SMF model

MHRA Inspectorate and Enforcement DivisionSite Master File

For Manuapplicants forsmall-scale ac

Inspec

Site Master File Model

facturing “Specials” Licence holders or Manufacturing Authorisations relating totivities, including investigational medicinal

products

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torate

1 N

Iss

Issued By

and Enforcement divisionMHRA

ine Elms RoadVauxhallLondon

SW8 5NQ

ued March 2004

Version-01-2004--

MHRA Guidance Note 30


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Table of ContentsItem Page

1.0 Introduction 3

2.0 Format 3

3.0 Site Master File - Suggested sections3.1 Title page 53.2 Copy of the current Manufacturing Authorisation(s) 53.3 Details of Products manufactured 53.4 Licensed organisation location 53.5 Licensed Organisation History 33.6 Site Drawing & Description 63.7 Personnel 63.8 Responsibilities 63.9 Production 73.10 Quality Management system 83.11 Training 83.12 Quality Control 83.13 Distribution & Transport arrangements 83.14 Third Party Contracts 9

4.0 Maintaining the Site Master File 9

5.0 MHRA Further information 9


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1.0 Introduction

A Site Master File (SMF) is a document that the MHRA requests the licence holder orapplicant to provide, that describes the structure of the organisation involved, the site, themanufacturing activities carried out, the facility and premises employed and also detailsof the quality management system in place.

The purpose of the SMF is to provide the Inspector with an introduction to the companyand its activities prior to the inspection taking place and to demonstrate to the Inspectorthat the site is ready for the inspection and has put a basic quality system in place. It alsoserves to be a foundation document for the company onto which other information can beplaced in order to build a holistic picture of how the unit operates. Companies have foundit useful in identifying gaps in their approach to the quality system. The SMF should bedesigned to be easily up-dated as the inspector will require an updated version prior toeach 2 yearly inspection.

This guide describes the core components of a SMF suitable for units holding or applyingfor licences relating to small scale manufacture, eg “Specials” manufacture or Phase 1and Phase 2 investigational medicinal products manufacture.. As each unit will be very different in its structure and activities there will be some partsof this guide, which will be more appropriate than others.

It is important that the content is not limited to just the items recommended in this guidebut that the SMF is inclusive of all relevant details.

2.0 Format

Section three of this guide gives details of the key areas, which should be considered forinclusion in the site master file.

The guide will indicate the usual length of each section by insertion of a box such as theone below. This is only a recommended length and some organisations may require theinclusion of details, which results in much longer sections while others will be muchshorter.Process flow charts and drawings are preferred to long narrative descriptions.The complete SMF should ideally be no more than 25 pages long.

Where a drawing is recommended the guide will indicate this using the followingsymbol.

Approx = 250 words

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Note:

If a SMF has already been submitted to MHRA Inspectors in support of otherManufacturing Authorisations,( eg a Manufacturing Authorisation for licensed medicinalproducts as well as a Manufacturing Authorisation for Investigational MedicinalProducts) then there is no need to provide separate SMFs for each licence held, theinformation can be amalgamated into one SMF if preferred. Generally a SMF relates to aManufacturing site not to a specific licence).

When applying for a Manufacturing Authorisation of any kind, the application formsometimes asks for details relating to the premises, equipment and procedures. In order toavoid duplication, applicants should cross reference the SMF and advise the licencingauthority that the information will be provided in the SMF in a structured format.


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3.0 Site Master File - Suggested sections

3.1 Title pageThis page should display the name of the manufacturing organisation and licence holderif different. The address, telephone number and key contact details should be included.The title page should also indicate the name of the author(s), the date of issue, the versionnumber and the date on which revision is due.

3.2 Copy of the current Manufacturing Authorisation (s)If the organisation already holds a UK manufacturing licence, please provide details ofthe licences held and the licence number. If the organisation is applying for a licence forthe first time this section will not be relevant.

3.3 Details of Products manufacturedIn this section the unit should give details of the products and pharmaceutical dosageforms the unit proposes to make or is currently making. Included should be details of anyother products handled in the same environment, facility or using the same equipment,which could adversely effect the quality of the products being manufactured under themanufacturing authorisation. Specific consideration should be given to the risk ofcontamination and the effectiveness of cleaning procedures.

3.4 Licensed organisation locationA short description of the location of the facility should be given. For example if theorganisation resides on a hospital site,details of the location with in the grounds andsurrounding departments should be given. Alternatively if the organisation is located inan industrial area a short description of the location and surrounding businesses should begiven.

3.5 Licensed Organisation HistoryIn this section the organisation should give a very brief history of how it has evolved.Details of any hospital or business mergers should be included and chronological detailsof when the unit commenced all the activities it now undertakes.

Approx = 250 words

Approx = 250 words

Approx = 250 words


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3.6 Site Drawing and DescriptionIn this section the unit should include a very brief description of the facility includingfinishes of processing areas and clean rooms if relevant. Basic schematic drawings of thevarious areas should be detailed below. Although computer aided diagrams (CAD) aremost useful it is not necessary for the diagrams to be of such a standard as long as theinformation is clear and easily understood.� Production Areas� Storage Areas including delivery and dispatch routes� Quality Control Labs � Office & Administration areas

A site drawing should be provided clearly marking all relevant areas

3.7 PersonnelThis should be a diagrammatic representation of the organisational structure It maybenecessary to include more than one organogram in order to capture all the relevant levelsand departments of the organisation. Job titles along with the names of individualsinvolved in the licensable activity should be included.

Details are required of the number of staff employed in relation to the licensed facility iein production; quality control; quality assurance and storage and distribution.

An Organogram of all the relevant organisational structures is required.

3.8 Responsibilities This section should give details of the qualifications, experience and responsibilities ofeach of the management team and any other key members of staff.There should be clear accountabilities for the various departments eg Manufacturing/Production, Quality Control, Quality Assurance, Batch release, Planning, and Stores.

In some smaller units several responsibilities maybe undertaken by the same person andthis may be satisfactory. However even in small organisations there should be separatenamed individuals responsible for product release and they should be independent fromthose responsible for production activities.

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Approx = 250 words


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3.9 ProductionA brief description of the following should be given:-

� Description or flow diagram for main processes� Equipment used in the process(es). Indicate whether it is dedicated to a particular

product or multi purpose� Batch sizes� Contamination Risks� Final pack presentations� Cleaning – detergents used in the facility and for equipment cleaning� Clothing required in the production areas� Validation policies for:-

Equipment Facility

� Process validation � Calibration and Maintenance of key equipment� GMP related Computerised Systems - including life cycle review

� Water system What specification of water is used in the process if any. Include details about whetherthe system is shared or stand-alone. Give details of how the system is tested andmaintained.

A very simple schematic diagram should be included.

� HVAC systemGive details of any room classifications including clean rooms if relevant. Indicatewhether there are any special precautions taken if handling highly toxic or sensitisingmaterials.Include details of whether the system is recirculated or single pass. Indicate the filterpositions and the air intake and extract positions.Give specific details about how the system is serviced and where access points arelocated. Include details of periodic testing undertaken to demonstrate the system isrunning effectively and any alarm system to indicate system failure.

A very simple schematic diagram should be included .

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Approx = 1000 words


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3.10 Quality Management systemThis section should describe the elements of the Quality Assurance system and explainhow the quality of the products are guaranteed. The following aspects should beincluded:-

� How the quality of starting and packaging materials is assured� General Documentation system ie what is documented and how are documents

controlled and how long they are kept.� Batch records – generation, control and traceability� Written procedures� Analytical results – who reviews them� How are finished product specifications generated� How “Out of Specification” results are handled� Complaints� Deviation reports � Recall procedures� Who takes ultimate responsibility for the quality of the product and its final release.� Self inspection system

3.11 TrainingGive details of how training is undertaken and recorded. Ensure that both core staff andancillary staff are mentioned.

3.12 Quality ControlDescribe what routine chemical or microbiological analysis is performed and describebriefly any laboratories on site . If the laboratories are not on site give the name andaddress of the site where testing takes place.

Explain who has responsibility for reviewing the analytical results and how the resultsaffect the final release of the products.

3.13 Distribution and Transport arrangementsDescribe how products are transported to either the purchasers or end users . Ifrefrigerated systems are used it is important to specifically cover this area in detail.

3.14 Third party Contracts

Approx = 250 words


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Give names and addresses of any other organisation that provides or receives a servicefrom your organisation together with a summary of the service provided eg analytical,manufacturing, packaging, maintenance of equipment etc. This contract work requires theissuing of a technical agreement , which should indicate the specific responsibilities ofeach party. The details of how such agreements are issued reviewed and maintainedshould be included in this section.

4.0 Maintaining the Site Master File

Details should be given on how the organisation plans to ensure that the SMF is revisedon a suitable periodic basis and at least two yearly prior to each MHRA inspection.The organisation should include information on how licence variations and thesubsequent changes will be routed through to the Site Master file.

5.0 MHRA Further information

If you require any further information on the preparation of a Site Master File or anyother GMP related issues please refer in the first instance to the current EU GMPguide.(details are available on the MHRA website www.MHRA.gov.uk

In addition you can contact your specific allocated GMP inspector if known .( see theMHRA website for locations and contact details)

If you need more general help then please write to the GMP InspectorateInspection and Enforcement Division,MHRA, Market Towers1 Nine Elms RoadVauxhallLondonSW8 5NQ

Or e mail us via the information centre at MHRA.- [email protected]

Approx = 250 words

http://www.mhra.gov.uk/

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SMF model