Sutton, S. 2014 Pharm Purch Prod 11(10):18-21
FDA Expectation s fo r
5038 Outsourcing Facilities
A
lthough the 2012 compounding traFdY at the New England
Compounding Center (NECC) is undoubtedly among the most
significant breakdowns of sterile practice on record in the US, it is
well known that similar sterile compounding misadventures have
occurred over the past 20 years. However, the sheer scope of the
hann caused by the events ar NECChas become a watershed moment, inspiring
action from regulators.
Within the past two years, dramatic changes have ocwrred in the regulation of com pounding pharmacies. Due to the concern that some compound.
ing pharmacies have been operating as national outsourcing s uppliers, the
Food, Drug, and Cosmetic (FD&C) Act has been amended to separate these
entities from the traditional pharmacy. While previously only the traditional
pharmacy was described in section 503, this preexisti ng text now appears as
section 503A and a com plerdy new entity is described-the O utsourcing Facility-in section 5038. 5038 entities fall under US Food and Drug Administration (FDA) regµlatory authority, and FDA is aggressively encouraging
rejpscration.1,1
Fifty-six companies have regisrered as 5038 entities (see ONUNE-C>NLY TABLE
for a list of these companies, the dates each registered, and the dace of their last
FDA inspection [accuraceasof Sepcember4, 2014)).' As 5038 entities, they can:
• Manufacrure large batches of compound sterile preparations (CSPs) without preregist ration (ie, New Drug Applicarion/Abbreviated New Drug Application), clinical srudies, and specific prescriptions for individual patients
• Ship across state lines
With the advent of the newly designated outsourc:~ facility, a clear under·
stand~ of FDA' s expectation s for these emi ties is vital to compliant operation.
FDA has published numerous 483 repons-official obserwtions based on FDA
inspections of pharmacies-in 2013 and 2014.~' Wbether you are considering
centralizing your health system's compounding operation, or simply looking to
oversee youroutsoun:ed compound~ "l:ndors, careful review of the recent483
reports will facilitate a thorough understanding of the statutory amendments
and gi"I: some insight into FDA's current regulatory focus.
It is important to note that USP <7'T7> Pharmaceutical Compounding Sterile Prepararions remains the primary source of guidance for the traditional
pharmacy (ie, SOJA) in the preparation of CSPs. This article will consider requirements as described in <7'17> only in relation to the demonstrated FDA expectations and the stated position that the 5038 facility will be held to d;MP
manufacturing standards.'-7
Recent FDA Regulatory Activity
In response to the even cs at NECC, and the subsequent congressional hearings,
FDA has embarked on an aggi:essive inspection schedule that focuses on compounding pharmacies chat either conduct a significant proportion of their business asoucsourc:ingservices shippingprcpamions across the US or have had issues
in quality in the past. This effort has res.deed in multiple 483 reports; ninecy-four
483 reports for com pounding manufaccurers producing sterile products are
currently posted on the FDA Web site.'·' The FDA also has audited several
TABLE 1
Frequency of FDA 483 Observation Topics
483 llsue
74.5%
r.onb'OI of Equipment
Inadequate FacHlty&noke Studies
Inadequate Cleanlng/Dl&lnlection
r.onb'OI d Pyrogenlc Conlamilatlon
llwesllgallon
Cklallty Asannce LWI Not Effecll\'9/Pnxlucllon S<Ps
ttJI Followed~llve
Separation d Clean and Dirty ~~torage
of Mata1al&
Inadequate Raw Matertal r.onb'OI
Container Preparation
SOP/Control of Production
Safeguard Agailsl FanicHlln/Cephaloepolln CrossContamination
Lllbelilg 18811•
Reoonls Not Available
Pl!lsonnel Not Tralnel1lndequately Trained
O>vtous Pl'Olklcl Contamination (MlcrolPalllculate)
Change Control
68.1%
61.7%
60.6%
60.6%
58.5%
51.5%
51.1%
36.2%
29.8%
24.5%
22.3%
16.0%
12.8%
12.8%
12.8%
11.7%
3.2%
3.2%
'Frequency lndlcUll . . P--*Dt of plllmllcy 483 111P0111 . .t '*9nce 1111 topic of . . 94
p1111nt on the FWi Web 1111. lnlltrprltatlon of , . 483 lndlngs llld aaBic.vnent to a P811iwlar
calltQDly wn perlcrmed llliely by , . author.
contract testing laboratories; howe\'Cr, the 483 repom specific to the contract
testing laboratories are not in duded in this analysis.
The most common challenges noted d uring FDA inspections include the following (see TABLI! 1):
• ln8dequ8te/lmproper Environmental Monitoring. Refers to a wide
range of issues with enYirorunental monitoring (EM), including insufficient
frequency, failure to qualify sampling sites, failure to trend dara, failure to
respond to exrursions, etc.
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fnlquencf*
81 .9%
78.7%
76.6%
76.6.%
lnadequatenmproper Envi'onmenlal Monltorilg
Validation of Sterilization: Media Riis
L11b Procedu191: Tes1i9'Conlracl Lab r.onb'OI
Inadequate Gowning
SOP& to Prevent Microbial Conlamilatlon
Non-existent or Not FOi iowed
Slablllty Prognim
Batch Release
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• Yalldatlon at Starfllzatlon: Media Fiiia. Dcsaibcs the failing of rerminally sterilized prepanu:ions to be subjected to a w.lidated sterilization cycle
in an autoclave or for aseptic fiU opetations to have performed a rdcwnt
media fill (simulated aseptic fill).
• lab T" tlng/Contrect lab Control. Includes noncompliant performance of requ~d tcsti~most commonly potency testing or USP <71>
sterility test~ Sending CSPs out fortestingto a lab thar asserts compliance
with USP test methods has not proven adequate. The phannacy is responsible for all aspects of the medicine's quality and safciy; therefore, it is vital
that the testing laboratory be qualified as GMP compliant and truly adherent to USP testing methods.
• Inadequate Gowning. This frequent citation for compounding pharm.
cics was most often documented in the 483s as inadequate clothing for job
function.. Common issues under this topic included lack of critical pieces of
personal protective equipment (cg, hair net, beard covers, foot covers, etc),
havinggaps in gl)Wll!I, poorgowningtcchniquc, and poor asq>tictcchniquc
with gowns in the aseptic area d the compow'lding suite.
• SOP9 to Prevent Microbial Contamination Nonexlatent Off Not Follo-4 "This pcral topic CO\ftl a wide ra,. d contanmalion control isaucs.
• Stabllty Progiwn. Peraiins to insufficient data supportins ihc p0ten c.y, sterility, and lack ofpyrogcnicity of prq>atlll:ions
might be ston:d fi:>rovcra year.
• Batch Relea•. Addresses the release of 5Cerilc product under improper
conditions-withour potency testirg su:rility test~ and/or bactcrilll cndotaxin testing.
• Control of Equipment. Describes a failure to ensure that compounding
equipment is appropriate for its intended use, induding high-efficiency
particulate air (HEPA) filtration in the heating, ventilation, and air conditioning (HVAC) systems; autoclave opetations; incubaton; pH meters; bat.
anccs; etc. This may be due to a failure to confirm chat the equipment is
functioning properly upon installation or at the time of compounding, a
lack of adequate preventive maintenance procedures, a lack of documentation to prove the equipment starus, or any combination ol these issues.
• lnadequatla FaclUty/ Smoke Studies. Pertains to the qu.Ufication .Wies
to en.sure the facility is meeting expectations for air balance and airflow in
aseptic areas.
• Inadequate Cleanlng/Dlalnfectlon. Refers to equipment or faciliiy
cleanliness, the carry-over of preparations from one batc;h to the next, or the
failure of pharmaq' to disinfect the aseptic area and ensure that the primary
cnginecringcontrol-s actually working.
• Investigations. Involves response to problems or crrcrs, whether they oc;
curred in process (cg, EM excursions), in finished product (cg, failure of
potency er sterility testing), or from products rcrumed from the field .
• Control at Pyrogenlc Contamination. Includes several cases where the
compounding pharmacy neglected to follow up on failed cnd<Xoxin results
for w.rious batches or did not perform testing on all parenreral CSP.s released. In several cases, the pharmacy was unable to document havu.i performed cndotaxin testing.
Several other catcgarics of issues arc cited in 483 repom at lesser frequency
(sec TABLE 1.)
The FDA recently released draft guidance for 5038 outsourcing facilities,'
whic;h clarifies that these facilities will be held to a standard more akin to pharmaceutical GMPs than to USP<797>. This seems appropriate, as FDA and industry have gleaned insight into how to manufacture sterile medications from
each public health crisis that has occurred over the past 80 years; every time
a problem is highlighted by a public health event, the GMPs have been modified to prevent recurrence. The most recent 5038 draft guidance specifically
addresses:
• Facility design
• Control systems and procedures for maintaining suitable facili tics
mar
• Em1ironmcntal and personnel monitoring
• Equipment, containers, and closures
• Components
• Production and process conuols
• General production and process conttols
• Asq>tic dl\lgprocessing
• Re lease testing
• laboratory controls
• Paclcaging and labels
• Quality assurance activities/ complaint handling
It is dear that the new FDA draft guidance was developed to address the 483
observations.
New Operational Expectations
The new Oulsourcing Facility category in section 503 of the ~C Act has created regulatory confusion in the industry. It is critical that pharmacists ha~ a
thorough understanding of the distinctions between traditional phannacics and
ouisourcing facilities. Pharmacies that adhere to the traditional practice of pharmacy will remain unc;hqed, described under Section SOJA of the revised act.
Pharmacies that wish to manufaaurc large batdtcs of non-paticnr-apecific CSPs
and seU those productsaaou state lines must register as 5038 ouuourcingfaciJj.
tics and follow basic GMP requirements.
The operational expectations of the FDA under GMP regulations compared
with the customary praaicc of pharmacy can be determined by analyzi• the
483 observations aw.ilablc on the FDA Web site and review of the newly released
draft guidance. This analysis shows significant diangcs, induding the ability to
demonstrate compliance with cGMP manufacturin11 standards, arc required for
many facilities to operate as oucsourccrs. 5038 phannacics that arc able to adapt
to these cxpcctarions may prosper, while those that arc unable or unwilling to
c;hangc to meet the new regulatory rcalitic 1 will likdy face dtallengcs o~r the
comingycan.
Conclusion
The NECC disaster clearly illustrates why the FDA's increased scrutiny of compounding pharmacies is warranted. With the FDA's renewed vigor to ensure
compliance, it is perhaps unsurprising that increased auditing has uncovered
concerns at numerous facilities. Thus, how a facility responds to a 483 obscrvarion is possibly the best measure of its capabilities; facilities that respond
with a detailed plan to address and amend the observations arc more likely to
fare well in subsequent inspections. FDA's increased auditin11 activities likely
wiU improve compliance at phannacies nationwide, with the goal of avoiding
future compounding tragedies on the scale of NOCC •
Scott Sutton, PhD, Is the principal of Mlcroblology Network, Inc,
and Is an active consutant and trainer In the pharmacy industry with expertise In GCP/GMP, FDA preparation and response,
environmental moritortng, contamlnatlon control, and microbiology laboratory audits and operations. The Microblology Network supplies
consulting, training, Weblnars, and email discussion groups. Dr. Sutton Is
a prollflc author and speaker for the Industry and has served with the USP
Analytical Microblology Committee of Exper1s since 1993. The opinions expressed In this article are t1s aone and do not neoessarily reflect the policies
or positions of a~ orgar1zatlon with which he Is associated. Scott may be
reached at scott.suttonOmlcroblologynetwak.com.
www.pppmag.com • October 2014 • 19
ONLINli·ONLY TABLE
5038 Registrations'
Finn rume
AdYanced Phann&, Inc,
Hous1Dn,TX
Alexander In fusion, UC ~Ila Avanll
Heallh care~ New Hyde Part!, NY
AUC·H>ell6, Inc,
Port W&ahlngtOn, NY
Al lelgy Laboratories, Inc,
adtlloma City, IJ<
Amerllab, UC,
Edmond,IJ<
Avella al Deel' Valley,
Phoenlx,'12.
B11111er Health,
Qmndler,'12.
~lfomia Phlrnlacf and~
Center. Newport Beadl, CA
cantre11 Drug COf111111Y,
UttlB Rod<, M
Central Admlxll.re Pharmacy
Se!Ylces, Inc, Allemown, PA
Central Admlxtln Pharmacy
Services, Inc, San Diego, CA
Complete Pharmacy and Medical
Solutions, Miami l.Jlkes, R.
Della Pharma, Inc, Ripley, MS
Edge Pharmcy SerW:as, LlC,
Colchesllr, VT
Essential Phanncy ~Ing
(Dlvllllon al Kohll's Pharmacy), Omaha. NE
Elf81a Pharma Sciences, UC,
Lenoir, NC
Greer Labofltollaa, Inc,
Lenoir, NC
Heallx Infusion Therapy, Inc,
Sugar Land, TX
Infusion Opllons, Inc, Brooklyn, NY
Institutional Phannacy Sokrtlona. UC,
Virginia Beach, VA
Institutional Phannacy Sokrtlona. UC,
Irwindale, CA
rJ Specialty Lid,
Austil, TX
JCB lilonlttrles,
Nu1h Wichita KS
.llbilant HolU8181Stler, UC,
Spokane,WA
Mings An Slope, Inc,
Brooklyn' NY
KRS Global Blotechnology, Inc,
Boca Ra1Dn, R.
l.aeSlr, Inc,
Fort Myer1, R.
Lelter's Co111KU1ding'
!Great Oaks Blvdl, San Joae CA
Omourclng Fac8y
Regllhllan
last FDA
laspecllan
1/22'2014
3117/2014
412112014
7N2014
&'312014
212!il2014
121:1)12013
4/2&'2013
512312014
ttJt yet Inspected
212412014
2125(2013
Lowllle lnveetmenta, Inc
4/3orl014
8125(2014
12116/2013
11/412013
212812014
8111/2014
&'412014
818/2014
&'&'2014
811212014
8/&'2014
1W212013
1121/2014
8/2W2014
7117/2014
Nol yet Inspected
&'6(2014
Nol yet Inspected
212412014
1111512013
(dba Olyll1Jll Phlnnacy), Orlando, R.
Medi-fare Orug & Home Heallll
C111ter, Inc, BladlslUg, SC
National P~tlon SeMces, Inc (dba
llll Pharmlcy), W&n9nvllle, L
Nephron Stl!rlle ~g
Cenbr, L1C (NSCC). West Columbia, SC
OPS lnllwnatlonal, Inc
(dba oir•
Pllannq, Orlando, R.
PhannD Sokltlons (dba PDS
~ndlng), West Houston, TX
Pharmaceutic labl, UC,
Albany, NY
Phamllgfll labOllltorles, Inc,
Stamfonl, CT
Pharmakon Phlrmaceullcals,
NoblesvtllB, IN
Pharmaloglc CSP Inc,
Btldgeport, WV
PharMedlum SeM:es, UC.
Cleveland, MS
PharMedlum SeMces, LlC,
Edl11111, NJ
PharMedium Semoes, UC, MeqJhla, TN
PharMedlum SeM:es, UC,
a.gar Land, TX
Pine Pharmaceutlcals UC.
Tonawanda, NY
Premier Pharmacy Lab8, Inc,
Weeki WBchee, R.
Plde8sblal l'hllmll:y & ~
211212014
511&'2014
RC C~dlng ServtCl8, UC,
112412014
412312014
31412014
712212014
31&'2014
M!W2014
212812014
7122/2014
1121/2014
2127/2013
6(312014
4/15(2014
12123fl013
311412014
1211512013
3117/2014
4/300014
818/2014
1/3112014
Nol yet lnapected
12126/2013
laltFDA
Inspection
FlrmNmne
W2014
(ln~lela)
SeMcee,L1C, Maml,R.
3117/2014
3121/2013
1211712013
1118/2013
811212014
Not yet illpected
7/1!il2014
Not yet lnllpectecl
311W2014
Not yet lnllpectecl
8/6/2014
Not yet lnllpectecl
311W2014
Not yet lnllpacl8d
1121/2014
8123/2013
112312014
3113fl014; 418/2014
71112014
Not yet lnllpected
12111/2013
2'22/2013
1211112013
2'28/2013
12111/2013
3122/2013
12111/2013
2'27/2013
6117/2014
Not yet lnllpacl8d
4/1&'2014
51912014
811312014
Not yet lnllpectad
fllland,OH
211212014
2n12013
Region C1111, Inc, Great Nedi, NY
SCA Phlrmaceullcals,
Little Rock, AR
SSM St Clare Health Cemer,
Fenlon. MO
Synerg'/ Pharmacy SeMcas, Inc
Palm Harbor, R.
Texa Haallh lnfualon,
The Woocllandl, TX
TrlanglB ~ndlng
Phwmacy, Inc, Clry, NC
UCSF Home Therapy SeMces,
San flancism, CA
U'*IUe Pharmaceutlcala, LTD,
T91l1118, TX
US Compomding, Inc,
Conway, AR
US Specialty FomUatlons, UC,
Be1hlehem, PA
1212412013
312W2014
1211312013
41112014
2118/2014
8/1412014
8127/2014
Not yet lnllpectecl
81812014
Not yel lnllpectecl
112412014
31112013
5129(2014
9120/2004
1117/2014
41212014; 6/2W2014
12/2orl013
3127/2014
1/31/2014
Not yet i1lpectecl
~s~ cl HMltl WIS Hunll'I s.vicea. Food aid Drug Al:tmlllnticn Wllb .... Drugs: A9gla.d OIDou'ci~ FacHias. ~=1-.bll.QOll~
~ldanc~-~~378645.lltm..Aooe!l8llCl.llle25,201-'.
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References
1. US Department of Health and Human Services. Food and Drug Administration Web site. Margaret A. Hamburg, MD, Commissioner of Food and Drugs. Letter to State Officials, January
8, 2014. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/
PharmacyCompounding/UCM380597.pdf. Accessed June 24, 2014.
2. US Department of Health and Human Services. Food and Drug Administration Web site.
Margaret A. Hamburg, MD, Commissioner of Food and Drugs. Letter to Hospital Purchasers, January 8, 2014. http://www.hpm.com/pdf/blog/FDA%20compounding%20letter%20
to%20hospitals.pdf. Accessed June 24, 2014.
3. US Department of Health and Human Services. Food and Drug Administration Web site.
Drugs: Registered Outsourcing Facilities.
http://www.fda.gov/Drugs/GuidanceComplianceRegulatorylnformation/PharmacyCompounding/ucm378645.htm. Accessed June 25, 2014.
4. US Department of Health and Human Services. Food and Drug Administration Web site.
2013 Pharmacy Inspections and Related Records. http://www.fda.gov/AboutFDA/Centers
Offices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/
ucm340853.htm. Accessed June 25, 2014.
5. US Department of Health and Human Services. Food and Drug Administration Web site.
2014 Pharmacy Inspections and Related Records.
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsand
Policy/ORA/ORAElectronicReadingRoom/ucm384667 .htm. Accessed June 25, 2014.
6. US Department of Health and Human Services. Food and Drug Administration Web site.
Center for Drug Evaluation and Research. Guidance for Industry: Interim Product Reporting
for Human Drug Compounding Outsourcing Facilities Under Section 5038 of the Federal
Food, Drug, and Cosmetic Act. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm377050.pdf. Accessed June 25, 2014.
7. Guidance for Industry: Current Good Manufacturing Practice - Interim Guidance for Human
Drug Compounding Outsourcing Facilities Under Section 5038 of the FD&C Act. http://
www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/
ucm403496.pdf Accessed July 21, 2014.
8. US Department of Health and Human Services. US Food and Drug Administration. 2013
Pharmacy Inspections and Related Records. http://www.fda.gov/aboutfda/centersoffices/
officeofglobalregulatoryoperationsandpolicy/ora/oraelectronicreadingroom/ucm340853.htm
Accessed September 9, 2014.
9. US Department of Health and Human Services. US Food and Drug Administration. 2014
Pharmacy Inspections and Related Records. http://www.fda.gov/AboutFDA/Centers
Offices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/
ucm384667 .htm Accessed September 9, 2014.