DEPARTMENT OF TEALTITAND HUMAN SERVICES EOODAND DRUG AOMINISTRATION 10903 New Hampshire Ave, Bldg S1,Rm 4225 10/05/2015 = 10/13/2015 Silver Springs, MD 20993 (301) 79863338" Fax: (301) 847-8738 Information: www. fda.gov/oc/industr, Mr. Sirjivan Singh, managing virector cP Pharmaceuticals Ash Road North Wrexham Industrial Estate Wrexham LL23 SUF, United Kingdom Sterile brug Manufacturer “This document sts observations made by the !DA represenatve(s) during the inspection of your facility. They are inspectional ‘observations, and donot representa final Agency dclemination regarding your compliance. Ifyou have an objection regarding an ‘observation, or hay implemented, of plat implement, corrective ation m responte 0 an observation, you may discus the objection or action with the FDA representaive(s) during the inspection oF submit thi information to FDA at the addeess above. Ifyou have any ‘questions, please contact FDA at the phone number and address above. DURING AN INSPECTION OF YOUR FIRM | OBSERVED: OBSERVATION 1 Provedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established and followed. Specifically, your firm has not established and followed all necessary procedures to prevent contamination of aseptically filled sterite drug products. Aseptic filling occurs in EU Grade A ®@ RABS systems that reside in a EU Grade B background. Control of aseptic interventions are described in SOP #SPOP-075-09-1643, ver 7, and personnel behavior in ISO Class 100 is described SOP #SPOP-121-06-1526, ver 5. A) My review of procedures noted that disinfection of RABS "opened during set-up operation is required to be performed at the ®"hf the set-up operation at not after each opening, B) On 1015/15, 1 observed the set-up off MOL ine {forthe aseptic filing off nt in a, P PE jot {noted the following. During the Engineering Setup, the RABS| "remained opened to Grade B for -PIMIl without being closed The [PMFor | remained opened until thel EM were instal par ee Pof the Engineering Set- up. The Pare reportedly removed during cleaning after the 19%) and the! "remain open until the next time the line is setup. PI pans forthe aseptic filler, which are|||) Pn a me PY ana stenlized are ‘exposed to Grade B and entered into the Grave A KABS without any disinfection. I observed multiple packages enter the RABS and come into contact with nigral equipment surfaces. I also cbserveé multiple packages ‘come into contact withthe In the Grade B as they were entered into the RABS, ‘The product tubing connected to the Bh®)-sterilized bulk product tank was entered into the RABS without disinfecting, ‘The internal surfaces of the RABS |" "*\vere not disinfected prior to closing on multiple occasions, by SRT RE SEE REVERSE | Zortenee J. Slayton, Investigator OF THIS PAGE 10/13/2018 ean tate INSPECTIONAL OBSERVATIONSDEPARTMENT OF HEALTH AND HUMAN SERVICES “Fe ARETE TET aa AON eae RSF 10903 New Hampshire Ave, Bldg 91,%m 4225 10/05/2015 ~ 10/23/2015 Silver Springs, MD 20993 al (301) 786-3334" Fax: (301) 847-8738 3003369660 Industry Information: www. fda.gov/oc/industs: ERE AouaTae = x To: Mr. Sirjiwan Singh, Managing Director CP Pharmaceuticals Ash Road North firexham Industrial Hotate OCHRE oR ET ~ Toe ara Wrexham 1513 UF, United Kingdom Sterile Drug Manufacturer _multiple employees. The wiping of the internal “surface was observed to not always be executed in aff) 'P)@soproach and the area near the bottom ofthe vas not wiped in entirety Movement of employees within the Grade A RABS and in the Grade B area (withthe RABS| open and closed) appeared brisk, abrupt and rapid. I also noted that each time the: vere pushed aside and allowed to 1 they potential created sir turbulence in the room. | observed multiple personnel, on multiple occasions, ouch surfaces and items in the Grade B area and then center the Grade A RABS and touch sterile surfaces without disinfecting gloved hands, including: 1) cart with supplies, 2) f"" s.rrounding the RABS, 3) filling equipment controls attached to the P21 4) the! on the RABS. ‘This included the engineer opening the RABS|°n| ®cuccossive occasions during set-up to adjust the filling PIE with a tool (1) without disinfecting gloved hands. ©) On 05, reeweracorded COTY agg of Aa ie tn cal. erento in te sune Gras ARABS, dng filing off BAS Phitampale ici Me ued 9297S Tebnened mmltple employees display the same benHVOTS a deseibed above on repent us D) The protective covering, post sterilization handling, and introduction into Grade A atcas for®)®H}/SOP equipment, ‘components and container closures (stoppers and 14) are not designed to prevent contamination of sterile drug products, For example, ‘+ Protective covering inchudes wrapping equipmenv/components in af )0/provided by PI) bagging, ‘material, as described in SOP #SPOP-051-10-1351, ver 10. There is no B14 tone) in Grade B areas prior to entering the Grade A RABS Receipt and storage of sterilized equipmenvicomponentsclosures into tho Class 100 area is described in SOP 4#SPTM.021-08-1611, ver 5. The procedure includes passing exposed itoms (in| bags) through Grade B forstorage in Grade A without any/4) Ty barr. ‘There is no requirement to disinfect hands prior to selecting! PMS toms forthe Grade A filling lines PHYitems (wrapped in BEN bags) are openty transported and held on a cart in Grade B area while ‘being used to set up filing equipment Ses gevense | "Zee 3 0/3/2035 omen com evoseenevonict INSPECTIONAL ORSEIRVATIONS pace son racesSR REET 10903 New Hampshire Silver Springs, MO (B01) 796-3338" Fax Industry Informacion set amr Yo: _Mr. Sirjivan Si eR Pharmaceuticals Wrexham L113 UF, DEPARTMENT OF HEALTIVAND HUMAN SERVICES FOOD AND DAUG ADMINISTRATION. ave, Bldg 51,Rm 4225 20993 (01) 847-8738 www. fda.gov/oc/industry ngh, Managing Director Ash Road North United Kingdom 10/05/2015 = 10/ 3003369660 Wrexham Industrial Estate Sterile Drug Manufacturer OBSERVATION 2 Aseptic processing areas are deficient regarding the system for monitoring environmental conditions. ‘Specifically, your firm has not established a suitable system to monitor for viable and non-viable particulates for sterile drug products as follows: ‘A) On 10/6/15, 1 observed fully incubated plates for monitoring of employee gloves (finger dabs) in the microbiology lab that did not bear any indication that fingers had been in contact with the media, The only evidence the plates had been contacted during sampling was where the thumb had left an imprint. A review of SOP #GTM-108-18-1131, ver 9. for monitoring techniques describes gently pressing digits ono the surface ofthe! and taking care not to damage the © The collection does not include any information related tothe contact time required. Further, your firm has not conducted any studies to demonstrate the capability and reliability for your methed of collection. “Monitoring of personnel gowning for the Class 100 area is according to SOP #QCOPMB-004-22-1260, ver 15. This Personnel present and participating during set. Procedure describes that monitoring only aceurs atthe up, filling, cleaning or any other activity in Class 100 are not monitored unless they participate in batch filling thet ow or they are part of ¢ routine audit, ‘The study protocol (TECHHP-09-0-1673) approved by the QCU to support the monitoring location of non-viable particulates in the Grade B background where aseptic filling occurs did nat include the location of sample points, ‘The production department executed the study and independently determined the sample locations. Monitoring locations for viable microorganisms for iNI®!Line in the Grade A RABS and Grade B background are justified in risk assessment document HRAS-026-2518, ver 2. A review of this document found the following areas were excluded from the assessment: A PU \where IPC tests are performed + The portable cart used to hold sterile parts/equipment which are assembled inside the RABS for filing ‘These locations have not been assessed for the need to monitor for viable microorganisms. OBSERVATION 3 Procedures describing the handling ofall written and oral complaints rcgarding a drug product are not followed, Specifically, complaint investigations according to SOP #QAP-005-17-1147, ver 8, do not ensure a root cause determination 1s made, when possible. Section 6 ofthe procedure includes a brief note on complaint samples; however, the procedure and SEE REVERSE | Toxsauce J, Slayton, Investigator OF THIS PAGE “es INSPECTIONAL OBSERVATIONS, 10/13/2015DEPARTMENT OF HEALTH AND HUMAN SERVICES 1000 AND DRUG ADMINISTRATION 10803 New Hampshire Ave, Bldg 51,Rm 4225 10/05/2015 - 10/13/2018 Silver Springs, uD 20993 ena (301) 796-3334" Fax: (301) 947-0738 3003369660 Industry Information: wuw.fda.gov/oc/industry TO: Mr. Sirjiwan Singh, Managing Director _ cP Pharmaceuticals Ash Road North Weexhan Industrial Estate Wrexham LL13 QUF, United Kingdom Sterile Drug Manufacturer {orm for documenting complaint investigations is not specific on the process of obtaining a complaint sample nor provides a suitable system of documenting what actions have been executed in order (o obtain a complaint sample, including when complaint samples are not available. 1 reviewed complaint #C15A03 and #C35A05 for reported forcign matter deseribed as, Stott" n wo btchescf BM hjoton end compat AC14KOA for pants in the same prod. ‘Theve is no documentation of any attempt to Tocover complaint samples for evaluation. Both investigations determined the event was an isolated incidence and no root cause was identified, These three complaints were reported as Field Alerts by the applicant holder. ‘This isa repeat observation. OBSERVATION 4 ‘The spools and procedures applicable tthe quai contol unite not ly followed Specialy, |A) You firm id wot excut change conto as described in SOP AGOP-744-5-1742, er 5 For example, 1) The root ease of deviation 46274 determined seized filing psn on Ampute Line rested in metal porta nile prodact The CAPA included an upto ine lean procedures and saben, Tit ‘was communicated to omplayees via Training Note #753; however, no change control was opened to update any impacted procedures and records. Anew (P1yystem was installed to be the wal For tne and 14. tems. The system qualification included®™? sampling for sample ail!) 4) Followed by PM) sampling for“ 9)(campling for B14) 9). A review of change controt #387 revealed that the qualification approach was based solely upon the requirements of Validation Master Plan for Sterile Products (VMP-219-0-13515), which is not scientifically based and isnot supported by any risk assessment. In addition, the QCU approves the plan for implementing changes, but does not review executed changes to ensure changes are implemented as approved ‘Your firm has not implemented the controls to ensure all data used to make quality based decisions is meintained. 1 reviewed deviation investigation #6374 for an action evel excursion for an environmental isolate recovered from a settling plate ina Grade A filling area, The investigation included the review of recorded CCTV video footage for the filling operation to asses if proper aseptic technique and employee behavior was followed. The incident occurred October 13,2014 and your firm reported this data is only maintained until the data is over-wrtten with neve data due to storage space limitations. The estimated time for CCTV data maintenance is~ | also observed wns/20:s INSPECTIONAL OBSERVATIONS race roversDEPARTMENT OF HEALTH AND HUMAN SERVICES SRS RTT FOOD AN ORG ADM STRATTON oF 10903 New Hampshire Ave, Bldg S1,Rm 4225 10/05/2018 ~ 10/13/2015 Silver Springs, MD 20993, Tomar (301) 796-3334" Pax: (301) 847-2738 3003369660 Industry Information: www. fda.gov/oc/indw: oT ee To: Mr. Sirjivan Singh, Managing Director CP Pharmaceuticals Ash Road North a Wrexham Industrial Estate Wrexham LL13 9UF, United Kingdon Sterile Drug Manufacturer OBSERVATION 10 ‘There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport orate represented to possess. Specifically, 'A) Your fim as not validated all manufacturing processes for EDL npn! [injction, PARI sterilized Pred files ino apa Your orga veanon repo, doc VAL e146 ae 1203 dom ot nade subjecting a batch toa 14 isterilization cycle. My review of records found on two occasions that your firm had subjected batenes tox OM herliaion eyce duc to deviations duvng the) @"@htriation. Vour frm has wot ally evaluated the impact of thepl™@berlizaton eye on the product. “The established reject action Jevel forthe manual visual inspection process of filled drug produets is not sciemtically based. The reject action level for defects are described in SOP #SPOP-2-1196, ver 14. A review of document #TECHR-531-0-1733, ver 2, found thatthe statistical limit for rejects was adjusted 10 a h ‘most categories and the justification includes, in par, for “practical expedliency”. OBSERVATION 11 ‘There is no weitten testing program designed to assess the stability characteristics of drug products. Specifically, your firm has not implemented a program to assess the stability characteristics for Snel injection, which has been subjected tol 14°) 4IY sterilization eyele. During my review of weeds for investigations (deviation #703] and #7058), I encounterod two lots that were subjected to 2| | sterilization cycle and there exists no data to ensute the quality characteristic ofthe product for the labeled shelf-life. Your eurtent study protocol, document #VALP.8469-013726, to support the WM) )Pexpiry is silent to any requirement to place any lot on stability subisstas ©. (HPN sterilization cycle. No past offcurrent lot on study was reported to have been subjected 10) sterilization cycle 8) OBSERVATION 12, Written procedures ate not established for evaluations conducted at least annually to review records associated with a representative number of batches, whether approved or rejected, Specifically, A) Your firm has not implemented a system to evaluate data from relevant process trends and quality of incoming — 1 ora RE — Foes OF Tris PAGE . ° 10/23/2008 sony pA guy routs ote INSPECTIONAL OBSERVATIONS ercerorsenais‘DEPARTMENT OF IFALTH AND HUMAN SERVICES 10903 Now Hampshire Ave, Bldg 51,Am 4225 05/2015 - 10/13/2015 Silver Springs, MD 20993 (301) 796-3334" Fax: (301) 847-8738 3003369660 Industry Information: ww. fda.gov/oc/industey Yo: Mi. Sirjiwan Singh, Managing Director © Pharmaceuticals Ash Road North _ Wrexham Industrial Wrexham L113 9UF, United Kingdom Sterile Drug Manufacturer materials or components, in-process material, and finished products, in order to detect unplanned departures from the process. Ths is necessary to allow detection of undesired process variability and to verify thet the quality attributes are being appropriately controlled throughout the process. a ‘The Setember 214 September 2015 APOR for L/min ated identity nd expan two batches that required a "bye sterilization cycle duc to deviations. The record only mentions that three ‘minor deviations occurred, but there is no reference to the products required a) | ™™ycle. OBSERVATION 13 Reserve samples from representative sample lots or hatches of drug,praducts selected by acceptable statistical procedures are not examined visually t least once year for evidence of deterioration Specifically, your firm does not perform an annual visual assessment of retain samples in order to deteet deterioration. SOP AQAP-124-5-1012, ver 8, states that an assessment will only be completed if deseribed in a tecknical agreement with the application holder _ SEE REVERSE | Torcgnce J. Slayton, Investigator : OF THIS PAGE Ze. Let tf) 20/13/2015 oon rmmanannas INSPECTIONAL OBSERVATIONS