Site master file

 

15.E.1 Introduction

The site master file provides a general company description with regard to the implementation of valid GMP Guidelines within this company. The contents of each chapter are aligned with the associated chapters of the EU GMP Guideline.

Article 2 of the agreement for mutually recognised inspections (PIC) concerning the manufacture of pharmaceutical products states the following: If a pharmaceutical product is to be introduced into a contracting state which is different to the contracting state in which it was manufactured, the authorities in the country of manufacture can issue information in the form of a report to the country in which the product will be introduced.

This report comprises three sections.

• Information from the inspector (observations made during the inspection)
• Summarised information and conclusions from the inspector (general impression, evaluation of GMP status, listing of GMP deficiencies and deadlines for their rectification)
• Company description compiled by the company with a list of the dosage forms and other products manufactured in the company (= site master file)

The site master file has its counterpart in the form of the Plant Master File.

15.E.2 Design

Format and structuring points of a site master file are set out in the European Commission document entitled "Harmonisation of Inspections in the EU - A format for a European Site Master File, 3^rd Draft". In terms of its structure, this document is identical to PIC document PH 4/93 ("Explanatory Notes for Industry on the Preparation of a Site Master File to be Part of the Information requested under Article 2 of the Pharmaceutical Inspection Convention").

The information required should not exceed a quantity of 25 to 30 DIN A4 pages in total; this information and further details on the maximum number of pages for each chapter is contained in the PIC document.

The site master file should be updated at regular intervals (every two years). Each of the individually numbered DIN A4 pages should have an issue number (version) and bear the date of its implementation. Each of the nine chapters must begin on a new sheet, so that the contents can be updated and the relevant pages replaced. Figure 15.E-1 contains an overview of the chapters in the site master file.

Each chapter is described in more detail in the following text.

15.E.2.1 General information

This chapter contains the "data sheet" style description of the company with its name, postal address and telephone/fax number. This information is rounded off with a brief illustration/description of the company, e.g. details on areas of research and development, number of employees world-wide, production, research and development locations world-wide.

The pharmaceutical (human/veterinary) 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.

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

15.E.2.2 Personnel

The requirements concerning "personnel" (see chapter 2 Personnel) start with organisation charts which should 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.

Key personnel must be mentioned in a further list together with their role, their professional experience and their 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").

A brief description of the quality management system (see chapter 1 Quality Management) is required in this chapter as much as the description of the annual training program (seechapter 2.C Training).

The following information is required for the latter.

• Scope of the initial training and of the continued training sessions
• Number of trained employees
• Time required for the training
• Information as to whether or not the training measures are carried out internally or externally

In addition, information on personnel hygiene (see chapter 11.B Personnel hygiene) is required - e.g. gowning procedures such as shoes, lab coat, overalls, gloves, head covering in individual hygienic areas (manufacturing area for sterile/non-sterile dosage form, packaging, quality controls). 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 who are ill do not present a contamination risk for the medicinal products.

15.E.2.3 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 A 4 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 each required.

• Site plan of the company with a general illustration of the manufacturing areas.
• Diagrams 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 localised.
• The level of detail will then be increased in the next type of diagram. Diagrams for each building and each floor are required. These diagrams must provide the various premises with a clear identification code 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. In addition, these diagrams must be provided with information on the respective pressure differential, number of air exchanges and direction of airflow.
• Finally, diagrams for personnel, material and product flows must also be added to the site master file. A visual differentiation (by using different coloured arrows, for example) between starting materials, packaging material, bulk, intermediate products and final products is expected in these diagrams. Entrance areas for personnel as well as personnel locks must also be clearly identified in the diagrams.

Furthermore, additional information on the manufacturing and packaging areas must also be provided. This information is segregated according to the dosage forms and shall comprise the number of rooms used for manufacture and packaging as well as their total area.

Information is also required in the following areas:

Premises

(See chapter 3 Premises.)

• Information on and a description of the room (with cross reference to the aforementioned layout diagrams)
• Description of the material surface areas
• Details on the operations which are carried out in these rooms
• Details of the ventilation system used to supply air to this room

This overview must be produced for each building

This information must be refined for clean rooms. Information on the construction/nature of the floors, walls and ceilings must be supplemented in this section.

Air systems

(See chapter 3.H Heating Ventilation Air Conditioning (HVAC).)

A diagram showing the different premises and the air systems which supply these areas is required. The following information is required for each air system:

• The system's capacity (m³/h) including data on the proportion of fresh air (%)
• The number of air exchanges per hour
• The number of rooms supplied by the system

Additional information for clean rooms

• Pressure differential
• Room class

For the handling of toxic and hazardous substances, a brief description of the special measures in place for the handling of these product groups is required.

Water systems

• Number of points of withdrawal
• Capacity of system
• Intervals for analytical assessment of water quality
• Intervals for sanitisation
• Material used

This information must be categorised depending on the water type (drinking water, purified water, water for injection).

Manufacturing and packaging equipment

• Location where the equipment is assembled (with cross references to the layout diagrams)
• Equipment designation
• Equipment capacity data
• Installation year

Equipment in quality control areas

• Location where the equipment is assembled (with cross references to the layout diagrams)
• Equipment designation
• Installation year

Maintenance/servicing and calibration

(See chapter 4.H Maintenance.)

• The department responsible for the respective maintenance/servicing program
• The department responsible for the respective calibration program
• Documentation for the planned activities

This information will be separated according to buildings/premises, manufacturing/packaging equipment and quality control equipment

15.E.2.4 Documentation

(See chapter 15.C Batch documentation.)

Firstly. a brief description is required which shows how the required documentation for the areas of manufacture, packaging and quality controls including batch production formulas, instructions and records in addition to specifications must be compiled, reviewed and distributed.

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 must 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 following 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.

15.E.2.5 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).

These flow charts must be provided in the event of the manufacture of zytotoxic or radioactive medicinal products or for the handling of living organisms with special information for the handling of the associated process/products.

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 (starting material, packaging material)
• Sampling (starting material, packaging material)
• Quarantining (starting material, packaging material)
• Initial weight (starting material)
• Manufacture, packaging
• Quarantining (finished product)
• Storage, distribution (finished product)

Information on the quality of the batch produced must be provided in a further overview (see chapter 15.F Annual product review). Data on non-suitable, reworked and rejected batches from the previous year must be listed in this overview. This information must be categorised with regard to the respective starting material, packaging material, bulk and finished product batches.

This chapter concludes with information on the subject of validation (see chapter 7 Process Validation). The corresponding validation documentation (with reference to the number of the validation report, date of report) must be listed.

15.E.2.6 Quality control

(See chapter 14 Laboratory and Analytical Controls.)

This chapter must contain a brief description of the quality control system including the implementation of the in-process controls and details on methods used (e.g. HPLC, microbiological testing).

Further information is also required for the various product categories (starting materials, packaging material, bulk, finished products) in order to organise the batch approval (see chapter 14.J Batch release). The name of the person authorised to approve the batch as well as their deputy should be given.

15.E.2.7 Contract manufacturing and contract qualitiy control

(See chapter 17 Contract Manufacturing and Analysis.)

This chapter of the site master file begins with a list of the manufacturing operations assigned for the suborder.

The following information is required for each contract acceptor:

• the products manufactured under the manufacturing contract
• listing each manufacturing operation
• Current contract date
• Frequency at which the contract acceptor is inspected

The following data is required if the company itself will carry out the manufacture as a contract manufacturer:

• 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 analysed in the manufacturing contract
• details of analytical testing
• Current contract date
• Frequency at which the contract acceptor is inspected

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 analyses carried out.
• Current contract date

If relevant, this chapter will 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.

15.E.2.8 Distribution, complaints and product recalls

If a company distributes products itself, the sales channels must be described in more detail in this section.

They must be described by identifying the following sales channels where relevant:

• Wholesalers
• Chemists
• Hospitals
• Export companies

In the next section of this chapter, the description of the processes for handling complaints and implementing product recalls is required.

This brief description must be able to answer the following questions:

• How are product recalls handled in the company?
• How and on which basis are decisions taken, and who takes them?
• How can it be guaranteed that possible effects on other batches/products are also considered when taking a decision or introducing measures?

Finally, an overview of the products recalled for GMP reasons is required, with the following information:

• Name of product
• Batch number
• Reason for recall
• Time of recall
• Observations which led to the recall

15.E.2.9 Self-inspection

(See chapter 18.E Self-inspection.)

The system under which self-inspections are carried out in the company must be briefly described here.

Furthermore, the following information must also be provided:

• 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

15.E.2.10 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 analysed in the order
• Clinical test preparations
• Other products (e.g. animal drug products, cosmetics)