11 U.S. FOOD & DRUG ADMINISTRATION

Via UPS Return Receipt Requested

09/1112018 Cynthia Hansen Director of Quality Pace Analytical Life Sciences, LLC 1311 Helmo Avenue North Oakdale, MN, 55128-6023 US

Dear Ms. Hansen:

PHARMACEUTICAL QUALITY INVESTIGATION BRANCH 300 River Place, Sth Floor DETROIT, Ml 48207 313-393-2027

www.fda.gov

{2t:.C61vt:;D \ L. SC::~ LOI t> ~ \l.. )~ f''lO I V

The U.S. Food and Drug Administration (FDA) conducted an inspection at Pace Analytical Life Sciences, LLC, FE1:3001452367, located at 1311 Helmo Ave N, Oakdale, MN, 55128-6023 US from 01 /09/2018 - 02/07/2018. FDA has detennined that the inspection classification of this facility is "voluntary action indicated" ("VAl'').1 Based on this inspection, this facility is considered to be in a minimally acceptable state of compliance with regards to current good manufacturing practice (CGMP).

A V Al inspection classification indicates that, although investigators found and documented objectionable conditions during the inspection, FDA will not take or recommend regulatory or enforcement action because the objectionable conditions do not meet the threshold for action at this time. Despite this facility inspection classification, FDA recommends that you address any observations noted on the Fonn FDA 483 issued at the the conclusion of the inspection or otherwise conveyed to you following the inspection. lfnot corrected, the same or similar conditions could lead to a future inspection being classified as "official action indicated" ("OAI").

This lener is not intended as an endorsement or certification of the facility. It remains your responsibility to ensure continued compliance with CGMP.

An inspection classification of VAi for COMP compliance will not directly negatively impact FDA's assessment of any pending marketing application referencing this facility. Please note, however, that application approval will depend on a product-and application-specific facility assessment conducted by CDER's Office of Pharmaceutical Quality. This letter does not address or reflect FDA's decision making with respect to any potential non-CGMP compliance issues.

FDA has concluded that this inspection is "closed" under 21 CFR 20.64(d)(3), and we are enclosing a copy of the narrative portion of the Establishment Inspection Report (EIR). It may reflect redactions made by FDA in accordance with the Freedom of lnfonnation Act (FOIA) and 2 1 CFR part 20. This, however, does not preclude you from requesting additional infonnation under FOIA.

If you have any questions regarding this lener, you may contact Patrick Cummings via telephone at 612-758-7193 or email at Patrick.Cummings@FDA.HHS.GOV.

Sincerell! Patrick~.

Cumminas-5 PATRICK CIJf.IMINGS

°'9:..Jr ..,ed oY P•ll'O 8. Cummll"MJ' ·!. or-. c-4,JS. ~U,S C.oYfol'NnHI\, OU'"HllS. -JOA.-0.9-l)O 19100.)00100 I 1• Xl0016719l. cn-htnO • c ... ,,,,,... s 0ott. 20110911 t• l1.ll M'OO'

SUPERVISORY CONSUMER SAFETY OFFICER PHARMACEUTICAL QUALITY INVESTIGATION BRANCH

1 Sec Inspection Classification Definitions, at https://www.fda.ga\'/IC'ECl/ lnspections/ucm22323 1.htrn.

Establishment Inspection Report Pace Anal yt ical Life Sciences, LLC. Oakdale, M 55128-6023

TABLE OF CONTENTS

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Summary ............................................................................................................................................................ 1 Administrative Data ............................................................................................................ .................... .. ........ 3 History .......................................................................................... ................. ..................................................... 4 Interstate Commerce ........................................................................................................................................ 7 Jurisdiction ....................................................................... ................................................................................. 7 Individual Responsibility and Persons Interviewed ....................................................................................... 7 Firm's Tra ining Program ................................................................................................................................. 9 Manufacturing/Design Operations ................................................................................................................ 11 Manufacturing Codes ............................................................................... ...................................................... 15 Complaints ........................................................................ ............................................................................... 15 Recall Procedures ................................................................. ....................... .. .................................................. 16 Objectionable Conditions and Management's Respon c ............................................................................. 16 Refusals ............................................................................................................................................................ 30 General Disc ussion with Management .................................................... ...................................................... 30 Additional lnformalion ................................................................................................................................... 30 Samples Collected ................................................................... .. ....................................................................... 30 Voluntary Corrections ................................................................................................................................. ... 30 Exhibits Collected ............................................................................................................................................ 31 Attachments ..................................................................................................................................................... 32

SU MMARY

The cGMP surveillance inspection of the Control Testing Laboratory (CTL), Pace Analyt ical Life ciences. LLC. (Pace or PLS hereinafter, FEI 3001 452367) was initiated on January 91

" , 201 8 as pan of DPQO 11 1 FY20 18 domestic drug inspection work plan, under program assignment code (PAC) 56002 Drug Process Inspection and eNSpect Operation ID No. 85043. Pace is a full-servi ce contract analytical testing laboratory providing chemistry and microbiology testing services to the pharmaceutical. medical device and biopharmaceutical industries. The comprehensive inspectional and repon fonnat was observed, including the assessment of the Quality, Facilities and Equipment, Materials and Laboratory Subsystems. lnspectional coverage for this contract testing laboratory (Profile Class Code: LCP) included. but was not limited to the assessment of a transdermal product (Product Code: 60MCD24). In the previous inspection (A pril 20 15) the lirm was issued a I-item FDA-483. lnspectional Observation, Voluntary Action Indicated. The observation was for a fa ilure to thoroughly re iew any unexplained discrepancy whether or not the batch has already been distributed. The firm formally respond to the observation and their corrective actions were evaluated. During the current in pection, regulatory deficiencies were identified in three of the four quality subsystems evaluated. Consequently. at the close of the inspection the firm wa issued a 3-item FD/\ 483, In pectional Observation ' . The observations cited include: 1) The responsibil ities and procedures applicable to the quality control unit are not in' riting and fully foll owed. 2) Routine checking of electronic equipment is not performed according to a written program designed to assure proper performance. Electronic records are used, but they do not meet requirements to ensure that they are trustworthy, re liable and generally equi valent to paper records. and 3) Laboratory records do not incl ude complete data deri ved from all tests, examinations and m;say necessary 10 a sure compliance with established specificat ions and standards. Overa ll , these represent inadequate revision control procedures and failures to recognize, evaluate and control risk through validation. in a manner consistent'' ith the practices of change management and quali ty risk management. The lirm committed to responding to the observations within 15-business day.

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Extended Summary

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The Profile Class Code covered for thi in pection as~ignmcnt \\a LCP (Laboratory. Chemical/Phy ical Testing), which included the evaluation of Pace· Quality, Facil itic and Equipment. Materials and Laboratory Control Subsystems. The Quality Subsystem evaluations were conducted in accordance'' ith se lect elements from Compliance Program Guidance Manuals (CPG M) 7356.002. Drug Quality Assurance. Drug Manufacturing In pections. Compliance with 21 CFR Part 11 (Part 11) was as e ed in a fash ion con istent with the FDA guidance for industry - Part 11. Electric Records; Electronic Signatures - Scope and Application . The field a sessment of establishment registration requirements wa-; conducted in accordance with section of the Investigation Operations Manual (2017. Exhibits 5- 12, 5-13) and agency established registration and control procedure (Document #: FMD-92. Ver. 1.0). General in pcctional coverage did not include the evaluation of NOA-Field Alert Reports (17 ARs). Drug Quality Reporting )Stem (DQR . MedWatch Reports) because DPQO Ill (MIN-DO) FAR and DQRS program coordinator!> did not identify any events (PL . Oakdale. M ). \\hich was confirmed during the current in pection.

Recent inspectional history (last two cycle ) include general surveillance inspections conducted in 2013 and 2015. These inspections conformed to the Abbreviated In pcctional and Summary of Findings report formats. The most recent general surveillance inspection occurred on April 23rd through May 4•h. 2015. This inspection (FACTS Assignment 462474. Op 10: 1623457) resulted in a I-item FDA-483 and was classified as Voluntary Action Indicated (VA i). The lnspectional Ob ervation cited a failure to thoroughly review any unexplained discrepancy whet her or not the batch has already been distributed. Thi ob ervation is related to the fai lure to investigate ignificant revision to Analysis Repom I CoAs. Specifically. there were no procedure or current pract ices to

manage change pecilic to Analysi Reports I CoAs within the Change Management ystem (CMS). Pace formally responded to the FDA Minneapolis District Office on May 19'11

, 20 15 de cribing their corrective action plan. The current inspection evaluated that corrective action plan and confirmed ignilicant effort to modify an existing operating procedure (SOP L30). including the add it ion of an investigative form ( OP L30, form A4) to record mitigation related activities. elect quality event \\ Cre reviewed to determine if this procedural modification' as completely integrated into the firm ' Qualif) Management )Stem (QMS) and consi tent!) practiced (i.e .. reduced to practice).

During the current inspection, regulatory deficiencies were identified in three (3) of the four ( 4) Quality Subsystems (Q ) evaluated. The e deficiencies occurred in the Quality, Facilitie and Equipment. and Laboratory Control Subsystems. There were no formal observat ions cited for the Material ub y tern. The Production and Packaging and Labeling subsystems \\ere not evaluated bccau e they are not part of Pace's CTL operations. At the close of the inspection the firm was i sued a 3-itcm FDA 483. lnspcctional Ob ervation, Voluntary Action Indicated (VA I). The observations cited include: I) The re pon ibil it ies and procedures applicable to the quality cont rol unit are not in writing and full) followed, 2) Routine checking of electronic equipment is not performed according to a written program designed to assure proper performance. Electronic records arc used. but they do not meet requiremem to ensure that they arc trust worth). reliable and generally equivalent to paper records. and 3) Laboratory records do not include complete data deri ved from all tests, examinations and assays necessary to assure compl iance with established specifications and standard . These observation rencct Pace's failure to actively identify risk. consistent with the practices of an effecti\'e Change Management (CM) and Qualit) Risk Management (QRM) ystem; ultimate!). resulting in the mitigation of risk through formal val idation a required by regulation . Basically. the failure to proactivcly recogn ize. e\aluate and control all forms of risk. In the context of the closing meeting Mr. Grego!) D. Kupp. Vice Pre~ ident and Chief Operating Officer, and Cynthia L. Hansen,

enior Director of Quality requested I clarify some of" the speci fi e examples under the primary observations. further, they expressed disagreement \\ ith elect observat ion examples and in e\eral instances directed our attention to ongoing Risk Assessment and Correcti ve Action processe . The e proce ses were recently initiated due to internal management review processes. that incidentall) coincided with the current inspection . Ms. I lansen committed to a formal response wi thin 15-busincss day . 'I here were multiple informal verbal observation

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discussed with the fi rm's senior management throughout the course of the inspection and/or at the closeout meeting. These verbal or informal ob ervations include eleven ( 11) primary items for discussion. In forma l observations are summarized in the Informal Items for Discussion section (pg. Error! Bookmark not defined.).

During the current inspection, no refu als were encountered and no amples were collected. The management was informed at the closeout that the observations (FDA-483) cited may, after further review by the Agency, be deemed violations of the Food. Drug and Cosmetic Act. and if not vol untarily corrected. sanctions available to the Agency include. but are not limited to regulatory meetings. untit led and warning letter . injunction. and civil and crim inal penaltie .

Ms. Hansen indicated there were no concurrent inspections or other government agencies/regulatory bodie on­site during the current inspection. However. on 17th and l 8lh of January Pace had a long-stand ing scheduled meeting with an accredited certification body for the International Organization for tandardization (I 0) regarding certification acti vities critical to the testing services they provide to the medical device indu try. This information was provided to the investigator at the start of the inspection. Consequently, due to the long­standing nature of the scheduled event. and potential significant implications for Pace' s regulated testing operations, we chose to suspend our on-site inspcctional effort during tho e day . In add it ion. activitie related to the government shutdown required suspension of the investigation for a period of approximately two days. These short delays did not impede the overall investigational processes or effect the inspectional outcome.

ADM INISTRA TrVE DAT A

Inspected Finn:

Location:

Phone:

FAX :

Mailing Address:

Dates of Inspection:

Days in the Facility:

Participants:

Pace Analytical Life Science . LLC.

13 11 Helmo A venue North Oakdale. M 55 128-6023

763-786-0302

763-786-09 15

1311 llelmo Avenue North Oakdale. MN 55 128-6023

01 /09-12. 16, 19, 24-26. 29/20 18. 02/07/2018

11 days

Scon A. Golladay, Investigator; teven A. kaar, upervi sory Con umer Safety Officer (SCSO); Mr. Skaar \\as present on 01 /09-11/20 18 and at the closeout on 02/07/20 18

Upon arrival at the firm 's reception desk on 0 1/09/20 18, tt!ven A. Skaar ( C 0) and I (Scott A. Golladay. Investigator) introduced ourselve and pre ented our credential to the receptioni t; ub equent ly, we were greeted by Ms. Cynthia L. Han en, Senior Director of Quality whereupon we introduced ourselves, presented our credentials and stated the reason (general surveillance inspection) for the visit. ext, Ms. I lansen e corted us to a small conference room a short distance from the main entry "a) I recept ion area whereupon I, lnve tigator, colt A. Gol laday. and SC 0 , Steven A. kaar presented our credentials a second time to al l individual joining in the opening meeting. These individuals include Gregory D. Kupp. Vice President and Chief Operating Officer (COO) and Cynthia L. Hansen, enior Director ofQualit). Mr. Kupp and Ms. Han en conduct PL operations from the Oakdale. M si te. Next. I stated the purpose of the in pcction was to conduct a cGMP sur.,,eillance inspection. including the assessment of pertinent Qualit) ubs)stems (Q ). I asked Ms. Han en and Mr. Kupp to

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assist me in identif) ing the most responsible person at Pace Analytical Life cience. LLC., Oakdale. M operations. Both individuals concurred that Mr. K upp "as the most respon ible per on at this site in absence of

teven A. Vanderboom. President and Chief Executive Officer (CEO) of Pace Anal) tical ervices. LLC. Pace Analytical ervice . LLC. is the parent company and it \1,holly-owned ub idiary operations include environmental. life science-, instrument support and scientific professional ervice operations. Mr. Vanderboom does not reside at the PL facility in Oal.dale, MN. but rather conducts daily operations from the firm' s headquarters located in Minneapolis. M . ubsequentl~ . I had a brie f but detailed di cussion with Mr. Kupp about his role and responsibilit ies. \\ hereby I i ndependent !~ confirmed Mr. Kupp was the most re pon ible person al Pace Analytical Life Science . LL . (Oakdale. M ). tr. Kupp i the top management official or mo t responsible corporate official at the Cal.dale si te. Mr. Kupp make monetary outlay decisions, including resourcing deci ion (human, equipment) for all FDA regulated operation . and i the senior mo t re pon ible si te corporate officer to be empowered \\ ith en uring regulatory compliance for all si te operations. Prior to is uing the FDA-482. otice of Inspection I re iterated to the management team the scope of the inspection \\ 3S to conduct cG MP surveillance inspection, including all appl icable Q . ext. I issued the FDA-482, Notice of In pection (Attachment 1) to Gregory 0 . Kupp. Vice President and Chief Operating Officer.

On January 12. 2018. I had the opportunit) to brieny peal." ith Mr. Vanderboom. Pre ident and Chief Executive Officer who was visi ting the Oakdale si te. This was Mr. Vanderbooms first visit to the site during the current inspection. In the context of that di cussion. Mr. Vanderboom made me aware of the significant role he plays in providing regulator) leadership. including the active role he pla) ed in addres ing previous FDA-483, lnspectional Observations. Mr. Vanderboom had an excellent command of the previous FDA in pectional even! , including the formal observation (FDA-483 ). Considering Mr. Vanderboom's description of his primary re ponsi bilities as President and CEO, including a prominent leadership role in addressing any potential regulatory ob erva1ions. 1 chose 10 issue a :!nd FDA-482, otice of In peclion (Attachment 2). Consequently. on January 3. 2018 1 issued a FDA-482 to te.,,en A. Vanderboom. Pre ident and Chief Executive Officer (CEO) of Pace Analytical en ice , LLC.

During the closing meeting, 1 pre ented the FDA-483. In pectional Observation (Attachment 3) to C) nthia L. Hansen, Senior Director of Qua! ii) . Is. Hansen is the most re pon iblc person in ab ence of Steve A. Vanderboom. Pre ident & CEO and Gregory D. Kupp. Vice Pre:-ident & COO. Mr. Vanderboom and Mr. Kupp were unable to anend the closeout due 10 prior work-related commitments (out-of-state). However. Mr. Kupp called in during the closing meeting. Ms. Han en scanned the ~ DA-483 and sent Mr. Kupp an electronic copy for review prior to me reading each ob ervation out loud. After reading each obscr at ion/example, I provided Ms. Hansen and Mr. Kupp wi th an opponunit) to respond.

Ms. Hansen was m) liaison throughout the course of the in pection. where she served to address questions. disseminate and di cuss documents. and led walkthroughs of the faci lities. Mr. Kupp vi ited the in pectional conference room on several occasions to address questions and indicated he was avai lable any time. as needed.

HISTORY

Pace Analytical ervices, LLC. (Pace) i a private!) held sampling and analytical te ling firm . It provide analytical services to the Nort h American and global marl.els for environmental and life cience le ling. Pace operates three divisions in two countries. employing approximately 2500 emplo)ee . The divisions include a network of 32 environmental testing laboratories, 6 laboratOr) operation (LabOps) locations, 48 service centers and 4 life science opera1ions/laboratorie located throughout the United late and Puerto Rico. Pace· F.nvi ronmcntal Division provides full -service sampling. testing and analytical support services to detect trace­level contaminants in water. waste\\ater. oil. biota. waste. air and other medias for industrial companies. environmental consultants, utili ties. and local, stale and federal government . Pace· Life cience Dh ision provides testing services to the pharmaceutical, biopharmaceutical and medical device industries including. but

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not limited to testing services for physical & functional attribute . analytical chemi try. microbiology. and stabili ty operat ions. Pace's Analytical Lab Ops Di vision provide complete profes ional scientific staffing services to augment the client's professional human re ources. In addition, Lab Op provides instrument support including sales. repair and quali fication erviccs, and rcgulatol') compliance related services.

Pace Analytical Life ciences. LLC. (PL ) i a network of full- ervice contract development and analytical testing laboratories providing formulation and proces development, CMC, chemi 1ry and microbiological testing services to the pham1aceutical, biopharmaceutical. and medical device indu tries. Pace·s li fe science laboratories are located in Oakdale, MN; Somerset. J; Woburn. MA ; an German, PR; and the ne\ ly acquired Wolfe Laboratories located in Boston, MA. Wolfe Laboratorie is a subsidiary of Pace Analytical Life Sciences. Wolfe is a contract research and development organization that provide integrated drug development solutions to the biopharmaceutical ind ustry. Wolfe expands Pace's life cience services to include formulation and process development. CMC support, and full- pectrum services from di covery through Phase 3 development and post approval.

Pace Analytical Life Sciences, LLC. (FEI: 300 1452367) located in Oakdale, Minne ota is the focus of the current urveil lance inspection. Pace Analytical Life Science . LLC. (PLS or Pace) is a wholly-owned subsidiary or

sister company of Pace Analytical ervices, LLC. Pace supports medical device manufacturers who are ubject to Quali ty System (Q ) regulation. and pharmaceutical drug manufacturers who operate under the umbrella of cGM P regulation. Pace' s microbiological ervices support the analysis of raw materials, finished products and medical devices. including facility envi ronmental monitoring. Pace offers analytical chemistry services for the qualitative and quantitative assessment ofraw materials, excipients, active pharmaceut ical ingredients (A PI), in­process and finished products, including stabi lity samples. Further, Pace supports the analytical testing of high­potency active phannaceutical ingredients (HPAPls) and/or controlled substances ( chedules I - V). Pace employs approxima1ely 200 people at the Oakdale life cience facili ty and their hours of operation are from 8 a.m. to 5 p.m. M - F. except holidays.

Pace Analytical ciences, LLC. and its wholly-owned subsidiar) or sister company Pace Analytical ervice . LLC (PLS. pass-through entity) were incorporated in Minnesota. As such, they have eparate Federal Tax ID numbers. Overall , PL provide services to customers globally in F.urope, Asia Africa and North American. Pace's busine s development and marketing strategies emplo) direct-to-client sales and marketing techniques via tradeshows, symposia and related industry forums/event . Currently, PLS's largest clients for pharmaceutical and/or medical device testing related services, by sales volume and/or revenue, include

A notable product that Pace provides extensive stabi lity storage and testing service for is Transdermal Patch. The corporate headquarters (I IQ) for the parent company. Pace Analytical ervices,

LLC., is located at 1800 Elm Street South East, Minneapoli. M 554 14.

Pace's Oakdale. Minnesota life science operations include l\\o primary operational spaces or commercial sui tes. The first is a 40.000ft2 facility designed for sample receiving. material characterization, physical and functional testing, and pharmaceutical chemistry. including extensive stability operations. In a second, adjacent facility (20,000ft2

) they provide microbiological services which include a dedicated clean room (commissioned - 2015) for steril ity testing. In addition, the second laboratory space supports material and In vitro compatibility test ing. Further, with the recent expansion in services to the medical device industry, thi pace is used to conduct In vi tro biocompatibility testing services. The e services include. but are not limi ted to In vitro cytotoxicity. hemocompatibility and genotoxicity {I 0 I 0993-5. -4. -J).

Analytical chemistry testing capabilitie at the PLS Oakdale facili ty include, but are not limited to liquid chromatograph). gas chromatography. thin-layer chromatograph) , ion chromatography, mass speclrometry. FTIR, UVNI . AA. ICP. Karl Fischer. TOC. pl I, conductivity. "'ater activity. melting point, D C. TGA. terility testing, endotoxin, HIAC/Royco liquid particle counter and di olution . Pace operations support an expan ive

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array of stabi lity studies across the pharmaceutical and medical device industrie . Consequently. the linn ha extensive environmental/stabi lity room and chamber capacit) . The storage and tability environment include. but are not limited 10 all ICH defined climatic zones. Lung term le ting condition include zone 1-111 . I Va. I Vb. refrigerated and frozen. Accelerated and intermediate conditions incl ude ambient. refrigerated, frozen and intermediate. In addition, there are extensive custom-condition tability environments. To support stability operations Pace ha extensive HPLC-UV and dissolution testing (USP Apparatus I- 4) instrumentation.

I asked Mr. Kupp and Ms. I lansen if they were aware of an) regulatory action including, but not limited to regulatory meeting , unti tled and warning letters. injunction. and civil and criminal penalt ies for violation of the Food, Drug and Cosmetic Act. They stated. in good faith. that they were not aware of any such action on the part of the l'DA, or similar regulatory body. A query of FDA databa!.es and review of di tric1 files did not reveal any regulatory actions incl uding, but not limited to regulator) meet ings. advisory action (warning and untitled letters), or enforcement actions (administrative action . legal action!.). Further. a revie\\ of FDA systems did not reveal any complaint (PLS, Oakdale. M ).

Recent inspectional history (last two cycles) include inspection in 20 13 and 2015. In the 20 IS in pection Pace was issued a I-i tem FDA-483 , lnspec1ional Observation. Voluntary Action Ind icated (VAi), citing a failure to thoroughly revie\\ any unexplained discrepancy whether or not the batch has al read) distributed. This observation is related to failures to investigate significant revi ions to Analysi Reports / CoA . pecificall). there were no mechanisms or current practices to manage changes to Analysi Report I CoAs (regulatory documents) within their established Change Management )Stem (CMS). In the 20 13 inspection Pace was i sued a I-item FDA-483 (VA I) citing a failure to conduct investigation!. of an unexplained discrepancy for drug products that may have been associated with the specific failure or discrepanc) . The inve tigator in the subsequent inspection conducted in 20 IS concluded the firm made procedural corrections to address the observation and the e procedures \\ere fully implemented. 1 he current in pec1ion (2017) revealed significant efforts to mod if) an exist ing operating procedure and the addition of an investigati e form to record mitigation related activities. A review of the 20 13, 20 15 and 20 17 (current) inspectional records reveals a consi tent fai lure to employ effective investigate measures. as requi red b) regulation and con i lent with current industf) practices.

Ms. I lansen, stated in good faith that she ''a not aware of the firm's efforts to upport a client recall event: however, they may have indirectly supported such an event '' i1hout their direct Imo\\ ledge, as their client do not always inform them of the reasons behind requests for additional information/documentation. As uch, Pace being a contract testing laboratory. without manufacturing operations, does not ha e recall related procedure'>.

Post-inspectional correspondence should be addressed 10:

1even A. Vanderboom, President and Cl:.O Pace Analytical Life Sciences, Ll .C. 131 1 Helmo Avenue orth Oakdale, M 55128-6023

FDA Registration

Pace Analytical Li fc ciences, LLC. located at 131 I I le Imo /\venue North, Oakdale. Minnesota 55 128-6023 is currently registered '' ith the FD/\ under Drug (D RG). both human and veterinary do age form product : Veterinary Medicine (VET); and GDUFA elf- Identified Firm ( JOF). The FE! and D S/Regi trant umbers arc 3001452367 and 797903197. respectively. The DRG and VET registration were renewed on 01101no 18. The initial GDF registration occurred on 0110112018. The previous registration date for DRG and VET occurred on I 01011201 5.

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INTERSTATE COMMERC E

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Pace docs not manufacture fi ni hcd drug products, biologics or medical device . In addition, they do not produce excipients. ra\\ materials or component for medical de ice or drug products. Currently. they are contract testing lab (CTL), ' ithout manufacturing operations. Ms. Han en e ti mated that a significant fraction of the samples tested at the firm are received from out-of-state customer . he also indicated that mo t reagents, materials, and supplies (>95%) arc received from out-of- tatc. Instrumentation to support all te ting operations is acouircd domestically, out ide of Minnesota. Pace's top four FDA regulated product clients include

One example of an FDA regulated product that is currently distri buted dome tically and that Pace supports extensively, including stability studie . is Tran dermal Patch.

JU RJSDICTION

Pace Analytical Life ciences perfonns contract testing services for 1he pharmaceutical and medical de ice industries, domestically and internationall) . Services include. bu1 are not limited to physical & functional. analytical chernistf) and microbiological te ting. The e resting . erviccs support the analysis of medical devices including componentry. raw materials. excipients, A Pis. in-proce . fi nished product and stability samples for the pharmaceutical. medical device and biopharmaccutical indu trie . In absence of any suspected violative product, I collected ad,enising or service brochures/li terature for Pharmaceutical (Exhibit 2). tabili ty Storage (Exhibit 3), and Medical Device Testing (Exhibit 4) operations.

lNDIVlD UAL R E PONSJBlLITY AND PERSONS INTERVI EW ED

The primary contacts during the inspection were Cynthia L. Han en, Senior Direc1or of Quality and Gregory D. Kupp, Vice Pre ident. Chief Operating Officer. Ms. Han en facilitated the in pection by arranging ,,afkthroughs of the facility, addre sing questions, providing documentation. and serving as a liaison for subject-matter expert . Ms. 1 lansen actively addressed multiple quality/regulatol) concerns and all reque t v.ere met in a timel) fashion.

Pace senior leadership or management include: (Unless exprcs~I) stated, they ma) nol have directly participated in the in pection or their participation may have been VCf) limited.)

• Steven A. Vanderboom, President and Chief Executive Officer (CEO) founded Pace Analytical ervices. LLC. in 1978 and has served as its President and Cl:..O incc that time. In addition, Mr. Vanderboom is the Pre ident and CEO of the sub idiary Pace Anal)tical Life cience , LLC. including all its life cience operations located in Oakdale. M : Woburn. MA: . omersct, NJ; San Gennan. PR; and Wolfe Laboratories. LLC., Boston. MA. Ir. Vanderboom hared owner hip \\ith a business partner until his associates passing. Subsequently, in a fashion consi tent wi th his personal commitment to his business partner. Mr. Vanderboom sought liouiditv to exoand Pace's operations. Consequently, Mr. Vanderboom forged a partnership with Los Angeles, CA. Mr. Vanderboom remains the largest minority owner of Pace. with a majority holding b) suppon Pace through investments in gr0\\1h initiatives. trategic posi tioning and add-on acquisitions. Mr. Vanderboom reports to the 1 board of directors. I tis core re pon ibilities include devi ing policies and strategies 10 ensure the completion ofcorporale goals. corporate go,crnance, business devclopmenl and provides direction to operational units across all Pace·s divisions. including the oversight of the firms budgetary and financial activities. ensuring the firm operations conform to all applicable regulation , including internal operating procedures and policic .Out ide of a brief introduction/discussion and the is uance of1he 2'"' FDA-482, Mr. Vanderboom did not directly participated in the inspection.

Grego!) D. Kupp, Vice Pre idcnt and Chief Operating Officer - Life cience . assumed hi current role in 2006 bringing more than 25 years of managerial and business development experience from the Life

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Science industry, including executive level management. information technology and laboratory operations. Mr. Kupp is responsible for the strategic growth. operational leadership and management of Pace's Life cience busine . In addition, Mr. Kupp's primary rcspon ibilit) is to ensure all PL operations. includi ng tho eat the Oakdale facilit}. conform to regulator) requirements, state and local laws. internal operating procedures and corporate policies. Mr. Kupp provided extensive commentary on current regulation and industry practices regarding the concept of·•1esting into compliance··. Mr. Kupp reports directly to Mr. Vanderboom. President and CEO.

• Angela trantz. Ph.D., enior General Manager. Pace I ife Science operation . Oakdale. M . Ms. trantz joined PL in 20 I 0 and ha been in her current role since 20 12. Ms. trant7 has more than 15 years of experience in the Medical Device and Pharmaceutical industries. he ha extensi ve experience with the microbiological testing ofterminall) steril ized and aseptically filled product and related proce e . including process val idation. qualit) control te!>ting. \\ater system mon itoring and environmental monitoring. Previously. M . trant7., was the Director of Microbiolog). Ms. Strantz offered her assistance on everal occasions and briefly an ended one of the inspectional di cuss ions in support of Ms. Hansen. M . trantz report directly to Mr. Kupp. VP and COO.

• Cynthia L. 1 lansen, Senior Director of Quali ty - Life Sciences joined PL in 2006 and has been in her current role since approx. 2012. M . Hansen has extensive experience in analytical testing and laboratory management. with over 20) ear of experience in the Life cience industf) . Ms. Hansen has occupied roles of increasing respon ibilit) at Pace includi ng Group Leader. Project Manager and Director of Quality. In her current capacity she is respon ible for Quality Assurance. Data Review. Document Management. Information Technology, Equipment and Facilities at all of Pace' Life Science operations. In addition. Ms. Hansen·s primary responsibi lity include ensuring all Pl , operations conform to regulatory requirements. state and local laws. internal operating procedures and corporate policie . Ms. Hansen has extensive knowledge of Pace's QM . including valuable hi torical commentary. Ms. Hansen provided extensive suppon to me throughout the cour e of the inspection. facilitating document retrieval and related technical discu sion . M . 1 lansen repon direc tly to Mr. Kupp, VP and COO.

• Mary Ryan, Director of Microbiology- Life Science (Oakdale, MN) joined PL in 2006 and has been in her current role since 201 7. Ms. Ryan has occupied role of increasi ng responsibili ties at Pace including Microbiolog) Group Leader. Ms. Ryan was emplo) ed at Part Three Corporation and P3 cientilic. Inc. prior to it acquisit ion by PL in 2007. Ms. Ryan repon directly to Ms. trantz, enior General Manager.

• Glenn Oslow ki , Director of Chemi try- Life cience (Oakdale, M ) ha been in his current role since 2016. Mr. Oslowski has occupied roles of increasing re ponsibility at Pace including, but not limited to Chemistry Group Leader. Mr. 0 lowski has over 20 years of experience in analytical chem istry. Mr. Oslo.,,, ski briefly supported Arielle Clarin, Area ' upervi or during a brief discussion regarding the dissolution testing of the Transdermal Patch . Mr. Oslowski reports directly to Ms. trantz, Senior General Manager.

Pace management and area specialist: (Un le s expressly tated. they may not ha' e directly participated in the inspection or thei r participation may have been very limited.)

• Joe Estrem. Area Supervisor - Life ciences (Oakdale. MN). Mr. Estrem has occupied roles of increasing responsibility at Pace. Mr. Estrem i the architcct/dcsigner/implementer of Pace· Continuous Monitoring ystem (CM ) "' hich provides the foundation for Pace's extensive tabi lity operation . Mr. Est rem worked at Part Three Corporation and P3 cientific, Inc. prior to it acquisition by PL in 2007. Mr. Estrem, as the archi tect of Pace's CM . directly supported/participated in cxten ive

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discussions regarding the PaceLink CMS including. but not limited to its development. setup. operation, qual ification and val idation. In addition, Mr. Estrem provided extensive commentary on the setup of the CM modules/loggers, including elements of the UP or backup power stem. Mr. Estrem has a remarkable eries of hybrid skills across multiple di cipline including. but not limited to engineering, programming and regulatory compliance. Mr. E trem reports to Steve Fritz. Group Leader.

• Felix Vazquez. Building Superintendent - Li fe cience (Oakdale, M ). Mr. Vazquez has occupied roles of increasing re ponsibility at Pace. Mr. Vazque7·s primary responsibility i the management of Pace's environmental controls. Mr. Vasquez described the technical features and functioning of Pace· H VAC system. In addi tion, he addressed several of my que lions concerning Pace' current environmental air handling practices. Mr. Vazquez reports to Joe Estrem. Area Supervisor.

• Aileen Van Bergen, Speciali t II - Li fe Sciences (Oakdale. MN). Ms. Van Bergen's numerou role and responsibi lities include the active management of controlled re ference tandards. The investigators had a brief interaction wi th Ms. Van Bergen in the controlled ubstance (C ) reference materials torage area. Ms. Van Bergen reports to Amanda DeRaad. Ra'' laterials PM, Group Leader.

• Nicole Rehberg, Speciali t 1- Life Sciences (Oakdale. MN). Ms. Rehbcrg's numerous roles and respon ibil itie include the active maintenance of controlled reference tandard . The inve ti gator had a brief interaction with Ms. Rehberg in the CS storage area where she served to address question about Pace's CS reference materials and related procedures. Ms. Rehberg reports to Amanda DeRaad. Raw Material s PM, Group Leader.

• Michael Merrick, Controlled ubstance Assistant - Life ciences (Oakdale. M ). Mr. Merrick pro ides support to the raw materials group. supporting controlled reference standards. The inve tigators had a brief interaction with Mr. Merrick in the controlled reference material storage area. Mr. Merrick reports to Amanda DeRaad, Raw Material PM, Group Leader.

• Arielle Clarin. Area Supervisor- Life Science (Oakdale, M ). Ms. Clarin upervises an analytical chemi try group which support pharmaceutical chemistry and related analy es. Ms. Clari n conducted dissolution analysis (select clements) for the Transdcrmal Patch tability operation . Ms. Clarin erved to discuss the technical clements of the di olution methodology for the Transdermal

Patch. M . Clarin reports to Jennifer Bois, Group Leader. Pharmaceutical Chemistry.

FIRM'S TRAINING PROG RAM

A series of SOP. including select attachments, were revie\\ ed to 11.!arn about Pace's trai ning program to determine compliance with regulatory requirements, including functi onal role or task specific and current Good Manufacturing Practice (cGMP) training. As part of this proce I reviewed OP that define the foundat ion for Pace 's general training program, including those containing cGM P training element . Further. in a fashion consistent with my inspectional focus on Pace's program to support the stabil ity analysi of Tran dermal Delivery System containing ( 12.5 and 50 mcg/hr), a highly potent active pharmaceutical ingredient (H PA Pl), I chose to review the training records of per onnel for .. task" specific methodology used to support the stabi lity testing operations. In addition. I reviewed select training record for individual(s) who supported the QA review of technical records for the stabi lity program.

The SOP Training Program (Exhibit 5). OP 4, Ver. 16. 1-.ffcctivc 31 AUG 2016 \\ 35 reviewed including attachments: SOP Training Guideline. OP 4 A 9; Proced11r1t Training Record. OP 4 A6. Annual Training Record, SOP 4 A 7; .Joh Descriplion Acknowledge111en1 Form. OP 4 A8; Depul)• Assignmenl Acknowledgemelll

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Form, SOP 4 A I I: and Employee Role Change Trai11inx Form . . OP 4 A I 2. Thi OP ( OP 4 A 12) describes the new employee training program, including GM Ps.

The OP Technique Based Training (Exhibit 6), SOP 1.2. Ver. 5. 1-:ffective 2 I 0 T 20 14 was reviewed. This OP outline the technique based 1raining program for PL .

The SOP Training of Technical Record.1 Re11iewers (Exhibit 7). OP L22. Ver. 5. Effective 23 JA 20 I 7 was reviewed. This OP de ·cribes the procedure for training of technical record re\ ic\\ers.

A series of modules were reviewed to as e s task-based training elements for analytical chemist supporting fentanyl stabili t) te ting operation . The e trai ning module include: HPLC Training, TM I, Ver. 9, Effective 12

EP 2017; HPLC Training Outline, TM I A I, Ver. 9. Effective I 2 EP 2017: I/PLC Training Competency Testing, TM I A3. Ver. 9, Effecti e I 2 EP 20 17; Empower trai11in~ l evel 2. TM 65. Ver. 3, Effective 06 JA 20 17; Empower Training Level 2 Competency Testing, TM 65 A2. Ver. 3. Effective 06 JAN 2017; Empower Training l evel 3, TM 76, Ver. 2. Effective 19 JUN 2017; Empower Training l e1·el 3 Outline, TM 76 A I, Ver. 2, Effective 19 JU 2017: Empower Training Level 3 Competency. TM 76 A2. Ver. 2. Effective 19 JU 2017: USP Dissolution Testing. TM I 9, Ver. 5. Effective 18 JA 2016: Dis.\Ollllion Testing, TM 19 A 1, Ver. 5. l::ffective 18 JAN 2016; Dissolution Basic Competency Erercise. TM 19 A2. Ver. 5, Effective 18 JA N 2016.

After reviewing Pace's task-based training program. I became increasingly concemed about their failure to conduct test method pecific training. In a discussion" ith Ms. I lansen she indicated that test method pecific training would be impossible to conduct due to the number of methodologies they uppon and re ource lim itat ions.

Additional training elements were revie" ed for select applications outside of those related to the stability program. pecifically. training procedure /modules for titrations were reviewed. Titration training procedures were selected for review for several reasons. These reason include: I) Pace' routine application of everal U P titration methods. 2) Technical and training challenges pccific to 1he e methodologie . including ignificant challenges to consi tently achieving titration end-points. and J) Quali ty event related to titration method challenge and/or deficiencies. I stated 10 the firm visual endpoints can be very challenging to consi tently achieve during titration. and of1en involve significant anal) t di cretion. Con equently, these methods are often taught through direct demonstration or observation of the methodologies, i.e., method-specific training. Basically, tit ration end-points can be consi tent!) achieved during testing when analyst ha e had adequate training opportunit ies to ob erve visual endpoints wi th a more experienced chemist.

A series of module ''ere reviewed in order to assess tas" speci lie training elements for analytical chemist "ho conducted select te ting operation for the I patch tabilit) program. The e trai ning modules include I/PLC Vi.ma/ Titration.~. TM 16, Ver. 3, 1-.ffective 19 AUG 2014; Vi ual Titratiuns Training Guideline. TM 16 A I, Ver. 3, Effective 19 AUG 2014: and l'isual Titration.1 Competency Exercise, TM 16 A2, Ver. 3. l:.ffective 19 AUG 2014.

The training record were asses ed for two (2) analyst who conducted or supported tability sample testing. and one ( I) QA speciali 1 who supported data review for the Transdermal ystem 12.5 mcg/hr stability study pecifically, select training records were as e ed to verify anal} t competencies for three (3) of the ten ( 10) methodologie emplo} ed to support the stabili ty tud). The training records were reviewed for GMP and task-specific rraining clements related to the following methodologies.

I ) 12. 5. 25. 37. 5. 50. 75.

& 100 111cgl lir Trw1sder111al Patches hy Hf'l.C. Method Ver. I. Release I 0/02/2013

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12.5. 25. 37.5, 50.

7 5, & 100 mcglhr Trunsderma/ Patches by 11 I' LC. Method Ver. I. Release 10/04/2013: Ver. I. Effective 0 I

APR 2014 3)

Method , Ver. 2. Release 07/24/201 7: Ver. I. Effective

28 OV201 7

The training records for the fo llowing two an11lysts were re ic\\cd. It must be noted. these analy ts may not have been responsible for conducting all procedural clements " ithin any given test method.

I) Ellie Clarin. Senior Chemi t. Date II ired 22 FEB 201 7 2) Eddie Halbi ch, Chemi t 11. Date !tired 23 OCT :!017

The Training Records for the following QA reviewer was asse ed.

I) Erika Roben , Senior Quality As urancc Speciali t. Date llired 01 JUL 2010

Pace's corrective action (CA) in response to the FDA-483. lnspectional Observations si ted in the April 2015 inspection included revisions to SOP L 12. Consequently. I chose to assess training re lated activitie associ ated wi th this CA. including the updated OP Quiz and Group Training records. Please see the Voluntary Corrections subsection (pg. 30) for addit ional di ·cu sion regarding the generation of quiz questions.

I ) Group Training Form, OP L 12. Trainer Cynthia I Ian en. Training Date 2 1 MAY 20 15

MANUFACTURING/DESIGN OPERATIONS

General urveillance I Quality Sy tern In pectional Approach (Overview)

I initiated my evaluation of the Quality Management System (QM ), including its sub ystems with a brief overview and discussion of Pace's Qualit) Unit (QU) infrastructure led by M . Hansen. As part of this di cu sion she provided a high-level overview of the basic structure. core clements and conventional work fl ow of Pace's Qual ity and Risk Management System (QRMS). Subscquentl) , I requested Pace's Qual ity Manual (Exhibit I ) and Quality Policy, whereupon Ms. Hansen introduced the manual and directed my attention to select qualit) systems within the policy. In addition. I requested a cornprehcn ive list of their operating procedure . Subsequently. Ms. I lansen gave a shon PowerPoint pre emation ummarizing Pace's operational units, including the QC and QA functionalities, and client services. At the conclusion of the presentation and discussion I could derive a fundamental understanding of Pace 's QMS, qualit) wor\..flow practices and related electronic content management systems. On the 9m and I o•h of January. Ms. Hansen led a comprehen ive walkthrough of Pace's facili ties, including the primary space which supports pharmaceutical chemistry. and a second facil it . located in an adjacent commercial space, where microbiological and cleanroom functions reside. This walkthrough emulated the sample introduction and production (i.e., te!.ting operations) workflow. including sample receiving and initial storage areas. laboratory (phy ical. functional and chemical), storage and stabi lity areas. !'he adjacent ite included a walkthrough of the microbiological and In itro biocornpatibi lity testing areas. We did not enter

the sterile proce sing area, as there were no ongoing activities; however, I was able to observe the entire workspace and entry area (airl ock). We vie\ ed and discus ed the environmental controls for the sterile workspace and observed pressure differential , nothing remarkable was noted. Thi enclosure was evaluated extensively in the previous inspection (20 15). A ftcr compl eting the walkthroughs. I made requests for additional documentation. including document index report (summary list) of ex isting OP . Test Methods. Equipment Inventories and Quality Events. Upon review of this documentation, and\ ith full consideration for earlier Page 11 of32

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quality system discussions and my walkthrough ob ervation . I cho e to refocu m. in pectional effort to include the review of qualit) S) stems and proces cs related to Transdcrmal Patch.

The evaluation of Pace's Pharmaceutical Quality System (PQ ) included the as e ment of its Quality. 1-acilitics and Equipment, Materials. and LaboratOf)' Control ubS)Stem . These assessments facilitated the determination of how Pace's QM infrastructure and related QRM processes/procedure were designed to achieve and maintain control over the faci lity and analytical tc ting operations. lnteg.ral to these assessments was the determination of how Pace's QM actively controls potential risks to qualit) . ext , was to determine if the QRM sy tern '"as completely integrated into the QM and ifit provides an effective mechanism to identify. scient ilically evaluate, and control potential ri ks to qualit). en uring consumer protection. The functional asse sment of the QRM could most effectively be achieved." ith limited time and re ource con traints. b) focusing on a ingle product and following it through the conventional proce scs of the QRM . U ing thi approach. not only could I determine ho\\ the QM works. but al o ho" it active!) mitigate!> ri k to consumer for a drug product containing a HPAPI with significant human health implications. I he election ofa lini hed drug product/proces for extensive revie\\ \\as based in part on an informal risk as c mcnt. Risk as es ment factors include. but \\ere not limited to sales olume/revenue, potcnc). HPAPls. human health impl ications. pre iou inspcctional coverage, factors internal 10 FDA operation and the complexity of testing operat ions. Con equent ly, afler the initial review of the QM . including my ob ervations of the facility and it operational workflo,, . and the completion ofa lim ited risk assessment, I concluded the Transdcrmal Patch Drug Delivery y tern would be a good candidate for inspcctional as e sment. A revie'' of Quality Events" as intended to focu on those related to the Transdermal product; however. there was not a sufficient subpopulation of the e events to ascertain the effectiveness of the quality systems. Consequently. a more random approach was taken in the init ial selection. with refinement in sub equent election cycle(s) based on themes. pertinent quali ty issue and fai lures to provide sustained or long-term solutions to reoccurring quality issues.

General inspectionaJ coverage did not include the evaluation of DA-Field Alert Reports (FA Rs) and Drug Quality Reporting y tern (DQR . MedWatch Report ) events because program coordinators (DPQ Ill. Ml -DO) did not identify any reports/e ents (PL . Oakdale, M ). M . Hansen indicated that they provide upport for these events if requested: however. the client or submi ion holder may not choo e to di close such e\ents to Pace. Further, the review did not reveal any complaints pccilic to Pace Anal) tical Life cicnce , LLC. (Oakdale, MN, FEI : 3001451367). Pace's procedure arc conducive 10 reporting quality events to their client as quickly as possible. pccifically, Pace's procedure for /,ahoratory bm!Sligations, OP L8. er. I 0, explicitly state to ··notify the client within 24 hours of discovering the su peel aberrant or out of Lrend re ult and include the status of Lhe investigation:· Further, Ms. I Ian en. enior Director of Quality. indicated this critical procedural element has been reduced to practice, and the Quality Unit (QU) ma"e extensive efforts to en ure conformance.

The primaT) area assessed include. but \\ere not limited 10:

• Core laboratory operational procedure , including laboratory records and documentation • Electronic/computer systems u ed to support tc ting operat ions, including qualilication and validations

proce e • The firm· ) stem to inve tigatc laboratory test failures. including out-of- pecifications (00 ). retesting

and resampling • Corrective action and pre,entati\e action (CAPA) ~ stem

• Risk and change management S) terns • Management review of proce:.s performance • Conformance to methodologie!> specilic to the transdermal product. including method

validation/transfer processes • As c srncnt of the firm ·s conformance to the stahilit~ protocol for the tran dem1al product

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I conducted extensive evaluations of the qualification or validation packages for Pace 's primary electronic/computer systems and application used to uppon testing operations. Cmphasis was placed on ystems that were internally developed or extensively modified to meet Pace's operating requirements. These

system include. but are not lim ited to LIM (EPI C PRO). PaccLink CM , PacePon. Validation Package. LIM (Facil ity and Equipment Calibration Tracking), LIM ( tabilit) Functional ity). ILAB Laboratory l:xecution

ystem (LE ) Electronic Laboratory otebook (EL ). and Empower (CD ).

Quality ub )' tern

I evaluated the Quality Management ystem (QM ' ) and related Quality Risk Management (QRM ) infrastructure. including related operational procedures to determ ine if the Qualiry System (Q ) achie ed effective control over all operations. en uring compliance with cGMPs, internal operating procedure and policies. Multi ple Qualify Work flows (QW) and related operating procedures. protocols and report \ ere reviewed as pan of the Q evaluation. Thi evaluation included the as essment of se\eral quality events (e.g .. OOS, PA, CA. DEV. CRF. OR I· , etc.) to determine if the Qualit) and Risk Management . ) tern (QRM ) maintai ns effective control. ensuring compliant testing operation . igni ficant observations are noted in the Objectionable Conditions ection (pg. 16).

The critical elements of the QM as essed include. but are not limited to I ) Proces perfonnance and product quality monitoring. and 2) Corrective and Preventative Action ( /\P/\) related y tern . including quality procedures required to eliminate the cause of an exi ti ng nonconformity (those pecific to a CTL) and to prevent recurrence of nonconforming product. processes, and other quality problems. peci fie procedural elements of the CAPA system assessed include di co ery. remedial action/immediate correction. quality review. inve tigation (root cause determination), correction (corrective/preventati e action), follow up (effecti veness check) and closure (track/trend). as applicable. Thi evaluation included the as essment of qualit) events, nonconformities. deviations (planned. unplanned), failure . OOS (QC & R&D). and complaint . The review period spanned approximately 3 years. with the as essment of a select population of events for in-depth evaluation. including primary (parent) and secondary (sibling) event proce e i.e .. linked CAs. Additional assessments of the Change Management y tern (CMS) were conducted. including management review of process performance (i.e .. analytical production operation ) and product quality. 0'verall. I assessed hO\\ element of the QM . including QRM procedures/worktlows effectively identify. report. ill\ e tigate (e.g., Laboratory Investigations. LIR) and remediate fai lures, nonconfonnance , deviations, and 00 e'vcnt ; mitigating ri k to the consumer. and en uring conformance to regulation and internal operating procedure . A part ofthi proces Quality Event over a period of approximately 2-3 years were revie\\ ed includi ng. but not limited to: Change Controls (CRFs, DCR.s). Investigations (LIR), Modification , Ri k /\ sessment . CAP/\!> (CAs and/or P/\ ) Deviations, Excursions, OOT, l::.quipment E\ent Due Dates and/or ornpleted (PM. Calibration!>. Qualifications). Complaints, Trending Reports, OOS (Investigation Only), Computer I Electronic System Qualifications and Validation . Quality y tern Events, andDoc lndex Repon (TestMethods. OP ,Equipment) (LIM. Datc Range: Ol/Ol/2015 - 0l/24/2018: LIMS Report Parameters: tat us: A II, Dept: A II. Owner: /\II )

Facilities and Eq uipment Subsystem

I evaluated the Facili ty and Equ ipment ubsystcm (FE ). including related risk management proccdurcs/processc to determine if the) adequately control faci lity and equipment re ources, pro iding an effective foundation for regulatory compliant analyt ical tc ting operations. Multiple Quality Workflo"s (QW) and related operating procedure . protocol . reports and related documentation were reviewed as part of the assessment of the FE . This asse sment included the evaluation of cveral Quality E\ents (00 , PA. CA. etc.) to ensure the FE provided an environment for compl iant testing operation . ignificant observation are noted in the Objectionable Conditions section (pg. 16).

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The elements of the FES assessed include. but were not limited to computeriLed/electronic systems. equipment qualifications. calibrations, preventative maintenance. and related change management events. A complete facility walkthrough \ as conducted during the inspection: hO\\Cvcr, additional targeted (e.g.. tabilit) Environment . CM controls) visits \\ere made to pccific environments/operation to reinforce technical discussions or to improve my under tanding of specific proce<,sc . These targeted ob ervations occurred primarily in the laboratory space ( related I IPL & di~solution systems). environmental control area . and utility space for componentry related to the CMS. The initial \\alkthrough follO\\ ed the now of material and samples into the facili ty and through various operational ta k . Much of the inspectional effort focu ed on the ample receiving areas. analytical laboratorie . and torage and stability environment . Evaluation of the FE

included the revie" of core sy tem and processes, including computer/electronic ) tem and as ociated application . The documentation revie\\ included. but \\as not limited to: 00 r. alidation Master Plans. U. er Requirement pecifications, Val idation and Qualification Protocols and ummal) Reports, Cleanroom Environmental Monitori ng, Equipment Qualification Related Documentation (e.g.. tabi lity Environment ). OPs, User Guide (CMS), Trending/tvlonitoring Repons or Documentation and Quality System E ents

Ma terials ubsystem

I evaluated the Material ub ystem (M ), including related risl-. management procedures/processes to detennine if they adequate!) control material and sample inventor) processes. storage. distribution controls and related records, providing an effective foundation for compliant anal) tical testi ng operation . Pace is a C fL that does not manufacture : con equently, I cho c to C\'aluate material/ toragc operational practice and reference tandard management systems, including those speci fic to Controlled ub tances (e.g.. USP Reference td .).

The elements of the M assessed include measures to control products. electronic and conventional imentory control proce e . storage (drug related products & component . reference tandard . laboratory material ). distribution controls. and associated record . Example of critical operating procedure reviewed include. but are not lim ited to tho e related to Work Order Generation. ample Management upplier Approval and Re\ iew. Reference tandard . and Controlled ub tances.

Laboratory Control Subsystem

I evaluated the Laboratory Control ub ) tern (LC ). including related risk management procedure proce e to determine if the ystem provides acceptable control over the laboratory environment. en uring compliant tc ting operations. Multiple Quality WorkOO\\ (QW) and related operating procedures. protocols, reports and documentation was reviewed as pan of the evaluation of the I C . This as c ment included the evaluation of several Quality Events (LI R, 00 . OCR. FCR. Deviation . facur ions, etc.) to en ure the LCS provided an environment for compliant testing operation . The clement. of the LCS evaluated include. but were not lim ited to systcms/procc c related to laboratory operating procedure . instrument qualification , test method , protocols, reports, method validation/Iran fer 'erification. analyst training (stabi lity TMs) and stability. These re\ ie>.\ s included as essment to ensure te t methods, transfer/verification procedures. and stabi lity protocols v.ere conducted in a fashion consistent >.\ith their approved protocols and procedure . ignificant observations arc noted in the Objectio nable Condition cction (pg. 16).

Examples of critical operating procedures. protocols. report . and quality system events reviewed include. but are not li mited to: OPs (e.g., LIR, Method Validation. Data I rending, Laboratol) Change Control. etc. ). Laboratory Equipment Qualifications (e.g., 1 IPI C . Dissolution ·y tern!>. r I ystcm. LI::. . . Work heel Distribution, etc.). Test Methods, Method Memos .• tabili t) Protocols and Report!. . . tabi lity Pull . chcdule , tabi li ty Memo . .

pecifications. Method Validations or Transfers, User Requirements, Validation Master Plans. and Electronic/Computer ystem Validation (e.g., Empo,,er CO ). There was an emphasis on documentation related to the Tran dermal Patch tabilit) program.

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The Production. and Packaging and Labeling Subsystems \\ere not evaluated because Pace Analytical Life ciences, LLC. (Oakdale, MN) is a CTL that docs not conduct manufacturing. packaging and labeling operations.

MANUFACT UR ING CODES

Pace docs not conduct manu facturing operations; con equently. manufacture codes are not generated. However, Work Order numbers are generated by the ample Management Group within the LIM in order to support production operations. i.e., sample analysis/testing. The OP Work Order Generation, Work Completion, and Reporting of Results. L 12, Yer. 17. Effective Date: 03 JA 2018 (Exhibi t 8) wa reviewed to determine the nomenclature and conventions for the assignment of Worl- Order Numbers. ection 5.1 of this procedure governs the assignment of work order numbers in the LI MS sample management application. Upon sample receipt and processing of ample according to OP 21 a Work Order( ) i generated by ample Management or other designated personnel. The Work Order umber(s) i recorded on the Analysis Reque t Form (J\ RF) that accompanies the samples throughout the operational workflo, or lifecycle. At PL Oakdale the Work Order

umbers arc as igned by LI MS in the format start ing with 17#. \>vhere #is a sequential number start ing with IOOO. The sample information entered into the LI MS Worl- Order includes information outl ined in section 5.2 of the procedure. ample information includes, but is not limited to sample identificat ion, purchase order. LIMS ··acode" (test requested), date received or pulled, and special instructions, including sample handli ng or analysis. Next, a sample receipt form is generated and is used to review the LIMS entry against the ARf- or stabi li ty protocols, quotations and other client suppl ied information. e l. the LI MS system generates a Sample Acknowledgement Form which is submitted to the cl ient for re iew. The final step is to conduct a LIM login review where the Work Order is reviewed for accuracy b)' laboratory management prior to assignment and execution.

COMPLAINT

The Complaint Handling, SOP 30, Ver. 6, tffective Date: 07 MAR 2017 (Exhi bit 9) descri bes the proces for resolving complaint from clients or other parties related to PL operations. The procedure describes the processes for receiving (Complaint Resolution Form. OP 30 Fon11 A3), resol ing, concluding and trending (Complaint Trending. SOP 30, Form A4) complaints. Notably. the procedure describes a complaint. in part. as ··something that negatively impacts the relationship bemeen the client and PL : · Although the business relationship i important, ensuring the safety of the consumer is paramount. Further, the procedure i proscriptive in terms of the Quality Metrics conventionally mitigated b) a CTL, pri marily 00 events. I lowever. provisions for all sources of complaints may not have been effectivel) addressed. Specifically, Pace' s complaint procedure, including its integration into the QMS, should provide mechanisms to effectively capture, investigate. po sibly redi rect and track all complaints. Just because 1:1 complaint is unconventional and/or was not conveyed convent ionally (consumer or medical professional to manufacturer) does not mean it should be disregarded. A fa ilure to mitigate complaints, regardless of the source. could have significant regulatory and human health implications. It is well understood that Pace does not have acce s to the sponsor/applicant quality systems which would allow them to effectively mitigate all events, and that many of these events are the responsibility of the product reporting establishment or submi ion holder. I IO\\e er. any source of complaint could reveal significant product quality and safety concerns. Consequently, they hould be tracked and reported in a fash ion con istent wi th regulation. Pace cannot dictate hO\.\ the product reporting e tabl ishment or manufacturer vet complaints, nor can they be assured they are being mitigated in a fashion con i tent with regulatory requirement ; ho\.>vever. they can en ure that their established procedure and working conventions do not inad\ertently create opportunities where critical product quality/safe!) information is lost. resulting in a failure 10 meet regulatory requirements and to provide con umer protection.

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The complaint log (04/0 I/201 5 - 0I /09/2018) was revie\\ ed. A subset of complaint \\ere selected for detailed review (COMP 031 and 026). Overall. complaints were rccei\ed from cl ients for a spectrum of reasons including, but not limited to 00 event (no root cause identified). fa il ure to pro ide correct microbiological sample paper work. and failures to conform to stability and \alidation protocol procedure . There was a subpopulation or event related to upplier corrective action requests. Overall. complaints were received from corporate clients and pharmacy services providers. Please see Ohjcctionablc Conditions section (Observation I, Example 5. pg. 22) for additional concern related to complaint procedures and practices.

RECALL PROCEDURES

Pace does not conduct manufacturing operations of an) type . Con equently. they do not have a recall procedure or conduct mock recall events. HO\\ ever. M . Hansen tated their quality ystem and business practice are conducive to supporting a manufacturer' recall event. Basicall). by addressing information request in a timely fashion. Further. she stated she was not aware of PL (Oakdale) participation in a client 's recall event: however, they may have chosen not to disclo e the event to Pace. Ms. Han en indicated reque t for additional information or documentation may have been to upport a recall; howe\er. they have never been made aware of their direct participation.

OBJECTIONABLE CONDJTION AND MANAGEM ENT' RESPONSE

The FDA-483 observations ci ted include (Attachment 3).

OBSERVATION 1 21 CFR 21 l.22(d)

The respon ibilities and procedure applicable to the qualit) control unit are not in \Hiting and fully folio\\ ed.

I. Specifically, your firm's Standard Operating Procedure ( OP) L 12, Work Order Generation, Work Completion. and Reporting of Results, ver. 17, effective 03 JAN 2018 i inadequate to manage and document change to client Analysis Report I Certi fi cate of Analy is (CoA) consistent\\ ith regulatory requirements and current good manufacturing practices (cGMPs). The procedure is omit of comprehensive investigative methodologies/procedures. including corrective and pre,entative actions (CAPA). Further. the practical application of the current procedure ma) result in the circumvention of establi hcd Laboratory lnve tigation (LI R. SOP L8) and Corrective Action (CA. OP 42) procedure~. A ~pecific example \\here a conventional LIR. including Ct\ \\-Ould have been warranted include. but are not limited to:

• Work Order 1747812. Rcvi ed Report Record of Change (SOP L1 2 A4. Date 07 APR 20 16)

Supporting Evidence and Relevance

Exhibits in support of this observation include: SOP L.12. ll'ork Order Generation. Work Completion. and Reporting of Results. ver. 17. (Exhibit 8): Laboratory lm estigations SOP L8 (Exhibit 10); and Work Order 17478 12, Revi cd Report Record of Change (SOP Ll2 A4. Date 07 APR 2016) (Exhibit 11) .

Summary/Overview: Pace's SOP L 12 Work Order Generation. Work Completion, and Reporting of Re ults (Exhibit 8) doc. not adequately establish procedures to conduct, record and report investigation which arc intended to support revisions to Analysi Reports I CoAs (regulatory records). including those critical to their client's ability to fulfil l predicate rule record requirements. 1-urthcr, a review of investigative records (Form A4 ), in pract ice. reveals the recording (A4) of inadequate explanation to reconstruct or de cribe the initiating event and to effecti' el) e plain

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the rational or logical basis for the course of action involved in the revision di po ition. including impact assessments on imilar proccs cs/procedure • and correcti ve and preventive actions. The current procedure may suffice for revisions due to typographical or entry errors. but it i inadeq uate for in e ligations supporting revisions/change to reported value for regulated drug product. including commercial drug product di po ition decisions. Further. some revision reque t, due to a clie111 ' failure to provide accurate information (e.g., inaccurate sample or lot description during work order initiation). may be t be re olvcd/mitigated b;, the client's QMS. Pace' s QM bears the burden to substallliate revi ions/changes to document ( oAs) critical to their client's abilit) to fulfil l predicate rule record requirements: hO\\e er, they have vel) limited or no access to many of the events (e.g .. inaccurate de cription ) that predicate their clients change reque t. Currently, in the e speci fic instances Pace compels their clients to consider internal mechanio;ms for re olution . It is extraordinaril) difficult for a CTL to support changes to sample descriptions (batch/log numbers) when they do not have acce to the clients QM . In the e in lances. the client or ubmission holder may be compelled to con idered procedures/mechanisms wi thin their QM to make and sub tantiate changes to CoAs. consistent with regulatory requirements.

The current procedure ( OP L 12) and its report form (A4 ) (Exhibit 12) do not have adequate/complete \Hillen procedure , including in truction for the description of critical details/elements to upport the revision to Analysis Report I CoAs (i.e., regulatory documents). The report form (Form A4) has multiple entry fields: however. the procedure ( OP L 12) does not provide adequate instructions for the content (required/critical) of these field . The revi ion dispo ition or in e ligation must be descriptive, objective and fully supportable. Further, there is an expectation that a corrective and pre\'entive action (CAPA) be initiated to revise and improve operations and/or procedures to prevent such events in the future . Investigative records should provide clear and concise wrillen descriptions of the event and provide cientific rationale for the re ision. The record of the investigation is the firm 's defensibilit) document/statement and it must conform to internal operating procedures. current industl') practices (cGMP ) and regulatory requirement . The written record of the investigation. including rational. should be done to a level of exactne that renects the eriou and far reaching implications these processes/documents have on the di position of regulated drug products. including those critical to the release of a product, prior to it introduction into commercial distribut ion. The e documents will undergo extensive scrutin) during commercial batch release, regulatory ubmissions, and quality event mitigation proces es including, but not limited to recalls, FAR and Med \! atch related event . The critical elements of the change control should include I) a complete description of the proposed change. 2) why the change i needed. and 3) why the change i acceptable. The investigation should be completed in a timely manner and additional elements may include, but are not limited to: event summaric . added detailed de criptions of the revision or supporting proce e , materials/lots affected and rationale. root-cause inve ligation. impact assessment. trending analysis. CAPA and training related events. The investigative report/form must be designed for the reader/revie\\er. pro iding critical information/content and evidence that fully support the revision dispo it ion. including findings. conclusions and actions. Overal l, the inve tigation report should relay a complete story or set of events that can be clearly understood b) a third-party years after the event occurred. without requiring input from fi rm representatives i.e., it hould stand alone. Training will be cri tical to improving the current procedure and/or report format. Currently. there may not be a complete under landing b) tho e' ho conduct these procedures, potentially due to deficiencies in training, to full) appreciate the implications on a failure to provide accurate and complete infonnation in the pre cribcd fonn (/\4) field.

Additiona l Detail : (Background)

Updates to thi!> procedure, incorporated in version 13. were intended to address previou inspectional ob ervations (FDA-483. April 2015). Consequent!), a more extensive di cu!> ion of thee re\i ion i included in the Voluntary Corrections (pg. 30) ection ofthi report. Brien) . updates to OP 1.12 \\ere intended to provide a mechanism to ill\estigate change revi ions made to Anal) . i Reports I oA . Revi ion to Analy i Reports could be ini tiated for many reasons. including but not limited to . ample misidentification, incorrect or revised

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batch or lot numbers. recalculat ions. method refinements/optimization resulting in data changes, entry errors, transcription errors. and cl ient reque t. Many event referenced in the previous EIR (April 20 15) include changes to the batch or lot numbers for reported re ults due to client errors during work order generat ion. including incorrect lot/batch numbers or sample de criptions. A re' ie,.,, of revision histories reveals a significant fraction of these events \vcrc initiated because the client fai led to provide accurate information during work order generation. A significant sub ct of events required changes to reponed values on CoAs. Traditionally, such changes would be vetted through a firms existing hange Management . ystem (CM ). This con entional pat hway would introduce the Quality Event into the QM . permitting mitigation u ing all estab lished/conventional mcchani ms including. but not limited to Laboratory lnve tigation (UR), Out-of- pecification lnve ligations (OOS), Corrective Actions. (CA), Preventive Actions (PA), Root-Cau c Analysis (R A). Impact Assessments and Effectiveness Check . I lowever, the current procedure ( OP I 12) provides an additional or parallel pathway for the mitigation of the e types of events that does not meet GMP requirements. Funher. it is inconsistent ,.,,ith the firms establi hed (i.e., more comprehensive) procedures for conducting invc ligations (LIR) and CAPA . The current OP \\as not adequately revi ed or procedurally reinforced through effccti e training to introduce these types of Quality Events into the existing Quality Management y tem (QM ). including established Laboratory Investigation (U R) and Correcti ve Action (CA) procedures. but provides an al ternate less comprehen ive inve tigati vc mechani m. That said, the procedures are not adequate to manage change consistent with regulatory requirements. Further, the current procedure in practice does not effectively triage revi ion event/request into categories that may require more in-depth inve tigation, and/or rely on existing and more comprehensive procedures within the existing QMS. Overall, it provides a less comprehensive and incomplete mechanism to investigate revision events. In practice, there is insufficient detail to describe the precipitating event and propo ed change, why the change is acceptable and needed, CAs, and implications for simi lar systems/processes when compared to the established laboratory investigation procedure ( OP LS). Section 13 of the procedure state that al l elements required in section 9 be pre ent; however. the ection i notably ab ent of investigative proced ures, or references to established procedures (LI, SOP L8). Clearly. not all procedural clements of a conventional laboratory or 00 investigation are ustainable (e.g .. Ph~e 11 procedure ) in the context of a contract le ting environment. due to sample restriction and the duration of time since the event occurred ; however. e cral critical core element ofa Phase I procedure remai n intact. including but not limited to the rcsponsibili tic of the analyst and supervi or as outl ined in the FDA OOS guidance document. Further. the current procedure ( OP L 12) inadvertently re ults in the circumvention of established Quality and Risk Management (QRM) worknows. including establi hed Laboratory lnve tigations (LI). Root Cause (RC) and Corrective and Preventative Action (CA PA) procedures. One specific instance is related to Work Order l 747812 \\here a client identified errors in the chromatographic procedure, when peaks in the blank solution were integrated in the sample and reported as impurities. (Please see Work Order 17478 12, Revised Report Record of Change ( OP L 12 A4, Date 07 A PR 20 16, Exhibit 11) However, the record of the investigative procedure is largel) omit of critical details, including a de cription of the initiating event, mitigation proce sand rational. In addition, there were no correcti e act ions, includi ng test method changes or training event , nor was there any explicit description of implications for similar proces cs and/or products. Further, the QU fai led 10 adequately revie"' the investigation to en urc critical clement of the investigation were recorded. This is not unexpected becau e they arc not procedurally defined/required ( OP L 12) or effectively reinforced during training. Overall. this is an example where a Pace representative was required to provide fundamental information about event. because the documentation is not sufficient to explain the event or substantiate the course of action. Clearly. if a quality event doc not fit into the current ly c tabli hcd QMS mitigation pathway. then mechani ms shou ld be pro\ idcd \\here an expert team can establish an investigative procedure/protocol that addrcsse the requirements peci fic/unique to that qual ity event. I lowever, this specific event could have been effectively managed u ing the establ ished LIR ( OP LS) procedure. That aid, how the firm choo es lo mitigate this class of Qualit) Events, whether through the convent ional application

of the CM . or through a new or adjunct procedure i not m) regulatory concern. My primary concern i. that the investigative procedure. includi ng the inve tigative record depicted in the Re i ed Record of hangc (e.g .. Work Order 1747812) effectively descri be and justify change . and provide for a clcar/conci e course of action to mitigate these events in the future. in a fashion consistent "' ith cGM Ps and regulatory req ui rements. Funher.

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efforts should be made, through procedure revision and/or training. 10 ensure the application of this procedure docs nol result in the inadvertcn1/uni111c111ional circumvention of trad itional and more comprehen ivc invc ti gate methodologie (LI)' hen required.

Discussion with Management

In the closing meeting. the fi rm indicated they would respond in writing wi thin 15-busincss days.

2. pecifically. your firms internally developed ··PacePort'' and "Validation Package" Oracle Database IOg applications (SQL) I tools, including as ocia1ed servers crit ical 10 Pace Analytical Life ciences, LLC. (PL.) GM P Quality ystem workllows are not managed and I racked under a centralized Change Management ys1em (CMS) consistent with regulatory requirements, cGMP and internal operating procedures, including Incoming Inventory Assessment (SOP 19 A3) outl ined in SOP 19 Lahora/ory Inventory and Change Cuntrol Procedures, ver. 7, effective 28 JUN 20 16.

upporting Evidence and Releva nce

Summary

Pace fai led to fol low their established procedure for Change Management. including on boarding activitie . for computer appl ications and their associated hardware (i.e., ervers) according to OP 19, Laboratory !11vent01y and Change Control Procedures (Exhibit 13). Pace Port is a web-based application (database) that allows Pace's clients to have access to their data. Further. during regulatory audits this appl ication is used to provide reque ted documentation. including but not limited to procedures. method and data package .

It is Pace's established business practice to disseminate analytical test result (CoA I Analysi Report . complete testing data package) for regulated drug products to their clients employing the PacePort computer/database application, accessible by their client through a conventional Web browser. Further, in this quality 1,,1,,orkllow Pace relies on electronic systems, as a replacement for paper proces es, to conduct their regulated acti itie including reviev. and approval proce e in their CDS (e.g .. Empower work.flow). Con eq uently, 21 CFR Part 11 (Part 11 ) applie to these electronic/computer system becau e their business practice employ electronic ystem to support GMP/regulatory functions. Clearly, individuals who conduct Pace' regulatory worktlow, which ultimately results in the di ssemination of client data in electronic format, do not rely on paper record to perform their regulated fu nct ions. This is c ident in thei r chromatographic data sy lem (CD , Empower) workllo' . which is considered by Pace to be 21 CFR Part 11 (Part 11) compliant. Electronic review and approval i conducted in the CDS and it is the e records. including tho e that must ultimately comply with all applicable predicate rule record requirements, that are disseminated 10 their clients using the PacePort system. Pace· s regulated workllows, and business prac tices, must enable their clients lo ful fill predicate rule record requi rements, and records that are requi red to be maintained or submitted mu t remain ecure and reliable in accordance with predicate rule record and reeordkeeping requircme111s. In cction I 1.3 of Part 11 . the FDA define ··electronic record" to mean "any combination of text, graphics, data. audio. pictorial, or other infon11ation representation in digi tal form that is created, modified, maintained, archived. retrieved, or distributed by a computer system:· This defi ni tion is quite broad; however, it clearly includes Pace·s business practice, which is to distribute by a computer system. In sum mary, it is Pace's regulatory worknov. and business practice to disseminate electronic records whose rcliabili1y, consis1cnc). and accuracy arc c scntial/critical to their client's ability to fulfill predicate rule record requireme111s. 21 CFR 21 1.68 and 21 CFK Part 11 requires electronic )Stems whi ch go em a cGM P process be validated. As such, the electronic processes (PaccPort, Validation Package), and associated GMP work flows which support the dissemination of electronic data to their clients mu t be validated. The trustworthines and reliabi lity of these systems is cri tical to their client's abili ty to fulfill regulatory predicate rule record requiremenls. including en uring ubmission document integrity.

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Additional Information

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Internally developed database application including PacePon (\\Cb-based data management tool) and Validation Package application /tools reside on tile ervers located at Pace' - corporate headquancrs (Minneapoli . Minnesota) where they are active!} maintained/updated. 1 he e application were not purchased commercially, but were developed internally by PL using the Procedural Language/Structured Query Language (PL/ QL) functionalit} of their Oracle I Og database. and may have emplo} ed PL/SQL package supplied by Oracle. which are inherent to the database. and are considered to augment the language. These applications are u ed through a Wide Area etv.ork (WAN) or equi\'alent connectivit) protocol by Pace located in Oakdale, MN. O' erall. the e applications are used to retrieve. manipulate and render ' ie,,able GMP electronic file located on PL (Oal..dale. Minnesota) file erver . More specificall}. the Validation Pad.age application elects specific files from Pace 's (Oakdale) fil e erver repository for incorporation into a ingle pdf file based on references or pointers e tabli hed or consistent" ith their LIM . whereupon PaccPon incorporate them into a format/ tructure/sy tern readily accessible by their clients for viewing through a Web-based bro\\ er (PacePon Online Data Management Tool). Clients evaluate their regulated drug products for conformance to GM Ps and pecifications using the output from PacePon . In addition, Pace's client incorporate document from PacePon into regulatory submi sions. many of these document are governed b) predicate rule requirement . Clearly, active phannaccutical ingredient (API) and drug product. including in-proce • fini hed product and tability sample arc e\ aluated for regulator) conformance based on the output from these appl ications. Pace·~ clients have a legal requirement to conform to predicate rule and record keeping requirements for man} of the e documents. on equent ly, the integrity. including the accuracy and completeness of these electronic records arc critical to their client's abili ty to fulfill regulatory record requirements. Overall. these database tools arc cri tical/central to PL (Oakdale, MN) GMP client services business/worknow practice • rendering final client data (Analy is Repons I CoAs and supporting data packages) suppon ing regulated drug product, including ubmission related documentation. I lowever. these computer y tern application are not managed or tracked under the Pace Anal)tical Life ciences. LLC (PL Oakdale. MN) CM . or an equi alent (GMP) quality sy tern located at their corporate headquaners. The corporate headquarters does not support pharmaceutical or GMP drug testing operation . but rather conduct environmental te ting. As such, they may not be aware of the regulatory requirements for the testing of drug products and/or effectively perceive the effects/implications of changes/update modifications to these critical SQL applications or their associated hardware (i.e .. ervers) on regulated drug testing operations, including conformance to appl icable sections of 21 CF R 2 11 at the PL Oakdale site. Consequently, there is no formal GMP process to monitor and manage change to these sy tern (database application and file servers) to prevent unintended consequences, or to evaluate the implication of change to the e y tern on PL regulated processe foorl..nows. Ultimate!). en uring e tabli hed qualit) s. tern worl..no" and critical client documentation i not negatively impacted, maintaining cffecti\c change control. including active risk management. fhe omission of thee ) tern from the umbrella of Pace's GMP CM . including the review and approval process by the QU, results in no forma l mechanism to init iate, evaluate~usti fy. approve and confirm/monitor change to these critical workllow tools. Funher. the failure 10 actively manage these resources though a CM could have signi ficant implications on their clicnt"s abil ity to ful fi ll predicate rule record requirements. Pace's cl ient data record can only be as accurate and complete a pre ented lo them through Pace's electronic )Stem (PacePon). 1-urther. failure to track thee ystem under a CM doc not permit the conti nuous management of change. including risk management. where previou change events can be effectively reviewed and tracked.

Discussion with Management

In the closing meeting, the fi rm expre~sed general di'>agreement wi th the obsenation: however. they indicated they would respond in writing within 15-business days. Mr. Kupp expres ed hi belief that these internal applications \\here analogous to an electronic drop box. and as such, did not require validation.

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3. Specificall}. your firm did not conduct a formalized ril.k as e smcnt consistent-.: ith regulatory requirements. cGMPs and internal operating procedure outlined in SOP 18 Risk Assessment, ver. 7. elTective 02 MAR 20 17 when implementing and updating database applications cri tical to PLS core GMP Quality System (Q ) work nows, including the internally developed ·'PacePon·· and ··Validation Package,. applications ( QL) I tools and the r:acilities and Equipment tracking applicati on developed in the Laboratory Information Management System (LIM . 1 IORI ZON/Epic Pro).

Supporting Evidence and Relevance

Pace failed to conduct a risk assessment for data base applications critical to thei r regulatory worknow and business practices in a fashion consistent wi th procedure required by SOP 18 Risk A sessment (Exhibit 14). These procedures are cri tical to identifying and asse sing risk. ensuring al l consumer risks are mi tigated and regulatory requirements met th rough active risk mitigation processes including. but not limited to formal validation.

The PacePort , Validation Package. and the Facilities and Equipment Qualification, Calibration and Pre entative Maintenance tracking (LI MS application, HORIZON/ EPIC PRO) applications have not been formally validated for their intended u e. These electronic or computer/data base appl ications are essential to Pace· cGMP regulated worktlov and busines practices. It is Pace's business practice to employ these electronic applications to support their regulated work now. Consequent ly. Pace has not demonstrated the reliability, consistency. and accuracy of computer systems performing funct ion defined by GM P regulation. The accurate and complete electronic output of these systems (i.e .. PacePort and Validation Package) enables their clients to fu lfill predicate rule record (regulatory) requirements. That aid, Pace's failure to introduce these sy terns into thei r QM via their CMS, assess ri k and prepare a plan to mitigate risk through formal and continuous val idation jeopardizes their client's ability to fulfill predicate rule record requirements. Pace has a risk as es ment procedure which initiates the onboarding process, resulting in the introduction of the system/eq uipment to the CMS, including the overall Quality Risk Management process. Quality Risk Management (QRM) is the systematic proce s for the assessment, control. communication & review of risks to qualit) of the drug product. The evaluat ion of risk to qual ity should be based on scientific kno" ledge, ultimately linked to consumer protection. In addit ion, the level of effort, formality and documentation of the QRM proce should be commensurate with the level of risk. Overal I, Pace fai led to actively manage these computer/electronic related re ources through the proce s of active change management (application awareness), risk assessment and mitigation through a process of pro pective and continuous validation.

Discussion with Management

The fi rm referenced a recent Risk As e sment that was completed duri ng the current inspection (Exhibit 25) in order to address concerns identi lied during the inspection. In addition, they referenced an additional ri k assessment either completed or ongoing. I indicated thi additional Risk Assessment can be included in the vol untary written re ponse. if they so de ire. Further. the) indicated they would respond in wri ting within 15-business days. 4. Specifically. a comprehensive/centralized operating procedure specilic to the use, administration. contro l. tracking, vcrsioning and validation, including element specific to data integri ty do not exist for custom fields/calculations constructed in the Empower Chromatographic Data System (CD ). These calculation are used to support the analysis of regulated drug products. including in-process. linishcd product and tability testing.

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Supporting Evidence and Releva nce

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Pace railed to establish cornprehen ive operating procedures speci fi c to the acti\ e management of Cu tom Calculations. critical to their GMP operations, employed in their 2 1 CFR Part 11 compliant Empower CD appl ication.

Discussion with Management

The fi rm ex pre ed their intention to respond in writing ' ' ithin 15-busine day .

5. Specifically. your fi rm did not conform to OP 30, Co111plui111 Handling. Ver. 6. effective 07 MAR 2017 including the initiation ofa Complaint Re olution Form when addre sing cl ient complaints. The cope of the procedure include , but is not limi ted to complaint resolution for ··poor servi ce. reporting errors, bill ing error , or performance of incorrect analysis:· pecific example ''here~ our firm failed to ini tiate the complaint re olution procedure include. but may not be limited to:

• Work Order 1747812, Revised Report and Record of Change, Form OP L 12 A4 (Date 07 A PR 20 16): The content of this document upported by discus ion conducted during the inspection renect a revi ion request by the client based on a chromatographic/test method type of error. This event constitute a " reporting error" .

• Stabil ity Protocol 60064593. Deviation 18 12, Rutio11alefor Accep1i11g 1he Deviation: "While reviewing an investigation related to project 1745354 the client informed lname redacted] that Pace Analytical Life Sciences (PLS) had deviated from the protocol 60064593 by analyzing 3 MCRD test units and not 9." This event constitutes an ··incorrect analysis" .

Supporting Evidence and Releva nce

SOP 30, Complain/ Handling, Ver. 6. effective 07 MAR 2017 i included as Exhibit 9: Work Order I 7-l78 I 2, Revised Report and Record of Change. Form OP L 12 A4 (Date 07 APR 20 16) as Exhibit 11; and tabil ity Protocol 60064593. Deviation 1812. Ra1ionalefor Accepting the Deviation as Exhibit 24

Stability Protocol 60064593, Deviation 18 12: Comment recorded during the inspection describe di cu sions Pace had with it cl ient. in conjunction \\ ith statements recorded on the investigative form (Exhibit 24. Deviation Form #: 1812, Rationale for Accepting Deviation subsection). indicate a client complaint was recei\ ed. Work Order 17478 12: Comments recorded during the inspection de cribe discus ions Pace had with it:. client indicati ng they observed peaks in the blank olution that were ult imately integrated as impurities in te t samples, in conjunction with statements recorded on the Revi cd Report Record of Change (Exhibit t t, Revision request subsection, "See attached email"). indicate a client complaint was received .

Pace failed to fo llow their written procedure SOP J O, ( '0111plui111 l /andling (Exhibit 9), including the fulfi llment of a complaint resolution process for events cited above. Pace· quali ty management y tern (QM ) is a collection of fonnalized policies. processes and procedures focu ed on consistently meeting product/client requirements and regulatory compliance. ult imately ensuring consumer protection. The QMS is a fonnali7ed system that documents processes, procedure . and responsibil ities for achieving regulatory compliance. including consumer protection. The complaint handling procedure is crit ical to introducing quality events (client complaints) into the QMS. en uring they arc addressed in a rcgulatorily compliant fashion. with full consideration for consumer protection. Failure to conform to established complaint handli ng procedures undermines the regulatory intent of the QM . A QM is only as effecti\c as management's dedication and insistence to adherence and accountability. The fa ilure to effectively cmplo) this com plaint mit igating procedure may rcnect

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deficiencies in training, or an inadequate understating of the role and function or th is critical QMS element to ensure regulate~ compliance and con umer protection.

Pace does not manufacture fin i hed medical devices, including acccs~orie or component to any de\ ice or fini shed drug product , including A Pis. excipients or raw materials. Pace as a contract testing laboratory. has the ame responsibi li ties to meet cGM P requirements as the manufacturer of a fini hed drug product. The regulatory

requirements for com plaint files is outlined in the CFR Part 2 11 .. ubpart J - Records and Report . ec. 21 1.198 Compliant file . Pace supports the testing (e.g., stabil ity) of regulated drug product after they have been released for distribut ion. Con equently. the O\\ ners and operators of an establishment that i engaged in the manufacture, preparation. propagation. compounding. or processing of a co\ered drug product. or an API used in the manufacture of a covered drug product, should maintain a complaint system, and as a site reporting e tablishment may submit quality metric data to the product reporting establishment and/or the FDA. In practice. the FDA intends for the product reporting establishments to submit a ingle comprehensive product report that includes quality metrics from all covered c tabli hments. Any communication that allege deficiencies need to be maintained includ ing. but not limited to tho e related to the identity. quality, durabilil). reliabi lity. safet}. effectiveness, or performance of a drug product after its been released for distribution. The covered establ ishment must maintain procedures for receiving. reviewing. and evaluating complaints by the QU to ensure they are reviewed, evaluated and investigated. Further, failure to report complaint event to the product reporting establishment make it challenging for them to fulfill their regulatory requirements. Current good manufacturing practices (cGMP ) fo r human drugs requires manufacturers to have an ongoing program to maintain and evaluated product and proce s data that relate to product qualit). rhe reporting of Quality Data/Metrics b) the manufacture is u ually recorded in a Periodic Product Review. Annually Product Review, or Prod uct Quality Review. The e reports often include quality metric data from each covered establishment wi thin the manufacturing supply chain. Pace' clients (i.e., product reporting establi hment ) should have effective mechanisms to triage complaint events received from their contractors (e.g ... CTL ), including all ite reporting establishments. Con entionally peaking. it i often thought that only quality metrics related to 00 result require tracking by contract te ting laboratories. However. the contract testing laboratory has the same responsibility to meet cGMP requirements as the manufactu rer. Clearly, complaint coming from the manufacture and expressed to the contract testing lab arc unconventional in that they arc not initiated b) a consumer; however, they are still viable complaints. potential!)' containing infom1ation cri tical to the qualit) and afcty of the drug product, and as uch should be mitigated and potentially reported through established

procedures. Te ting laboratories ma) not have been pro idcd adequate or sufficient informati on to mitigate quality events; however, this does not negate the requ irement to comply with regulatory requ irement for complaint mitigation. This include . but is not limited to 00 quality metric .

Discussion with Management

The firm indicated that the establ ished procedure (SOP JO) w~ not intended to address these type of event . Further, they expressed their intent to respond in writ ing " ithin 15-business days.

OBSERVATION 2 21 CFR 211.68(11)

Routine checking of electronic equipment is not performed according to a wriuen program designed to assure proper performance. Elcclronic records are used, bul lhe~ do not meet requirement to ensure that the) are trustworthy. reliable and generally equivalent to paper record .

I. Specifically. "Validation Package" an internally developed Oracle Databa e I Og appl ication (SQL), critical to the dissemination of client GMP data. including in-proce s. fini<ihed product and tabi lity testing for regulated

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drug products, has not been qualified for it intended purpo c according to an established protocol and acceptance criteria, including all appropriate operational and Qualit) Unit (QU) reviews and approvals.

Supporting Evidence and Relevance: (For Observation 2, Exa mples J a nd 2)

Please refer to the upporting Evidence and Relevance section for Observation I. Example 2 (pg. 19) for the foundation to thi discussion. The intcrnally/PLS developed ··Validation Package"' and ' 'PacePon'" applications upport a GMP function and businc practice that i critical to their client' s ability LO fulfi ll predicate rule record

requirements. A uch, the accuraC}. integrity. and complctenc of the system output (regulatory documentation via PacePort) mu t be demonstrated through formal validation in a fashion consi tent with its imended use (Pace's workflow). ll is Pace's business practice lo conduct GMP/regulatory function . including electronic document review and approval pecific to their 0 workflow (Empower), and to disseminate elements of these record , governed by predicate rule record requirements, by a computer y tern. 13asically. Pace mai ntain record . and in some instance in paper format; hO\\ Cvcr. it is the electronic format that is relied on to perform regulated functions, including tc ti ng for compliance against defined acceptance criteria. Consequently, 2 1 CFR 2 11 .68 and 21 CFR Part 11 requires GMP computer systems and applications (i.e .. Validation Package) to be validated. Val idation i required for processe that support GMP functions. even if Part 11 ''ere not to be applicable. However, records and signatures subject to Part I I include. but may not be lim ited to I) any record required by the FDA that is in electronic format. 2) any electronic signature that appears in an FDA-required record. whether the signature is required by predicate rules or not, and 3) electronic submission to the FDA, whether or not the documents arc covered under predicate ru les. Clearly, Pace' s clients have, and will continue to review and approve electronic records retrieved from Pace Portal and submit them to the FDA in support of a regulatory requirement (e.g .. application, annual report, etc.) and there is no way to ensure electronic record integrity (i.e .. regulatory compliance) outside of S) tern/process validation (i.e .. database applications).

In summary. Pace failed to employ critical elements of their QM .. c sential to en uring regulatory compliance and conformance to current indu tr} practices to identify and mitigate ri k to con umer of regulated drug products through the process of active change management. ri k assessment and alidation. Validation of the ··validation Pad.age" and ""PaccPort" applications result in the confirmation byte ting and provision of objective evidence that programmatic computer applications conform to runctional and user requirements. ensuring a correct. complete and con i tent output.

Discussion with Management

The firm , both Ms. Hansen and Mr. Kupp. expressed general disagreement with the requirement to validate thei r imended use of an internally development application. I lo\\ ever. they indicated the) \\ ould respond in writing within I S-busincss days.

2. Specifically. ··Pace Port" (Web-ba ed portal) an internal I) developed Oracle Databa c I Og application (SQL) or tool, cri tical to the dis em inat ion of client GMP data. incl uding in-process, fini hcd product and stability testing for regulated drug products. has not been qualified for its intended purpose according to an establi hcd protocol and acceptance criteria. including all appropriate operational and QU revie-.: and approvals.

Supportin g Evidence and Relevance

Please refer 10 the Supporting Evidence and Releva nce cction for Observation 2. Example I. above.

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The firm, both M . I Ian en and Mr. Kupp. expressed general disagreement \.\ ith the requirement to validate their intended use of the internally development PacePort application. I lowever. the} indicated they' ould re pond in writing within 15-bu iness days. During the latter phase of the in pcction M . Han en provided me with a copy of the Risk As essment which had been conducted in rcspon e to my inquiries concerning PacePort (Exhibit 25).

3. pecifically. Cu tom Fields I Calculation (user-defined calculation ) con tructed in the EmpO\\er 3 Chromatographic Data System (CD ) u ed to support the analysis or regulated drug products employ complex mathematical calculations/formulas u ing advanced synta,x and rules beyond the cope or the internal calculations wizard's base functionality, have not been qualified/validated for their intended use according to an established protocol and acceptance criteria, with all appropriate operational unit approval and reviews, including the QU. Positive external confirmation of a ub et of calculations i in ufficient to ensure perfonnance for uch complex software applications, including ident ifying. understanding and controlling all re levant modes of failure. many of which may exi t out ide of the pure mathematical opemtions. and may not be renected in abbreviated equivalency testing (external confirmation of calculation).

Supporting Evidence and Relevance

Please refer to the upporting Evidence (pg. 22) discussion for Observation I. Example 4, above as the foundation for thi section i.e .. it is a prerequi ite to thi ection.

Background

Custom calculations and custom field employ tool pro ided by the CDS vendor to perform calculations on the data generated by the CDS. Their value comes from replacing a spreadsheet that typically requires the CD to be u ed as a hybrid sy tern, completely incorporating the calculation within the CD application, where the abstraction and calculation is within a ingle application. The custom calculation(s) can be incorporated into the sequence file or custom reports. The custom calculation need to be correctly and formally specified. This often includes the name of the calculation and version number. equation to be used and the way it will be implemented in the CD using the mathematical operand provided by the upplier, each parameter in the equation specified as to the data format. and each parameter\\ ill have a range of value to be used. Once approved, the calculation will be implemented and formally tested using approved procedure/protocols u ing te t cripts and/or case resulting in formal documentati on supporting the testing results and outcomes. Testing is ofien conducted aero a range to ensure the calculation works. The te t document often has a release statement built into it so when the process is complete. the calculation can be released through a formal change management proce sc and copied into the appropriate master project. Simi lar approaches can be taken'' ith custom report . When a calculation i incorporated in a report. it need to be pccified. Testing should follow to ensure that the report function as required. Testing plans often specif) as e smcnts throughout the full range ofte ting condition or a ubset of calculation level . and may specify continuation for a sufficient time to allow the y tern to encounter a"' ide spectrum of conditions and events in an effort to detect latent fault~ that are not apparent or identified during more conventional or normal ac tivities/conditions. Ovcral I. the introduction, revision and retirement of cu tom calculations should be managed through the c tablishcd CM . including elements of additional validation. upon calculation rcvi ion or update, to en ure data integrity .

In Empower 3 (CD ). when pcrfonning administrative ta k in the Configurat ion Manager, a list of custom calcu lations can be found within a specific regulatory project under the "'Propertie ··selection (or similar mechanism). The properties windo\\ \\ill open in the General tab where the Custom rield Tab can be elected . If these custom field or calculations are u ed to support the analysis of a regulated product, then they require validation. Further. the aud it trail to the level or the method et. including the in trument, processing and report

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method should be maintained, and should also include audi t/data integrity mechanisms to ensure the correct/validated custom calculation version was employed. and i tracked under a GMP compl ianl change managemenl proce . Access conlrol arc crilical/e seniial clemcnls: however. the) arc inadequate to en ure regulatory compliance considering Pace· current prac1ice to period ically updale the e fields and/or revi e codes/operand . The calculation/exprc ion ofa GM P tc t re ult is often addres cd during test method validation; however, there are al ternate approachc to meeti ng requirements. hangcs lo all method set clements arc required to be tracked under a CM , th is include cu tom ca lculation-.. Changes to custom calculations to shorten or make the syntax more pccific must be upported through active change management and a process of continuous validation. Pace employs data integrity as essments which include. but are not limited to ensuri ng appropriate method version. imilar mechanisms/procedures should be observed for custom calculat ions. Pace' Analy i Reports include the calculation synta,x for cu tom calculation : however, it is not apparent if the syntax has changed (vcr ion control) throughout the method lifecycle. Custom calculation. including syntax, are not convenlionally transferred from the client during verification procedures, and ma)' be wi thout significant historical use. Further, Pace's currem practices for cliem method transfer include a limited calculation assessment: however. it may not be ufficient to confi rm the calculations performance under all expected conditions.

Discussion with Management

Ms. Hansen asked that I provide addi tional clarification. Con equent ly, I confirmed an earlier slatement made during the in pection. However, the firm indicated they would respond in writing wi thin 15-busine day .

4. Specifically, your firm 's HORI ZO Laboratory Information Management y tern (EPIC PRO) application for the management. tracking, scheduli ng and notification ( ia report) of facilitie and equipment qual ification . calibrations and preventative maintenance events has not been qualified for it intended purpose (PL Work flow) according to an e tablished protocol and acceptance criteria" ith all appropriate operational unit revie\\ and approvals, including the QU.

Supporting Evidence and Relevance

Pace's calibration management sy tern has not been validated according to an established protocol and acceptance criteria, including all appropriate operational unit review and approvals. Thi y tern supports a critical GMP function. According to the GMPs and 21 CFR Part 11 requirements, a software application must be validated, as it is a central/critical part of the qualit) assurance of a regulated drug sub tance or product. Validation provides assurance that the ystem is reliable and suitable fo r its intended u e, according to PL pccific workflows. and ensures the sy tern operates in a state of control, with all attribute validated in a fashion consistent with regulatory requirements. Pace employ a HOR IZON Laboratory In formation Management System (LIM ) applications to manage qualificalion. preventative maintenance and calibration related events. Purportedly. the hierarchy of tructures in this application is identical to their LIM stability application. Further, the faci lity and tracking application is considered b) Pace to be a commercial-off-the-shelf (CO r ) application of the LIM , where no configuration and cu tomization elements were required to meet the PL \\Ork fl ow (User/Functional) requirement . The HORIZO LIM system has the capacil) for user-defined Configurations and Customizations consistent within Good Automated Manufacturing Practice (GA MP) established oft ware definitions (Category-4, Configurable: Category-5, Customi7able). Unfortunatel). the definition of .. configurable" can be very expansive according to LIMS vendors and the pharmaceutical industry. Conseq uently, this could provide many significant challenges to understanding validation requirements pecific to an end-u er's workflow. At thi point, it is important to outline some critical/key difference bct\\Ccn configuration and customization.

Reference: Good Automated Manufacturing Practice (GAMP) oftware Categoric.

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• Configured products provide tandard interfaces and functions that enable configuration of the application to meet user-speci fic bu ine s processes

• Configuration using vendor-supplied scripting language should be handled as custom components or category 5.

GA MP Category 5: Customized oftware • These applications are developed to meet the pecific appl ications and \\Orkflow requirements of the

regulated company. • Includes internal application macros, LIMS language custom izati ons, VBA spreadsheet macros. QL

programming to meet user-specified applications or ,.,,orkfl ows. Also. include PLC logic and cu tom scripts wri tten within a SCA DA I DCS system

• l ligh inherent risk wi th these types or appl ication

The further down the GAMP software classification. the more specific the soft\\ are function become and the implications for programming to directly influence the u er-defined operation or calculations and hence the final result or output. In other words, the further the user gets away from the primary vendor established applications or worknows. the more likely there is for an output error to occur. requiring more extensive validation efforts.

Current industry working definitions include:

Configuration: A con figurat ion option should requi re no programmatic code and be completely tested by the vendor before oftware re lease. Ideally, configuration should be done through the u er interface; however. configuration file may be employed, provided that all appropriate testing has occurred. Basically, modifications to the software applications to meet ' orkflow or user requirement using tools supplied by the vendors. The e tools include. but are not limited to u er-defined text strings for drop-down menus, turn ing software functions on or on: graphical dragging and dropping of clements and the creation of user reports using the software's tandard functionality.

Customization: Customization is any form or permeation of programmatic code including, but not limited to those issued from a SQL *Plus command line interface in an Oracle Database. These include, but are not lim ited to SQL, PL/SQL and special SQL *Plus commands. Basically. the writing of software modules, scri pts, procedures, or appl ieations to meet user-defined requirement . This can be achieved using an external programming language (e.g., C++, Visual Basic, PL/ QL. etc.). macro instruction . or an internal scripting language.

Subsequently, after a review and discussion of the PLS \vorkfl ow for the management and tracking of faci lities and equipment related events, in conjunction with observation of the programmatic code (SQL) used to achieve the informal user/functional requirement , it was concluded that this specific application was customized (using

QL) to meet PL specific workflow requirements. Consequently, this LIM application requires formal val idation. In the context of my review, Pace claims thi is a commercial ofT-the-shelf (COTS) LI I application; however, this cannot be adeq uately ubstantiated, as GAMP and industry element of customization, including extensive programmatic cod ing ( QL). were identi fi ed in LIM associated documentation. Regardless of it COTS status, validation effort s must be completed to support Pace's intended worknow and expected outcomes, and is an essential process to demonstrate regulatory compliance. Further. informal efforts to demonstrate equivalency, in absence of formal validation master plan. \alidation protocol, user/functional requirement and acceptance criteria. user traceability matrix, including al l appropriate operational and QU reviews and approvals, are inadequate/unacceptable to demonstrate a state of system validation consistent with current industry practices, cGM Ps and regulatory requirements. peci fically, informal equivalency testing practices, using an earlier generation of Pace·s internally development cal ibration management system (Access Database), which was not

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val idated (see Exhibit 21 , page 2, BACK-OUT PROCEDURE ). does not demonstrate a state of validation consistent with current industry practices (cG MPs) and regulatory requirement . Failure to validate the previous database tool. as sub tantiated through inve tigative di!.cus ion and absence of documentati on. demon trate this has been a long- tanding practice to not validate th is critical GMP application.

Discussion with Management

Ms. Hansen indicated that they had conducted validation activit ies. I lowever, I believe Ms. I lansen·s re ponse was in reference to their LIM Phase I & II alidation acti\itie which supported their business operations (work order conception to completion) and/or the LIMS stabilit) functiona lity/application. That aid, I am unaware of any formal validation process that directly supports the calibration and PM tracking funct ions of their LIM .. Ms. I lansen expressed her intent to respond in writing within 15-business days.

5. pecitically. the teris Reliance SOOXL Laboratory Glassware Washer (PL #: 4613) has not undergone an adequate perfomiance qualification (PQ) according to cGM P and regulatory requirements. The PQ (QP 208. ep 20 16) does not include procedures or testing results that demon trate the succes fully removal of residue(s) or analyte(s) specific to PLS regulated drug testing operations. incl uding acceptance levels/criteria.

upportin~ Evidence and Relevance

Pace failed to establish adequate procedures for the performance qualification of the 500XLS Laboratory Glassware Washer (PLS#: 46 13) in a fashion consistent with current industry practices and regulatory requirements (Exhibit 26). Current qualification procedure!.. including a re idual detergent assessment. are inadequate to demonstrate the removal of analyte speci fie to PL complex regulated drug testing operation .

Discussion with Management

Mr. Kupp and Ms. Hansen did not express agreement or di agreement with the ob ervation; however, they informed me of their intent lo reevaluate the content of the exi ting validation. con idering additional mechanisms/procedure /challenges that could improve their o erall understanding of the system's performance. In addition, they expressed their intent to respond in writing" ithin 15-business days.

OBSERVATION 3 21CFR211.194(a)

Laboratory records do not include complete data deri ved from all tests, examination and assay necessary to assure compliance with established specifications and standards.

I . Specifically, your firm excluded fail ing testing results on the linal Certilicate of Analysis (CoA) when conducting individual impurities assessment for Mesalamine (U P 38/NNF 33; \! ork Order 1754363; amples 1754363003. 175-063004; LIR 1634) without a valid. documented. scienti lie ju titication for its exclusion. The QU reponed only the passing re ult on the linal CoA, thu di regard ing the original fai ling results. The initial results were not invalidated by a valid laboratory investigation (LIR 1634). Further, re-test procedures stipulate the reporting of only passing results even if the investigation i ~ inconclusive. peci lie examples of these instructions/procedures include:

• LIR 1634. Re-test Plan: ·The original suspect re ults \\ill be compared to the four individual retest results for each sample. For each ample. if the four rete t results agree with each other, meet cli ent specifications and disagree ' ith the result from the original preparation. the four sample retest results will be reponed.'"

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• LIR 1929 Re-test Plan: .. The original suspect re ult .. -.ill be compared to the four retest results. If the four retest result agree with each other and pass the client provided specification for D3J\ Alcohol and disagree with the result from the original preparation. the ample retest will be reported."

Supporting Evidence and Releva nce

LIR 1634 and LIR 1929 Re-test Plans are included as Exhibit 16 and 17 (Analysis Report & Investigation), respecti vely

Pace is a CTL that docs not manufacture. Consequent!). Pace is unable to conduct a conventional Phase 11 investigation. Further, it is not thei r QU that ultimately revie'' and approves the product test result . ultimately making the decision to release the regulated drug product for commercial distribution.

There arc two primary issues: I) The Out-of-Specification retest ample size, and 2) Calculating and/or expressing the reportable result from retest data. The currcm FDA guidance states .. If no laboratory or calculation errors are identified in the first test, there is no scientific basi for invalidating ini tial OOS results in favor of passing retest results. All test results, both passing and suspect, hould be reported and considered in batch release decisions" according to the FDA guidance for industry Investigating Out-ofSpeciflcation (OOS) Test Results for Pharmacewica/ Production (Rockville, MD, Oct. 2006). Basically, in absence of an extensive investigation beyond the scope of Pace's current operations (i.e., Phase 11 ), and retesting based on a clear statistical understanding of the test measurements inherent variabi lity, it cannot be concluded with a definable measure of certainty that the initial test result is invalid. Fur1her, it is highly (statistically) improbable that the initial fail ing test result (OOS) can be effectively (stat istically) determined to be invalid based on four (4) passing results (2 replicate sets). This calls into question Pace's retesting procedure. including cri tical elements of statistical validity. That said. in the absence of no assignable cau e the ini tial fai ling result mu t be considered jut as valid as the four (4) passing retest results. Consequently, since it is not Pace's QU making the final product quality or disposition assessment (i.e., release), it would be the best practice to ensure all te 1 re ults are including on the final CoA, o their client can quickly as e s pertinent data, consistent with regulatory requirements. 10 detennine the products ultimate disposition. Providing a footnote on the CoA to an "UR I 634", in absence of the failing test result, wi thout a reference/footnote specific to an .. 00 ·· test result, may lead a reviewer (client) to inadvertently conclude, in absence of a more extensive as essment, that the initial failing result had been fonnally invalidated. Further. absence of the 00 test result directl) on Pace' final CoA erves to obfuscate or blur the complete result et. potentiating a failure on the part of the client to fulfill the regulatory requirement to conduct a complete revie\\ of all test results. Ultimately, the client or ubmi sion holder may choose to expre the re ults differently based on an extension of their QM , including a more comprehensive inve tigat ion. retesting plan and a clear statistical assessment of the inherent test variability, and a tatistical valid approach to evaluate and express the retest data following an OOS result. Clearly, client may not want CoAs listing OOS test results that have not been effectively invalidated, as they may be aesthetically unappealing; however. it is the most accurate. complete, and straightforward representation of the te ting resul ts. Further. it ensures the client QMS has seen the failure, anticipated question , and has prepared efTective rcspon e , including effective mitigation processes according to procedures inherent 10 their QMS.

Overall , when investigations fail to in alidate the 00 or are inconclusive, the failing re ult should be recorded directly on the final CoA, so it can be given full considerat ion during dispo it ion and final release acti itie by the applicant.

Discussion with Managemen t:

Mr. Kupp and M . I Ian en did 110 1 expre s agreement or disagreement with the ob crvation; however. they informed me they wi ll respond in writing within I 5-busine s day . That said. I had a lengthy discussion' ith Mr.

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Kupp and Ms. Hanen regarding these specific practices and my regulatory concern in the days preceding the closing meeting.

REFUSALS

No formal refu als were encountered.

GENERAL DI CUS ION WITH MANAGEMENT

At the close of the inspection on the afternoon of February 7th. 2018. a 3-item FDA-483, lnspectional Observations (Attachment 3), was issued to Cynthia L. I lanscn. cnior Director of Quality. Mr. Kupp. VP & COO and Mr. Vanderboom, Pre ·ident and C~O were not in attendance, as they were out-of-state due to a prior commitment. In addit ion to Ms. Hansen and myself ( cott Golladay. lnve tigator). Mr. Skaar ( C 0) attended the closing meeting. Further, Mr. Kupp cho e to participate via conference call. At my request, M . Han en provided Mr. Kupp with an electronic copy of the FDA-483 via email prior to the reading of the ob ervations. Subsequently. I read each of the FDA-483. In pect ional Ob ervations, including all examples out loud. olicited questions/clarifications, and ask for a response. Further. I tated that a written re ponse. although not required, would be revie\\ ed and included in the district fi les if submitted within 15-busine s days. In addition. I indicated that these voluntary responses are highly valued and \\eigh heavily on the FDA' decision-making proce s. including considerations for compliance action (if any). A part of this discussion. I supplied the Program Division Director's name (Art Czabaniuk) and emai l addre (ORAPHARM3_RE PO ES@fda.hh .gov) on a typed handout sheet generated prior to the closeout. Further, I req uested that their email response include the finn· s name and FEI# in the subject line. and that the enclo ed written respon e include the dates of inspection. indicated it was the FDA 's current preference for voluntaf) re pon es to be submitted electronically via email; however, I indicated the finn could elect to mai l their re pon c. Ms. 1 lansen tated their preference v.as to respond by email: consequently, I chose not to provide a ph) ical mailing addre .

At the closeout meeting, Ms. I lansen tated that the Finn\ ould re pond in writing to the FDA 483 lnspectional Observations within fifteen ( 15) busines days. A brief di cus ion ensued between Ms. 1 lansen and Mr. kaar concerning FDA Action Levels where it \\BS implied that the ob ervations (FDA-483) cited may, after further review by the Agency, be deemed violations of the Food. Drug and Cosmetic Act, and if not voluntaril) corrected, sanctions are available to the Agency.

ADDITIONAL INFORMATION

A current cu tomer list specific to FDA regulated product le ting wa collected: hO\\ever, it was returned to Pace via UPS Second Day (Tracking#: I ZA4 796Y024340628 I) based on Ms. Han en 's request. No additional information i recorded in this seclion.

SAMPLE COLLECTED

o samples \\ere collected during thi inspection.

VOLUNTARY CORRECTION

At the close of the general surveillance in pection on Ma} 5th. 20 15 Pace was i ued a I-item FDA-483. lnspectional Ob ervation for a failure to thoroughly review any unexplained di crepancy whether or not 1he batch has already been distributed (21 CFR 21 I. I 92J. This ob ervation was related to fai lures to investigate significant revisions to Analysis Reports I CoAs. peci fically, conventional change management practice" including investigative procedures, were not employed to manage/approve changes to Analysi Reports I CoAs within

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Pace's Change Management System (CMS). The impetu for these revisions could be for a host of reasons; however, they were often due to errors in reported value or incorrect ly identified batch/lots based on the client 's failure to provide accurate information during work order development. In one in tance, the client identified errors in how the chromatographic analysi was conducted, re ulting in a higher than expected impurity assessment.

Pace submitted a response to the FDA M inncapolis District Office on May 21. 2015 ' hi ch included the statement of·'Corrections and/or Corrective Actions, as appropriate, along with Responsible Person and Target Completion Date." (See Exhibit 20, Document Change Record 7135) In her response, Ms. Hansen, Director of Quality, commitment to addressing each of the revised Work Order cited on the FDA-483 us ing updated procedure ( OP L 12, Ver. 13 ), including a new investigat ive form (1. 12 A4 ). /\ review of document change management during the current inspection revealed significant efforts to addre s the ob ervation through revision to an existing operating procedure Work Order Generation, Work Comp/e1io11, and Reporting of Results, SOP L30, Yer 13, Effective 21 MAY 20 15 (Exhibit 18 Ver. 12, Exhibit 19 Ver. 13), including the addition of an investigative form (SOP L30, A4) used to record mitigation/investigation related activi tic . Pace initiated corrective actions for each of the Analysis Reports listed on the FDA-483 that had undergone revision out ide of an acceptable change management process, which included the addition of inve tigati ve procedure to upport the revision of Analysis Reports I CoAs. in an attempt to comply with regulation. In Pace's initial respon e they indicated that the examples (Work Orders) listed on the FDA-483 would undergo change management. including investigative procedures, in a fashion consistent with the revised procedures. During the current inspection select Wori.. Orders ci ted on the FDA-483 were reviewed to ensure Pace conformed to their revised procedure, commitments to corrective action (FDA-483 response), and regu latory requirements. rurther, I asked for a LIMS report summarizing all revisions to Analysis Reports since the revised procedures went into effect. Basically, I intended to determine if the revised procedures \\'ere reduced to practice within Pace's QM . ubsequently. I selected several revision events to ensure Pace's conformance to the re\ i ed procedure, including the completion of investigative procedures i.e., form A4. Form A4 was intended to be a record of the investigative process. Finally, I reviewed training records associated wi th the updated procedure to ensure full compliance with their regulatory commitments. The SOP Quiz (SOP L 12 A I) was updated with the transition from Yer. 12 to 13: however. it did not highlight or renect critical SOP changes (section 6 and 13). including que tions specific to the new investigative procedures. That aid, the inve tigative form (A4) was a significant addition to Pace' QM . Please refer to the OBJECTIONABLE CONDITIONS AND MA AG EM ENT' RE PONSE (Observation I. Example I, pg. 16) section for additional concerns re lated to thi corrective action.

EXHIBITS COLLECTED

I . Quality Management Manual, 17 pages 2. Sales Brochure, Pharmaceutical Chemistry Services, I page 3. Sale Brochure, Stability Storage Services for Pharmaceuticals and Medical Devices, I page 4. Sales Brochure, Medical Device ervices, 2 pages 5. Training Program, 6 pages 6. Technique Based Training, 7 page 7. Training of Technical Records Reviewers, 4 pages 8. Work Order Generation, Work Com pletion, and Reporting of Results (Ver. 17), 9 pages 9. Complaint Handling, 4 pages I 0. Laboratory Investigation , 18 page 11. Revised Report Record of Change. Work Order 17478 12. 4 pages 12. Rcvi ed Report Record of Change. OP L 12 A4 (Blank). J pages 13. Laboratory Inventory and Change Control Procedure , 19 pages 14. Risk As essment, 5 pages 15. Empov. er Custom Calculations for 'f ransderma l tabi lity Program, 6 pages

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Establishment Inspection Report Pace Analytical Life Sciences. LLC. Oakdale. MN 55128-6023

FE I: El tan: El End:

16. Laboratory Investigation Repon Initiat ion, Investigation #: 1634, 19 page

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17. Analysis Report, Laboratory lnve tigation Report Additional Testing/Retest Plan, Investigation #: 1929, 15 pages

18. Work Order Generation. Work Completion. and Reporiing of Result (Ver. 12). 9 pages 19. Work Order Generation, Work Completion, and Reporiing of Re ults (Ver. 13), 9 pages 20. Document Change Record # 7135 (Change Record for OP 12, and initiation for Form A4). 12 pages 21 . Change Control Record, CRF #: 1422, 4 pages 22. CoA. Work Order 1747812. Report Date 23 SEP 2015, 2 pages 23. CoA, Work Order 1747812, Repon Date 15 APR 2016. 2 pages 24. Deviation Form, Deviation #: 1812, 2 pages 25. Risk Assessment Form, RA #: 296, 5 pages 26. Steris Reliance Model 500XLS Operational and Performance Qualification (OQ/PQ), 6 page

ATTACHMENT

I Issued FDA 482, (Notice of Inspection), 3 page (Gregory Kupp, VP & COO) 2 Issued FDA 482, (Notice of In pection), 3 page (Steven Vanderboom, President & CEO) 3 Issued FDA 483 ( lnspectional Observations), 4 pages

Scott A. x Golladay -S

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Dig11ally sign~ by Scotl A. Golladay S ON: C• US. o-U.S. Government. ou• HHS. ou• FOA. ou• People, 03.2342.19200300.100. 1 . 1 ~200198637

o. en- Scott A. Golladay -5 Dal~ 201&.o907 16:2):01 05'00'