food and drug administration - fdanews

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

DISTRICT ADDRESS AND PHONE NUMBER

300 River Pl a c e, Suite 5900 Detroit, MI 48207 (313) 393-8100 Fax: (313)393- 81 39

NAME AND TITLE OF INDIVIDUAL TO WHOM REPORT ISSUED

Paul J. Elmer, President and Owner FIRM NAME

Pharmakon Pharmaceuticals, Inc. CITY. STATE. ZIP CODE. COUNTRY

Noblesville, IN 46 060- 3303

DATE(S) OF INSPECTION

2/18/2016- 3/16/2016* FB NUMBER

30082 13711

STREET ADDRESS

14450 Getz Rd TYPE ESTABLISHMENT INSPECTED

Outsourcing Facility

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 in1plemented or plan to implement, co11"ective 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. If you have any questions, please contact FDA at the phone mm1ber and address above.

DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:

OBSERVATION 1 Testing and release of drng product for distribution do not include appropriate laboratmy detennination of satisfacto1y confo1mance to the final specifications and identity and strength of each active ingredient prior to release.

Specifically,

i. Finished lots of sterile injectable drug products are not tested for potency prior to release and distribution. Mmphine Sulfate (PF) 0.5mg/ml in 0.9% Sodium Chloride 1ml fill in a - syringe lot #E52418EV1 IC was processed, released, and distributed on 2/3/16. Potency results were repmted as 2460% on 2/10/16, acceptance criteria is - %. This lot was recalled by your finn on 2/11/16.

ii. Finished lots of sterile injectable dmg products containing prese1vative are not tested ~1vative content, for example, Morphine Sulfate 5mg/ml in 0.9% Sodium Chloride 25ml fill in a -syringe lot #E51192DK18C. This lot was processed and shipped on 2/18/16 without such testing.

OBSERVATION 2 There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been ah·eady distributed.

Specifically,

SEE REVERSE OF THIS PAGE

FORM FDA 483 (09/08)

AMENDMENTl

EMPLOYEE(S) SIGNATURE

Emily J Orban, Investigato r Emilie Kahn , Investigator Gary C Pecic, Chemist/Biologist Lisa T Michel, Chemist/Biologist

X Emily J Orban

PREVIOUS EDillON OBSOLETE INSPECTIONAL OBSERVATIONS

DATE ISSUED

3/21/2016

PAGE I OF 17 PAGES

DEPARTMENT OF HEALTH AND HU!\fAi"I SERVICES FOOD AND DRUG ADMINISTRATION


300 Rive r Place, Suit e 5900 Det roit , MI 48207 (313) 393- 8100 Fax : (313) 393- 8139

NAME ANO TITLE OF INDIVIDUAL TO WHOM REPORT ISSUED

Paul J . Elmer, President and Owner FIRM NAME

Phar makon Phar maceut icals, Inc . CITY. STATE. ZIP CODE. COUNTRY

Noblesville, I N 46060- 3303

OATE(S) OF INSPECTION

2/18/2016- 3/16/2016* FEI NUMBER

3008213711

STREET ADDRESS

1 44 50 Getz Rd TYPE ESTABLISHMENT INSPECTED

Out sour cing Faci l i t y

i. Since 4/2014,11 batches were released prior to receiving potency results that were out of specification. No investigation was conducted into these out of specification test results. Some examples of batches released and shipped include:

Lot#

E290653A8R

E14240A2R

E133348.17R

E34082DK8C

E0228143R

~Q9232S3QRQ7 E09232530R E40292DK9C

E39250DK31C

E42428DK4C

E40292DK4C

E1106133R

E40292DK7C

E083327Z2R

E30152DK5C

E39250DK27C

E15058A13R

E34082DK3C

E600949121R

E290653A10R

EJKP0412A1R

E102F0147R


FORM FDA 483 (09/08)

Active Ingredient

EPINEPHRINE

NOREPINEPHRINE

PROMETHAZINE

M IDAZOLAM

PHENYLEPHRINE

PHENYLEPHRINE

M IDAZOLAM

M IDAZOLAM

M IDAZOLAM

M IDAZOLAM

PHENYLEPHRINE

M IDAZOLAM

PROMETHAZINE

FENTANYL CITRATE

MIDAZOLAM

NOREPINEPHRINE

M IDAZOLAM

OXYTOCIN

EPINEPHRINE

VECURONIUM

CEFAZOLIN


%

Potency

0

0.4

1.8

7.1

25.3

25.9

27.6

33.8

34.7

37.7

39.4

44.2

45.6

52.9

55.7

66

68.4

75.6

77.6

77.6

80.4

AMENDMENT l

Emily J Or ban, Invest igat o r Emilie Kahn, Invest igat o r Gary C Pecic, Chemist /Biologist Lisa T Michel, Chemist /Biologist

Date

Tested

11/ 6/ 2014

2/ 24/ 2015

1/ 15/ 2015

1/ 2/ 2015

7/ 29/ 2014

7/ 25/ 2014

6/ 9/ 2015

7/ 14/ 2015

10/ 20/ 2015

5/ 15/ 2015

5/ 6/ 2014

6/ 1/ 2015

5/ 18/2015

7/ 14/ 2014

6/ 23/ 2015

10/ 26/ 2015

7/ 22/ 2014

6/ 30/ 2015

11/ 14/ 2014

8/ 28/ 2015

9/ 10/ 2015

'"''""'

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PREVIOUS EDmON OBSOI.ETE INSPECTIONAL OBSERVATIONS

DATE ISSUED

3/21/2016

PAGE 2 OF 17 PAGES







Noblesville, IN 46060 - 3303

E60083313R OXYTOCIN 85.5

E06334312R ATROPINE 85.6

E16HL01222R PROPOFOL 86

E1243458R PROMETHAZINE 114

E46342DK6R BUPIVICAINE 116

E61055602R HEPARIN 116

E43187DK36C MORPHINE SULFATE 116

E600949149R OXYTOCIN 118 i;~:;zie5eA~~ E27135A2R EPINEPHRINE 119.9

E40292DK10C MIDAZOLAM 120.9

E37235DD21C HYDROMORPHONE 121.6

E0353613R PHENYLEPHRINE 124.2



E02330736C MORPHINE SULFATE 207.9

E460953A2R VANCOMYCIN 0.4


2/18/2016- 3/16/2016* FEI NUMBER

3008213711

STREET ADDRESS

1 4450 Getz Rd TYPE ESTABLISHMENT INSPECTED

Out sour cing Facilit y

11/ 14/ 2014

12/31/ 2014

11/ 24/ 2015

11/ 10/ 2015

8/ 25/ 2015

6/ 3/ 2015

11/ 19/ 2015

8/ 11/ 2015

4/ 2/ 2014

6/ 11/ 2015

6/ 26/ 2014

10/ 13/ 2015

9/ 19/ 2014

6/ 8/ 2015

8/ 15/ 2014 1/19/201§ 1/23/2015

ii. No investigation was perfo1med into the following test results for diu g products ah-eady released and distributed:

a. Midazolam HCl lmg/ml in 0.9% Sodium Chloride 2ml fill in a - syringe lot #EMS3063C tested positive for sterility on 5/20/14. b. Ephedi·ine Sulfate 5mg/ml in 0.9% Sodium Chloride 5ml fill in a - syringe lot #E0714148R, :fe~aa;rl Ciffate 2Bieg/fftl. eH:e :Qaf)ivaeaifte W:Cl Q.1259~ iH: Q.99~ gseilHB Cltleriee ~ 250ml Bag lot #E45248DK1 IC, and Ephedi·ine Sulfate 5mg/ml in 0.9% Sodium C~Oml fill in a-syringe lot #E0725 141R were rep01ted as "Cancelled or Sample Untestable" on 3/02/15, 4/16/15, and 6/10/15, respectively. No additional test results were provided for these three batches.


FORM FDA 483 (09/08)

AMENDMENT l


Emily J Orban, Invest igator Emilie Kahn, Invest igat o r Gary C Pecic, Chemist /Biologist Lisa T Michel, Chemist /Biologist

"'I'""'"'


DATE ISSUED

'"''""' 3/21/2016

PAGE 3 OF 17 PAGES


DISTRICT ADDRESS AND PHONE NUMBER OATE(S) OF INSPECTION

300 Rive r Place, Suit e 5900 Det roit , MI 48207

2/18/2016- 3/16/2016* FEI NUMBER

3008213711 (313) 393- 8100 Fax : (313) 393- 8139


Paul J . Elmer, President and Owner FIRM NAME STREET ADDRESS

Phar makon Phar maceut icals, Inc . 1 44 50 Getz Rd CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Noblesville, I N 46060- 3303 Out sour cing Facilit y

OBSERVATION 3 Procedures designed to prevent microbiologica l contamination of drug products purpo1ting to be sterile are not established , written and followed.

Specifically,

i. The following aseptic practices were observed: a. Operators were not observed to exhibit slow, deliberate movements while perfonning aseptic operations in the ISO 5 laminar flow hood. For example, durii.10 the filling of HYDROmo1phone HCl 0.4 mg/ml iii 0.9% Sodium Chloride 30ml fill in a - vial lot #E52l05DD25C on 2/18/16, an operator was observed to spray gloved hands with sanitizer and wave them around in the laminar flow hood to diy. b. On 2/19/16, an operator was observed leaving the ISO 5 Suite9'nd perfo1med a .in the ISO 6 anteroom using the hand sink. After completion of this task, the operate- · not :nge gloves or sanitize theii· hands prior to leaving the anteroom and returning to Suit o continue aseptic processin~nyl Citrate 2mcg/ml and Bupivacaine HCl 0.125% in . % Sodium Chloride 200ml in ..... 250ml Bag lot #B345QDK9C E53450DK9C. c. Sterile utensils are not alwa s usecl to handle sterile materials. For example, on 2/23/16, an operator was observed t vials containing Bupivacaine PFllmg/1 w en ~l Citrate 2mcg/ml & Bupivacaii1e 0.125% in 0.9% So o · e 150ml in a 150ml_b_. d. On 2/25/16, an operator was observed to ofNorepinephrine Bitaitrate with their gloved hands used in Nore ·ate 8mg added to 5% Dextrose 250 ag lot #E1 5229B3R. AdditionaU is used for sterile diu com onents


FORM FDA 483 (09/08)

s observed in this process even though the . Your fum management stated they were

uring this process.

AMENDMENTl



"'I'""'"'


DATE ISSUED

'"''""' 3/21/2016

PAGE40F17 PAGES





2/18/2016- 3/16/2016* FEI NUMBER

(313) 393- 8100 Fax : (313) 393- 8139 3008213711


Paul J . Elmer, President and Owner FIRM NAME STREET ADDRESS

Phar makon Phar maceut icals, Inc . 1 4450 Getz Rd CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Noblesville, IN 46060 - 3303 Out sour cing Facilit y

~the filling ofHYDROmorphone HCl 0.4mg/ml in 0.9% Sodium Chloride 30ml fill in a - Vial lot #E52105DD45C and Ephedrine Sulfate 5mg/ml in 0.9% Sodium Chloride 10ml fill in a- syringe lot #E091305Al 1R on 3/15/16, both operators were observed to rest their gowned anns and/or elbows on the ISO 5 work surface. f. During the filling of Cefazolin 2GM added to 100ml 0.9% Sodium Chloride bag lot #E157085.24R on 3/15/16, the operator's gloved hands were observed to block first air while removmg Cefazolin with 0.9% Sodium Chloride

ii. Adequate validation of aseptic processing operations, specifically, process simulations (media fills), have not been perfo1med under worst case conditions to assure that sterile processing techniques are adequate to ensure the sterility of drng products. CmTently, each o erator involved in ase tic rocessing must erfonn a "Personal Ase tic Techni ue Test", in which

. This process does not include, for example, use of all representative container closure systems, worst case lot sizes (ex:. syringes), mos~ lex/difficult aseptic operations, or equipment used in normal aseptic processmg such as sterile-and repeater pumps.

This is a repeat observation of that written on the FDA 483 dated 3/13/2014.


FORM FDA 483 (09/08)

AM ENDMENTl



""I'""'"'


was not in mg attire.

DATE ISSUED

'"''""' 3/21/2016

PAGE 5 OF 17 PAGES






Pharmakon Pharmaceut icals, Inc . CITY. STATE. ZIP CODE. COUNTRY


OBSERVATION 4


2/18/2016- 3/16/2016* FEI NUMBER

3008213711

STREET ADDRESS

1 4450 Getz Rd TYPE ESTABLISHMENT INSPECTED


Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions.

Specifically,

i. Accordino to SOP PHlOO Environmental Control and Monitorin

management stated these logs were not being reviewed.

No investigation has been conducted into these pressure readings.

Negative to the investigation was con

ecbon, your finn man~ ecame aware t at the last time data was .... in the ISO 5 Suites


FORM FDA 483 (09/08)

AMENDMENTl



"'I'""'"'


'"''""'

synnge Log

IS

DATE ISSUED

3/21/2016

PAGE60F17 PAGES









2/18/2016- 3/16/2016* FEI NUMBER

3008213711

STREET ADDRESS



on 2/3/1-in Suite. n 2/4/16. Additionally, Suitel oes not have a. Pressur~ .

iv. Pressure gauges in Suit . sed to aseptica lly process Cephalosporin drng products, were not calibrated prior to 2/20/16. s suite has been in use since 6/2/14.

v. The anteroom for Suite. as observed to have a pressure reading of zero on 2/19/16. This room is considered ISO 6 and is c nected to Suit. hich is classified ISO 5.


OBSERVATION 5 Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the room to produce aseptic conditions.

Specifically,

a ents used in the classified areas are sterile. For example, are not pmp01ted to be sterile. Also, between 4/30/14"::i

5/23/14, a mixture of items were also state

was used to clean Suites - , all classified ISO 5; these nm's management not to be sterile.

ii. SOP PH109 Sanitization (Disinfection) requires the use of a sporicidal agent- to reset microbial resistance. The- Sanitization Log for each suite did not doclun~use of a s oricidal aoent:


FORM FDA 483 (09/08)

AM ENDMENTl



"'I-""'"'


DATE ISSUED

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PAGE 7 OF 17 PAGES









2 / 18/2016- 3/16/2016* FEI NUMBER

3008213711

STREET ADDRESS



iii. Disinfectant efficacy studies have not been perfo1med to demonstrate that the disinfectants and the application methods used to clean the ISO 5 a1·eas can sufficiently reduce bioburden .

iv. Scientific justification was not provided to suppo1i that-is an appropriate contact time for all disinfectants used in the sterile suites.

v. On 2/18/16, a white colored residue was observed on the HEPA filter grate oflaminar flow hood ~processing ofHYDROmo1phone HCl 0.4 mg/ml in 0.9% Sodium Chloride 30ml fill in a - Vial lot #E52105DD25C. On 3/10/16, white residue was also observed on the HEPA filter grate of laminar flow hoods-

vi. No documentation was provided to suppo1t that Suit&,as sanitized- from 4/23/14-9/22/14 or that Suitellvas sanitized- from 6/2/14 to 11/5/15, according to SOP PW 09 Sanitization (Disinfection). In addition, n~entation was provided to suppo1t that Suiteavas cleaned. according to SOP PHlO- Hood/Floor C~ ·om 6/2/14-11/24/14 and 2/12/15-10/28/15. Cefa. lGM in Sterile Water 10ml fill in a- syringe lot #El02F00916R was processed in Suite. n 8/4/15.

vii. On 3/15/16, residue was observed on the metal surface on top of the following laminar flow hoods in the ISO 5 suites:


OBSERVATION 6 Clothing of personnel engaged in the processing of drng products is not appropriate for the duties they perfo1m.

Specifically,


FORM FDA 483 (09/08)

AM ENDMENTl



"'I'""'"'


DATE ISSUED

'"''""' 3/21/2016

PAGE80F17 PAGES









2/18/2016- 3/16/2016* FEI NUMBER

3008213711

STREET ADDRESS



The CUITent gowning method may leave facial skin exposed. For example, on 2/25/16, an operator aseptically processing Norepinephrine Bitalirate 8mg added to 5% Dextrose 250ml bag lot #E15229B3R in the ISO 5 laminar flow hood 1 was observed with several inches of skin on their forehead exposed.


OBSERVATION 7 Aseptic processing areas are deficient regarding air supply that is filtered through high-efficiency particulate air filters under positive pressme.

Specifically,

On 2/19/16, two ceiling tiles in the Suite rocessing area were observed to be exposed and not flush with the other ceiling tiles in this room. Y om fnm classifies this room as ISO 5.

OBSERVATION 8 Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.

Specifically,

i. Environmental monitoring is not perfo1med at least daily dming drng production in the critical areas to evaluate the quality of the aseptic processing environment and assess whether aseptic. conditions are maintained.

a. Non-viable pa1ticulate monitoring is perfo1med in the aseptic processing areas once every six months. b. Viable monitoring:


FORM FDA 483 (09/08)

Passive air monitoring is performed but was not observed to occm in the laminar flow hoods where processing occms. On 2/23/16, dming processing of Cefazolin 2GM added to 5% Dextrose 50ml USP lot #E157084.114R in

AM ENDMENTl



"'I'""'"'

PREVIOUS EDmON OBSOLETE INSPECTIONAL OBSERVATIONS

DATE ISSUED

'"''""' 3/21/2016

PAGE 9 OF 17 PAGES





2/18/2016- 3/16/2016* FEI NUMBER

(313) 393- 8100 Fax : (313) 393- 8139 3008213711


Paul J . Elmer, President and Owner F IRM NAME STREET ADDRESS

Phar makon Phar maceut icals, Inc . 1 4450 Getz Rd CITY. STATE. Z IP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Noblesville, IN 46060 - 3303 Out sour cing Facilit y

late for viable passive air monitoring was set , away from the lruninar flow hood.

ii. On 2/18/16, an operator processing HYDROmo1phone HCl 0.4mg/ml in 0.9% Sodium Chloride 30ml fill in a - ~ial lot #E52 l 05DD25C was observed to spray disinfectant on the laminru· flow hood surface ~ ost immediately after, a surface sample was collected using - plates in this location.

Date 12/8/14

2/ 10/15 10/ 13/ 15

10/20/ 15


FORM FDA 483 (09/08) PAGES


Product Ropivacaine HCl lot#E61080474R Promethezine lot#E143044.113R Rocuronium lot#ERT4 16X4R Bupivacaine HC1 lot#E50379DK1R HYDROmoiphone HCl lot#E4 7345DD l 8C

HYDROmo1phone HCl lot#E50055DD33C HYDROmo1phone HCl lot#E50055DD32C Ephedrine Sulfate lot#E05 l 4 l 515R Fentanyl Citrate lot#E48234DK3 l C Fentan 1 Citrate/Ro ivacaine HCl

AMENDMENTl

Emily J Or ban, I nvest igat or Emilie Kahn, I nvest igat o r Gary C Pecic, Chemist /Biologist Lisa T Michel, Chemist /Biologist

PREVIOUS EDmON OBSOLB1E INSPECTIONAL OBSERVATIONS

CFU 5

4 16

14

0ATE '5SUE0

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PAGE IOOF17

D ISTRICT ADDRESS AND PHONE NUMBER



300 River Place, Suite 5900 Detroit, MI 48207

2/18/2016- 3/16/2016* FEI NUMBER

(313) 393- 81 00 Fax: (313) 393- 8139 3008213711


Paul J. Elmer, President and Owner F IRM NAME STREET ADDRESS

Pharmakon Pharmaceuticals, Inc . 1 44 50 Getz Rd CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISH MENT INSPECTED

Noblesville, IN 46060 - 3303 Out sour cing Facility

! lot#E48234DK32C

The followino are exam les of CFUs re orted on oowns: Date Hood Product CFU ------,1---------------------+------I 7/30/14 HYDROmorphone HCl lot#E37235DD24C TMTC

12/31/14 1/13/15 3/18/15

7/21/15

10122/15 10/20/15

Ketamine lot#E121005A21C Fentanyl Citrate/Ropivacaine HCl lot#E32266DK16C Fentan 1 Citrate lot#E32266DK15C Oxytocin lot#E60087905R 23 Succin lcholine Chloride lot#E44378EV2R TMTC Morphine Sulfate lot#E44l52DK1C TMTC Fentan 1 Citrate lot#E45078DK2C Ceftriaxone lot#E4900208M3R 20 E490208M3R Cefazolin lot#E102F0079R Cefazolin lot#E15702311R Provocholine lot#EP5032H4R £t1feBtaBtl Cltfate/Bt1f)iYaeaiBe lot#E I O l 3 4 417G HYDROmorphone HCI lot #E50055DD33C HYDROmorphone HCI lot #E50055DD32C Ephedrine Sulfate lot #E05141515R

105

137 No investigation has been conducted into these results, nor has any identification been performed on the microorganisms.



AMENDMENTl


Emily J Orban, I nvestigat or Emilie Kahn, Investigato r Gary C Pecic, Chemist / Biologist Lisa T Michel, Chemist / Biologist


0ATE '5SUE0

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PAGE 11 OF 17









2 / 18/2016- 3/16/2016* FEI NUMBER

3008213711

STREET ADDRESS



iv. No documentation was provided to suppo1t that media plates used for operator glove monitoring contain disinfectant neutralizers to assme Inicrobial containination can be detected.

v. On 2/15/16, the white colored residue observed on the HEP A filter grate of laminar flow hoodlvas analyzed and 1 CFU was recovered from a swab sample. No investigation has been conducted nor has identification been perfo1med on the Inicroorganism.


OBSERVATION 9 Each batch of drng product pUiporting to be sterile and pyrogen-free is not laborato1y tested to dete1mine confo1mance to such requirements.

Specifically,

Given the observed inadequate environmental controls, testing is deficient in that aseptically filled sterile injectable drng products are released and distributed prior to receiving laborato1y results for sterility.

i. M01phine Sulfate (PF) 0.5 mg/ml in 0.9% Sodium Chloride 1ml fill in a - syringe lot #E0833054C was not sent for sterility testing. This batch was processed o:wi47i4 and distributed on 9/25/14.

ii. Mo1phine Sulfate (PF) 0.5 mg/ml in 0.9% Sodium Chloride 1ml fill in a - syringe lot #E08330552C was sent for sterility testing but results were not received. This lot was processed on 8/19/15 and distributed on 8/19/15.




AMENDMENTl


Emily J Or ban, Invest igat or Emilie Kahn, Invest igat o r Gary C Pecic, Chemist /Biologist Lisa T Michel, Chemist /Biologist


0ATE '5SUE0

"'''""' 3/21/2016

PAGE 120Ft7


D ISTRICT ADDRESS AND PHONE NUMBER

300 River Place, Suite 5900 Detroit, MI 48207 (313) 393- 8100 Fax : (313) 393- 8139


Paul J. Elmer, President and Owner F IRM NAME

Pharmakon Pharmaceuticals, Inc . CITY. STATE. Z IP CODE. COUNTRY


OBSERVATION 10


2 / 18/2016- 3/16/2016* FEI NUMBER

3008213711

STREET ADDRESS



The operations relating to the processing of penicillin are not perfo1med in facilities separate from those used for other drng products for hlllllan use.

Specifically,

Procedures have not been established for the separation of tasks and segregation of personnel handling cephalosporin drug products from those for all other human diug products. For example, on 2/13/15, Cefazolin 2GM added to 5% Dextrose 50ml USP lot #El02E0232R was processed in Suitellso 5 laminar flow hoo. ollowed by- (Brevital Sodium) lOmg/ml 10ml syringe lo #E6929448C. Suite. s dedicate~ cephalosporin diug products; however, Suite.is also u~cess these products, as recently as 2/10/16 for Ceftriaxone lGM in Sterile Water l~l fill in a- syringe lot #E570078M3R.


OBSERVATION 11 Drng product containers and closures were not sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use.

Specifically,

i. No doclllllentation was provided to suppolt that diug product containers and closures are always received with a Ce11ificate of Conformance or are tested for sterili and endotoxin levels rior to use. These containers and closures are evaluated by

For example,. 30ml vials lot was use~e HYDROmmphone HCl 0.4mg/ml in 0.9% Sodilllll Chloride 30ml fill in a-vial lot



AMENDMENTl


Emily J Or ban, Investigator Emilie Kahn, Investigator Gary C Pecic, Chemist /Biologist Lisa T Michel, Chemist/Biologist


0ATE '5SUE0

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300 River Place, Suite 5900 Detroit, MI 48207 (313) 393- 8100 Fax: (313) 393- 8139


Paul J. Elmer, President and Owner FIRM NAME

Pharmakon Pharmaceuticals, Inc . CITY. STATE. ZIP CODE. COUNTRY

Noblesville, IN 46060-3303


2/18/2016- 3/16/2016* FEI NUMBER

3008213711

STREET ADDRESS



#E52105DD25C, however, a Ce1tificate of Confo1mance was not received for this batch of vials, nor was testing perfo1med by your finn prior to use.

ii. No documentation was provided to support that caps used as closures for sterile dmg products packaged in syringes are pyrogen-free. For example, the Ce1tificate of Confo1mance for the "Tamper Evident Caps (White) Sterile" lot - does not state they are pyrogen-free. These caps were used to package Midazolam HCl lmg/ml in 0.9% Sodium Chloride 2ml fill in a- syringe lot #E091075A4C.

OBSERVATION 12 The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed.

Specifically,

i. SOP PHl 17 Quality Management states "The quality unit has the authority to approve or reject all components, dmg product, closures, packaging material, and labeling." Finished dmg products are released and distributed prior to review of the batch record. For example, Mo1phine Sulfate (PF) 0.5mg/ml in 0.9% Sodium Chloride 1ml fill in a- syringe lot #E52418EV11C was processed on 2/3/16 and released and distributed on 2/3/16. Th~ record was reviewed by Compliance on 2/15/16 and the Phaimacy Operations Manager on 2/18/16, both members of the Quality Unit.



. On 2/3/16, an and proceeded to process Mo1phine Sulfate (PF) 0.5mg/ml in

AMENDMENT l


Emily J Or ban, Inves tigator Emilie Kahn, Investigator Gary C Pecic, Chemist /Biologist Lisa T Michel, Chemist/Biologist


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2 / 18/2016- 3/16/2016* FEI NUMBER

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0.9% Sodium Chloride 1ml fill in a- syringe lot #E52418EV11C with the wrong active ingredient.

This batch of Morphine Sulfate (PF) 0.5mg/ml in 0.9% Sodium Chloride 1ml fill in a- syringe lot #E5241 8EV11 C was recalled 0 11 2/11/16 by your fum due to potency results of 2460% received 0 11

2/10/16.

OBSERV,A .. TION 12 OBSERVATION 13 The labeling of your outsourcing facility's chu g products does not include infonnation required by sections 503B(a)(IO)(A) and (B).

Specifically,

The following infonnation is not found on your chug product labeling:

• Info1mation to facilitate adverse event reporting: www.fda.gov/medwatch and 1800-FDA-1088.

Examples of ch11g products that do not contain this infonnation: o Adenosine lmg/ml o Bupivacaine HCL 0. 125% o Promethazine HCL 25mg o Hepaiin 25,000 USP Units

AMENDMENTl



Emily J Or ban, I nvest igat or Emilie Kahn, Invest igat o r


Gary C Pecic, Chemist /Biologist Lisa T Michel, Chemist /Biologist


0ATE '5SUE0

"'''""' 3/21/2016

PAGE 150Ft7


DISTRICT ADDRESS AND PHONE NUMBER OATE(S) OF INSPECTION

300 River Place, Suite 5900 2 / 18/2016- 3/16/2016* Detroit, MI 48207 FEI NUMBER

( 313) 393- 8100 Fax: (313)393 - 8139 3008213711


Paul J. Elmer, President and Owner FIRM NAME STREET ADDRESS

Pharmakon Pharmaceuticals, Inc . 1 44 50 Getz Rd CITY. STATE. ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Noblesville, IN 46060- 3303 Out sour cing Facility

QR~~Wi~~+IQ~ U OBSERVATION 14 Your outsourcing facility has not submitted a complete report to FDA identifying all products compounded at your facility during the previous six months as required by section 503B(b )(2)(A). Specifically, The fellov1iag Some examples of products that you stated to have were compounded fl:H:4 were not identified on your report dated December 11 , 2015:

• Sodium Citrnte 4% injection

• Tetracaine 0.5% injection

• Nalbuphine lOmg/ml injection

• :Woref)iBef)hri-e.e Bitartrate gmg iajeetioa

• Norepinephrine Bitartrate 16mg injection

• M01phine Sulfate Oral Solution 1mg liquid

• Ropivacaine HCL 0.5% injection

• Sodium Phosphate l 5mMOL injection

• Sodium Phosphate 3mMOL injection

• Labetalol 5mg/ml

• Not'etJiH:etJhti-e.e Bitartntte 4mg (16 me§'ffll) iRjeetioa

• Phenylephrine HCL 400mcg

• Nitroglycerin 50mcg/ml injection

• Neostigmine lmg/ml injection

• Sufentanil Citrate/Bupivacaine 0.4mcg/0.1 % injection

*DATES OF INSPECTION 2/ 18/2016(Thu),2/ 19/2016(Fri),2/22/2016(Mon),2/23/2016(Tue),2/24/2016(Wed),2/25/2016(Thu),2/26/

2016(Fri),3/09/2016(Wed),3/ 10/2016(Thu),3/ l 1/2016(Fri),3/ 15/2016(Tue),3/16/2016(Wed)

AMENDMENTl

EMPLOYEE(S) SIGNATURE 0ATE '5SUE0

SEE REVERSE Emily J Or ban, I nvestigat or "'''""' 3/21/2016 OF THIS PAGE Emilie Kahn, Investigator X Em;ly J Oli>an

Gary C Pecic, Chemist /Biologist &nlfJOl'tlle ~-Lisa T Michel, Chemist /Biologist $ipd 1¥: enti, l. Ort:M-$

FORM FDA 483 (09/08) PREVIOUS EDmON OBSOLB1E INSPECTIONAL OBSERVATIONS PAGE 160Ft7 PAGES




300 River Place, Suite 5900 Detroit, MI 48207

2 / 18/2016-3/16/2016*

(313) 393- 8100 Fax: (313) 393- 8139


Paul J. Elmer, President and Owner F IRM NAME

Pharmakon Pharmaceuticals, Inc . CITY. STATE. ZIP CODE. COUNTRY


X Emilie Kahn Emlet<am in,estigator Sgned by: &rile E. l<am ·S

3/21/1!)16


FEI NUMBER

3008213711

STREET ADDRESS



AM ENDM ENT l


Emily J Orban, Inves tigator Emilie Kahn, I nvestigato r


Gary C Pecic, Chemist /Biologist Lisa T Michel, Chemist/Biologist


"'''""' 0ATE '5SUE0

3/21/2016

PAGE 170F 17

DEPARTMENT OF HEALTH AND H UM AN SERVICES FOOD AND DRUG ADMIN1STRATJON

DISTRICT ADDRESS AND PHON£ NU"Bffi DATE(S) OF INSPECTION

300 River Place, Suite 5900 4/18/2016-5/6/2016* FEJNUMBERDetroit, MI 48207 3012248018( 313) 3 9 3- 8100 Fax : ( 313 ) 3 9 3 - 8139

NAME AND TITl.E OF INDIVIDUAl TO WHOM REPORT ISSUED

Jason E. Prokopik , Chief Operating Officer FIRM NAME

Pharmakon Compounding Pharmacy, Inc . CITY, STATE, ZIP CODE , COUI'll"RY


STREET ADDRESS

14460 Getz Rd Ste 300 TYPE ESTABliSHMENT INSPECTED

Compounder of sterile drugs

This document lists observations made by the FDA representative(s) during the inspection o f your facility. They are i nspectional observations, and do not represen t a fina l Agency determination regarding your compliance. If you have an objection regarding an observation , or have implemented, or plan to implement, corrective actio n in response to an observation, you rna} discuss the objection or action with the FDA rcprcsentative(s) during the inspection or submit th is information to FDA at the address above. lfyou have any quest ions, please contact FDA at the phone number and address above.


OBSE RV ATIO N 1 Procedures designed to prevent microbiological contamination ofdrug products purporting to be sterile do not include adequate validation of the sterilization process.

Specifically,

i. Adequate validation of aseptic process simulations (media fills) has not been performed under worstcase condi tions/scenarios to assure that sterile processing techniq ues are maintained throughout the process, thus ensuring steri lity of drug products. must demonstrate the

does not include, for example, use worst-case lot sizes (e.g . • units), and representative vV. closure systems (e.g. eye droppers) used in typ ical and often I H<lLU

routine aseptic processing operations.

Individuals performing aseptic processes have not been validated for proper technique via a media fill test. Batch records covering the following lots of steri le products indicate that they were produced by an individual without a documented media ti ll test, as evidenced by the personal aseptic technique test log:

• Epinephrine 1 mg/ml in 2 ml vial, lot #C 16723 159, . units produced on 04/05/2016 by technician

EMPl OYEE($) SIGNJ, TURE DATE ISSUED


Constantin Y Phi lopoulos, Investigator Charles L Zhou, Investigator X Conslilntln Y PnQopoulos

5/6/2016

~-~~..... S~'Y<'.tMilJIIU.M . Pti~.S

1'0 RM fl O A 483 (09!~8) PRE\'IOUS £I)IT ION OBSOLETE INSPECTIONAL OBSERVATI ONS PAGE I OF 10 PAGES

DEPARTMENT OF II EALTH AND HUi\IAN S ERYI CES FOOD AND DRUG ADMINISTRATION


300 River Place , Suite 5900 Detroit, MI 48207 (313} 393 - 8 1 00 Fax: ( 313 ) 393 - 8139

DATE( $) OF INSPECTION

4/18/2016-5/6/2016 * FEINUMBER

3012248018

NAME AND TITlE Of INOIVIO\JAI. TO WHOM REPORT ISSUED


Pharmakon Compounding Pharmacy, I nc .

STREET ADDRESS

14460 Getz Rd Ste 300 CITY, STATE, ZIP CODE, COUNTRY

Noblesville, IN 46060 - 3303 TYPE ESTABLISHMENT INSPECTED

Compounder o f sterile drugs .. • Epinephrine 1 mg/ml in 2 ml via l, lot #C 16723 160, . units produced on 04112/20 16 by

pharmacist • • Cefuroxime 10 mg/ml in balanced salt solution 0.5 ml in 1 ml slip tip syringe, lot # 146025.204, .

units produced on 03/2112016 by technician .

ii. "In Situ" smoke studies performed by qualification/certification of the A comment in the certification

Moreover, there was no documentation stating that these studies were performed under dynamic cond itions simu lating aseptic processing to show a sweep ing action over and away from the critical processing area.

OBSERVATION2 Procedures designed to prevent microbiological contam ination of drug products purporting to be sterile are not established and written.

Specifically, during the production of epinephrine 1 mg/mL, lot #C16723161 on 04/19/20 16 and phenylephrine 2.5%/tropicamide 1%, lot # 125441/B59 on 04/20/2016 we observed:

i. Syringes containing non-sterile not sanitized before being

The ins ide of to

ii. Airflow appears to be obstructed by the rack of supplies placed on the Top(b)(4 ) of rack is approximately 8-10 inches from the HEPA fi Iter, and boxes of syringes were placed on the

(b)(4 ) higher shelves. Buildup of wrappers/waste in the during

Il l.

of epinephrine was also observed. uently

are not checked vJJ!Civ,,u with new, sterile

before use .



Constantin Y Philopoulos, Invest i gator Char les L Zhou, I nv estigator X Const>ntln V PholopO<Jios

.._,._ $19hld.,-.C...lltf"'-M, PIIIo~·$

DATE ISSUED

5/6/2016

FORM FDA 483 (09/08) PREVIO US ED ITION 0BS()LETE INS PE CTIONAL OBSER VATIONS PAGE 2 OF 10 PAGES

DEPARTMENT OF HEALTH AND HUMAN SEIWICES FOOD AND DRUG AOMfNISTRATION

DISTRICT AOORESS AND PHONE NUMBER

300 River Pl ace, Suite 5900 Detroi t , MI 4 8207 (313) 393-8 1 00 Fax: (313) 393-81 39

NAI.'E AND TITLE OF IN~VIDUAL TO W HOM REPORT ISSUED

OATE(S) Of IN SPECTION

4 / 1 8 / 2016 - 5 / 6 / 2016* FE! NUMBER

301 2248018

J ason E. Prokopik , Chief Operating Off icer FIRM NAME STREET A000E$S

Pharmakon Compounding Pharma c y, I n c. 14 460 Getz Rd S t e 300 CITY. STA TE, ZJP CODE, COUNTRY TYPE ESTABLISHMENT INSPECl EO

Noblesville, IN 46060 - 33 0 3 Compounder of steri le drugs

OBSERVATION 3 Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions.

Specifically,

; (b)(4) i. Th (ISO 5), used in aseptic processing ofsterile drug products, are located in an unclassified room/area:

• serial number (b)(4 ) , with (b)(4 ) used

• (b)(4) serial number (b)(4 ) , used for (b)(4) drugs only

11. ualification/certification of the -

(b)(4) are located within an unclassified room, the potential for contamination is increased; especially, when considering that personnel frequently

a failure

(b)(4 ) activities are during the course of asep tic processing, environmental monitoring, or cleaning/sanitizing operations, as necessary. For example, observed during production of the following lots:

• Epinephrine 1 mg/mL (EPIO 1 ), lot #C 16723161, II units produced on 04119/2016 • Phenylephrine 2.5%/Tropicamide l% (PT002), lot # 125441/B59. units produced on 04/20/2016

under static condi ed and it is not clear whether

EMPLOYEE($) SIGNATURE OATEISSUEO

0 -·Constantin Y Philopoul os , InvestigatorSEE REVERSE 5 / 6 / 2016 Charles L Zh o u , InvestigatorOF THIS PAGE X Constantin YPhll(lj)Oulos

fORM FDA <83 (09/0 8) PREVIOUS EDITION OBSOI.ETE JNSPECTIONAL OBSERVATIONS PACE 3 OF 10 PAGES

DEPARTMENT OF HEALTH A ND HUMAN SERVI CES FOOD AND DRUG ADMINISTRATION

DISTRICT ADDRESS AND PHONE I<UMBER

300 River Place , Suite 5900 Detroit, MI 48207 (3 1 3 ) 393 -8100 Fax: (313)393 - 8139

DATE(S) OF INSPECTION

4/18/2016-5 / 6/2016 * fEr NUM6ER

3012248018

NAME AND TITLE OF INDIVIDUAL TO WHOM REPORT ISSUED


Pharmakon Compounding Pharmacy, Inc.

STREET IIDORESS

14460 Getz Rd Ste 300 CITY. STATE, ZIP CODE, COUNTRY

Noblesville, IN 46060 - 3303 TYPE ESTABUSHMENT INSPECTED


, used for sterilization of the following has not been

nor 1s peno mamtenance emg on as r Pr,,..,rrP /1

• Finished drug product batches ofhydroxyprogesterone (17HP/1 7I-:IPS), (b)(4) • ) used in glycerin 48%/lidocaine 1%/epinephrine 1: I00,000, [1111](b)(4)

(b)(4 ) iv. The , used to sterilize glass vials, rubber stoppers, and aluminum lids for production ofhydroxyprogesterone (17HPS/ 17HP), has not been adequately qualified (not

(b)(4)

v. The~ incubators, (b)(4 ) used to incubate media for sterility testing, media fills, and environmental monitoring, have not been adequately qualified (temperature mapped). Thermometers used in . incubators have not been calibrated, as reported. Additionally, there is no record of the date when media is visually examined so as to assure that the required incubation time period has been met ; only the - in the corresponding logs. For example:

• incubation on 02116/16 • on 02/ 18/16(b)(4 )

OBSERVATION 4

(b)(4 )

Aseptic processing areas are deficien t regarding the system for monitoring environmental cond itions.

Specifically,


EMPLOYEE($) SIGN/\TURE

Constantin Y Philo poulos , Invest i gator Cha rles L Zhou, Investigator

0 ~~- -

X Conslanlln Y PhilopotAos

DATE ISSUED

5/6/2016

FORM FDA 483 (09/08) PREVIOUS EDinON OBSOlETE INSPECTIONAL OBSERVATIONS PAGE 4 OF 10 PAGES

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMTNlSTRATlON

OISl'RICT AOORESS AN D PHONE NUM6EI'l

300 River Place, Suite 5900 Detroit, MI 48207 (313) 393-8100 Fax: (313) 393-8139

OATE(S)OF INSPECTION

4/18/2016-5/6/20 1 6* FEINVM8ER

3012248018

NAME AND TITLE OF INDIVIDUAl TO WHOM REPORT ISSUED


Pharmakon Compounding Pharmacy, Inc.

STREET ADDRESS

14460 Getz Rd Ste 300 CITY, STATE. ZIP CODE. COUNTRY


TYPE ESTABliSHMENT INSPECTED


i. Environmental sampling listed below is not performed at least daily during production in the processing areas, to evaluate the quality of the aseptic processing environment and assess whether aseptic conditions are maintained.

a. Non-viable mo nito ring ofthe (ISO 5) is performed (b)(4 ) (b)(4)

b.

located. c. Active air monitoring of the (ISO 5) is performed(b)(4 ) (b)(4 )

monitoring is not performed under dynamic aseptic processing conditions. Active air monitoring is not performed fo r the room in which the IGJIUIIare located.

ll (b)(4 )

iii. Media plates used for surface and fingertip sampling prior to February 2016 did not contain disinfectant neutralizers to assure microbial contamination can be detected, as reported.

OBSERVATION 5 Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the room and equipment to produce aseptic conditions.

Specifically, the suitability, efficacy, and limitations of cleaning equipment and disinfecting agents have not been appropriately assessed to ensure potential contaminants are adequately removed from surfaces in the (ISO 5). (b)(4)


EMPLOYEE!S) SIGNATURE

Cons tant in Y Phi lopoulos, I nvestigator Charles L Zhou, Investigator

m ... ,..,.

X Constantm Y Pl>llopovlos CQ.r.~,-~

••••:11apw $llfi'ICd W C:..-H I~·S

OATEISSUEO

5/6/2016

FORM f'DA 483 (09/08) PReVIOUS EDITION OBSOLE're lNSPECTIONAL OBSERVATlONS PAGE 5 OF 10 PAGES

Otl' ARTMENT OF' HEALTH AND H UMAN SERVICES FOOD AND DRUG ADMTNISTRAT!ON

DISTRICl ADDRESS AND PHONE NUMBER

300 River Place, Suite 5900 Detroit, MI 48207 (313) 393-8100 Fax: (313)393-8139

DATE(S)OF INSPECTlON

4/18/2016-S/6/2016* FEI N\J"'8ER

3012248018

NAME AND TrnE OF INDIVIDUAL TO VMOM REPORT ISSUED

Jason E . Prokopik , Chief Operating Office r FIRM NAME

Pharmakon Compounding Pharmacy, Inc .

STREET ADDRESS

14460 Getz Rd Ste 300 CllY. STATE. ZIP CODE, COUNTRY

Noblesville, IN 46060-3303 TYPE ESTABLISHMENT INSPECTED


Disinfectant efficacy studies have not been performed to demonstrate that (b)(4 ) and its lication method, including contact time and worst-case ...........· _ IHYI ... -. . -

can sufficiently reduce bioburden. (b)(4 ) . (b)(4 ) is used to sterilize the (b)(4 ) J (b)(4 )

'lized are (b )( 4 )

in addition to supplies to be used for the next week such as sterile, packaged syringes, vials, caps, etc., which are (b)(4 ) -OBSERVATION 6 Clothing of personnel engaged in the manufacturing , processing and packing of drug products is not appropriate for the duties they perform.

Specifically,

During the production of epinephrine 1 mg/mL, lot #C 16723 161 on 04/19/2016 and phenylephrine 2.5%/tropicamide 1%, lot # 125441/B59 on 04/20/2016 we observed:

i. Not all garb worn into is sterile. Examples include hair nets, beard nets, cotton gloves , and street clothes and shoes not covered gar .

ii. Exposed skin (hands, forehead) in iii. Street clothes and shoes are worn into and are not completely covered by sterile

garb. Sterile gown is open in back, leaving non-sterile street clothes partially uncovered.

OBSERVATION 7 Testing and release of drug product for distr ibutio n do not include appropriate laboratory determination of satisfactory conformance to the identi ty and strength of each active ingredient prior to release.

Specifically,

EMPLOYEE(S) SIGNATURE DATE ISSUED

I'J •Constantin Y Philopoul os, Investigator 5/6/2016SEE REVERSE Charles L Zhou, InvestigatorOF THIS PAGE X Constanlln YPhilopoulos

FOIUvl FDA 483 (09/08) PRE\10US EDITION OBSOLETE fNSPECTIONAL OBSERVAT JONS PAGE 6 Of 10 PAGE.S

DEPARTMENT OF HEALT H AND Hl iMAN SERVICES FOOD AND DRUG ADMINISTRA110N

DISTRICT ADDRESS AND PliONE NUIJJBER

300 Rive r P l ace, Suite 5900 Detroit, MI 48207 (313) 393 - 8100 Fax : (313} 393-8139


4/18/2016-5/6/201 6 * FEI NUMBER

3012248018

NAME AI<D TITLE OF INDIVIDUAL TO WHOM REPOilT ISSUED

J ason E. Prokopik , Chief Operating Officer FIRM NAME

Pharmakon Compounding Pharmacy, I nc .

STREET ADDRESS

14460 Getz Rd Ste 300 CI'TY. STATE, ZIP CODE. COUNTRY

Noblesville, I N 46060 - 3303 TYPE ESTABI.ISHMENT INsPECT EO


i. Aseptically processed sterile drug products are released and distributed without having been tested for potency, as reported. For example:

• Epinephrine 1 mg/mL (EPIO I), lot #C 16723161, produced on 04/19/2016 • Phenylephrine 2.5%/Tropicamide 1% (PT002), lot # 125441/859, produced on 04/20/2016 • L idocaine 4%/Epinephrine 0.18%/Tetracaine 0.5% (LETO 1 ), lot # 5C95A12, produced on

03/03/2016. This product is (b)(4 )

ii. Finished lots of sterile drug products containing preservative are not tested for preservative content. Examples include:

• Cyclopentolate l%/Phenylephrine 2.5% (CPOO 1 ), contains as a (b)(4 ) preservative, refrigerated

• Phenylephrine 2.5%/Tropicamide 1 %/Ketoraolac 0.5% (PTK002), contains (b)(4 ) as a preservative, refrigerated

• Lidocaine 4%/Epinephrine 0.18%/Tetracaine 0.5% (LETOl), , refrigerated (b)(4 )

OBSERVATION 8 Each batch of drug product purporting to be sterile and pyrogen-free is not laboratory tested to determine conformance to such requirements.

Specifically,

i. No method suitability studies using the required organisms and appropriate testing media (TS8 and FTM), as per USP <71> Sterility Tests, have been performed in support of the following ste rility MGJIQII used by your firm when determining sterility results for finished drug product batches produced: . For example:

• Epinephrine l mg/mL (EPIOl), lot#C16723161, produced on 04/19/2016, (b )(4) • Phenylephrine 2.5%/Tropicamide 1% (PT002), lot # 125441/859, produced on 04/20/2016, 11

(b)(4 ) • Hydroxyprogesterone (17HPS), lot # 126199/C04, produced on 02/ 17/16, (b)(4)

SEE R EVE RSE OF THIS PAGE


!i! . .... ...Constantin Y Phi l opoulos, Investigator Charles L Zhou, Investigator X Constanlln Y Phllopoufos

DATE ISSUED

5/6/2016

FORM FDA 483 (09/08) PRE VIOUS EDIT ION OBSOLETE INSPECTI ONAL OBSERVATIONS PAGE 7 OF 10 PAGES

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUO ADMfNISTRATION

DISTRICT ADDRESS AND PHONE NVMSER DATE(S)OF INSPECTION

300 River Place, Suite 5900 4/18/2016 - 5/6/2016* FEI NUMBERDetroit , MI 48207 3012248018(313) 393-8100 Fax : (313) 393-8139

NAME AND TITLE OF INDIVIDUAL TO WHOM REPOAT ISSUED

Jason E. Prokopik , Chief Opera t ing Officer FIRM NAME

Pharmakon Compounding Pharmacy, Inc. CITY. STATE, ZIP CODE. COUNTRY

Noblesville, I N 46060-3303

STREET ADDRESS

14460 Getz Rd Ste 300 TYPE ESTABLISHMENT IN SPECTED


ii. Aseptically processed sterile injectable drug products produced from non-sterile ingredients are released and distributed without having been tested for endotoxins, as reported. For example:

• Epinephrine 1 mg/mL (EPIOl), lot #C16723159, . units produced on 04/04/2016 • Epinephrine l mg/mL (EPIOl), lot #C16723161 , . units produced on 04/19/2016 • Phenylephrine 2.5%!Tropicamide 1% (PT002), lot # 125441/BSSII units produced on 04/20/2016

OBSERVATION 9 There is no \vritten testing program designed to assess the stability characteristics of drug products.

Specifically,

i. Potency and sterility testing has not been performed in support of assigned Beyond Use Dates (BUDs) for several sterile drug products that are aseptically prepared. Unless stability studies have been performed, BUDs are, by default, 7 or 14 days for refrigerated sterile drug products with no preservatives and 14 days for sterile drug products containing preservatives stored at ambient temperature, as reported. Examples include:

• Lidocaine 1 %/Bupivacain 0.75%/Hylenex 150U/mL MGJIIJII no preservative, refrigerated, BUD 7 days; pertains to all [1111] products.

• Mitomycin lmg/mL (MITOl), no preservative, refrigerated, BUD 14 days • FluorouracillmL (5FU01), no preservative, ambient storage, BUD 14 days

ii. Testing results provided by the contract laboratory in support of BUDs for the following sterile drug products were purported to have used analytical methods that are not considered validated or have not met all the requirements for sampling and/or method suitability:

• Hydroxyprogesterone Caproate (sesame oil) 250 mg/mL (17HPS), no preservative, ambient storage, BUD 45 days (tested for potency and particulate matter)

• Epinephrine HCL 1 mg/mL (EPIOl ), no preservative, refrigerated, BUD 14 days (tested for potency aiGJIQI)

• Vancomycin 10 mg/mL (Vanc l ), no preservative, refrigerated, BUD 30 days (tested for potency)


SEEREVERSE Constantin Y Philopoulos, Investigator 5/6/2016 OF THIS PAGE Charles L Zhou, Investigator X CMstartin Y Phil<>poulco-·FORM f'f)A 483 (09/ 08) PREVIOUS EDI'fiOI>I OBSOLeTE INSPECTIONAL OBSERVATIONS PAGE 8 OF 10 PAGES

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMTNlSTRATION

DISTRICT ADDRESS AND PHQI>.'E NUMBER

300 River Place, Suite 5900 Detroit, MI 48207 (313) 393-8100 Fax: (313) 393-8139

DATE( S) OF INSPECTION

4/18/2016-5/6/2016* FEII<liMBER

3012248018

NAME AND TinE OF INDIVIDUAL TO WHOM REFORT ISSUED

J ason E . Prokopik , Chief Operating Officer FIRM NAME

Pharmakon Compounding Pharmacy , Inc.

STREET ADDRESS

14460 Getz Rd Ste 300 Cl"l'l, STATE. ZIP CODE, COUNTRY

Nob l esville, I N 46060-3303

TYPE ESTABLISHMENT INSPECTED


• Phenylephrine HCL 1 0%/tropicamide 1 %/ketorolac 0.5% (PTKOO 1 ) , IGJIQJ as a preservative, refrigerated, BUD 30 days (tested for potency, sterility, endotoxins, and particulate matter)

• Phenylephrine 2.5%/tropicamide 1 %/ketorolac 0.5% as a preservative, refrigerated, BUD 30 days (tested for potency and sterility at

• Cyclopentolate 1 %/phenylephrine 2.5% (CPOO 1 as a preservative, refrigerated, BUD 30 days (tested for potency at and sterility aiGJIQJI)

CoAs for the following products carried a notation that methods for potency testing are not considered validated: 17HPS, EPIOl, Vancl , CP00 1, and PTK002

CoAs for the following products carried a notation that sterility testing does not meet all requirements for sampling and/or method suitability specified in USP<71 > Sterility Tests: PTKOO 1, CPOO1, and PTK002

OBSERVATIO N 10 Routine calibration of equipment is not performed according to a written program designed to assure proper performance.

Specifically, equipment used for confirmation/assurance ofsterility is not calibrated, as reported. For example, the used in the production of epinephrine 1 mg/mllot #C16723161 produced on 04/19/20 16 and phenylephrine 2.5%/tropicamide 1% lot#125441/B59 produced on 04/20/20 16.

OB SERVATION 11 The operations relating to the processing ofpenicillin are not performed in facilities separate from those used for other drug products for human use.

Specifically,

No evidence was provided that sterile would be effective in mitigating beta-lactam (b)(4 ) residues on contact surfaces should a spill occur in the (ISO 5) during aseptic (b)(4 )

SEEREVERSE OF THIS PAGE

E MPLOYEE($} SIGNATURE

Constantin Y Philopoulos, Invest igator Charles L zhou, Investigator

0

X Constantin Y PI'Oiopoolos c-·Y!IIIIY~...,,.._, s..- tr¢arl•~<~"""· ~• '

DATE ISSUED

5/6/2016

FORM FOA 483 (09'08} PRE \'IOUS EDI'l'IOI< DBSO~ETE INSPECriONAL OBSERVATI ONS I'AOE 9 OF 10 PAGES

--

DEPARTMENT OF HEALTH AND IIUI\lAN SERVICES FOOD AND DRUG ADMTNISTRATlON

DISTRIC T ADDRESS AND PHONE NUMBER OATE(S) OF INSPECTION

300 River Place, Suite 5900 4/18/2016-5/6/2016 * FEINUMBERDetroit, MI 48207 3012248018(313) 393 - 8100 Fax: {313) 393-8139

NAME AND TITlE OF INDIVIDUAL TO \MiOM REPORT ISSUED

Jason E . Prokopik , Chief Operat i ng Officer F IRM NAME STREET ADDRESS

Pharmakon Compounding Pharmacy, Inc . 14460 Getz Rd Ste 300 CITY, STATE, ZIP CODE. COUNTRY TYPE ESTABLISHMENT INSPECTED

Noblesville, IN 46060-3303 Compounder of sterile drugs

processing. Cefuroxime 10 mg/mL (O.SmL in 1 mL syringes) is routinely aseptically processed in the (b)(4) (ISO 5) that are also used for non-beta lactam products. Following production ofa

beta-lactam product, a sporicidal agent is not used before a non-beta-lactam product is produced in the sam«GJJQI, as reported.

*DATES OF INSPECTION 4/18/20 16(Mon),4/ 19/20 16(Tue),4/20/20 16(Wed),4/21120 16(Thu),4/22/20 16(Fri),5/05/20 16(Thu),5/06/ 20 16(Fri)

X Charles l Zhou _..., Signed by. 0\lrles L Zhou ·S


EMPLOYEE($) SIGNATURE

Constant in Y Philopoulos, InvestigatorCharles L Zhou, I nvestigator

0 ''ot·~

X C<lnst•nton YPhliq>oulos C<OI~~Ym~

~...brc-t~PMI'l~ t

FORM I'DA 483 (09/08) PREVIOUS EDITION OOSOLfl'l'E INSPECTIONAL OBSERVATIONS PAGE 10 OF 10 PAGES

DATE ISSUED

5/6/2016

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

16-5/11/2016*

3011756326

Inc.

Noblesville, IN 46060-3303 Producer of Sterile Drug Products

This document lists observations made by the FDA representative(s) during the inspection ofyour facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance. Ifyou 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.


OBSERVATION 1 Aseptic processing areas are deficient regarding the system for monitoring enviromnental conditions.

Specifically,

1. Enviromnental monitoring is not performed at least daily during drug production in the critical areas to evaluate the quality of the aseptic processing enviromnent and assess whether aseptic conditions are maintained.

a. Non-viable particulate monitoring is petformed in the aseptic processing areas MGJIIJII MIDIIJM

b. Active viable air monitoring is performed in the aseptic processing areas every II UIQI Passive air monitoring is performed in the aseptic processing areas every II

(b)(4)

c. Viable surface monitoring is performed in the aseptic processing areas every MIDIQ8 (b)( 4)

d. Personnel fmgertip monitoring is performed for (b)( 4) (b)( 4)

n. Environmental monitoring excursions are not investigated. Management indicated ~...........,..~.,

the anteroom are classified as ISO 6. According to SOP Environmental Control and


Robert M Barbosa, InvestigatorSEE REVERSE 5/11/2016 Emily J Orban, Investigator Bei Y He, Investigator

OF THIS PAGE

JIORrolllJlA 483 (09/08) 1'!\EVIOUSEDntONOOSOLiml INSPECfiONAL OBSERVATIONS PAGe I OF6PAGES

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUGADMINISTRATION

3011756326

Counsel

Inc. 14460 Getz Rd, Suite 200

Noblesville, IN 46060-3303 Producer of Ste rile Drug Products

Monitoring, the microbiological active air action level for ISO [1111] CFU/m. During the anteroom certification on IIDIUJ, 8 CFUs were recovered.

· iii. No data was provided to support that the incubator used to incubate media fill containers and envii:onmental monitoring surface and fingertip samples is qualified for its intended use. Management stated this incubator is maintained between ltmQI. In addition, there was no documentation provided to support that the IIIJ thermometer was calibrated.

OBSERVATION 2 Clothing ofpersonnel engaged in the processing ofdrug products is not appropriate for the duties they perform.

Specifically,

i. Gowning ofoperators performing aseptic operations in the ISO 5 laminar flow hoods is inadequate in that protective gowns, face masks, shoe covers, and hair nets worn during aseptic processing are not sterile. In addition, the current gowning method leaves facial and neck skin exposed, as well as personal clothing. For example, gowning worn as observed during the aseptic pmcessing ofAmikacin 400 mg/1 00 ml (Rx No. IUJJmiiinvanz 500 mg/100 ml (Rx No. IGJDJI and Gentamicin 240 mg/1 00 ml (Rx No.IGJIUJII in on 4/18/16.

il. On 4/19/16, prior to the aseptic processing oflnvanz 1 gm/100 ml ~No. iltlthe operator was observed straightening the sterile glove located

ungloved left hand during gowning.

OBSERVATION 3

EMPI.OYeE(S) SIGNATURf DIITEISSUfO

&/It/a>.. 5/11/2016SEE REVERSE Robert M Barbosa, Investigator OF THIS PAGE Emily J Orban, Investigator

Bei Y He , Investigator

FORMJIDA I'IU!VIOUS l!llffiOHOllSOl.ETJl INSPECTIONALOUSERVA110NS PA<ll!20F6PAGI!S

DKPARTMEN'f OF HEALTH AND HUMAN SERVICES f.OOD AND DRUGADM.INISTRATlON

DISTRICT AOORE6S ANOPHONE NUMBER

300 River Place, Suite 5900 De t roi t , MI 48207 (31 3) 393-8100 Fax : (313)393-8139

Elizabeth A. Prokop i k , Corporate Counse l

DATe{S) OF !NSPE CTIO"

4/ 18 / 20 1 6- 5/11 / 2016* FEI ,.,UMBER

301175 6 3 26

Pharmakon Long Ter m Care Pharmacy, Inc. 14460 Get z Rd , Suite 2 00 CITY, ST lE, Zii>OOOE. COUNTRY TYPE ESTNIUS MEHT I"'SPECTEO

Nob lesville, I N 4 6 060-3303 Pr oducer of Ster i l e Drug Product s

Procedures designed to prevent microbiological contamination ofdrug products purp01ting to be sterile are not established , written and fo1lowed.

Specifically,

The following aseptic practice was observed:

While exiting the ISO 6 Roo.mllhe operator was observed to elbow forearm to activate the door mechanism leading into the ISO 6 anteroom. After this,

o..nm,f•ll forearm and elbow were observed making contact with the ISO 5 laminar hood work surface during aseptic operations.

The above example was observed during processing ofAmikacin 400mg/1 OOml for Rx No.lti)Jml Invanz 500mg/100ml forRx No.IGJDJII and Gentamicin240mgl100ml for Rx No.IG)mJJ on 4/18/16.

OBSERVATION 4 Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the room and equipment to produce aseptic conditions.

Specifically,

i. Bll]cleaning using to clean floors, laminar flow hoods, and work surfaces in ISO 5 and ISO 6 aseptic processing is not documented for all operational days. For drug products were aseptically processed including Ampicillin Sulbactam, Cefazolin, and Cefepime; IIIJ cleaning was not docwnented MIDIIJ8. Similarly, from 4/16/16 to 4/17/16. sterile drug products were aseptically processed; however, III cleaning was not documented (b)(4) ofaseptic operations.

OAT!! ISSUEOEMPLO'IEE(S) SiGNAliJ!1E

SEE REVERSE Rober t M Barbos a , I n vestigator """'"' 5/11 / 2016 OF THIS PAGE Emily J Orban , Investigat or _jx EmllylD<I>en

,.,J0t11UIBe i Y He, I n vestigator .._ ~----------~------------------------------ ~~==~=-==k~~--~----------~· ·~ ··

FORM FDA 483(09/08) PRIMO US llDmON Oll30U!1li JNSPECTIONAL OBSERVATIONS PAG£l 0 1'6 PAGBS

OEl'A.RTMENT OF JfEALTfl AND llUMAN SERVICES FOOD AND DRUG ADMlNJSTRATION

NAM EANDTmEOFINDMOUAlTO WHOMREP 'W <i< D ---- - ---·- ---L...-------------------1'i>.oRT.TJSsue

DISTRICT AOIJRESS /\NO PHONE NUMBER

300 Ri ver Place, Sui t e 5900 Detr oit , MI 48207 (313 ) 393-81 00 Fax: (313 ) 393- 8139

;;;;r;-

El i z abeth A. Pr okopik , Corporate Counsel f iRM NAME

Pharma kon Long Term Care Pha rmacy , Inc . CITY, STATE, ZIP cOOE, COUNTRY

Nobl esvil l e , IN 46060- 3303

ii. Non-sterile sanitizing agents are used

DATE(S) OFINSPECl iON

4/18/20 1 6-5/11 / 2 0 16* FEIMJM8ER

3011756326

STREETADDRESS

144 60 Get z Rd , Suite 200 TYPE ESTABliSHMEm INSPECTED

Producer of Ste ril e Drug Products

(b)(4) , for sanitization ofthe aseptic processing areas. Sanitizing agents used by your finn include

(b)( 4) in the ISO 5 and ISO 6 areas.

111. On 4/ 18/16, prior to and during the aseptic ces~;mg, ofAmikacin 400 mg/100 ml (Rx No. Invanz 500 mg/100 ml (Rx No. and Gentamicin 240 mg/ 100 ml (Rx No. the operator was observed sterilelt;Jld then reswning operations before

was allowed to dry.

OBSERVATION 5 Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions.

Specifically,

i. The pressure differentials between different air quality in the ISO 6 Areas (anteroom and Rooms IQ)IUI and unclassified area are monitored. such pressure differentials are checked and documented by Additionally, no documentation of lltl pressure checks was ofRoom Pressure Log before 3/02/ 16.

ii. In addition, the return air supply located in the anteroom on the adjoining wall to Room!awas observed to be partially obstructed by a cart containing the gowning materials and various supplies used in the aseptic areas.

EMPLOYEE(S) SIGNAlURE OATE ISSIJEO

!oll>(11n< 5/11/ 201 6 SEE REVERSE Ro b ert M Barbosa, I nvestiga t or OF THIS PAGE Emily J Orba n , I nves t i gator _X Emily J art>'"

Bei Y He , Investiga t or

JIO.RM JIDA 433 (09/08) .I'IUMOIJS llDITIONOBSOtEtE INSPECTIONAL OBSEltVATlONS PAGB 40H PAGBS

D:El'ARTMENT O:FH.I<!AU'HAND llUMAN SERVICES FOOD AND DRUG ADMU.1STRA110N

DISTRICT1\00ReSS 1\N!> PHONE NUMBER 0.\lE(S) OF INSPECTIOH

300 River Place, Suit e 5900 4/18/2016-5/11 /2016 * FEINUMBERDetr o it, MI 48207 3011756326(3 1 3 ) 393-8100 Fax: (313 ) 393-8139

NAMEI\NOTlnEOF INDIVIDUALTO\~OM ReJ>ORlr.;IS..,SUE~O;;------------....I....-----------------1

Elizabeth A . Prokopik , Corporate Counsel FJ RMNMlE

Pharmakon Long Term Care Pharmacy, Inc. CITY, STillE, ZIP CODE, COUI'tTRY

Noblesville, IN 46060- 3303

STREET ADDRESS

14 460 Getz Rd, Suite 200 lYPE ESTABLISHMENTINSPECTED

Producer of Sterile Drug Products

The above examp1es were observed during processing ofAmikacin 400mg/100ml for Rx No. IIDIGJI Invanz 500mg/1OOml for Rx No. Etml and Gentamicin 240mg/l OOml for Rx No.IIDIGJJ on 4118/16.

OBSERVATION 6 The operations relating to the processing ofpenicillin are not performed in facilities separate from those used for other drug products for human use.

Specifically,

Procedures have not been established for the separation oftasks and segregation ofpersonnel handling cephalosporin drug products from those for all other human drug products. Your finn hasIIIhoods, none ofwhich are dedicated to handling cephalosporin drug products. For example, on 2/14/ 16, the

(b)(4)

OBSERVATION 7 The responsibilities and procedures applicable to the quality control unit are not fully followed.

Specifically,

SOP Compounding Sterile Preparations Guidelines states (b)(4)

Such examinations were not observed, nor are they documented for each fin ished drug product.

EMPLOYEE($) SIGNATUllE DAlE ISSUED

Robert M Barbosa, I nvestigator 5/11/2016SEE REVERSE Emily J Orban , InvestigatorOF THIS PAGE l$.5mllyJOrbi!n.,.,.,_Bei Y He, Investigat or

-Sip4~c.t,·J.~t1 *5 -"' FO.RM PDA ~U (119/08) PJWVIOUS EDfl'ION OBSOI.Ii1E JNSPECfiONAL OBSERVATIONS PAGES OF 6 PAGES

DEl! AltTMENT OF HEAL'rl[ AND HUMAN SERVICES FOOD AND DRUG ADMJNISTRATION

DISTRiCT NlORESS AND !'HONE NUMBER DATE(S) OF INSPECTION

300 River Place, Sui te 5900 4/18/2016-5/11/2016* FCIN~BE~Detroit, MI 48207 3011756326(313) 393-8100 Fax : (313)393-8139

NAME ANDTl'rt.E OF INO!VI!l\JAL TO WHO!A REPORT ISSUI':P

Elizabeth A. Prokopik , Corporate Counsel FIRM NAME

Pharmakon Long Term Care Pharmacy, Inc . CITY, STATE, ZIP CODE. COUNTRY

Noblesville, IN 46060-3303

STREET ADDRESs

14460 Getz Rd, Suite 200 TYPE ESTABLISHI.ISNT INSPECTED

Producer of Sterile Drug Products

OBSERVATION 8 There is no written testing program designed to assess the stability characteristics ofdmg products.

Specifically,

Docwnentation was not provided to support beyond use dates assigned to sterile drug products. For example, Invanz 500mg/1 OOml (Rx No. EJII is given a beyond use date of3 days, refrigerated. The Invanz product insert from the manufacturer states the product is stable for 24 hours at 5°C.

*DATES OF INSPECTION 4/18/2016(Mon),4/19/2016(Tue),4/20/2016(Wed),4/21/2016(Thu),5/10/2016(Tue),5/ll/2016(Wed)

Sill/2016 5/11f1JJ16

X Robert M Dorboso X BeiY He Rollo<\ Milo,_ lleiYHc !lt~lor lnvo.sl.ll>tof Sl)ned 17(: Robe.~ M. Balbooa -s Signedl>y: Bel Y. He -5


EMPLOYEE(S) SIGW\1\JRE

Robert M Barbosa; Investigator Emily J Orban, Investigator Bei Y He, Investigator

X Emily J Orban tllftJ(I(b,&,.-"' $IIJitflldW:"""J.~n ..f

$/IJ.I»i~

DA'TE ISSUED

5/11/2016

-

FORM FDA 483 (09/08) PRP.vrousrnmoi'lOBSOL!m! 1NSPECfiONAL OBSERVATIONS PAGB 6 01' ~ PAGES

food and drug administration - fdanews

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