivo diagnostics, allergenic products hematopoietic cells and CELL/GENE THERAPIES products hematopoietic cells and CELL/GENE THERAPIES

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products, hematopoietic cells and CELL/GENE THERAPIES. products, hematopoietic cells and CELL/GENE THERAPIES.

–– Typically stationed in a field office.Typically stationed in a field office.

–– Responsible for ensuring the quality/safety of biologic Responsible for ensuring the quality/safety of biologic products and working with industry and Agency officials to products and working with industry and Agency officials to quickly resolve inconsistencies and bring products into quickly resolve inconsistencies and bring products into compliance. compliance.

–– Conducts inspections both domestically and internationally.Conducts inspections both domestically and internationally.

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8/10/2011

LET’S TALK NUMBERSLET’S TALK NUMBERS

•• Inventory of regulated firms:Inventory of regulated firms:–– Plasma derived products/recombinant analogues: Plasma derived products/recombinant analogues:

4646

1010

–– Vaccines/related products: 35Vaccines/related products: 35

–– IVD: 25IVD: 25

–– Allergenic extracts: 11Allergenic extracts: 11

–– CELL THERAPY: 2CELL THERAPY: 2

–– Licensed cord blood banks: zilch, nada, noneLicensed cord blood banks: zilch, nada, none

ONLY 2 CELL THERAPY FIRMS?ONLY 2 CELL THERAPY FIRMS?

•• This means that most of you cell therapy folks This means that most of you cell therapy folks are conducting studies under IND to prove that are conducting studies under IND to prove that your product is safe and effective.your product is safe and effective.

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WHAT IS AN FDA INSPECTION?WHAT IS AN FDA INSPECTION?

•• We call it an EIWe call it an EI–– An establishment inspection is a careful, critical, An establishment inspection is a careful, critical,

official examination of a facility to determine its official examination of a facility to determine its

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compliance with the laws enforced by FDA.compliance with the laws enforced by FDA.

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8/10/2011

WILL I KNOW YOU’RE COMING?WILL I KNOW YOU’RE COMING?

•• FDA inspections are generally unannounced, FDA inspections are generally unannounced, with a few exceptions:with a few exceptions:–– Medical devicesMedical devices

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–– Inspections under the BIMO program, unless they Inspections under the BIMO program, unless they are forare for--cause/directedcause/directed

–– PrePre--licensing biologics inspectionslicensing biologics inspections

WE LOVE HAVING YOU HERE, BUT WE LOVE HAVING YOU HERE, BUT HOW LONG ARE YOU STAYING?HOW LONG ARE YOU STAYING?

•• Inspection length will depend on the complexity Inspection length will depend on the complexity of operations, product(s) being manufactured, of operations, product(s) being manufactured, size of firm, number/type of problems found size of firm, number/type of problems found

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and the level of cooperation the firm provides.and the level of cooperation the firm provides.

WHAT HAPPENS FIRST?WHAT HAPPENS FIRST?

•• Investigator(s) will identify themselves and ask Investigator(s) will identify themselves and ask to see the most responsible individual (MRI) to see the most responsible individual (MRI) available.available.

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•• FDA 482, Notice of Inspection, issued to MRI.FDA 482, Notice of Inspection, issued to MRI.•• FDA credentials displayed.FDA credentials displayed.•• Investigator(s) will explain the purpose of their Investigator(s) will explain the purpose of their

“visit” and inform you of the records to review “visit” and inform you of the records to review and personnel to interview.and personnel to interview.

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8/10/2011

WHAT CAN I DO IN ADVANCE WHAT CAN I DO IN ADVANCE (1)(1)??

•• Designate one or more persons to facilitate the Designate one or more persons to facilitate the inspection.inspection.

•• Determine how you will handle requests for Determine how you will handle requests for

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y qy qphotocopies.photocopies.

•• Don’t expect the facilitator(s) to have all of the Don’t expect the facilitator(s) to have all of the answers to questions asked, designate in answers to questions asked, designate in advance who is best suited to answer them.advance who is best suited to answer them.

IN ADVANCE IN ADVANCE (2)…(2)…

•• Consider having an SOP on how to handle FDA Consider having an SOP on how to handle FDA inspections, e.g. think of logistics (space, etc.) inspections, e.g. think of logistics (space, etc.) ahead of time.ahead of time.

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•• SOPs: keep an updated hardcopy or at least a SOPs: keep an updated hardcopy or at least a table of contents.table of contents.

IN ADVANCE IN ADVANCE (3)…(3)…

•• Know which CPs Know which CPs ((www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatorywww.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceActivities/Enforcement/CompliancePrograms/UCM095419.Information/ComplianceActivities/Enforcement/CompliancePrograms/UCM095419.

pdfpdf) and Guidances for Industry ) and Guidances for Industry

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pp ) y) y((www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformationwww.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation

/Guidances/CellularandGeneTherapy/default.htm/Guidances/CellularandGeneTherapy/default.htm) apply to you.) apply to you.•• Stay current with the FDA Stay current with the FDA

((www.fda.gov/AboutFDA/CentersOffices/CBER/ucm125685.htmwww.fda.gov/AboutFDA/CentersOffices/CBER/ucm125685.htm).).

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8/10/2011

DURING THE INSPECTION DURING THE INSPECTION (1)(1)

•• Don’t be afraid to ask questions … avoid Don’t be afraid to ask questions … avoid miscommunication.miscommunication.

•• Okay fine, your policy is to never let the investigator Okay fine, your policy is to never let the investigator roam around unescorted roam around unescorted –– but really … to the but really … to the

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restroom?restroom?•• If you don’t know the answer to a question ... find If you don’t know the answer to a question ... find

someone who does.someone who does.•• The investigator will take lots of notes … don’t you The investigator will take lots of notes … don’t you

hate it when someone attempts to read over your hate it when someone attempts to read over your shoulder?shoulder?

DURING THE INSPECTION DURING THE INSPECTION (2)(2)

•• Don’t be evasive.Don’t be evasive.•• Investigators will need time alone to discuss amongst Investigators will need time alone to discuss amongst

themselves.themselves.•• Provide requested records ASAP explain why there Provide requested records ASAP explain why there

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•• Provide requested records ASAP; explain why there Provide requested records ASAP; explain why there might be any delay.might be any delay.

•• You might use different terminology; ensure everyone You might use different terminology; ensure everyone is “on same page”.is “on same page”.

•• At the end of each day, ask the investigator what At the end of each day, ask the investigator what he/she covered and if there are any deficiencies.he/she covered and if there are any deficiencies.

WHAT DOES THE FDA WHAT DOES THE FDA INVESTIGATOR KEEP LOOKING INVESTIGATOR KEEP LOOKING

AT?AT?•• IOMIOM

•• CP 7345.848, Inspections of Biological Drug CP 7345.848, Inspections of Biological Drug Products (CBER)Products (CBER)

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( )( )

•• Guidances for IndustryGuidances for Industry

•• Previous EIRsPrevious EIRs

•• His/her assignment (FDA eyes only)His/her assignment (FDA eyes only)

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8/10/2011

CP 7345.848, INSPECTION OF CP 7345.848, INSPECTION OF BIOLOGICAL DRUG PRODUCTS BIOLOGICAL DRUG PRODUCTS (1)(1)

•• CPs are used by FDA investigators to, in CPs are used by FDA investigators to, in conjunction with the CFR, help guide them conjunction with the CFR, help guide them through the inspectional processthrough the inspectional process

2222

•• Current version: 10Current version: 10--11--1010

•• Addresses preAddresses pre--approval, preapproval, pre--licensing and licensing and postpost--market inspectionsmarket inspections

CP 7345.848 CP 7345.848 (2)(2)

•• EI is performed to ensure that manufacturers EI is performed to ensure that manufacturers are making product that:are making product that:–– Meet provisions of regs: 21 CFR 200, 201, 210, Meet provisions of regs: 21 CFR 200, 201, 210,

2323

211, 600, 601, 610, 640, 660, 680, 1271211, 600, 601, 610, 640, 660, 680, 1271

–– Meet BLA conditions (if licensed product)Meet BLA conditions (if licensed product)

•• SystemsSystems--based, riskbased, risk--management inspectional management inspectional approachapproach

SYSTEMS APPROACHSYSTEMS APPROACH

•• SYSTEMS:SYSTEMS:–– QualityQuality

–– Facilities/equipmentFacilities/equipment

M lM l

•• CRITICAL ELEMENTS OF CRITICAL ELEMENTS OF EACH SYSTEM:EACH SYSTEM:–– SOPsSOPs

T i iT i i

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–– MaterialsMaterials

–– ProductionProduction

–– Packaging/labelingPackaging/labeling

–– Laboratory controlLaboratory control

–– Donor eligibilityDonor eligibility

–– TrainingTraining

–– RecordsRecords

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8/10/2011

QUALITY SYSTEM, WHAT ARE WE QUALITY SYSTEM, WHAT ARE WE LOOKING FOR?LOOKING FOR?

•• Has the QC unit fulfilled its responsibilities to review/approve Has the QC unit fulfilled its responsibilities to review/approve SOPs related to production, QC and QA, and to ensure the SOPs related to production, QC and QA, and to ensure the SOPs are adequate/current for their intended use?SOPs are adequate/current for their intended use?

•• We will review records related to release of components/inWe will review records related to release of components/in-- i l d ll d d i i i l d ll d d i i

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process materials, product recall, product deviations, process materials, product recall, product deviations, complaints, out of specification results, rejects and failure complaints, out of specification results, rejects and failure investigations. investigations.

•• We will verify that the firm reviews its records pertinent to the We will verify that the firm reviews its records pertinent to the manufacture of lots prior to their release or distribution.manufacture of lots prior to their release or distribution.

•• We will assess the data collected in order to identify quality We will assess the data collected in order to identify quality problems that may be linked to other systems. problems that may be linked to other systems.

FACILITIES/EQUIPMENT SYSTEMFACILITIES/EQUIPMENT SYSTEM

•• We will verify the appropriateness of We will verify the appropriateness of buildings/facilities, including maintenance; equipment buildings/facilities, including maintenance; equipment qualifications (installation/operation); equipment qualifications (installation/operation); equipment calibration/preventative maintenance validation of calibration/preventative maintenance validation of

2626

calibration/preventative maintenance; validation of calibration/preventative maintenance; validation of cleaning processes as appropriate; prevention of cleaning processes as appropriate; prevention of contamination/cross contamination; and utilities that contamination/cross contamination; and utilities that are not intended to be incorporated into the product; are not intended to be incorporated into the product; such as HVAC, compressed gases, and steam and such as HVAC, compressed gases, and steam and water systems.water systems.

MATERIALS SYSTEMMATERIALS SYSTEM

•• This system includes the measures and activities to This system includes the measures and activities to control finished products, such as components, source control finished products, such as components, source materials, water/gases that are incorporated into the materials, water/gases that are incorporated into the product and containers/closures product and containers/closures

2727

product, and containers/closures. product, and containers/closures.

•• We will review the validation of computerized We will review the validation of computerized inventory control processes, product storage, inventory control processes, product storage, distribution controls and records. distribution controls and records.

•• We will evaluate routine monitoring of the utility We will evaluate routine monitoring of the utility systems.systems.

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8/10/2011

PRODUCTION SYSTEMPRODUCTION SYSTEM

•• Are you following/documenting performance of Are you following/documenting performance of approved manufacturing SOPs?approved manufacturing SOPs?

•• We will review batch formulation, inWe will review batch formulation, in--process testing, process testing, lot release, and process validation.lot release, and process validation.

2828

•• Are records: complete and relate to the Are records: complete and relate to the history/disposition of products produced/distributed; history/disposition of products produced/distributed; legible/indelible; identify the person performing the legible/indelible; identify the person performing the work, including dates of the various entries; show test work, including dates of the various entries; show test results/interpretation; show expiration date assigned results/interpretation; show expiration date assigned to specific products; and as detailed as necessary to to specific products; and as detailed as necessary to provide a complete history of the work performed?provide a complete history of the work performed?

PACKAGING/LABELING SYSTEMPACKAGING/LABELING SYSTEM

•• We will review your SOPs regarding We will review your SOPs regarding packaging/labeling controls.packaging/labeling controls.

•• We will observe how you examine, store, issue We will observe how you examine, store, issue

2929

y , ,y , ,and use labels.and use labels.

LABORATORY CONTROL SYSTEMLABORATORY CONTROL SYSTEM

•• This system includes all the various measures and activities that This system includes all the various measures and activities that are related to laboratory procedures; analytical methods are related to laboratory procedures; analytical methods development; validation or verification; and the stability development; validation or verification; and the stability program. program.

•• We will review your SOPs for control of microbiological We will review your SOPs for control of microbiological

3030

y gy gcontamination and environmental monitoring; review of records contamination and environmental monitoring; review of records for source materials, infor source materials, in--process and finished product testing; process and finished product testing;

•• We will evaluate your methods for sampling and testing We will evaluate your methods for sampling and testing products for identity, potency, safety, sterility and conformance products for identity, potency, safety, sterility and conformance with final specifications.with final specifications.

•• We will review a sampling of records for operations We will review a sampling of records for operations performed and verify that they are complete and maintained performed and verify that they are complete and maintained as required.as required.

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8/10/2011

DONOR ELIGIBILITY SYSTEMDONOR ELIGIBILITY SYSTEM

•• This system includes the measures/controls that are related to determining This system includes the measures/controls that are related to determining the donor eligibility of allogeneic and familythe donor eligibility of allogeneic and family--related allogeneic HCT/P related allogeneic HCT/P products, including donor screening and testing. products, including donor screening and testing.

•• We will review your SOPs for all steps performed in screening, testing and We will review your SOPs for all steps performed in screening, testing and determining donor eligibility, including who made the determination, and the determining donor eligibility, including who made the determination, and the results and interpretation of all donor screening and testing for relevant results and interpretation of all donor screening and testing for relevant

3131

p g gp g gcommunicable disease agents. communicable disease agents.

•• We will assess your SOPs for quarantine of biological drug products We will assess your SOPs for quarantine of biological drug products pending completion of the donor eligibility determination, the identification pending completion of the donor eligibility determination, the identification and storage of products from donors determined to be ineligible, and the and storage of products from donors determined to be ineligible, and the labeling and limited use of such products under the provisions of urgent labeling and limited use of such products under the provisions of urgent medical need.medical need.

WITHIN EACH SYSTEM, WE COVER WITHIN EACH SYSTEM, WE COVER (1)…(1)…

•• SOPsSOPs–– For each system, you should have approved written procedures and For each system, you should have approved written procedures and

associated records, e.g., testing, maintenance, cleaning, etc., that associated records, e.g., testing, maintenance, cleaning, etc., that document adherence to the procedures. document adherence to the procedures.

–– We will verify through actual observation whether or not you adhere to We will verify through actual observation whether or not you adhere to

3232

We will verify through actual observation whether or not you adhere to We will verify through actual observation whether or not you adhere to the SOPs. the SOPs.

–– We will determine if the SOPs include all steps to be followed in the We will determine if the SOPs include all steps to be followed in the processing, testing, labeling, and distribution of biological drug processing, testing, labeling, and distribution of biological drug products. products.

–– We will verify the most current version of approved SOPs is readily We will verify the most current version of approved SOPs is readily available for use by key personnel in the areas where the procedures available for use by key personnel in the areas where the procedures are performed. are performed.

WITHIN EACH SYSTEM, WE COVER WITHIN EACH SYSTEM, WE COVER (2)…(2)…

•• Training/personnelTraining/personnel–– Do you have an adequate number of trained personnel, Do you have an adequate number of trained personnel,

including supervisors, for all assigned functions and including supervisors, for all assigned functions and operations, for each of the systems?operations, for each of the systems?We will verify that all personnel responsible for supervising We will verify that all personnel responsible for supervising

3333

–– We will verify that all personnel responsible for supervising, We will verify that all personnel responsible for supervising, processing, testing, packing, and distribution of biological processing, testing, packing, and distribution of biological drug products have the appropriate educational drug products have the appropriate educational background, training and experience to perform their background, training and experience to perform their assigned functions. Training should also include CGMP assigned functions. Training should also include CGMP regulations, as necessary; to ensure the final product has the regulations, as necessary; to ensure the final product has the safety, purity, potency, identity and effectiveness it purports safety, purity, potency, identity and effectiveness it purports or is represented to posses.or is represented to posses.

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8/10/2011

WITHIN EACH SYSTEM, WE COVER WITHIN EACH SYSTEM, WE COVER (3)…(3)…

•• RecordsRecords–– Are records maintained concurrently with the performance of each Are records maintained concurrently with the performance of each

significant step in the processing, testing, and distribution of biological significant step in the processing, testing, and distribution of biological drug products so all steps can be clearly traced and documented?drug products so all steps can be clearly traced and documented?

–– If any records, which are required by regulation, are maintained in an If any records, which are required by regulation, are maintained in an electronic format in place of paper format the record keeping system electronic format in place of paper format the record keeping system

3434

electronic format in place of paper format, the record keeping system electronic format in place of paper format, the record keeping system should comply with 21 CFR Part 11 (see Guidance for Industry, Part 11, should comply with 21 CFR Part 11 (see Guidance for Industry, Part 11, Electronic Records; Electronic Signatures Electronic Records; Electronic Signatures –– Scope and Application, Scope and Application, August 2003).August 2003).

–– Are records legible and indelible, and must identify the person Are records legible and indelible, and must identify the person performing the work, including dates of the various entries; show test performing the work, including dates of the various entries; show test results as well as the interpretation of results; show the expiration date results as well as the interpretation of results; show the expiration date assigned to specific products; and be as detailed as necessary to assigned to specific products; and be as detailed as necessary to provide a complete history of the work performed? provide a complete history of the work performed?

THE INSPECTION IS OVER (THE INSPECTION IS OVER (), ), NOW WHAT?NOW WHAT?

•• The investigator(s) will have a closing meeting The investigator(s) will have a closing meeting with, at minimum, the MRI.with, at minimum, the MRI.

•• If objectionable If objectionable

3535

jjconditions/deviations/deficiencies were found, conditions/deviations/deficiencies were found, an FDA 483, Inspectional Observations, might an FDA 483, Inspectional Observations, might be issued (be issued ())..

FDA 483, INSPECTIONAL FDA 483, INSPECTIONAL OBSERVATIONSOBSERVATIONS

•• Observations made by the FDA representative(s) Observations made by the FDA representative(s) during the EI.during the EI.

•• In the experience, judgment and knowledge of the In the experience, judgment and knowledge of the A ( ) h dA ( ) h d

3636

FDA representative(s), the enumerated issues are FDA representative(s), the enumerated issues are potential violations of FDA laws and regulations.potential violations of FDA laws and regulations.

•• The citations do not represent the final Agency The citations do not represent the final Agency determination regarding compliance or whether/not determination regarding compliance or whether/not the product or license is approved.the product or license is approved.

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8/10/2011

DISCUSSION ITEMSDISCUSSION ITEMS

•• The FDA representative(s) may bring up issues The FDA representative(s) may bring up issues of concern that are not placed on an FDA 483.of concern that are not placed on an FDA 483.

•• These “discussion items” will be included on the These “discussion items” will be included on the

3737

narrative EIR and will be reviewed by narrative EIR and will be reviewed by Compliance Branch.Compliance Branch.

RESPONDING TO AN FDA 483RESPONDING TO AN FDA 483

•• It is encouraged, but not required, to respond It is encouraged, but not required, to respond to the discussion items or FDA 483.to the discussion items or FDA 483.

•• You can respond verbally during the final You can respond verbally during the final

3838

p y gp y gdiscussion and/or in writing to the District discussion and/or in writing to the District Office address as noted on the form.Office address as noted on the form.

•• If you choose to respond in writing, do so within If you choose to respond in writing, do so within 15 business days.15 business days.

GOOD LUCK!GOOD LUCK!

I LOOK FORWARD TO I LOOK FORWARD TO

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MEETING YOU IN PERSONMEETING YOU IN PERSON

30

Preparing for a FDA InspectionPreparing for a FDA Inspection

Speaker Contact ESpeaker Contact E--mailmail

Robert Lindblad, MDRobert Lindblad, MDpactinfo@emmes.compactinfo@emmes.com

Fran Rabe, MS, CQM (ASQ)Fran Rabe, MS, CQM (ASQ)Fran Rabe, MS, CQM (ASQ)Fran Rabe, MS, CQM (ASQ)rabex022@umn.edurabex022@umn.edu

Kip J. HanksKip J. HanksKip.Hanks@fda.hhs.govKip.Hanks@fda.hhs.gov

Web Seminar Presentation SlidesWeb Seminar Presentation Slides

Web seminar presentation slides and presentation slides from previous web

seminars are available publicly at

www.pactgroup.net www.pactgroup.net Select Education PACT Web Seminars

31

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PhysiciansAABB is approved by the Accreditation Council for Continuing Medical Education (ACCME) toprovide continuing medical education for physicians (Provider number 0000381). AABBdesignates this education activity for a maximum of 1 category 1 credit toward the AMAPhysicians Recognition Award. Each physician should claim those credits that he/she actuallyspends in those activities.

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Thank you for attending!Thank you for attending!

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