1.

General information

This chapter contains the "data sheet" style description of the company with its

Name,

Postal address

Telephone/fax number and 24 hour contact telephone number.

This information is rounded off with a brief description of the company (no more than 250 words), its
activities, and other sites.

The pharmaceutical licensed manufacturing activities are then set out in accordance with the permit issued
by the competent authority. To this end, the associated products are named together with information on
which manufacturing step (manufacture, packaging, analysis, storage) is carried out in which facility.

Particular attention must be paid when listing toxic and dangerous materials (e.g. antibiotics, hormones,
zytostatics).

Such conditions and/or limitations should be listed in the permit certificate.

Non-pharmaceutical products (such as cosmetics, dietary supplements, reagents) must also be listed.

Details on professional and technical support are also required, as well as information regarding the extent to
which scientific, analytical or other technical support from a third party company is used during manufacture
or analysis. The contractual partners must be listed with their name/address and telephone/ fax number.

Finally, a short description of the quality management system (see chapter 1 Pharmaceutical Quality
System (PQS)) is required, which includes the firm's Quality Policy, the responsibility of Quality Assurance,
the organizational structure, responsibilities, procedures and processes of the quality assurance system, audit
programs, description of how the results are reviewed to insure quality, efficacy and safety of products, list
of standards used (e.g., ISO 9001-9004), assessment of suppliers and a description of the finished product
release for sale procedure.
 2. Personnel

The requirements concerning "personnel" (see chapter 2 Personnel) start with organization charts, which
identify only senior managers and supervisors, and illustrate the areas of production, quality control and
quality assurance.

An overview of quantitative data regarding the staff employed in the areas of purchasing, production,
engineering, quality control/assurance and storage/distribution must be provided. Both full-time and part-
time staff must be included in this overview.

The data provided includes descriptions of academic and work related qualifications, years of experience
and responsibilities for key personnel and details of the basic and in-service training programs (see chapter
2.C Training). This category covers the relevant heads of department and other persons charged with an
activity/responsibility listed in Article 22 of Directive 75/319/EEC (e.g. "qualified person").

The following information is required for the training program.

Responsibilities for identification of training needs

GMP training requirements

Type of training (e.g., internal, external) and how practical experience is acquired and
who is responsible

Assessment of training efficacy

Identification of retraining needs

Maintenance of records

In addition, information on personnel hygiene (see chapter 11.B Personnel hygiene) is required, e.g.
availability of suitable washing, changing and rest areas, suitability of clothing for the activity, availability
of instructions on the proper use of protective clothing and when it should be changed, and use of internal or
external laundries. This information must be completed with a brief description of the medical examination
programs for staff and of the measures in place to guarantee that staff members who are ill do not present a
contamination risk for the medicinal products.
 3. Premises and equipment

Layout plans are a major part of this chapter in the site master file. The layout plans should be in the DIN A4
format and be larger than this in exceptional cases only. If necessary, the plans can be enhanced with a
description of the direct surroundings of the company (e.g. industrial estates in the direct vicinity).

The following plans are required.

Premises

(See chapter 3 Premises.)

Site plan of buildings with information on the various manufacturing areas (e.g. goods
receiving areas, production areas, storage/distribution areas, office areas). These
diagrams must show where pharmaceutical or non-pharmaceutical areas are located.

A simple labeled plan of each of the manufacturing areas with an indication of scale.
These diagrams must provide the various premises with a clear identification which
also enables cross-referencing to information supplied at a later stage (e.g. room
numbers).

In clean room areas, a diagram is required for each room. The diagram should include
information on the respective classification, pressure differential, number of air
exchanges and direction of airflow and summary of the most recent
qualification/requalification results.

Nature of Construction and Finishes

The information should be limited to no more than 500 words or two A4 pages. For this category, a narrative
format is preferred.

Information on and a description of the room (with cross reference to layout diagrams)

Description of the construction and nature of the floors, walls and ceilings and other
material surfaces. For a large complex plant, only critical areas should be described

Details should be provided on the operations which are carried out in these rooms
including critical storage areas

Ventilation System

The following information is required for the ventilation system. Expanded details should be provided for
critical areas with the potential risk for airborne contamination. The use of schematic drawings is preferred.
The information should also be limited to no more than 500 words or two A4 pages.

Description of the design criteria (e.g., system capacity, temperature, humidity,

pressure differentials, air exchange rate) (see chapter 3.G Heating Ventilation Air
Conditioning (HVAC))

A diagram showing the different premises and the air systems which supply these
areas,

Filter design, efficiency and change schedule

Details of alarms on the system

 The point where dioctylphthalate (DOP), if used, is introduced

Frequency of revalidation of the system

Summary of the most recent qualification/requalification results for sterile product

areas

Handling of Highly Toxic Hazardous and Sensitizing Materials

For the handling of toxic and hazardous substances, information similar to that
requested for Premises above should be provided

Water System

For water systems a schematic drawing is preferred with a brief description (maximum of 500 words on two
A4 pages). The information required includes:

Tracking of the system to the city supply

Capacity of the system (e.g., liters/hour)

Description of the materials used in the system and pipes,

Identification of filters in the system and their specifications,

Temperature at the point of return for stored and circulated water,

Specifications for chemical, conductivity and microbiological quality,

Location of the sampling points and frequency of testing,

Description of the procedure and frequency of sanitation.

Maintenance

For the maintenance of the premises, it is assumed that maintenance activities are performed by the
manufacturer while the servicing of the premises is contracted to a third party. Further requirements include:

Description of the preventive maintenance program

Availability of written procedures and reporting process for maintenance and servicing,
which captures frequency and details of service, repairs and modifications

Assessment of the maintenance routines for potential impact to product quality

Availability of maintenance reports to the user

Equipment
Manufacturing and Control Laboratory Equipment

The make and model numbers of the manufacturing equipment are not required. The following information
should be included.

Description of the materials used in the construction of machinery and demonstrate

that they are appropriate for the intended use
 Description of any work done to validate other materials, such as polypropylene,
chrome-plated brass and PVC.

Verification that the equipment was designed to facilitate ease of cleaning

General description of the manufacturing equipment but include details about any add
on devices present

General description of the quality control laboratory and microbiological equipment,

such as pH meters, HPLC, incubators and facilities for LAL testing

Brief details of the use of computers and microprocessors

Maintenance

(See chapter 4.H Maintenance)

Identification of who is responsible for equipment maintenance and servicing

Demonstration that written procedures and contracts for outside work exist

Clear identification of maintenance procedures which could impact product quality

Maintenance of records of type and frequency of service work and details of service
repairs and modifications

Demonstration that reports of work performed on equipment are available to the users.

Qualification, Validation and Calibration

The information should be limited to a maximum of 750 words and three A4 pages.

Description of the company's qualification and validation policies

Description of protocols for prospective and retrospective validation

Providing the program for revalidation of critical equipment

Outlining the process validation program

Description of the procedure for the release for sale or supply of development and
validation batches

Explanation of how computer and software validation is managed

Description of the equipment calibration policy and the maintenance of records

Sanitation

(Maximum of 250 words on one A4 page)

Availability of written specifications and procedures for cleaning, which includes the
cleaning agents and their concentration for the method of cleaning and the frequency

Description of the policy for rotating or changing cleaning agents periodically

 Providing the validation of the cleaning procedures and the evaluation of the
effectiveness of cleaning

Description of the routine monitoring of cleaning methods by chemical and

microbiological methods

Explanation of the cleaning methods and frequency for the water supply system, air
handling system and dust extraction system.
 4. Documentation

(See chapter 15.C Batch documentation.)

First, a brief description is needed, which shows how the required documentation for the areas of
manufacture, packaging and quality control including batch production formulas, instructions, records and
specifications must be compiled, reviewed and distributed; and who is responsible for these activities. Also
required is the identification of the location, where the master documents are stored, availability of
instructions and format for the preparation of documents and evidence of the existence of documents for
various processes (product, process, and raw materials specifications, batch records, packaging records,
analytical methods, QA release procedures), description of the control of the documentation, and process for
retention and archiving. The existence of other documents is shown (e,g., equipment specifications,
specifications for disposables, sops, training procedures, computer program specifications, document control
of process deviations, calibration and test documents, validation documents, reconciliation of batches of raw
materials and components, and any other documents that are used routinely.

Figure 15.E-2 Reference matrix for procedures or operating procedures

Reference matrix for procedures or operating procedures

Operating procedure(s)
Section in the
Topic to be regulated
EU GMP Guideline
of the company

Self-inspection 1.2ix

Sampling (procedure) 4.22, 6.11, appendix 8

Environmental monitoring 1.4, 4.26, 6.9

(Personnel) hygiene 2.13, 4.26

Cleaning of rooms 3.2, 4.26

Cleaning of equipment 3.2, 4.26 (5.19)

Cleaning/disinfection of water piping 3.43

Incoming goods procedure 4.19, 5.2

Quarantine, storage area 4.21, 5.2

Approval of finished products 1.4, 4.24, 5.58

Measures to combat vermin 4.26

Validation 4.26, 5.21

Processing/recovering materials 4.26, 5.65

Complaints 4.26, 6.2, 7.13, 8.2

Recalls 4.26, 7.13, 8.9

Preparation of starting materials 5.32

Returning of unused starting materials/packaging 5.2, 5.57

materials

Reworking of unsuitable products 5.62

Re-using previous batches in a current batch 5.63

Stability program for finished products 6.2

Retained sample 6.2

Handling of narcotic substances National

requirements

The site master file must pay specific attention to areas where computer systems (see chapter 9 Computer
Validation) are used to produce documentation.

These systems should be described as follows:

Hardware data

Information on the most important software packets (developed in-house/purchased

externally)

Number of screens/terminals

Date the computer system was validated

In the overview table (see

Figure 15.E-2) under the various themes of the EU GMP Guideline, the company's internal procedures or the
operating instructions upon which they are based (see chapter 15.D Standard operating procedures
(SOPs))must be listed.
 5. Production

(See chapter 11 Production and chapter 12 Sterile Production.)

This section of the site master file requires first and foremost flow charts for the most important
manufacturing processes (e.g. capsule filling, wet granulation, direct compression, manufacture of liquids).

If only packaging is performed, a brief description should be provided. Also, the procedures for the
identification of products during production and the storage of in-process materials are described. Flow
charts and details are required for any zytotoxic or radioactive medicinal products that are manufactured.

Furthermore, the various production stages must be shown and the respective area of responsibility and
place of implementation given in an overview list.

Information on the following production stages is expected:

Receipt of goods and correlation of the supplier's lot number with the company's lot
number

Sampling plans

Labeling as to status (use of labels or by electronic means)

Materials issue

Control of weighing

Methods

Release and identification of materials used in manufacture

Manufacturing

o Key parameter checks and records

o In-process checks and records

o Compliance with the regulatory filing

Packaging

o Bulk, semi-finished and packaging materials release

o Identity and line clearance

o In-process checks

Quarantining (finished product)

Storage, distribution (finished product)

Role of the Qualified Person

The procedures for reprocessing or reworking batches are described along with the procedures for labeling
and isolating rejected materials and products and assigning final disposition and destruction.

A brief description of the process validation policy is provided (see chapter 7 Process Validation).
 6. Quality control

(See chapter 14 Laboratory Controls.)

This chapter contains a brief description of the quality control activities including preparation of
specifications, methods, data collection and analytical testing (e.g. HPLC assay and impurities/degradation
products determinations, component and microbiological testing).

Information is provided on the review of batch records (see chapter 14.J Batch release) and release of final
documentation. The name of the person authorized to approve the batch as well as his/her deputy is
included.

The process for the preparation, revision and distribution of documents (e.g., specification test methods,
release criteria) is described.
 7. Contract manufacturing and analysis

(See chapter 17 Contractors and Suppliers.)

In this section, the guidance states to "describe briefly the details of the technical contract between the
contract giver and the acceptor and the way in which the GMP compliance is assessed to ensure product
compliance with the Marketing Authorization". This chapter of the site master file begins with a list of the
manufacturing operations assigned for the suborder.

Based on the description above, information which should be provided include:

Contract acceptor (name, address, telephone/fax number)

o "The products manufactured under the manufacturing contract

Listing of each manufacturing operation

Current contract date

Frequency at which the contract acceptor is inspected and the process used to assess
compliance with GMPs and with the marketing authorization

If the company itself will carry out the manufacture as a contract manufacturer then the following should be
provided:

Contract provider (name, address, telephone/fax number)

Details of the products manufactured

Type of manufacturing operations carried out

Current contract date

Analytical testing that is assigned to third parties must be described in the following terms:

The products analyzed in the manufacturing contract

Details of analytical testing

Current contract date

Frequency at which the contract acceptor is inspected and process used to assess
compliance with GMPs and with the marketing authorization

If the company will also function as a contract acceptor for this testing, the following information must be
provided:

Contract provider (name, address, telephone/fax number)

Details on the products tested

Type of analyzes carried out.

Current contract date

If relevant, this chapter can conclude with a list of further activities which are either assigned to third parties
or are carried out by the company itself as the contract acceptor.
 8. Distribution, complaints and product recall

Two areas are covered in this section, "Arrangements and recording system for distribution" and
"Arrangements for the handling of complaints and product recalls".

For distribution, a description of the storage and distribution practices at the company should be described.
Areas of importance include:

Security of the warehouse

Environmental controls

Availability of refrigerated storage

Storage of materials (e.g., palleting)

Control of materials status (manual, computer)

Methods of distribution

Order of distribution (e.g., first in/first out)

Lot order identification on dispatch order

For the handling of complaints and recalls, distribution records should include full batch traceability to assist
in complaint resolution and product recalls. These include:

Date of sale

Customer details (names of wholesalers, chemists/pharmacies, hospitals, exporters)

Quantity dispatched

Another important piece of data that should be included is batch number.

Additionally, for complaints the following information should be provided:

Availability of a written complaints procedure

Responsibility for logging, classifying and investigating complaints

Availability of written reports

Responsibility for review of the written reports

Retention period for complaint records

For product recalls:

Availability of written procedure for

o Retrieval of distribution data

o Customer notification
 o Receipt, segregation and inspection of returned product

o Conductance of an investigation and assigning cause

o Determining corrective action

Responsibility for coordinating product recalls

Notification of Competent Authority

Involvement of Competent Authority

Opportunity to effect recalls below the wholesale level

This brief description for recalls should also address the possible extension to other batches/products.

Finally, an overview of the products recalled for GMP reasons should be prepared with the following
information:

Name of product

Batch number

Reason for recall

Time of recall

Observations which led to the recall

 9. Self-inspection

(See chapter 18.E Self-inspection.)

The systems under which self-inspections are carried out in the company are briefly described.

The self inspection system should:

Insure that the system is effective

Provide for the existence of written procedures for the self inspections and for follow up
actions

Have provisions to inform the responsible persons about the results of the inspection

Insure that timely corrective actions are put in place to address the noted deficiencies

Furthermore, the following information should also be available:

A list of self-inspections conducted including subjects and times of the inspections

Details on inspections carried out by the national authorities including name of the
inspector(s) and the reason for the inspection

Details of inspections conducted by international authorities including name of the

authority and reason for the inspection

10.Appendix

A list of all medicinal products manufactured in the company is expected in the form of an appendix. The
following structure should be used for this:

Sterile products

Non-sterile products

Biological products

Special products (e.g. toxic products or products which cause skin irritations)

Products which are packed only

Products which are manufactured in the order

Products which are analyzed in the order

Clinical test preparations

Other products (e.g. animal drug products, cosmetics)