UI!:J)ARTMENT OF IlEALTfi AND IIUMAN SERVrCES POOI> AN!

) DRUG ADMINISTRATION
DATE(B) 01' I SPEC

4040 North Central Expressway, Suite 300 Dallas. TX 75204 (214) 253-5200 Fax: (2ll]) 253-5314 Information: www.fda.gov/oc/industry

- 04/27/2012 3009499974

Corporation Su arland, TX 77478

Blvd, Biolo ical Drug Manufacturer

This document lists observatlons made by the FDA representative(s) during the Inspection of your facll.ity. They are inspectional observations, and do not represent I\. final Agency determination regarding your compliance. If you have an objection regarding an , observation, or have implemented, or plan to Implement, corrective action In response to an obsorvution, you may discuss the objection or action with the FDA represontatlvcts) during the inspection or submit this information to FDA at the address above. If you have any questions, please contact FDA at the phone Dumber III1daddress above.

DURING AN INSPECTION OF YOUR FIRM WE OBSgRVEO:

OBSERVATION 1 Control procedures are not established which validate the performance of those manufacturing processes that may be .responsible for causing variability in tho characteristics ofin-process material and the drug product. Specifically, You have manufactured (mesenchymal stem cells) MSC's which you have released for distribution at leas.irues 7/1/11 and to the present, however:
A. You have not performed a process validation for manufacturing related to each of the following finished product characteristics: and appearance of cells.

between

MSC's to assure batch uniformity and integrity as viability of cells, the specified cell count, cell typo,

B. ~rmedwmaanalyscs

~e

on the final product to assureWJlUJoftb.e fmalMSC's.

(b) (4)

C.

You have not verified the final product with the final MSC's.

:(b) (4) (4)

o assure the identity of the cell type in
the MSC's.

D. You have not performedrmmassay B. F.

to verify th .(b)

You have not performed installation qualification, operational qualification, biological safety cabinets, the incubators, and the centrifuges.

and performance qualification
of MSC's.

on the

You have not performed a validation of your banking and thawing process to assure viability

G. You have no requirement for pressure differential between the clean rooms and the exterior rooms to assure that non-controlled air does not flow in the cleanrooms. H. You have not monitored the temperature or humidity of the processing rooms where you manufactured SEE REVERSE OF THIS PAGE Joel Martinez, Investigator Linda M. Hoover, Investigator ,
~r'

7'u-.-.:iJI en? ~~
OBSERVA nONS

~

,/

04/27/2012
PAOElI

JNSPECTlONAL

or 9 PAUIIS

-

OJ)

2012

Corporation

Blvd,

mesenchymal stem cells (MSC's). The manufacturer's manual for states that should be in environmental conditions of
OBSERVATION 2

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, and followed. Specifically, You have manufactured MSC's which you released for distribution at leas. times between 711111 to the present. The MSC's are intended to be administered to patients either intravenously or injected intra-articularly and must be sterile. This inspection revealed:

,(b) (4) B. You have not validated your aseptic gowning process in order to prevent microbiological contamination. In addition there is no data to support the validation/quallflcatlon of the autoclave cycle, The autoclave is used to sterilize gowning wardrobe (lab coat) and parts of the incubators. C. You have not performed environmental swabbing of biological safety cabinets 8S part of your environmental monitoring program. In addition not been performed to assure IIIl adequate air flow pattern underneath the biological safety cabinet. The biological safety cabinets are used to aseptically manufacture the MSC's. D. Environmental test results of the clean room, blosafety cabinets, and gowning area show the isolation of microorganisms as the result of the use of settling plates. Some of the microbiological counts documented are beyond the established specifications. There is no data to show that the microorganisms isolated have been identified or investigated.

OBSERVATION

3

Written records are not made of investigations into the fai lure of a batch or any of its components to meet specifications. Specifically. A failure Investigation was not performed for the following out of specification results underlying reason or source of the failure:
SEE REVERSE OF THIS PAGE
JIOltM

Wld/OT

failures to determine the

Joel Martinez, Investigator ~ , Linda M. Hoover, Investigator ~~

04/27/2012

I'D"

413

DEPARTMENt'
DIS

roon AND DRUG ADMINISTRAnON

OF HEALTH AN}) HUMAN SEltVlCES

4040

North

Expressway,

Suite 300
3009499974

AR

TO:

David G. Eller" Therapeutics TX 77~70

CEO and President Corporation

~

Celltex
CITY. 8TA TE. Z

12621 Manufacturer initial and repeat testing for sterility; MSC's failed initial sterlllty

Sugarland,

A.

. T ti B. E d E dotoxin test records show the following MSC's uni_, failed initi 1e (b) (4) on 12-20-11 , on 12-7-U "I. • (b) (4) on 11-10-11. C.

testing: td

Environmental Testing: BacterJa and Fungl test resul~e been exceeded for the B~(Biosafety CabinetClean Room. Gowning Area, _(Clean Roo. _CCleanRoom. and BSCUEBioSafety Cabinet-Clcsn RoomIlBSC-M (Blosafety Cabinet-Manufacturing), BSC-Q (Biosafety Cabinet-Quality Control), ClcanRoorrii

In addition there is no written procedure for conducting failure investigations.

OBSERVATION 4 Drug product production and control records, are not reviewed by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Specifically, You manufactured MSCs which you released for distribution at least.imes between 711111 to the present. However, you have not reviewed all manufacturing rccordsJGIIGJ __ test records, endotoxin test records, or sterility test records prior to the release for distribution of the m()senchym~MSC's) that you manufactured as evidenced the following: by A. ~ The inspector signature line on the manufacturing record dated 10-20- 11 is blank, however, according to the outgoing log the MSC's were released for intravenous infusion on 10-21-11. B. ~ The inspector signature line on the manufacturing record dated 7-26-11 is blank, however, according to the outgoing log the MSC's were released tor intravenous (IV) infusion on 10-11-11. C. ~ The inspector signature line on the manufacturing record dated 10-6-11 is blank, however,according to the outgoing log the MSC's were released for intravenous (lV) infusion on 10-7-11.

SEE REVERSE OF THIS PAGE
FORM PlJA 03 Ot/OI)

Joel Martinez, Investigator Linda M. Hoover, Investigator
"OBVIOUS IlIlmON OOSOUITEI

..

::1'M·

DI\

e I88U

'/IJIH+-ODSERVA TIONS

04/27/2012

fNSPECTIONAl.

DEPARTMENT 011HEALTH AND RUMAN SERVICES
~OOLJ AND DlWO ADMINlSlRATION

gxpressway,

Suite 300

04/16/2012
~I R

- 04/27/2012

3009499974

FlRM

TO:

E

David G. Eller" Therapeutics TX 77478

CEO and President Corporation

ST

Celltex
ClTY.DTA'Ie,ZI

12621

Blvd, Manufacturer

Su arland,

8iolo

OBSERVATION

6

Batch production and control records do not include complete information relating to the production and control of each batch.
Specifically: A.

You do not document the addition oft_to MSC's. You do not document the addition of[(DlU}o You do not document the~ec1cs

yourttDlCland[UJlI)}:nedia the mlUJrnedia

used in tho manufucture of the

B. C.

used for tho banking of the MSC's. for evidence of contamination.

of your culture-expansion flasks ofMSC's

D. Manufacturing records lack required signatures. For example: 1. ~ signature. 2.
3. E. _

Lacks a biopsy date, signature of tissue acceptance, inspector signature, performer Lacks a signature of tissue acceptance, inspector signature, release signature for banking. Lacks a signature of tissue acceptance, inspector signature, release signature for banking

You do not document the identity of personnel involved in the packaging of the finished product (MSC's) for release and delivery to tho consignee/physician for use. You do not document in the Manufacturing Record the lot numbers used, or the expiration dates, of the following supplies and reagents used during the manufacture of the mesenchymal stem cells (MSC's): I.

F.

2. 4.
3. 5. 6. 7. 8. 9. 10. The lot number II. The sterile saline for injection used to
8)8

ii.iiI••••

to prevent bacterial and fungl growth culture expansion used to rinse tho MSC's. harvest the MSC's tubes III~ls~lI'olo~lcal pipettes is not recorded suspend the MSC's in the finished product

SEE REVERSE

OF THIS PAGE
FORMI'DAW
O!I

Joel Martinez, Investigator Linda M. Hoover, Investigator
flUMOUS BDITION 00SQU1TlJ

~t1
~

f

04/27/2012
OBSERVA TlONS

[NSPECnONAL

DEPAUTMIl.'NTOF IIEALTII AND IIUMAN SERVICES
FOOD AND DRUO ADM1N!SmATION
016 R

4040 North

Expressway, Suite 300

04/16/2012 - 04/27/2012 3009499974

Corporation Su arland, TX 77478 Biological Dru Manufacturer

12. The (b)

(4)

added to the culture media as cryopreservative

OBSERVATION

6

Equipment used In the manufacture, processing, packing or holding of drug products is not suitably located to facilitate operations for its intended use. Specifically, Table-top type centrifuges andtmJmncubator that you used for the manufacture of during this were observed to have been operated while on the floor. centrifuges, incubator modelmm and on the Stem your standard of practice since your on/about July 2011, All steps in the manufacture of mesenchymal stem cells (MSC's) requiring the use of these centrifuges OI{E)J1)]incubatol's was performed with these pieces of equipment on the floor.

OBSERVATION

7

HCTlPs made available for distribution were not labeled accurately. Specifically, You distributed mesenchymal stem cells (MSC's) which were not labeled accurately in that the labels did not include the following: A. The identity of the product (type oft issue), including whether or not it Is sterile B. The strength of the product (such at the number of MSC's per milliliter or syringe) C. The statements "AUTOLOGOUS D. The Biohazard legend E. lnstructions for use related to the prevention, transmission, or spread of communicable diseases USE ONLY" or "NOT EVALUATED FOR INFECTIOUS SUBSTANCES"

RE

SEE REVERSE
OF THIS PAGE
fORM FDA.w 891GB)

Joel Martinez, Investigator Linda M. Hoover, Investigator
I'IUIVIOU8llDntoH

.::rH·

D

;t!r.t-6l~.

04/27/2012
PAOD S OF 9 PAOIlS

0DS0Ll!'nl

INSPECIlONAL ODSEllVATIONS

OIWAUTMENT OF IJEALTH AND HUMAN SERVICF..5 FOOD AND DRUG ADMINISTRATION

Expressway,

Suite 300 3009499974

- 04/27/2012

Corporation Su arland, TX 77478

12621 W·. Airport Suite BOO
TYPE T

Blvd, Manufacturer

Biological

Dru

OBSERVATION

8

The dlatinctlve code for each lot of components is not used in recording the disposition of each lot. Specifically, A. You did not maintain a record ofthe receipt of supplies and reagents that you used to manufacture mesenchymal stem cells (MSC's), including: 1. 2.
3.

4. 5. 6. B.

Reagent or supply type Quantity Manufacturer Lot number Date of receipt Expiration stem cells (MSC's) include:

Supplies and reagents that you regularly use during the manufacture of mesenchymal

to prevent bacterial end fungi growth culture expansion to rinse the MSC's. harvest the MSC's ""nrrrrIlO'F! tubes serological pipettes added to the culture media as cryopreservative

OBSERVATION

9
identified as to its status in terms of being quarantined, approved or rejected.

Each lot of components was not appropriately Specifically,

Your process for verifying that your supplies and reagents used in the manufacture of MSC's met specifications before use did not include:
EIIPl

SEE REVERSE OF THIS PAGE

Joel Martinez, Investigator Linda M. Hoover, Investigator

.:1.1'1.
~
ObSERVATIONS

04/27/2012
P"'OIl~ OP 9 PAOBS

INSPECflONAL

nEPARTMF.NT OF HF:ALTH AND HUMAN SERVICES FOOD AND DRUG ADMrNJSTRATJON

Expressway, Suite 300 3009499974

- 04/27/2012

Celltex Therapeutics Corporation Sugarland, TX
A.

77478

Manufacturer used to prevent bacterial and fungi growth in culture media

Th .(b)

(4)

The Certificate of Analysis that you obtaIned for the Investigatcrs during this inspection for thetmJQ-tates, "FOR RESEARCH USE ONLY. CAUTION: Not Intended for human or animal diagnostic or therapeutic uses." B.
C.

Thc\llmand.flasks The (b)

used for cell culture expansion used to rinse the MSC's.

(4)

The Certificate of Analysis for thellllhat you obtained for the Investigators during this Inspection states, "CAUTION: Not for human or animal therapeutic use. Uses other than the labeled intended use may be a violation of local law," D. The_ed
to harvest the MSC's

The Certificate of Analysis for the~press states, "FOR RESEARCH USE ONLY. CAUTION: Not intended for human or animal diagnostic or therapeutic uses . E. Th •(b)

(4)
(b)(4)

centrifuge tubes

F. G.
H. The(b)

pipettes

(4)

~ dded

to the culture media as cryopreservatlve

You did not maintain certificates of analysis related to each lot of supplies and reagents that you used. According to your General Manager in. charge of Processing, this has been your standard of practice since your operations be an on/about Jut 2011. . OBSERVATION 10

Routine calibration and cbecklng of equipment is not performed according to a written program designed to assure proper performance. Specifically, A.
You do not document the temperature and~in

mesenchymal stern cells (MSC's).

your incubators used for storage/culture-expansion Your manufacturIng record specifies that culture is to be performed
OiIT

Ill.

of

SEE REVERSE OF THIS PAGE

Joel Martinez, Investigator~. Linda M. Hoover, Investigator

~/,fOBSERVATIONS

04/27/2012
PAOll 7 or 9 rAGES

INSPEC'l10NAL

DI!:PARTMENf OF llEAL1H AND HUMAN SERVICES
FOOD AND DRUG ADMlNIS'fRI\
0\8

nON

4040 North Central Expressway, Suite 300 Dallas, TX 75204 (214) 253-5200 Fax: (214) 253-5314 Information: www.fda. ov/oc/industr

- 04/27/2012 3009499974

Corporation

Biologioal degrees Celsius andtIDIQJ

Drug Manufacturer

B. C. D.

You did not calibrate your Incubators for temperature and .to

assure that their displays are 'accurate.

(b) (4)

You do not document checks of incubators for contamination, or tho routine of changing You do not document the temperature of the [mlCllncubator used during isolating MSC's. Your manufacturlng record specifies that the temperature of degrees Celsius for themUstop. You do not document thetemperature of the record specifies that the temperature of the
to b.degrees

thellUln the

E. F_

to thaw banked MSC's. Your manufacturing Celsius for the thawing procedure.

You do not document the temperature of the refrigerators and freezers used to store culture media, saline, and rea ents used to manufacture MSC's.
11

OBSERVATION

The batch records do not record the distinctive identification number and code to identify major equipment to show the specific equipment used in the manufacture of a batch of a drug product. Specifically. the distinctive Identification number is not always recorded In the manufacturing record fur the biosafety cabinets and incubators used in the manufacture of the rnesench mal stem cells.
OBSERVATION 12

Written procedures are lacking which describe in sufficient detail the identification and handling of components. Specifically, During this inspection, I (LH) observed misidentification/mislabeling manufacturing area, as follows.
A.

of components

in your mesenchymal stem cell (MSC)

(lDm on the ~~~
and' ' n the lid.

A bottle labeled

,.. """" '''' on one side was labeled .... the MSC culture mediun\llUwas ' labeled

[(Dlpafor_

B. A bftiJmontaining
C.

t.Xthe base for manufacturing.]

A bottle labeled ~as
HlllURE;

used to hold used pipette tips (waste).
Investigator
I

SEE REVERSE OF THIS PAGE
PORMJlDA •• 3 09/0

Joel

Martinez,

Linda M. Hoover

Investigator

~)1.

f?fIJ 14OBSEll.VATlONS

04/27/2012
PAOBIOHrAO[l8

PRllYIOUI!RDmotl onsourra

INSPECfIONAL

DEPARTMENT OIIIl£ALTIl AND HUMAN SEltVICF..S FOOD AND DRUO ADMINISTRATION

Expressway,

Suite 300 3009499974

- 04/27/2012

Ce11tex
OITY.

Therapeutics 77478

Corporation Manufacturer English was also labeled as a cleaning/senitizlng chemical in Korean (translated for me

Su arland, TX

Further, a bottle ofmm.in L b our Vice President
OBSERVATION Distribution 13

records do not contain the name and strength of the drug product, description of dosage form, name and address of consignee, date and quantity shipped, and lot or control number of drug product. Specifically, There are no destruction records for the following MSC's that failed sterIlity testing: A. 2012:(b) (4) B. 2011: (b)

(4)

OBSERVATION

14

Washing and toilet facllities are not easily accessible to working areas. Specifically, Specifically. you have no hand washing facility in the Stem CeU Laboratory where you manufacture mesenchymal stem cells (MSC's) Going to the nearest employee restroom entails going through strip curtains in the ttDlDlean room withinthe Stem Cell Laboratory followed by at least 3 doors. It Involves un-gowning. The worker must re-gown prior to re-enterlng the Stem Cell Laboratory.

8'1i

SEe REVERSE OF THIS PAGE
FORM fDA W ,,~

Joel Martinez, Investigator Linda M. Hoover, Investigator
P1BVI(>U.1lDIT1ON

04/27/2012
PAOR 9 OP 9 MOBS

omamu

JNSPRCT(ONAI, OBSERVATIONS

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