CBER Compliance Update

16th Annual GMP by the Sea

Tampa, Florida

August 9, 2011

Mary Malarkey, Director

Office of Compliance and Biologics Quality

Office of Compliance and Biologics

Quality

OCBQ – Director, Mary Malarkey

OCBQ - Deputy Director – Jalena Specht

Division of Case Management

DCM Director, Bob Sausville

Division of Inspections and Surveillance

DIS Director, Gill Conley

Division of Manufacturing and Product Quality

DMPQ Director, Jay Eltermann

DMPQ Deputy Director – Laurie Norwood

Division of Biological Standards and Quality Control

DPQ Director - Dr. Bill McCormick

DPQ Deputy Director – Dr. Rajesh Gupta

Summary

• Regulatory science update

• Enforcement

– Warning letter closeout update

– Recalls

– Biological Product Deviation

Reports

– Compliance actions

Regulatory Science

http://upload.wikimedia.org/wikipedia/commons/e/ea/H1N1_navbox.jpg

Sterility Testing Proposed Rule

21 CFR 610.12

• “Amendments to Sterility Test

Requirements for Biological Products,” 76

FR 36019; June 21, 2011.

• Developed by CBER/CDER working group

with input from ORA

• Would eliminate the need to submit

supplements under 21 CFR 610.9 for

alternate sterility test methods

Goals of Proposed Amendments

• Promote improvement and innovation in

sterility testing methodologies

• Increase flexibility for sterility testing to

address the needs of newer products

coming to the market

• Enhance the testing of currently approved

products

• Advance regulatory science

Highlights of the Proposed Rule

• Allow any validated sterility test method

that is appropriate to the material being

tested such that this material does not

interfere with or otherwise hinder the test.

– Eliminate references to specific test methods

and prescribed media

– Expand potentially acceptable test

methodologies to include non-culture based

methods in addition to culture-based methods

Highlights of Proposed Rule,

continued . . .

• Elimination of requirement for sterility testing of

most bulk material

– Generally require sterility testing of each lot of each

biological product’s final container material

– If due to the nature of the product, it is determined

that sterility testing should be performed on material

other than final product, details of the testing

(including process and rationale) should be described

in the BLA or supplement

Highlights of Proposed Rule,

continued. . .

• Modification of repeat testing requirement, so that repeat tests would occur only once for each lot and would be limited to situations when a thorough investigation by the quality control unit definitively can ascribe the initial evidence of contamination to laboratory error or faulty materials used in conducting the sterility testing

– Consistent with USP

Highlights of Proposed Rule,

continued . . .

• Discussion of validation and verification activities

• Replace sample number requirement with

requirement that the sample be appropriate to

the material being tested

• Replacement of Interpretation of Results section

with requirement that manufacturers establish,

implement, and follow written procedures for

sampling and testing

• Simplification of the Exceptions section

Next steps

• Comment period open until September 19,

2011.

Guidance

• “Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products,” issued January 2011.

• “Guidance for Industry on Process Validation; General Principles and Practices,” issued January 2011.

• Continued implementation of the guidance for submission of BLAs for cord blood, with October 2011 as end of two-year period for submission of BLAs and/or INDs– Final Guidance for cord blood INDs was issued on

July 29, 2011.

OCBQ

Division of Biological Standards and Quality

Control:

Regulatory Science Activities

• Laboratory Accreditation

• Development and validation of alternate

test methods

• FDA NOTE TO CORRESPONDENTS

For Immediate Release: Oct. 25, 2010

Media Inquiries: Shelly Burgess, 301-796-4651, shelly.burgess@fda.hhs.gov

Inquiries: 888-INFO-FDA

FDA laboratory receives accreditation

13 testing methods recognized under ISO/IEC 17025 standard

The U.S. Food and Drug Administration today announced that the American Association for Laboratory Accreditation has accredited the Laboratory Quality System program in the Center for Biologics and Evaluation Research (CBER) under ISO/IEC 17025 in the fields of biological and chemical testing.

The ISO/IEC 17025 is a standard developed by the International Standards Organization (ISO) and the International Electrotechnical Commission (IEC) to merge requirements for technical competence in testing and calibration laboratories with requirements for quality systems.

CBER received accreditation for six methods to test influenza vaccines, including those for sterility and potency, and seven methods for evaluating blood donor screening kits that detect the presence of HIV, HBV, HCV, HTLV-I/II, Trypanosoma cruzi, and West Nile virus. These laboratory activities have a direct impact on regulatory decisions. The Laboratory Quality System program supports the development and evaluation of national reference materials and standards, as well as evaluation of manufacturers’ assays.

Accreditation of CBER’s Laboratory Quality System provides additional transparency and acknowledgement of a program that has been recognized as an international leader in biological products regulation.

For more information:

About the International Standards Organization

http://www.iso.org/iso/about.htm

About the International Electrotechnical Commission

http://www.iec.ch/helpline/sitetree/about/

http://globalmessaging1.prnewswire.com/clickthrough/servlet/clickthrough?msg_id=6723673&adr_order=73&url=aHR0cDovL3d3dy5pc28ub3JnL2lzby9hYm91dC5odG0=http://globalmessaging1.prnewswire.com/clickthrough/servlet/clickthrough?msg_id=6723673&adr_order=73&url=aHR0cDovL3d3dy5pc28ub3JnL2lzby9hYm91dC5odG0=http://globalmessaging1.prnewswire.com/clickthrough/servlet/clickthrough?msg_id=6723673&adr_order=73&url=aHR0cDovL3d3dy5pc28ub3JnL2lzby9hYm91dC5odG0=http://globalmessaging1.prnewswire.com/clickthrough/servlet/clickthrough?msg_id=6723673&adr_order=73&url=aHR0cDovL3d3dy5pZWMuY2gvaGVscGxpbmUvc2l0ZXRyZWUvYWJvdXQ=http://globalmessaging1.prnewswire.com/clickthrough/servlet/clickthrough?msg_id=6723673&adr_order=73&url=aHR0cDovL3d3dy5pZWMuY2gvaGVscGxpbmUvc2l0ZXRyZWUvYWJvdXQ=http://globalmessaging1.prnewswire.com/clickthrough/servlet/clickthrough?msg_id=6723673&adr_order=73&url=aHR0cDovL3d3dy5pZWMuY2gvaGVscGxpbmUvc2l0ZXRyZWUvYWJvdXQ=

Applied Research on Alternate

Methods

• Rapid Methods to facilitate faster availability of products during emergencies (pandemic situation)– Rapid Sterility Method ( 5 – 7 days)

– Rapid Mycoplasma Detection Method ( 7 – 14 days)

• Accurate and Precise Methods for use in calibration of influenza reagents and for testing– Alternate protein determination

– SDS-PAGE with MALDI-TOF-TOF (in collaboration with other Offices and Divisions)

– RP-HPLC for quantitation of HA

– Alternate approaches to raise HA antibodies

Importance of Alternate

Sterility Test Methods

• Manufacturing Aspects

– Faster Screening of Raw Materials/In-Process

– Faster Resolution of Process Problems (PAT)

– Faster Implementation of Corrective Actions

• Changing Nature of Products (Biologics)

– Shorter Shelf Lives

– Smaller Quantities Available to Test

• Emergency Use (Influenza Pandemic)

Lot Release Gateway

• CBER developed an Electronic Gateway

for submission of H1N1 lot release

protocols, and worked with the individual

manufacturers to further expedite the lot

release process.

• A hugely successful endeavor that was

rolled out to seasonal influenza vaccine

Lot Release Gateway - 2

• Pilot for further expansion has begun

• Randomized sampling of all biological product manufacturers subject to lot release.

• Invited to participate in the electronic submission of lot release protocols and will be instructed in the preparation and submission of the electronic protocols.

• Evaluation of the 1st phase of the pilot by August 31, 2011.

Enforcement

Warning Letter Closeout:

Update

• For Warning letters issued on or after

9/1/09, FDA close out letter date posted

on the website when issued in accordance

with the Regulatory Procedures Manual

(Chapter 4; 4-1-8).

• Fourteen CBER issued warning letters

(does not include letters CBER concurred

with; issued by districts.)

Stats

• 7/14 have been closed and letters posted

• 2 of the remaining 7 are more recent i.e.–

not yet ready to close out

• 1 of the remaining 7 - corrective actions

continue – not ready to close

• 4 of the remaining 7 are internet letters

that will likely remain open

Stats - 2

• Time from issuance to close out varied by

type of firm/letter focus, with BIMO

generally sooner than other types.

• Range – 30 days – 10 ½ months

• Median – 2 months

The Numbers

FY06-10 – RecallsProduct FY06 FY07 FY08 FY09 FY10

Blood 1633 1240 1325 1035 1514

Source

Plasma150 132 119 171 331

Derivative 0 0 6 1 0

IVD 4 1 3 0 4

Vaccine 1 3 1 1 6

Therapeutic 0 0 0 0 0

Allergenic 0 0 1 0 0

Device 17 17 31 16 10

Tissue 36 22 23 13 16

TOTAL 1841 1415 1509 1237 1881

There was one Class I recall in 2010 – involving an HCT/P

Biological Product Deviation Reports FY08-FY10 #1

Number Of Reporting

Establishments Total Reports Received

Blood/Plasma Manufacturers FY08 FY09 FY10 FY08 FY09 FY10

Licensed Blood Establishments

247

(120*)

246

(113*)

250

(113*) 26,655 25,481 24,282

Unlicensed Blood Establishments 417 413 425 3,798 3,940 3,850

Transfusion Services 541 575 545 1,858 1,932 1,760

Licensed Plasma Centers

328

(43*)

374

(53*)

392

(48*) 11,814 18,168 20,173

Sub-Total 1,544 1,609 1,611 44,125 49,521 50,065

Total 1,675 1,745 1,749 44,740 50,282 51,012

*Number of license holders; one or more establishments

operate under one biologics license.

Biological Product Deviation Reports – FY08-10 #2

Number Of Reporting

Establishments Total Reports Received

Licensed Non-Blood Manufacturers FY08 FY09 FY10 FY08 FY09 FY10

Allergenic 7 8 7 169 192 197

Blood Derivative 17 19 23 49 64 99

In Vitro Diagnostic 8 11 14 77 83 117

Vaccine 15 18 17 98 168 242

351 HCT/P 0 1 2 0 2 6

Sub-Total 47 57 63 393 509 661

361 HCT/P Manufacturers

Cellular HCT/P 48 40 43 140 131 160

Non-Cellular HCT/P 36 40 32 82 123 126

Sub-Total 84 80 75 222 254 286

Total 1,675 1,745 1,749 44,740 50,282 51,012

FY10 Total BPD Reports By Manufacturing System

Licensed Non-Blood

Manufacturing

System Allergenic

Blood

Derivative

In Vitro

Diagnostic Vaccine

351

HCT/P TOTAL

Product

Specifications 179 25 52 91 2 349 52.8%

Quality Control

& Distribution 2 9 31 93 1 136 20.6%

Process Controls 9 35 6 13 0 63 9.5%

Labeling 7 4 14 16 1 42 6.4%

Testing 0 9 9 14 0 32 4.8%

Incoming

Material 0 15 4 11 2 32 4.8%

Miscellaneous 0 2 1 4 0 7 1.1%

Total 197 99 117 242 6 661

BPDR FY10 Notes

• 152 more reports submitted in FY10 than in the previous year (FY09-509)

• Vaccine manufacturers submitted 74 more reports (FY09-168; FY10-242). There were increases in the following areas: – Broken or cracked vials (FY09-78; FY10 - 84).

– Product specifications, general (FY09-43; FY10 91)

– Product not meeting specifications increased from 28

in FY09 to 33 in FY10.– Stability failures for potency (FY09–7; FY10-30)

• Allergenic manufacturers – no significant change from FY09-FY10

BPDR FY10- Notes - 2

• Plasma derivative manufacturers

submitted 35 more reports (FY09-

64;FY10-99). The process controls area

increased, specifically:

– Process/procedure not performed or

performed incorrectly (FY09-5; FY10-21)

– Processing performed using incorrect

parameters (FY09-1; FY10-11).

Compliance Actions

• Premarket - inspectional

• Postmarket - inspectional

• Advertising and Promotional Labeling

• Internet Surveillance

Premarket - Bioresearch Monitoring (BIMO)

FY07 FY08 FY09 FY10 FY11

Warning Letters 8 1 6 3 0

Untitled Letters 2 0 0 0 1

NIDPOEs 1 2 0 0 2

Disqualifications

/Restrictions1 1 1 2 2

Inspections

classified113 114 103 124 70*

*As of July 15, 2011

BIMO

• CBER continues random surveillance to focus

on agency priorities and vulnerable populations,

e.g. pediatric and elderly

• The 70 inspections classified thus far in FY11

represent:

– 42 clinical investigators

– 3 GLP

– 16 IRB

– 8 sponsor/monitor/CRS

– 1 sponsor investigator

Proposed Rule

• “Disqualification of Clinical Investigators,”

21 CFR 312.70; Proposed Rule; published on

April 13, 2011- 76 FR 20575

• For those disqualified, would extend to all FDA

regulated articles.

FY11 NIDPOEs/Disqualifications/

Restrictions• Wayne Spencer, M.D.

– NIDPOE – 4/20/11

– Disqualified by consent agreement – 5/11/11

– Indicted on federal charges of one count of conspiracy, three counts of mail fraud, and one count of falsifying information required by the FDA on June 2, 2011, in the District of Kansas

– Lisa Sharpe, a clinical research coordinator was also charged in the indictment.

http://www.justice.gov/usao/ks/PressReleases/2011/jun/June2a.html

http://www.justice.gov/usao/ks/PressReleases/2011/jun/June2a.htmlhttp://www.justice.gov/usao/ks/PressReleases/2011/jun/June2a.html

NIDPOEs/Disqualifications/

Restrictions - 2

• Alan Niederman, M.D.

– NIDPOE – 11/1/2010

– Restricted by consent agreement – 7/25/11

Other BIMO Items

• Stem Cell Pharma Inc.

– Untitled letter issued to Dr. Alfred Sapse November 22, 2006, for implantation of allogeneic amnion tissue to treat a variety of illnesses, without an IND and without screening and testing of donors.

– Indicted on federal charges of 7 counts of mail fraud, 13 counts of wire fraud and criminal forfeiture on July 15, 2010, in the District of Nevada.

http://www.justice.gov/usao/nv/press/july2010/sapse07152010.htm

http://www.justice.gov/usao/nv/press/july2010/sapse07152010.htmhttp://www.justice.gov/usao/nv/press/july2010/sapse07152010.htm

Postmarket/Inspectional:

Drugs and Devices

0

1

2

3

4

5

6

FY04 FY05 FY06 FY07 FY08 FY09 FY10 FY11

Warning Letters

Untitled Letters

Biological Drugs and Devices

GMP/GTP Compliance Actions –

FY11

• Warning Letters = 3

– Access Bio Inc.

– Octapharma AB

– CSL Ltd

• Untitled Letters = 2

– Parcell Laboratories

– National Genetics Institute

As of July 31, 2011

FY11 GMP Citations – Biological

Drugs

Citation Citation Language211.192 “You failed to thoroughly investigate any unexplained discrepancy or

the failure of a batch or any of its components to meet any of its

specifications, as follows…”

211.113(b)

211.94(a)

600.14

601.12

“Your firm failed to establish and follow appropriate written

procedures designed to prevent microbial contamination of drug

products purporting to be sterile and to assure that such procedures

include validation of sterilization processes.”

“You failed to assure that drug product containers or closures are

not reactive and additive so as to alter the safety, identity strength,

quality and purity of the drug beyond the official or established

requirements”

“You failed to report biological product deviations for lots of bulk and

final drug product that represent marketed product and have failed

stability at various time points”

“You failed to inform FDA about each change in the production

process established in your approved license application(s)”

FY11– Biological Drug

Intermediates and Substances

• Failure Investigations

• Production and Process Controls

• Control of Microbiological Contamination

• Equipment Cleaning and Maintenance

• Laboratory Controls

• Control of Components

Advertising and Promotional

Labeling

0

1

2

3

4

5

6

7

FY04 FY05 FY06 FY07 FY08 FY09 FY10 FY11

Warning Letters

Untitled Letters

* As of July 25, 2011

Advertising and Promotional

Labeling FY11 Untitled Letters

• Novartis Vaccines and Diagnostics, Inc. –

Fluvirin – 2/4/11

– Misleading presentation

– Lack of adequate directions for use

• Novartis Vaccines and Diagnostics, Inc. –

Menveo – 6/24/11

– Misleading presentation

Vision for CBERCBER uses sound science and regulatory expertise

to:

Protect and improve public and individual health in the US and, where feasible, globally

Facilitate development, approval of and access to safe and effective products and promising new technologies

Strengthen CBER as a preeminent

regulatory organization for biologics

INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH

http://images.google.com/imgres?imgurl=illuminations.nctm.org/images/pieces/vision.gif&imgrefurl=http://illuminations.nctm.org/pages/vision.html&h=215&w=168&prev=/images?q=vision&svnum=10&hl=en&lr=&ie=UTF-8&oe=UTF-8

I am among those who

think that science has

great beauty. A scientist in

his laboratory is not a mere

technician: he is also a

child confronting natural

phenomena which impress

him as though they were

fairy tales.

Marie Curie (1867-1934)

Public Access to CBER

CBER website:

http://www.fda.gov/BiologicsBloodVaccines/default.htm

Phone: 1-800-835-4709 or 301-827-1800

Consumer Affairs Branch (CAB)

Email: ocod@fda.hhs.gov

Phone: 301-827-3821

Manufacturers Assistance and Technical Training Branch (MATTB)

Email: industry.biologics@fda.gov

Phone: 301-827-4081

Follow us on Twitter

https://www.twitter.com/fdacber

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