MHRA Inspectorate and Enforcement Division

Site Master File

Site Master File Model

For Manufacturing “Specials” Licence holders or

applicants for Manufacturing Authorisations relating to
small-scale activities, including investigational medicinal
products

Issued By
Inspectorate and Enforcement division
MHRA
1 Nine Elms Road
Vauxhall
London
SW8 5NQ

Issued March 2004

MHRA Guidance Note 30

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Table of Contents
Item Page

1.0 Introduction 3

2.0 Format 3

3.0 Site Master File - Suggested sections

3.1 Title page 5
3.2 Copy of the current Manufacturing Authorisation(s) 5
3.3 Details of Products manufactured 5
3.4 Licensed organisation location 5
3.5 Licensed Organisation History 3
3.6 Site Drawing & Description 6
3.7 Personnel 6
3.8 Responsibilities 6
3.9 Production 7
3.10 Quality Management system 8
3.11 Training 8
3.12 Quality Control 8
3.13 Distribution & Transport arrangements 8
3.14 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 or
applicant to provide, that describes the structure of the organisation involved, the site, the
manufacturing activities carried out, the facility and premises employed and also details
of the quality management system in place.

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

This guide describes the core components of a SMF suitable for units holding or applying
for licences relating to small scale manufacture, eg “Specials” manufacture or Phase 1
and Phase 2 investigational medicinal products manufacture.
.
As each unit will be very different in its structure and activities there will be some parts
of 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 guide
but 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 for
inclusion in the site master file.

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

Approx = 250 words

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

D
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Note:

If a SMF has already been submitted to MHRA Inspectors in support of other

Manufacturing Authorisations,( eg a Manufacturing Authorisation for licensed medicinal
products as well as a Manufacturing Authorisation for Investigational Medicinal
Products) then there is no need to provide separate SMFs for each licence held, the
information can be amalgamated into one SMF if preferred. Generally a SMF relates to a
Manufacturing site not to a specific licence).

When applying for a Manufacturing Authorisation of any kind, the application form
sometimes asks for details relating to the premises, equipment and procedures. In order to
avoid duplication, applicants should cross reference the SMF and advise the licencing
authority 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 page

This page should display the name of the manufacturing organisation and licence holder
if 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 version
number 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 of
the licences held and the licence number. If the organisation is applying for a licence for
the first time this section will not be relevant.

3.3 Details of Products manufactured

In this section the unit should give details of the products and pharmaceutical dosage
forms the unit proposes to make or is currently making. Included should be details of any
other products handled in the same environment, facility or using the same equipment,
which could adversely effect the quality of the products being manufactured under the
manufacturing authorisation. Specific consideration should be given to the risk of
contamination and the effectiveness of cleaning procedures.
Approx = 250 words

3.4 Licensed organisation location

A short description of the location of the facility should be given. For example if the
organisation resides on a hospital site,details of the location with in the grounds and
surrounding departments should be given. Alternatively if the organisation is located in
an industrial area a short description of the location and surrounding businesses should be
given.
Approx = 250 words

3.5 Licensed Organisation History

In 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 details
of when the unit commenced all the activities it now undertakes.

Approx = 250 words

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3.6 Site Drawing and Description

In this section the unit should include a very brief description of the facility including
finishes of processing areas and clean rooms if relevant. Basic schematic drawings of the
various areas should be detailed below. Although computer aided diagrams (CAD) are
most useful it is not necessary for the diagrams to be of such a standard as long as the
information 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

D

3.7 Personnel
This should be a diagrammatic representation of the organisational structure It maybe
necessary to include more than one organogram in order to capture all the relevant levels
and departments of the organisation. Job titles along with the names of individuals
involved in the licensable activity should be included.

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

D An Organogram of all the relevant organisational structures is required.

3.8 Responsibilities
This section should give details of the qualifications, experience and responsibilities of
each 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 and
this may be satisfactory. However even in small organisations there should be separate
named individuals responsible for product release and they should be independent from
those responsible for production activities.
Approx = 250 words

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3.9 Production
A 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 whether
the system is shared or stand-alone. Give details of how the system is tested and
maintained.

A very simple schematic diagram should be included.

D

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

A very simple schematic diagram should be included .

D

Approx = 1000 words

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3.10 Quality Management system
This section should describe the elements of the Quality Assurance system and explain
how the quality of the products are guaranteed. The following aspects should be
included:-

· 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 Training
Give details of how training is undertaken and recorded. Ensure that both core staff and
ancillary staff are mentioned.

3.12 Quality Control

Describe what routine chemical or microbiological analysis is performed and describe
briefly any laboratories on site . If the laboratories are not on site give the name and
address of the site where testing takes place.

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

3.13 Distribution and Transport arrangements

Describe how products are transported to either the purchasers or end users . If
refrigerated systems are used it is important to specifically cover this area in detail.

Approx = 250 words

3.14Third party Contracts

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Give names and addresses of any other organisation that provides or receives a service
from your organisation together with a summary of the service provided eg analytical,
manufacturing, packaging, maintenance of equipment etc. This contract work requires the
issuing of a technical agreement , which should indicate the specific responsibilities of
each party. The details of how such agreements are issued reviewed and maintained
should be included in this section.
Approx = 250 words

4.0 Maintaining the Site Master File

Details should be given on how the organisation plans to ensure that the SMF is revised
on a suitable periodic basis and at least two yearly prior to each MHRA inspection.
The organisation should include information on how licence variations and the
subsequent 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 any
other GMP related issues please refer in the first instance to the current EU GMP
guide.(details are available on the MHRA website
www.MHRA.gov.uk

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

If you need more general help then please write to the GMP Inspectorate
Inspection and Enforcement Division,
MHRA,
Market Towers
1 Nine Elms Road
Vauxhall
London
SW8 5NQ

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

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