TffiZQf' INDIVIDUALTOWHOM RV'ORTISSUED FIRM … · SEE REVERSE Alurl e N. Alonso. M1crob: ... These bulk stock solutions are tested commonly for ... There is no documented evidence

OAT_,o;....,u:S)

Ramon a . Mar'tinez. • Investigator ~ [1'fx> .ruatJ..ne M. Corson. Investigator All 1aon A. Rodriguez. , Micr-obio l ogist Lauren H . Lavr..nce. Investigator Pamela 1. . Lee . ln~atigator

P..e la 1. . Ogonowski . Investigator Douglu S . Joslin, l<;>ve&t~gato~ 9~0"' Alurl e N. Alonso. M1crob:.olog1st /! ..SEE REVERSE Aabley N. Whi tehurat. Invest iga.tor 11/09/2012

OF THIS PAGE Bartlett, ~ ~~~

Pll11ip lreiter, Investigator ,.e-. Rory Geyer . Investigator Ni c:llole B. Mllrphy . Invee tig!tor ~ . ld Q •• ~-Mary~ Mcgarry. tnve&tlgator ...1 ...... \

..,Slater.. 1<··~~.. ··~··Investigator..~·· ~~l '~;/tnz:..~nv~igatrru:- 1), ~uv-'?f.t..~J'1

' )

FORM FDA 41J (09/01) psu,VlOIIS EDITION OBSOLETE INSPECTYONALOBSERVATIONS PAGE I OF 20 PAGES

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUO ADMINISTRATION

v- n~ -~~• ANO """"",..._~

One Montvale Avenue Stoneham, MA 02180 (781) 587-7500 Fax: (781) 587-7556 Industry Information: NAMt: NI/J TffiZ Qf' INDIVIDUAL TOWHOM RV'ORT ISSUED

DAl'E(I) OF IH8f't!Cl10H

10/10/2012 - 11/09/2012*

3005881167

TO: Gregory A. Conigliaro, Vice President and General Manager FIRM ""-'ME

Ameridose, LLC ...Ht.l """""""

201 and 205 Flanders Rd ClTY,ISTATE. ZP ........,, <;UU't l<T

Westborough, MA 01581-1032

This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a 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 observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA at the address above. Ifyou have any questions, please contact FDA at the phone number and address above.

rYPe ~

Sterile Drug Manufacturer

DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:

OBSERVATION 1

Testing and release ofdrug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the identity and strength ofeach active ingredient prior to release.

Specifically,

Your firm manufactures admixtures from stock solution ofactive pharmaceutical ingredients or commercially available finished products. However, the firm does not test the potency of the final drug product after numerous lots are further diluted from these bulk stock solution. Moreover, your firm has received approximately 33 complaints claiming lack of effect, patient response events and ineffectiveness for products. For example: Ephedrine lot 021420 12@3 72, Fentanyl lot 09042012@820, Oxytocin lot 12272011@ 1099 in 2011 and 2012. These lots were not tested for potency before release for commercial distribution.

This is a repeat item to the FDA 483 issued on 08/06/2008.

OBSERVATION 2

Each batch ofdrug product purporting to be sterile is not laboratory tested to determine conformance to such requirements.

Specifically,

www.fda.gov/oc/industry

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG AOMINlSTRATION

DISTRICI """""'SSAHOPHClHE ~

One Montvale Avenue Stoneham, MA 02180 (781) 587-7500 Fax: (781) 587-7556 Industry Information: NAaoiE AND "''"""" lfOVIOUIII. TOWHOIII RUQR ISSUED

DAT£(S) OF INSPECTION

10/10/2012 - 11/09/2012* I'!IIMIIIER

3005881167

TO: Gregory A. Conigliaro, Vice President and General Manager FIRM NAME SlRB<T ADDRUS

Ameridose, LLC 201 and 205 Flanders Rd CITY, SOAll:, UP CODe, COUtiTRY TYPE' E'STAIII.I&...ENT 1NSP£CTED

Westborough, MA 01581-1032 Sterile Drug Manufacturer

OAn:r~oucuEMPI.OYE'E(S) SIONAT\JRI! ~

Ramon E. Martine•. Investigator :Jy-- f JUetlne M. Coraon, Investigator Allioon A. Rodriguez . Microbiologist Lauren M . Lavra.nce, Jnve-otigator Pamela t. . Leo. Investigator Pamela L. ogonowetl, Investiga tor DouglasS . .:loslin , Investigator ~- . ~~~ Alaaris N. Alonso, Hicrobiologi•t ~~SEE REVERSE Asbley M. lfhitehurst, Invutigotor 11/09/2012

OF THIS PAGE Pmy C. Jordan. Inveatigator ~ Slater K. Bartlett, tnveatigator ~ -~L---Philip Kreiter . lnveotlgator _l "l::i:A-Rory Geyer. lnveatigator Nichole 8. MUrphy. Investigator In ~A. uNary.- Hcgarry, Investigator ':"0' -_- ft. R':.-" ~.J Nr'E· ~~eot~atr"""' H~~..binlrr,;a

FOR.\1 FDA 4IJ (09/U) PREVIOUS EDrTIOHOIISOI.ETE INSPECTigAL OBSERVATIONS PACE 2 Of 20 PAGES

Your firm manufactures admixtures from stock solution ofactive pharmaceutical ingredients or commercially available finished products. These bulk stock solutions are tested commonly for sterility, and only the ones manufactured from active pharmaceutical ingredients are tested for the presence of bacterial endotoxin. The firm performs numerous manual aseptic manipulations in the filling of the sterile injectable drug products intended for patient use. Your firm does not test final units of finished product lots for sterility and the presence of bacterial endotoxin in finished sterile drug product lots after aseptic manual filling operations before release (e.g. Ropivacaine 0.2%, Lot 09262012@104.)

This is a repeat item to the FDA 483 issued on 08/06/2008.

OBSERVATION 3

There is a failure to thoroughly review any unexplained discrepancy and the fai lure ofa batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.

Specifically,

A. Your firm failed to investigate microbiological contamination observed at least fifty three (53) times noted during (b) f.l) sterility testing of sterile stock solutions intended to be used in the manufacture ofsterile injectable drug products, including lots of Fentanyl, Ropivacaine, Morphine, etc. In approximately eighteen (18) instances your firm retested the affected stock solutions and microbiological contamination was also observed in at least one of the retest samples.

I. There is no documented evidence that suggests that a health hazard evaluation was initiated or conducted in order to assess the potential quality impact of microbiological

4isolates noted during the~b) ( ) terility testing.

2. There is no data to support your firm's claim that all the sterility failures were attributed

SEE REVERSE OF THIS PAGE

EMROYEE(S) SIGNATURE

Ramo':' E. Martinez , Investigator '1t.-.... f.~ JUSt.l.ne M. Corson. Inve&tlg&tOr "'r''"' ..-f'\J Allison .>. . Rodriguez . Hicrobiologht Lauren M. Lawranee , Investigator Pamel• t.. J,oe. tnveetigat.or P....,la L. ogonoweki, Invenigator DouglasS . Joelin, Investigator ~A -~~AliNiris N. Alonoo, Microbiologil t ~ .>.anley M. 111\ltehurot , Inveetigator ~ Amy C. Jordan . Invest igator · ..

UAII:III<iUI:U

11/09/ 2012

Slater K. eartl•tt, Inveetigator ~~ Phi lip Kroiter, Inveetigator :;/, ,A, Rory Geyer; , Invest igator Nicl!ole B. MUrphy. Investigator ~h Mary- Mcgarry, Investigator

~a:::, N_t"t:.:,;.J:=:igato~nr~ fit-.......b~'-'nid FOR!It fDA .W (0!~

I ....J PUVIOUS £DmotiOBSOLETE INSPECTIONAL OBSERVATIONS PAGEl OF 20 PAGES

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

OISTRIC ADDRESS AN/0 PKONE NUMBER

One Montvale Avenue Stoneham, MA 02180 (781) 587-7500 Fax: (781) 587-7556 Industry Information: www.fda.gov/oc/industry

OATE(S) OF INSPECT10H

10/10/2012 - 11/09/2012* l'tl NUMBI:A

3005881167

NAME AND 'I1TIZ Of' IMOI\IIDUAI. TO WHOM REPORT ISWEO

TO: Gregory A. Conigliaro, Vice President and General Manager

Ameridose, LLC STREETADOfiESS

201 and 205 Flanders Rd CITY. STA~ ZP CODe, COUI'fTRY

Westborough, MA 01581-1032 TYPE ESTAIIUSHMENT INSPECTED

Steri le Drug Manufacturer

to contamination during the perfonnance ofthe{6)l:i:O~terility method.

3. There is no documented evidence that your finn implemented pennanent corrective actions to prevent these sterility events from recurring.

Furthennore, approximately(b) lots of sterile injectable drug products were manufactured and released from the affected stock solutions lots.

B. Your finn failed to adequately investigate three (3) sterility failures (OOS 12135 dated 04/26/2012 and OOS 12145 dated 05/03/2012). For example, the following was observed regarding two 2012 sterility failures (Sodium Bicarbonate stock solution lots S05022012@388 and S05022012@390 on 5/3/2012; and Hydromorphone 0.3 mglmL stock solution lot S04242012 on 04/26/2012).

I. The investigation into the two sterility failures did not detennine possible root causes of the contamination. Notably, it also lacked any meaningful corrective or preventive actions to prevent future non-sterility events.

2. The investigations failed to extend to all associated lots that may have been manufactured under the same inadequate practices or conditions that led to the microbial contamination of these lots.

3. Sterility test positive results were routinely considered questionable by the laboratory, and re-testing done justification. More specifically, when a positive result is

4 obtained using sterility testing method, your considers the initial positive to be an "inconclusive" or "suspect" result and re-testing. This is done although no ofcontamination has been identified. It is noteworthy that

was done, the testing often revealed additional non-sterile

wasr. witnr ut thcl{ <b)

4when further(b) { ) lesting units. This includes but not limited to all lots that are named in this observation.

finn perfonns

laboratp..D::.Jiause

~O'I'E£(S) SIGNAT\JIW

Ra110n E. Martinez. Jultine H. Cor•on.

Inveat~gator tnveatlgator

~~ J'l.-... f, r~·- 1

Alliaon A, Rodrig~>e z , Microbiolc>9iot t.auren M . L.avranee, Inveotiga.tor Pam• la L, Lee, Inveotigator Panela L . Ogonowskl, Invu tlgator


Douglas s . Joalin, Invest i gator ~~~ Almaria N . Alons o. Mleroblol0918t ~,-7-- A.ohley M Wh itehurst, Invest igator

~c. Jordan, Inveetigator ~~~~ -...........Slater IL S.rtlett . I nvestigator ~ L. ... .._,, _) Philip ltrei ter, l nveetigator :1.: / L- ..4/..L.---Rory Geyer , Inveet !gator "'

ll/09/2012

Nichole B. MUrphy, Investigat or Mary~ Mcgarry , I nvestlgetor 1

tl ~ • J. : -\

"B:or::t,• w.• /~rn'l'~Dt;t"~i;:to{ln.e-ik ,,A...J,;., l~ I ·~

FORM FDA 43(09101) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS PACE 4 OF 20 PACES

4. Your firm did not adequately differentiate or subculture microbes found in sterility test positives. Both lots that failed sterility were assumed to be cocci based on observation under microscope. However, despite multiple findings of contaminated units, no attempts were made to subculture the bacteria av.~rther differentiate the microbe to determine its identity (e.g., gram stain, use ofth~b) ( ) _pvailable in your microbiology lab).

5. Insufficient relevant EM/personnel monitoring data was available from the production operations to correlate possible contamination sources in the environment with microbes found in sterility tests. Without knowledge of identity of microbes found during environmental monitoring, your firm lacked critical information to investigate possible root causes of the sterility failures.

C. The Quality Unit failed to adequately investigate, and implement permanent corrective actions after 45 environmental microbiological excursions (bacterial and mold) were isolated from critical areas such as personnel fingers inside class 100 hoods and controlled manufacturing areas (surfaces and air) during the manufacture of sterile injectable drug products in 2012. There is no documented evidence that suggests that a health hazard evaluation was initiated nor conducted in order to assess the potential quality impact of isolates present during the manufacture ofsterile drug products. Furthermore, your firm does not perform identification of the observed microbiological isolates.

D. Your firm failed to adequately investigate complaints for the following reason(s):

1. Your firm's Quality unit failed to appropriately classify "patient response" complaints as adverse events. Additionally, your complaint investigations failed to address patient outcome or patient intervention.


015TRIC ADDReSS Ale) PHOHe NUMIII!R

one Montvale Avenue Stoneham, MA 02180 (781) 587-7500 Fax: (781 ) 587-7556 Industry Information: www.fda.gov/oc/industry HAM!: AND~ Of' INDIVIDUAl. TOWHOM R£P0RT INIJeO

l)A~INSPECnON

10/10/2012 - 11/09/2012* FEINUIIB!R

3005881167

TO: Gregory A. Conigliaro, Vice President and General Manager FIRIINAMI! SlREETAODRI!SS

Ameridose , LLC 201 and 205 Flanders Rd I'll , IIIATE, ZIPCODE,<;O\MIR' VPE~$ AILISMoENT I~TEO



DISTRICT ...ooREISS AND PHONE NUMII~

One Montvale Avenue Stoneham, MA 02180 (781) 587-7500 Fax: (781) 587-7556 Industry Information: NAME NfD TITU! DP INDIVIOUAI. TO IM10MRePORT ISSUED

ClATE(S) 01' INSPECTION

10/10/2012 - 11/09/2012* FEI~

3005881167

TO : Gregory A. Conigliaro, Vice President and General Manager fiRM NAME

Ameridose, LLC """'''' ADORe"" 201 and 205 Flanders Rd

Cll , ~ATE. ZAP COD!!, COUNTRY Pll 1!5TAIILISHMENT IN..,t!CTED


DAre.......,.,E-.OYU(S) SlGNAT\RE ~

Ra100n £ . Martinn. Investigator )~ £1J\u1tine M. coraon. Investigator Allieon A. Rodriguez. Microblologllt Lauren H. Lavcance , Inveltiga tor Pa.aela L. t.ee . tnveet.igator Pamela L. Ogonowski, Inves~igator

Dougl.. s. Joslin , Investigator ~~-Almaria N. Alonso, ..icrobiologiat SEE REVERSE 11/09/2012As~l"Y M. Whitehurst. Investigator ' • ~

OF THIS PAGE .. '· ..~. '""""""' ~Slater K. hrtlett, Jnveotigatoc /. A Phi lip Kreiter, Invest lgator Rory Geyer. tnveet lgator Nichola e. MUrphy , Investigator , t '"" . ~ Mary- MCgarry, Investigator t"'"jJ>:!:..;,/r~.. .II\ H.· .~,.,•. ) ...,i.

I

FORM FDA .U(09/H) PRfVlOUS EDmON OBSOLETE INSPECTtONAL OBSERVATIONS PAOE S Of 20 PAOES

This includes the fo llowing complaints:

Complaint Date

Received Drug

Produet Lot Description

AC11589 12/22/11 Oxytocin 12122011 @451

Communications between the firm and the complainant referenced "fetal distress and hyper stimulated uterus".

AC12430 9/6/12 Oxytocin 08252012 @73

Accompanying documentation states "customer called to report increased cases (5) of post partum hemorrhaging".

AC12118 2/15/12 Oxytocin 12 1620 11 @131

Accompanying documentation states "patient had shortness of breath, the throat was closing, and coughing".

AC12070 1124112 Heparin 010620 12 @336

Accompanying documentation submitted by the complainant states that the outcome of the adverse event to be "lifethreatening".

AC12428 9/7/12 Fentanyl 09042012 @820

Accompanying documentation states "Patient was over sedated, unresponsive".

DEPARTMEI'IT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMJNISTRATION

01$TRICT ADDftfSS AND PHON£ MJ-" One Montvale Avenue Stoneham, MA 02180 (781) 587-7500 Fax : (781) 587-7556 Industry Information: www.fda.gov/oc/industry -AND TITU:<X II<I>IVDUAL TO WHOioii'IV'QftT '"""""

DAa(ll) ~INSPECTION

10/10/2012 - 11/09/2012* FEINUMBIOI<

3005881167

TO : Gregory A. Conigliaro, Vice President and General Manager FIRM MANE 5TR£ET ADDRE$8

Ameridose, LLC 201 and 205 Flanders Rd CITY &TATE. ZIP COOl<, COUNTRY TYPE E&TAIILIIIHMEHT IH&I'ECTED


AC12131 12/27/12 Fentanyl 01272012 @61

Communications between the firm and the complainant refer to 2 patients going into "respiratory distress" after receiving the medication.

2. Your firm's Quality unit failed to evaluate complaint sample(s) associated with the following complaints:

This includes the following Midazolam complaints which are associated with a "patient response" and low potency claims:

Complaint Date Received Midazolam Lot AC 12244 5/9/12 05012012@41 AC12186 3/26/12 02112012@245 AC12195 4/2/12 03282012@674 AC12120 2/23/12 12222011 @157

This includes the following Oxytocin complaints which are associated with a "patient response":

Co~plaint Date Received Oxytoxin Lot AC12030 01/11 /12 12272011@1099 AC11589 12/22111 12122011@45 1

AC12179 03/19/12 0216201 2@295, 02232012@260,

02242012@308 AC12409 08/27/12 080720 12@30 1

EMPI.OYCE(S) SlGNAnJRE OATEISSUI!.D

Ranoon E. Martinet. Investigator ~ t'Jl]Juet.ine M . Cor-aon. Investigator Allioon A. Rodriguez, Microbiologht La.u.ren M . La\llrancf:. Investigator Panela s.. . Lee. Investigator Pamela 1.. Ogonowaki. Inve.et.igator Dougl~s S . Joelin, lnvest~gator ~~- • Aluns N. Aloneo, Hicroblologist • ~ Aehley H. Whitehurst. Investigator

SEE REVERSE 11/09/2012

Azrty C. Jordan, tnveatigatorOF THIS PAGE Philip Kreiter, Invoat igator...... ' · '>«'""· '""""""' i~ Rory Geyer . Investigator Nichole B. HUrpny, Investigator Ma~t Mcgarry, lnvsstigator

;.c:~;A 'irn~: !J'vestigat~~f).. ..Jll':t9hlnh•,'ld FOJl\f rDA .aJ (09M) PUVIOUS E011'10H OBSOI.EIE INSPEcr'i'ONAL OBSERVATIONS PAOE 6 Of20 PAOES


DISTRICT ACOftU$ AN0 PHONe NUMIII!R DATE(S) OFIN,...,.Cn<>N

One Montvale Avenue 10/10/2012 - 11/09/2012* FEINUWIERStoneham, MA 02180

(781) 587-7500 Fax: {781) 587-7556 3005881167 Industry Information: www.fda.gov/oc/industry NA"" AND~D1' IHDMOUAI. TO WHOM llf:POIH ISSUI!D

TO: Gregory A. Conigliaro, Vice President and General Manager FIRM NAME STREET AOORESS

Ameridose, LLC 201 and 205 Flanders Rd CllY, STATE. ZIP CODE. COUHTIIY TYPt! NT IHSP!CT~O

Sterile Drug ManufacturerWestborough, MA 01581-1032

EMPI.O\'EE(S) 6ICOHAlUI£ OATEISSUEO

R4110n E. Mart i nez. I nvestigator ~ f ~ JUatine M . coraon . Investigator Allhon A. Roclrig\lez. Microbiologist Lauren M. Lawrance. Jnveatigator Pamela L. Lee, Jnveotigator Pamela L, Ogonowski. Investigator DouglasS. Josli.n, Investigator ~~ .., Almaris N. A.lonso . Mierobiologilt """SEE REVERSE Aahley M. Whitehurot, Investigator - -~ 11/09/2012

OF THIS PAGE My C . J orc:1an . tnveetigator _

"•••• '· k•U~•. -""•'« 5!:~ _.-Phil i p Kreiter. Investigator y-Jtory Geyer f lnve..atigator N1ehole B. MUrphy, Investigato.r Ma~t Mc:9arry, Invutigator

rh...".:..tr2~~.!:l~~t~r C!n6'~ H.~~,,~~d .)

FORJ\1 FDA 413 (~.ro&) I'RfVIOUS EomoN OBSOI.ETE INSPECTION~L OBSERVATIONS PAOE 7OF 20 PAGES

3. Your firm's Quality unit failed to investigate a trend of complaints associated with Midazolam for low potency I lack of effect.

The Table below summarizes this information:

Date Received

Complaint Midazolam Lot Additional Information

02/23/2012 AC12120 122201 1@157

Made reference to an unspecified adverse event and the involvement of more than one patient being affected.

03/02/2012 AC12133* 02222012@654 02172012@24802122012@1

Made reference to more than one patient being affected and that a few physicians were concerned about potency.

03/08/2012 AC12144* 03032012@39 02122012@1 01312012~42

Made reference to reports from more than one anesthesiologist about product response.

03126/2012 AC12186 02 112012@245 Made reference to more than one Qatient being affected.

04/02/2012 AC12195 03282012@674 Made reference to lack of effect despite using the max allowable dose.

05/09/2012 AC12244 05012012@41 Made reference to more than one patient being affected and reports from more than one nurse.

09/06/2012 AC12427 08272012~43 Accompany documentation states

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMrNISTRATION

()I~TRICT AOORESS AND PHONe NUMBI!R

One Montvale Avenue Stoneham, MA 02180 ( 781) 587-7500 Fax: (781) 587 -7556 Industry Information: www.fda.gov/oc/industry NAME AN0 TTnE Of' INOMOUAI. TO WHOM A !:PORT ISSUED

DAlECS) 01' INSPECTION

10/10/2012 - 11/09/2012* F£1 NUMIIE!l

3005881167

TO: Gregory A. Conigliaro, Vice President and General Manager FIRMW.~

Ameridose, LLC Cl , lJJATE ZlP CODE, COUNTRY


SlREET ADORES&

201 and 205 Flanders Rd TYPE ESTA8USHIAENT INSPEClED


*Complaints AC 12133 and ACI2144 reference the same lot (02122012@1) and were received from independent customers. The final, Quality approved reports state "No trends associated with this lot".

4. Your firm fai led to investigate the following complaints as they were defined as "noncomplaints" by your firm's Quality unit:

Drug Date Received

Lot Description

Norepinephrine 09/28/2012 09242012 @553

Concerns related to potency; related to an adverse event.

Succinylcholine 09/17/2012 06212012 (a)309

Concerns related to potency; associated with an adverse event.

Meperidine 08/31 /2012 08272012 @598

Complaint stated "bubbles of drug along the rim, outside of the drug reservoir"; sterility concerns

Fentanyl Bupivacaine

09/07/2012 07132012 @472

Under-filled product concerns.

Nalbuphine 08/30/2012 08282012 ~978

Syringe fill volume concerns.

Furthermore, all of these complaint files were reviewed and deemed acceptable by your Quality Unit.

E. Your firm failed to investigate aberrant peaks in HPLC chromatograms associated with finished sterile product. This includes the following:

DATE ISSUEDEMI'\.0\'EE(S) SIGNAl'-""

Raaon E. Martinet: . Inveeeigator ~~ Juatine M . Corson , Inveetigator .. Alliaon A. Rodrigues, Microbiologiat Lauren M. Wwconce, Investigator Pamela L. Lee , Investigator Pamela !.. Ogonowaki , Inveotigator

SEE REVERSE Douglass. Joolln , Investigator ~. Almaria N. Alonao, Microbiologia

11/09/2012OF THIS PAGE

Ashl ey M. llhitellurot , Investigator lo"'f c. Jordan , Invenlgator ~ / slat e r K. Bar.:lett , Inveotigator ~ ~~ Phi lip Krei ter, Inve stigator ' Rory Geyer , Inveatigator Nichole B. ,_.rpt>y, Investigator ~1.~ Mary-'- Mcgarry, Inveotigator &...\ 1J.":'t.. ~·.r?e'L~':J':::~•to~nG.f>... : '· • -:r ,id

I

FORM f"l>A 43 (89/01) PREVIOUS EDIT10N 08SOt.ETE INSPECTI.~ALOBSERVATIONS PAGEl Of 20 PACES

08092012@786 "they have had three (3) pediatric patients require extremely large doses for relief'.


DISTM!CT ADDfti:SS N<O

One Montvale Avenue Stoneham, MA 02180 (781) 587-7500 Fax: (781) 587-7556 Industry Information: www.fda.gov/oc/industry HAMI! AND TinE OF INDIVIDUAl. TO WHOM RI:POAT ISS\JED

""'et")D" INSPeCTION

10/10/2012 - 11/09/2012* I'E....,._R

3005881167

TO: Gregory A. Conigliaro, Vice President and General Manager FIRM NAME STREET ADDRESS

Ameridose, LLC 201 and 205 Flanders Rd CITY STATE.ZIPI.OUUO:,I.NUNIH'



FO RM FDA 48J (119/U)

.......o~e(S)SKINAlURE

Ramon E. Martinez. tnveat igator il...____ £~ Juatino M . Coreon. tnve1tigator "' ~fll'!o ··1~ Alliaon A. Rodriguez, Miccobiologiot wauren M. ttawrence , Investigator Pamela. L. Lee , Inveatigator Pamela L. Ogonowski, Investigator oouglaa s. Joslin, Investigator ~~~~ __ Alturh N. Alonao, Microbiologist-,...,...--- • ~·

A.ehley M. Whitehurat, tnveaeigator - ~ 11/09/2012 My C. Jord•n. Inveatigat.or ~ Sl•ter K. a&rtlett. , Investigator Philip Kreiter , Investigator Rory Geyer, Investi gator Nichole 11 . MUrphy, Investigator ~ MAry~ Mcgarry. Inve.etigator • I fJ.."'::;:,;Jn..:::r::..~t:>rcD€.P-. H,: .d

n.EVIOUS EDJ'OOtol ~ 1

INSPECTIO~ALOBSERVATIONS ,AGE 9 Of 20 PAGES

I On 03/23/2012, a Diltiazem,lot 02152012@318 complaint sample (AC 12165) was evaluated by HPLC analysis to determine potency. The chromatograms associated with the sample exhibited several unknown peaks when compared to the control (reference standard). Additionally, the complaint was associated with a "patient response" in which the recipient of the drug "developed a phlebitis-type reaction with tracking up the veins". The unknown peaks have not been investigated nor have they been evaluated with respect to the "patient response".

2. On 08/08/2012 a Ropivacaine,lot 07022012@344 complaint sample (Complaint AC12382) was evaluated by HPLC analysis to determine potency. The chromatograms associated with the sample exhibited an unknown peak when compared to the control (reference standard). Additionally, the complaint was associated with a "patient response" in which the product "was not giving relief to 4 patients". The unknown peak has not been investigated nor has it been evaluated with respect to the "patient response".

3. The HPLC chromatograms used to evaluate potency for Morphine stock lots 809252012@381, 809252012@382, and 809252012@448 exhibited an unknown peak when compared to the control (reference standard). The lots were released on 09/27/20 12 for further manufacture. The unknown peak has not been investigated nor has it been evaluated with respect to patient risk.

OBSERVATION 4

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process.

Specifically,


01" ltd<.; I AUUKo.SS AND PtiONUIUMBER

One Montvale Avenue Stoneham. MA 02180 (781) 587 - 7500 Fax: (781) 587-7556 Industry Information: www.fda.gov/oc/industry

10/10/2012 - 11/09/2012* FEINUMBER

3005881167

NAME NW TIILo. ....-....,.,........._TO WHOM REPQR ISSUUJ

TO: Gregory A. Conigliaro, Vice President and General Manager FIRM NAME

Ameridose, LLC STREET ADDRESS

201 and 205 Flanders Rd CllY, STATE, l .. CODf. COUNTRY



EMPI.OYEECS) SIGNATURE : ~ Ramon a . Mart inez. Investigator ~"""" ( Justine H . Coraon . Investigator J J Allieon A. Rodr igue< , Hi erobi ologiet Lauren M . L.avrance . Investigat or P....,..la L. Lee . Inveaugator Pa:oela L. Ogonowaki. Invest igotor Dougl~ s. Joal 1n, Inves t igator c:;e::e /'""Z «-= _ Alnaar1s N. Al onso, Microbi o l ogi s t -- - --7-~ Ashl e y M. Whi tehur•t. I nves t i gator

Sla te r ac . Bar t l e t t . Investigator111ay c . Jocdan, Inveatigator ~~

llA TE ISSUI!D

11/09/2012

Philip n e i ter, I nvestigator '/ Rory Geye r , I nveat 1guor Nichole B. Murphy , Inves tigator lk.f-.L~ Ha~t MCgarry, Invutigator ,...~ ~ono&e 11 . erner.:. tnvc;ot i gator . _ ~" ~ 1 0 • 1 .~ I .... _t:. 1 . 'L-i'IPriNV">"" I'll~>'I" Hlr'Vrlhlr,/• n ff

FORM FDA 41J (09/N)

~

PREVIOUS EDITION OBSOlETE INSPECTIONAL OBSERVATIONS PAGE 10 Of 10 PAGES

A. The sterile technique qualification (media fills) do not represent your routine operating conditions and does not evaluate worst-case activities that can provide a challenge to manual aseptic operations. Specifically,

1. Your media fills do not challenge the maximum number of times drug product lots can be filled from sterile stock solutions or the maximum number of units filled without increasing the risk ofcontamination of the manufactured sterile dryg_12roduct. For example stock solutions can be stored and used to fill over a course of{b) ays. Stock solution of Ropivacaine 0.2% lot S09132012@312 was used to filllfbproximately!~final products lots in 09/2012.

2. Your aseptic process validation does not challenge representative container closure systems currently used at your facility that reQ!esents a worst case challenge. For example, your firm performs media fill studies with ~6} (4>1 bags when the following sizes: 25mL, SOmL, 150mL, 250mL, SOOmL, 1000mL, 3000mL and 4000mL bags are used during routine production.

3. Your media fills do not simulate aseptic manufacturing operations that incorporate worstcase activities and conditions that provide a challenge to aseptic operations. For example: maximum number ofpersonnel and their activities, and an evaluation ofcritical routine and non-routine interventions (e.g. the continuous entering and exiting of the class 100 hoods used in the manufacture of sterile drug products.)

B. Sterile Filtration has not been validated for its intended use. For example:

I. not ~ff<if"'•'--'•"''oo ""-11~ ho ~"1)o<lfo nwdnr,t conlac til (~) ~ 4

{b) < > filters used to sterile filter injecta6 e drug products intended for patient use for example Fentanyl, Ropivacaine, etc.

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINlSTRATION

OISTl!ICT ADDRESS ANC """""" NIJM""" DATE(S) Of' INSPECTION

One Montvale Avenue 10/10/2012 - 11/09/2012* FEl NUMIIER Stoneham, MA 02180

(781) 587-7500 Fax: (781) 587-7556 3005881167 Industry Information: www.fda.gov/oc/industry NAME ANI> T<n.eOf INDIVIOUAI. TO WHOM RV'<>KI 1HUW

TO: Gregory A. Conigliaro, Vice President and General Manager STR££1' ADDRESS

Ameridose, LLC 201 and 205 Flanders Rd CITY, STATE, ZIP COllE, COUNTRY TYPE E5TA8l.I~NT JNJIP1;CTED

Westborough, MA 01581- 1032 Sterile Dr~g Manufacturer

DATE ISSUE!>EMPI.OYEe(5) SIGNATURE ~

Ramon £ . Mart ine:r; , Investigator /~f.. Justine M . Cocoon, Invest i gator J" Allison A. Rodr iguez , MicrObi ologist Lauren H . Lavrance, Inve stigator P• ..,la L. 1.9, Inve atlgator Pame l a L. Ogoi\OIIak1 , I nvestigator Douglass. Joalin . I nvest i gator ~..,~......,.--AlN.rie N. AlorliO , Miecobio log iat ~--~~ Ashley H. Wh i tehuret, Investigator ~

SEE REVERSE 11/09/ 2012OF THIS PAGE 1Vwf C. Jordan, lnve&tigator ~

slater K. Bartlett, Investigator • ~hi ~

Philip Kreite r, Investigato r Z/"Rory Geyer , !nveatigator Niehol e 8 . Hurplly , Inveseigator • ,_ ' · Mary~t Mcgarry. Investigator "N'"'p..uy"'~

~o;:i.::.J'L,."ol:....~"~rtigat~rC.f'li'-J)._ ,:/,ri. ,~.,.,;gr ~ ...)

FORM FDA 41J (t9111) ..u111ouSED1TJONOBSOL£TE INSPECTIONAL OBSERVATIONS PAGE II Of 20 PAGES

2. 6J ~ Js recommended to be use for general laboratory use and not intended for direct patient care applications.

3. The firm does not have the data, procedures, and controls to assure that additional rounds of filtration do not adversely impact product. Your firm re-filtered, at least one time, all sterile stock solutions lots involved in the sterility failures before releasing final drug product lots for patient use.

OBSERVATION 5

There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

Specifically,

Your firm utilizes a~t:i) {4~pump to manually administer drug product to individual units from stock solutions during the processing ofsterile finished products. The number of pumps ("pump count") is not routinely reconciled with the total number of units manufactured to ensure labeled potency. This includes the following lot which was also associated with low potency complaints and a "patient response":

For example: Midazolam, lot 02122012@1 (released on 02/1212012) which is also associated with lack of effect I low potency complaints AC12133 (approved by Quality on 03/12/20 12) and AC12144 (approved by Quality on 03/16/2012).

DEPARTMENT OF HEALTif AND HUMAN SERVICES FOOD AND DRUG ADMlNISTRATION

DISTRICT AOORfSS AHO PHONE NUMS~;R DAT£(S) 0#' INSPECTlON

One Montvale Avenue 10/10/2012 - 11/09/2012* FEI NUMSER Stoneham, MA 02180

(781) 587-7500 Fax: (781) 587-7556 3005881167 Industry Information: www.fda.gov/oc/industry NAME AND TrTU! ur INDIVIDUAl TO WHOM Kl;I'UI<T ISSVW

TO: Gregory A. Conigliaro, Vice President and General Manager FIIWNAME ST>a:IOJ ADOtcl:l>OI

Ameridose, LLC 201 and 205 Flanders Rd CITY, S II~ i<IP OO<liO, COUNTJ<Y TYPE ESTAIII.I......u<l IN"""CT£0


EMPLOVEE($) SIONAWRB DATEISSUEo

Rat110n E. Martinez . Investigator ~~f-~ 3\a8tine M. Coruon, Inveetigator Allison A. Rodriguez, Hicrobiol oglet Lauren M. Lawrance, Jove,stigator Pamela L. Lee . Investigator Pac>ela L. Ogonovaki. Invenigator DouglasS. Joslin , Investigator ~9'c!!:.. AliiiAria N. Alonao , Microbiologist -ASEE REVERSE Ashley M, Whitehurst . Invest igator ... 11/09/2012

OF THIS PAGE Mr'f c. Jordan, Invea<igator ~ ,k_,0-:. Slater K. Bartlett. Inveotigator ~ / ~ ..<! Philip Kreiter, Inveetigator "//.,--Rory Geyer, lnvutigator .u. Nichole B. MUrphy, Investigator \h.&. .l'~Q,. ""Mary~ Hegarry. Investigator ..., ~J ~'d?.i!..:..x?'/eatig~trl"l~;'rHI~." .L.;. ,

fOib\t fDA 413 (09101) PIIEVIOUS EDrTT<lN OIISOLETE INSPECTI~NAL OBSERVATIONS PAGE 12 Of 20 PAGES

OBSERVATION 6

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, and followed.

Specifically,

A. The environmental monitoring and conditions of the aseptic core are deficient for the following reasons:

1. Gowning used to manufacture sterile drug products is inadequate:

a. Personnel gowns, eye-protection and ~e~oyes are ot sterile. In addition gowns 4are only laundered and re-used for up b < > fore they are sent for cleaning.

b. Personnel exposed foreheads were observed as part of their gowning procedures. These operators can work inside the open-faced class I 00 hoods in the manufacture of sterile injectable drug products.

2. Environmental monitoring of the class 100 ' 6) (~) oods in not performed in association with daily operations. Sterile drug proaucts are aseptically manipulated in these hoods as part ofdaily operatioPlirtl)e_v~ , envirorunental monitoring for nonviable particulates is performed everl( and monitoring for viable particulates is performed ~15[@> 1in the class 100 hoods.

3. The firm failed to perform environmental monitoring during the manual aseptic connections from the stock solutions or during the manual filling ofsterile injectable drug products.

4. Personnel monitoring is limited to the assessment of the manufacturing technician s

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADM!NJSTRATION

DISTRICT ADDRESS AND PHOI£ NUMBER

One Montvale Avenue Stoneham, MA 02180 (781) 587-7500 Fax: (781) 587-7556 Industry Information: www.fda.gov/oc/industry NAME AND TmE CF IHCIVICVAL TOWHOM REPORT ISSIJEO

TO: Gregory A. Conigliaro, Vice President and General Manager STREET ADDRESSFIRM NAME

201 and 205 Flanders RdAmeridose, LLC TYPE ESTABI.ISHMENT INSPeCTEDCITY, STATE. ZIP CODE. COUNTRY

Sterile Drug ManufacturerWestborough, MA 01581-1032

DATE(S) 01' INSPEC'TfON

10/10/2012 - 11/09/2012* FEINUMBER

3005881167

OATEISSUEOEMPLOYEE(S) SlGNAT\lRE

RalliOn 1!:. Martine~. Investigator Justine M . Corson, Invest igator rf'~ Allison A. Rodriguez . Mi crobiologist Lauren H . L.awra.nee. Investigator Pamela t.. Lee. Investigator Parnel o L. Ogonows ki . Invest igator oouglas s. Joslin, Investigator ~ Almarie tl. Alonso. Kicrobiologist • ~SEE REVERSE 11/09/2012

OF THIS PAGE ::.:·~ ;;..-:;~·:-..:::; ,::;::"~'"~~~ . Slater IC Bartlett , Investigator ~ Phi lip Kreiter. Invest i gator Rory Geyer, I nvestigat or Nichol e B. Murphy, Investigator Do 1<4~ Kcgarry, Investigator ~ '(\

fj:~j,':,..Ar._rne;.;;,.,I')l~torC Dt f). H~r. ~ ·I ~i <J. 'J J

FORM fDA 413 (09101) f RI:VlOIJS EDillON OBSOI.tm: INSPECTIONAI.. OBSERVATIONS PAGE 13 OF 20 PAGES

fingers and this sampling is done onfy(b) (4) 1 Other critical areas such as forehead, forearms, chest and shoulders are not monitored.

OBSERVATION 7

The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established and documented.

Specifically,

4Method validation and performance qualification for the~t>) < > to test the sterility of sterile injectable drug products manufactured is inadequate for the followmg reasons:

1. Your firm did not adequately execute a side by side comparison of this method with Tb~rP !U)o_iss~rt_icompendia sterility method as require~ in "nur ,~Jid.ation i fic.atinn_fnr

0 4comparing the(6) (4Jiresults with a ) ( ) ij t>) (:II) lwhen the current USP method requires a 14 day incubation.

2. The population for the challenge microorganisms used in validation was never evaluated.

6 43. The method was validated by~ ) < > Iofthe challenge microorganisms. Furthermore, there is no data to support that the lowest level of detection was challenged during validation.

44. There is no adequate data to support the reproducibility of thf(t>) ( ) l nethod.

Specifically, on numerous occasions the firm performed multiple[{IDJ!)] ofthe same sample


OISTRICl AOORfSS NI1J- NUMBER

One Montvale Avenue Stoneham, MA 02180 (781) 587-7500 Fax: (78 1) 587-7556 Industry Information: www.fda.gov/oc /industry ......, AND TITU OF INDMIAW. TO'M10M I<U<li<T ISSUH>

C.O.'II!(S) ~ IHSPI!CTION

10/10/2012 - 11/09/2012* FEINUMBER

3005881167

TO: Gregory A. Conigliaro, Vice President and General Manager FIRM NAME STREET AOORESS

Ameridose, LLC 201 and 205 F l anders Rd CITY. STATI:, ZIP lYPE ESTIIIIUS-NT II'ISPEC'II!D

Steri l e Drug ManufacturerWestborough, MA 01581-1032


FORM FDA 41J (09/01)

DATE ISSUEDEMPLOYE£(&) 61GHAT\.RE ~ JIMIC>n £ . Martinez. Inveatiguor ~ (•1

J\lat.lne H. Coraon. Inveet.lgat.or Alllaon A. Rodriguez. N1crc.biologist lAuren " · Lavranee Investigator P&~~ela t. t.ee. Jnveat1gato.r Pamela L agonowsH , Investigator DoUglas $ . .:Joslin , Investigator ~-~· M•do • · M- ""-~'~'" ~ Atlhley H. Whiteburat . Investigator 11/09/2012A11ty C . .Jordan , Investigator Slater K. llartleu tnveetigator~~ Philip Jtreiter. Investigator f' Rory Geyer . Investigator Nichole B. Murphy, Investigator Mary..- Mcgarry , Investigator~~~, -~ ~~~iiNel."'J:..:.::r:toh>£J">\ H,,.. , ·1• ~:st.

..)

PREVJOQS eomoN OBSOI.ETE INSPECTIONAL OBSERVATIONS PAGE 14 OF 20 PAGES

6rendering all negative results in the firs f.iJ and showing viability in the following~ ) (.ifJl All samples are~Dr{4J s part of routine production.

OBSERVATION 8

The operations relating to the manufacture, processing, and packing ofpenicillin are not performed in facilities separate from those used for other drug products for human use.

Specifically,

There is no data to support that the firm's processing procedures will not increase the risk of cross-contamination between products. For example: the firm manufactures beta-lactam drug products in a non dedicated facility where sterile injectable drug products are manufactured. Your firm's employees can manufacture beta-lactam and non beta-Iactam products in any hoods interchangeably. Furthermore, the firm does not test/assess for the presence of beta-lactams in other sterile manufactured drug products at buildin

OBSERVATION 9

Buildings used in the manufacturing, processing, packing, and holding ofa drug product are not maintained in a good state of repair.

Specifically,

A. The firm failed to perform a microbiological assessment after penetrating leaks were found in building~A' dripping above the clean room in 06/2012. During the inspection 10/2012 we observed totes placed in the location of the penetrating leaks containing water. There is no documented evidence that the leaks were permanently corrected.

B. Walls were observed to be crac~~U~orroded, and covered with what appeared to be adhesive material in Room A of Buildin U , where sterile drug products are aseptically prepared.


DAn(S) IN CTION

One Montvale Avenue 10/10/2012 - 11/09/2012* Stoneham, MA 02180 F MJMBER

(781) 587-7500 Fax: (781) 587-7556 3005881167 Industry Information: www.fda.gov/oc/industry

TO: Gregory A. Coni liaro, Vice General Mana er FIRM NAME RESS

201 and 205 Flanders Rd TYPE ESTABLISHMENT INSPEC D


Th w Nern , I nve &t l gato r •


EMPI.

Ra""'n I . Martinet, Investigator "iJ..- t JUstine M. Corson. Investigator o~ T'•P' ~ Al11oon A. Rodriguez. Mierobiologiet LAur·en M. Lawrance , Investigator Pamela L. t.ee , Inveotigator PM>ela L. ogonowski , Investigator Douglas S . Joolin , Inveetigator Alma ria N. Alonso. Mierobi ologilt As hley M. Wl\ltenurot. Investigat o r , 11/09/2012A1fftJ C . Jorc1&n , Investigator Slate r IC . aarclett , xnveat igato~?',-: h Philip Kreiter, Inves tigator (?'-f/fl)'~ Jtory Geye r, rnve ecigator NLehole a MUrphy , t_nv-e at.igacor l h ~ Mary- MCgarry, Investigator ~\. I""(~'V'A--r-1

FORJ\1 FDA 4IJ(~108) PllEVIOUS EDITION 08SOUlE INSPECTIONAL OBSERVATIONS PAGE IS OF 20 PAGES

OBSERVATION 10

Equipment and utensils are not cleaned, maintained, and sanitized at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.

Specifically,

During the inspection we observed the following conditions:

A. The followin !{6J ~ oods, utilized in the preparation of sterile drug products, were observed to contain what appeared to be brownish structures, atypical in shape, upon the metal. surfaces between the lighting apparati ~g{~)HEPA filters, within the hoods at approximately face-level to\~) o erator: hoo .ll~d(l>n4) h<j>odt6J 41 hood~~~ ,

4hood(b) < ~ hood~6J hond~ hood 6J hood~b) hoo~l:)) j hoo•(b) boo~ hood b) fA\ ' ~b\) tj) ' (LA\ ' A\ > " """ ( hood eg ~~} and hoo~

B. utilized in the preparation ofcomponents for sterile drug pro uc IOn, was o serve o contain what appeared to be whitish, opaque structures upon the metal diffuser, below the HEPA filter, within the hood at approximately face-level to the operator.

C. The followin {ofQJ) hoods, utilized in the preparation ofsterile drug products, were observed to contain what appeared to be thick residues that were Or!N}a._e brown. and green in colorat~% within the front int~e of the hoods: hood~ hood~~~ hood~!~ hood~!)) , hood CAJ , hood~!N and hoot~ Moreover, metal surfaces compnsmg the tront intakes were observed to be held to the hoods with plastic straps.

a.ti'\.OVU(S) SIOHATURE ~ OATEISSUEO

Ramon ! , Martinez . Investigator J)C"Y""'- e .JU• tlne M. Coreon. tnveatigator Allioon A. Rodriguez, Mierobiologiot Lau ren M. Lawro.nce . Inveotigator Pamela L. Lee . Investigator P~ut\ela L.. Ogonowsk1, Investigator Oouglae s. Joslin, Inveotigator ~~

SEE REVERSE AltiArls H. Alonso, Microbiologist • 11/09/2012Ashl ey M. Whi tehurst. Investigator

OF THIS PAGE .., o. •orooo. '""'"'""'"' .<#'~Slater x . BAr-tlett, Investigator UA ~ Philip Jtreiter, Investigator '/. ~ ~tory Geyer. tnve•tigator NiehOle a . MUrphy . Investigator d Mary~t Mcgarry. Investigator

~~l. ~ NL~f: .In~:atigatrJXPJ un:·~JJ l.: .I , >I

FORM FDA 433 (M/H) PUV!OUS I!OITIO!J OOSOLETE INSPECTIONAL OBSERVATIONS PAGE 16 0120 ~1\0ES


DISTRICT ADDRESS N<O PliONf HUMei!R OATE(S) 01' INSI'ICTlON

One Montvale Avenue 10/10/2012 - 11/09/2012* Stoneham, MA 02180 FEl-BER

(781) 587-7500 Fax: (781) 587-7556 3005881167 Industry Information: www.fda.gov/oc/industry NAM~ AND T1T\.E OF INDMOUAI. TO WHOMIIePORT IS8U~O

TO: Gregory A. Conigliaro, Vice President and General Manager FIRM NAill! STREET ADDRESS

Ameridose, LLC 201 and 205 Flanders Rd CITY, STATE, ZIP cove. CO\HTRY TYPE ESTABLISHMENT ~&PI!CTEO


DD..tbl tbl {'f) {'f) Hoods Hoods (D (D and{t:i) and{t:i) utilized utilized in in the the preparation preparation ofof sterile sterile drug drug products, products, were were observed observed to to contain contain whwh~~appeared appeared tto o be be brownish brownish discoloration discoloration within within tthe he HEP HEP A A filters filters of of the the hoodhoodss. .

5 4E. fl >< > ] class 1 oo~t:i) (4) !hoods in Buildin Ko) used to manufacture sterile products were observed to contam the tollowing:

Ho~d* ObservationtJb> ( ) Exterior: visible rust on exterior. Interior: damaged light cover; foreign material (red substance on HEPA filter). Interior: broken glass; foreign material (red and white substance on HEPA filter). Interior: broken glass; foreign material (white substance on HEPA filter) . Interior: exposed, uncovered strip lights Interior: damaged light cover; foreign material (red substance on HEP A filter and white substance on interior wall). Interior: foreign material red substance on HEP A filter).

*All hoods were indicated to be clean and available for steri le processing.

OBSERVATION 11

Buildings used in the manufacture, processing, packing, or holding of a drug product do not have the suitable to facilitate cleaning, maintenance, and proper operations.

Specifically,

Of' 1HDM00A1. 10 WHOM REPOIIT ISSUED

DEPARTMENT OF HEALTH AND HU~IAN SERVICES FOOD AND DRUG ADMINISTRATION

One Montva l e Ave nue - 11 / 09 / 2012* St oneham , MA 02180 (781) 587-7500 Fax: (7 8 1) 587 -7556 30058 81167 Indu s t ry Inf or mat ion : www.fda.gov/ oc / indust

Presi dent and Gene r a l Ma nager S8

201 a nd 205 Flande rs Rd TYPE ESTAIIUSHMEHT INS E

Wes tbo r ough , MA 0 1581 - 1 032 S t e rile Dru Manu facturer

EMPI.OYef(S) SIGW.TURE

Dc>ugl.. S. Jool1n. 1nve s t19ator --~---Almarls N. Alonao. Hlcrobiologist ~t...,...c.-c. l<atll ey M . wni tehurot. I nvest i gat o r

Slate r JC. Bartlett. tnvestig:at oz;.O'/ Philip Kr e iter . Inves t igator ~,t{(,.

Allly C. J o rclan, Investigato r ~

A.ory Ceyer , Investigator Nl.ehole ll . Murphy. I nve stigator Mary~ Mcgarry . Inves t i ga.t.or Th!>"'AI w Ne rn.!!Y. Invest! ga t o r

INSPECTIONAL OBSERVATIONS

DATE ISSUED

Ramon £ . Martinez:. I nve stigator fl..""""""o.. f, Juatine H. Corson, Inve st i gator "r·- . All i son A. Rodrigue:.. M.icroblolog l at Lauren M . Loav rance , Investigat.or Pamela L. We , I nvestigato r Pallela L. Ogonoweki. t nve atigator

SEE REVERSE 11/09/2012

OF THIS PAGE

FORM FDA 4&3 (t9191) PAGE 17 OF 20 PAOES

A. Doors accessing Isolation Room t> of Building~l (Class 1,000), where sterile drug product is prepared, were observed to be o¢ened simultahebusly with doors accessing the Vestibule (Class 10,000).

B. Gaps were observed beneath doors located between Roon~~~ of Building~1 (Class 1,000), where sterile drug products are prepared, and the Gowning Room (Class 10,000).

c. l6J (i:l) oading bay doors which separate the outdoors from the unclassified area in Building ~~~ were observed contains gaps ofapproximately 1 inch. Sterile finished product is packaged and stored in the unclassified area.

D. Several gaps of approximately 0.25-0.5 inches were noted in the "pass-through boxes" and under doors which connect the unclassified area and classified area in Buildin f'l) Sterile finished product is manufactured, packed and stored in these areas.

E. The aseptic processing clean room design was inadequate. Specifically;

l . Several aseptic processing rooms at the facility Jack adequate space and segregation to prevent contamination and mix-ups. Numerous lots of different products are produced simultaneously in a single room. Aseptic processing and labeling operations OCP,.PH n very close prox~m·ty in an open room (e.g., Aseptic Processing Rooms 6J and~>~). For example, up to~2 personnel generally operate in Aseptic Processing Room ~t> the same time. This operation requires products to be produced in separate hoods at the same time, which generally requires~t> personnel per operation.

2. The facility is not adequately designed and controlled to prevent influx of contamination from lesser controlled areas. Staffenters through the Ante room (which connects to the gowning room) to initially access the clean room area from an uncontrolled, unclassified


One Montvale Avenue Stoneham, MA 02180 (781) 587-7500 Fa x: (781) 587 -7556 Industry Information: www.fda.gov/oc /industry

O..TE(S) Of' IHSI'~C:TlON

10/ 10/2012 - 11/09/2012* FEINUMIIER

30058 81167

NAME AND TITlE OF INOMDUAI. TO WHOM IU<P<>Rr IG5UOU

TO: Gregory A. Conigliaro, Vice Pres i dent and General Manage r fiRM NAME

Ameridose, LLC STR!~T ADDRESS

201 and 205 Flanders Rd CIT • $TA~ ZlP c;ooe, COUNTRY


TYPE ES Alll _,., INS,..,C:TEO



EMPlOYEE($) SlGNA lURE ~~ Ra110n E. Martinez. Investigator lh..- .... [,f{Juatine M. coreon. Inveatigator I r··· · I ~ Allioon A. Rodriguez . M!erob!ologiot Lauren " · L•wrance, Investi gator Paw.cla L, ~e . Investigator Pamela L . Ogonowek l. Inveetigator oouglu s . Jool1n . Investigat o r ~ <7~ Almarle N. Alonso, Mlcroblologiat ~· p·Aohley H . 11h 1t e huret . Investigator~ A1fr1 c . Jorctan , Investigator ~# 'Z); 11/09/2012 S.l at e r K, Bart1e t t . Investigato r ../~, Phi lip Kreite r . tnveltiga.tor ~ kory Geyer . t nveat igat.o r Nici\Ol e B ._,rplly . Investlga<or tUiry...-.et Mcgarry. Inveatiga tor

~· ~ /~rnp__: .1~veatigarlYi>\ .1.. .1...' /, ,,:1d FORM FDA 4&3 (191111) ruVIOUsmJTlON~ 1

INSPtc!noNALOBSERVATIONS PAGE II OF 20 PAGES

hallway. This hallway has many activities and offices, and multiple insects were observed in this area. Furthermore, there are no interlocking door or other design controls were in place to assure there was control over the entry to the facility from the controlled, unclassified hallway.

OBSERVATION 12

Buildings used in the manufacture, processing, packing or holding ofdrug products are not free of infestation by rodents, birds insects, and other verm in.

Specifically,

A. Insects were observed to be located in the unclassified area (Buildin~1 ) where finished sterile product is packaged and stored. The insects were also located within approximately 310ft of the controlled area where sterile products are manufactured.

b) B. At least one (1) bird was observed flying in the unclassified area (Building(4) where sterile

finished product is packaged and stored.

OBSERVATION 13

Equipment for adequate control over air pressure is not provided when appropriate for the manufacture, processing, packing or holding ofa drug product.

Specifically,

Differential pressure is not adequately balanced and controlled between clean rooms. Specifically:

A. The firm does not monitor the pressure differential between all adjacent clean rooms, and any adjacent uncontrolled areas


EMPI.OYEE(S) SIOW.TURC f~ Ramon E . Martina:. Investigator Justine M . Coreon. lnve•~igator f Allison A. Rodr i!JUU, Hicrobiolog l < t.a.uren M Lawtance . I.nvestigator Pa-lll L Lee. lnvee< i ga<or PAJIIela L Ogonovolti. Investigator Dougllls S. Joolln , Investigator ~- r2, . Al maria N Alonso , Microbiologi • t ~ Aahley H. Wltitehuut. Inveo<i gator" ~ My c:. Jordan, Invoatiga.t.or ~·• //' Slllter K. Bartlett , Invcotiga<or .......-:::::; ff_<'~__(' / Philip Kreiter , t nveotigator V~ ,l""Rory Geyer , Investigator

DATE ISSUED

11/09/2012

Nichole B. MUrphy . Investigator ~ . 0 _ ""'~ HaryW.....t MCgarry, Investigator • ~

~1.wJ/m~ ;:J:.:!iga<t!nr/A ·j_Jv';/1. .i.d J

PttVIOUS EDrTJONOIISOI.E're INSPECTIONAL OBSERVATIONS PAGE 19 OF 20 PAGES

DEPARTMEI'IT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

'"'"""" IIUUtcE.5S AND PHON!: NIJMIIfll

One Montvale Avenue Stoneham, MA 02180 (781) 587-7500 Fax: (781) 587-7556 Industry Information: www.fda.gov/oc/industry

DATE{$) 011' INSPCCTION

10/10/2012 - 11/09/2012* FEINUMBER

3005881167

~~ ·•~~ I"""VIOUA~TO W10M REPOR ISSUW

TO: Gregory A. Conigliaro, Vice President and General Manager

Ameridose, LLC STREET ADIJRESS

201 and 205 Flanders Rd Cl , STAlE. Zl' COO'!!, COUNTR1 TYn UTAIIU&.-NT INIII'I!CTED


r (."-{

B. The finn does not evaluate any alarms resulted from their air handling system. Specifically, multiple events where air went from a higher classification toward a lower classification.

C. Not all alarms are configured to detect pressure reversal events.

D. The finn did not investigate the potential product impact of these events. Furthermore the firm has not evaluated the potential for ingress ofmicrobial contaminants to the manufacturing areas.

E. The finn does not keep more th~ ays of pressure data. The Quality Unit does not routinely assess these alarms.

F. There are no formal limits for delta P between adjacent rooms, or between rooms and the adjacent uncontrolled corridors.

G. There are no visible or audible alarms when differential pressure problems occur.

OBSERVATION 14

Procedures describing the handling of written and oral complaints related to drug products are deficiently written or followed.

Specifically,

Your firm maintains a separate file of "non-complaints" which were not processed according to your approved procedure. Additionally, your firm has not adequately defined "non-complaint" in your current approved procedure.


0<6TRJCT All0Rf58 ANO PHONE NUMBER

One Montvale Avenue Stoneham, MA 02180 ( 781) 587 -7500 Fax: (781) 587-7556 Industry Information: www.fda.gov/oc/industry NAME AHO TITI.E Of' INOIVIOU.'Il TO WHOM REPORT lssuetl

OA'n(G) Of' INSP£CTION

10/10/2012 - 11/09/2012* FEINUMI!ER

3005881167

TO: Gregory A. Conigliaro, Vice President and General Manager FIRM NAME

Ameridose, LLC CllY, 8 ATE. ZIP CODE. COUHTRY


STREET AOORESS

201 and 205 Flanders Rd TYP!e8TA8i.ISHM!NTINSP£CTEO



FORM FDA olllj09/0I) I'UVIOUS EOITlON OSSOl.ETE INSPECTIONAL OBSERVATIONS PAGE 10 OF 10 PAGES

OBSERVATION 15

Written complaint records do not include, where known, nature ofcomplaint.

Specifically,

A. The formal complaint record does not include the initial communication between your firm and complainant. This information was frequently observed to contain more descriptive information regarding adverse events when compared to your firm's Quality approved complaint record.

B. Your finn's Quality approved complaint records contain vague, canned language to describe adverse events. This includes the wording "patient did not achieve the expected response" (or a subtle variation).

* DATES OF INSPECTION: I0/1012012(Wed), 1011 t/2012(Thu), 10112/2012(Fri), 1011512012(Mon), 10/1612012(Tue), I0/1812012(Thu), 1011912012(Fri), 1012212012(Mon), 10123/2012(Tue), I0/26/2012(F'ri), I I/06/2012(Tue), I J/0712012(Wed), 1110812012(Thu), 1110912012(Fri)

EMPI.OYEE(S) SIGNATURE

Ramon E. Mart i nez, Investigator ·Y)t:"('{\ll\. t·~ JUstine M . Corson. Investtgator AllitJon A. Roclrigu... Microb iologiot t..auren M. Lawr-ance, Investigator Pamela L. Lee, Investigator Pamela t... Dgonowskl. Invest igator Douglas s . Joslin , Investigator ~0~-Almaria 11. Alonso, Microbiologie •

My c. Jordan. I nveotigator""ey" '""~"'· '"~""'"0' Slater K. Bartlett, Investigator ~~ Philip Kreiter. Invcotigator Rory Geyer , I nvestigat or llichole B. Hllrphy . Investigator Mary- Mcgarry, Investigator

jnvestiga(.'/yp, ;]~LJ~r~!· JI.Nnbl(l£,>)>+' ,

~~

t J

DATE ISSUED

11/09/2012

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