Safeguarding public health

EHR]A

INSPECTION REPORT

Guy’s Hospital Pharmacy St Thomas’ Street

London SE1 9RT

Head Office: Inspection & Standards Division, Market Towers, I Nine Elms Lane, Vauxhall,

London, SW8 5NQ Tel: 0207 084 2580 Fax: 0207 084 2676

Medicines and Healthcare products Regulatory Agency

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GMP INSPECTION OF Guy’s Hospital Pharmacy

SECTION A INSPECTION REPORT SUMMARY

Inspection requested by: MHRA

Scope of Inspection: Routine fee paying

Licence or Reference Number: MS 11387

Licence Holder/Applicant: Guy’s & St Thomas’ Hospital NHS Trust

Details of Product(s)! Clinical trials/Studies: CIVAS (under the scope of the licence)

Activities carried out by company:

YIN

Manufacture of Active Ingredients N

Manufacture of Finished Medicinal Products Y

Manufacture of Intermediate or Bulk N

Packaging Y

Importing N

Laboratory Testing Y

Batch Certification and Batch Release Y

Other: Development, specials and IMP activities N

Name and Address of site(s) inspected: Guy’s Hospital Pharmacy, St Thomas’ Street, London, SF1 9RT

Section Site Contact: 40

Date(s) of Inspection: 29th April - 1 May 2008

Lead Inspector: Neil Raw

Accompanying Inspector(s): Ian Thrussell

References: None

Final Conclusion/Recommendation:

Name and Dated Signature of Lead Inspector:

Signed: Dated: 6th August 2008

Name

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SECTION B GENERAL INTRODUCTION

BI Background information There are a number of distinct operations on this site. Those supervised by pharmacy and those supervised by Medical Physics management. The Quality Assurance Unit has oversight over both operations. The pharmacy operations on this site are in two separate facilities; the satellite pharmacy, where aseptic oncological products are formulated is adjacent to the oncology wards; other pharmacy operations are based in the main pharmacy department where CIVAS and TPN operations are based as well as a small non sterile area. All aseptic operations on this site involve the formulation of the finished product by the aseptic manipulation of other Specials or licensed products. The larger part of operations performed in the licensed units is the preparation and dispensing of short shelf life product against individual prescriptions although there is a limited amount of batch TPN and CIVAS. The Trust licences also covers operations at St Thomas’s Hospital where there is a full licence and classical formulated products are manufactured. The main aseptic batch manufacture is performed at Guy’s. There is a common senior production and QC/QA management structure covering the two hospital sites and it was stated that there are common procedures for common activities

Previous Inspection Date(s): 8119th May 2006

Previous Inspectors: Paul Tomlinson & Paul Hargreaves

B2 Inspected Areas Quality Systems including complaints, recall, deviations, documentation control and self inspection Aseptic compounding - Radiopharmacy, CIVAS, TPN, Oncology satellite Product set up, inspection and packaging. Microbial monitoring of aseptic areas, HVAC control and maintenance Supply chain, TSE compliance, inspection and storage

B3 Key Personnel met/contacted during the inspection

Section 40

Position Associate Chief Pharmacist Radiopharmacist Chief Radiopharmaceutical Scientist QA Specialist QA Pharmacist Senior Aseptic Services Pharmacist Senior Chemotherapy Pharmacist QA Manager Aseptic Services Manager

B4 Documents submitted prior to the inspection None

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SECTION C INSPECTOR’S FINDINGS

Cl Summary of significant changes

Section 43

Section 43

C2 Action taken since the last inspection Acceptable responses were received. A copy is on file. Remedial actions were confirmed as successfully completed or in progress according to timetable.

C3 Assessment of the Site Master File The site master file reflected current facilities equipment and procedures.

C4 Compliance with TSE Guidelines All starting materials handled at this site are either licensed pharmaceuticals, CE marked medical devices or one of a limited number of specials sourced from Torbay Hospital.

C5 Quality Management One quality system operates over both manufacturing sites on the licence, those being St Thomas’ Hospital and Guy’s Hospital. The bulk of Licensed, more traditional manufacture is performed on the St Thomas’ site and only the manufacture of pre-filled syringes as part of the CIVAS service is considered as licensable at the Guy’s hospital site. A number of quality exception investigations were reviewed and were satisfactory. There was evidence of good investigation and appropriate RCA. The change control procedure SOP and a number of examples were reviewed

Section and were satisfactory. 43 The SOP for the QA release of aseptic batches was reviewed and was satisfactory. A QA

checklist is used to ensure consistency.

C6 Personnel The company had an appropriately qualified and experienced management team. Appropriate numbers of adequately qualified and experienced staff were available for all functions. Training records for two aseptic technicians were reviewed and were satisfactory.

C7 Premises and Equipment The premises have been described within previous reports and in the SMF. The cytotoxics unit has been upgraded since the last inspection and is much improved. This is currently all section 10 dispensing.

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Currently throughout the facility max/min thermometers are used for temperature monitoring. The unit is currently trying to validate the ICESPY temperature monitoring system. Estimated completion is by Q3 2008, and the system will also monitor the microbiological QC incubators.

C8 Documentation The current license MS 11387 was reviewed regarding all sites (Guy’s & St Thomas’) and a number of discrepancies were noted see deficiencies. MIA (IMP) 11387 was also reviewed and deficiencies were noted.

C9 Production The procedure distinguishing between batches (licensed) and dispensed (section 10) items (SOP was reviewed and was satisfactory.

Section Aseptic licensed product is manufactured using closed systems with either licensed sterile 43 medicinal products as the ingredients of sterile products manufactured on a licensed site

(i.e. other specials). Aseptic products are given a 7 day shelf life. The procedure for the generation of labels through theIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIabel system was reviewed and was satisfactory. A number of batch records were reviewed and were generally satisfactory.

ClO Quality Control QC laboratories for the Trust are physically located within the pharmacy manufacturing facility at St Thomas’s Hospital where there are laboratories for both Microbiology and Chemistry. The environmental monitoring programme is typical of that usually found in hospital specials units performing aseptic preparation, involving settle plates, finger dabs on a session basis supplemented by Biotest and contact plates and swabs less frequently. The procedure for actions to be taken in the event of an out of specification environmental monitoring result (SOP was reviewed and was satisfactory. A number of

Section associated investigations were also reviewed and a number of deficiencies were noted. The environmental data for 2007/8 was also reviewed. It was noted that there had been some high finger dab counts in the Oncology isolator B in Jan/Feb 2008. The associated exception report was reviewed and was satisfactory. There is currently no continuous particle monitoring in any of the Trust’s aseptic fill areas. The Trust presented a rationale to support this approach. The unit do not keep retained samples as the longest product shelf life is 3 months. There have been four failed batches since Feb 2007. The quality exception reports fro these were reviewed and a number of deficiencies re noted. Analytical testing is currently only performed on There is a programme in place to generate analytical specifications for products which undergo some bulk manipulation.

CII Contract manufacture and Analysis The technical agreement witl was reviewed and was satisfactory.

Section 43 C12 Complaints and Product Recall

The complaints and recalls procedure (SOP was reviewed. Complaints are logged through the quality exception system. Since the last inspection the trust have had one complaint/recall for Fentanyl. The investigation was reviewed and a number of deficiencies were noted. Recalls of raw materials are also described in this procedure.

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C13 Self Inspection __________

The internal audits procedure (SOP was reviewed and was satisfactory. The Section

2007/8 schedule has been adhered to and the resulting actions are tracked through quality exception reports.

C14 Distribution and shipment Currently all distribution is within the trust.

C15 Questions raised by the Assessors in relation to the assessment of a marketing authorisation

None

C16 Annexes attached None

SECTION D LIST OF DEFICIENCIES

DI Critical None

D2 Major 2.1 The control & monitoring of aseptic practices is deficient in that; 2.1.1 The investigation into the failed post session broth fill was inadequate with respect to

the determination of root cause and subsequent preventative actions. 2.1.2 The recording of session environmental monitoring in the associated log is not

contemporaneous. Consequently it is difficult to ensure that all the required environmental monitoring results to support aseptic batch release are present. A number of instances were noted with missing data and batches were still released without additional comment.

2.1.3 There are no guidelines to allow the release of aseptic batches with incomplete environmental monitoring data.

2.1.4 The process used to label environmental monitoring plates in the assembly areas prior to transfer into the Grade A isolators provides unnecessary contamination risks.

2.1.5 There has been no consideration of the potential for inhibition of microbial growth by

Section the product in the iedia simulation test.

2.1.6 isolates from failed media simulation tests and critical environmental monitoring are not identified in sufficient detail to enable effective investigation.

2.1.7 There is no documented justification for the absence of session surface monitoring of critical areas to support batch release of aseptic product.

2.1.8 There is no procedure in place detailing the actions that need to be taken in the event of a glove tear on the class A isolators.

2.1.9 There is no schedule for routine changing of gloves on the class A isolators. 2.1.10 There is no monitoring of gloves for the technician spraying materials into the class

A isolator. Ref EU Guide to GMP, Annexe I sections 5, 6, 40, 42,

D3 Others 3.1 The control of production activities is deficient in that;

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3.1.1 Use by dates are not applied to ’in use’ disinfectants used in the cleanrooms. 3.1.2 Sticky residues were present on various surfaces in the cleanrooms. 3.1.3 Storage cabinets in the cleanrooms were not of a design to facilitate effective

cleaning of the surrounding floor. 3.1.4 The wire baskets used for the storage of infusion bags in the oncology assembly

room would not ensure the protection of the contents from contamination during cleaning activities.

3.1.5 There were a number of uncontrolled aide memoirs used in the production area. 3.1.6 There is no documented check to confirm that label printing and production areas

are clear of previous product prior to starting a new batch. 3.1.7 Whilst the new SOP issists with the requirements for ordering of

Section

preparations and the checking to be performed, there is currently no record to verify steps have been performed in the correct order.

3.2 The scope and level of documentation of the Quality Management System was deficient in that;

3.2.1 Planned deviations are currently not logged, tracked or trended. 3.2.2 There is a lack of evidence in the change control documentation and Quality

Exception Reports to demonstrate that the appropriate actions have been completed.

Section 43 3.2.3 The change in scope of Change Mwas not appropriately documented. 3.2.4 The current process which allows bonded product to be released early without the

need for a quality exception is not satisfactory.

3.3 The control of IMP activity is deficient in that; 3.3.1 The Technical Agreement (TA) with has not been subject to a recent

review and a number of discrepancieswere noted. These included; 3.3.1.1 The TA was out of date with respect to the current individuals responsible for Quality

at Guy’s, and it was not clear if the trust had informed of the changes. Section 43 3.3.1.2 Appendix B in the TA does not refer to the date of the master agreement.

3.3.1.3 The TA fails to fully discuss the role of the QP in certification of the IMP batch and the release of that batch for administration in a specific trial.

3.3.1.4 Clause 4.1 of the TA states that master work sheets will be approved by There was no evidence that this has been enforced.

3.3.1.5 The TA does not deal with the arrangements for retention samples of either raw materials or finished product.

Section 43 3.3.2 Two batches of and one batch of HI have been accepted and

used in aseptic manipulation to prepare IMP in the Tmuva trial. The Certificates of Analysis supplied were ambiguous as to whether or not these materials were sterile. There was no evidence that clarification of status was sought.

3.4 The control and content of the current licences is deficient in that; 3.4.1 There is no procedure in place to document responsibilities for controlling licences

with respect to updating, checking etc. During review a number of discrepancies were noted.

3.4.1.1 MS 11387, Site 27444 3.4.11.1 1.1.1.6 Should be ’Not Licensed’ 3.4.1.1.2 1.4.2.1 Should be ’Licensed’ 3.4.1.1.3 1.5.1.5/6 Should be ’Not Licensed’

3.4.1.2 MS 11387, Site 351560

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3.4.1.2.1 1.1.1.1 Should be Not Licensed’ 3.4.1.2.2 1.1.1.6 Should Specify ’Radio pharmaceuticals’ 3.4.1.2.3 1.2.1.5 Should be ’Licensed’ (foods with labelling) 3.4.1.2.4 1.3.1.7 Should be ’Not Licensed’ 3.4.1.2.5 1.5.1.5/6 Should be ’Not Licensed’

3.4.1.3 MS 11387, Site 31430 3.4.1.3.1 1.6.3 Should be ’Licensed’

3.4.1.4 MIA (IMP) 11387 3.4.1.4.1 The Radiopharmacy (site 351560) is not named on the licence. 3.4.1.4.2 The PET (site 31 430) is not named on the licence. 3.4.1.4.3 Site numbers for the other sites listed are incorrect.

3.5 There is no formalised procedure for ensuring that appropriate independent approvers are always available to release product from the Radiopharmacy.

3.6 The procedure for determination if a product is manufactured under licence or section 10 does not detail subsequent steps on the respective processes. In addition the terminology used to distinguish product manufactured under the MS licence and that manufactured under the section 10 exemptions is inconsistent in the associated procedures/documentation.

3.7 There is no process in place to ensure that approved product label templates are held in a protected database and can be recovered for.

3.8 The replacement of the failed batch of batch was not appropriately Section

documented with regards the rationale for the decisions taken. In addition there was no formal reconciliation of returned material performed.

D4 Others 4.1 There is no procedure in place to describe how risk assessments are performed and

the tools which may be used. 4.2 There are no procedures in place for the process for Guy’s supplying specials

outside of the trust. 4.3 Once products move to the bulk preparation manufacturing process greater

consideration should be given to process validation, analytical testing, sterility testing, stability testing and retention samples. The trust is required to submit a documented rationale to the inspector once the approach has been agreed.

SECTION E SUMMARY AND EVALUATION

El Closing Meeting The deficiencies noted were presented to management and accepted, with assurances of remedial action.

E2 Assessment of response(s) to inspection report An initial response was received on 1 1li June 2008. Further clarification was requested. A satisfactory updated response was received on 21st August 2008.

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E3 Documents or Samples taken None

E4 Comments and Evaluation of Compliance with GMP The new site generally meets GMP requirements.

SECTION F FINAL RECOMMENDATIONS/CONCLUSION

Fl Recommendations Continue to support the licence.

F2 Conclusion Section 43

SECTION G INSPECTORS’ NAMES, SIGNATURES AND DATE

Signed: Dated: 1st September 2008 Lead Inspector:

Signed: Dated: Inspector

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