As a part of regulatory requirements, we prepare numerous documents. Preparing documents shall not be treated as a burden but shall be considered as an activity of creating proofs or evidences that shows one’s true self. There are many types of documents such as policy documents, standard operating procedures, standard testing procedures, specifications etc. But one of the foremost policy documents is Site Master File (SMF).

In this article we shall be discussing in detail about various requirements of SMF and how to draft a regulatory compliant SMF.

What is a Site Master File (SMF)?

SMF is a concise document which contains specific information about the quality management policies and activities being performed at the manufacturing site. It contains information about the infrastructure, surroundings, Good Manufacturing Practices, Organization Structure, Personnel, Utilities etc and any other closely integrated operations. If only part of a pharmaceutical operation is done at the site (for example, testing, packaging), the SMF describes only those operations performed at the site.

How Site Master File is useful for Regulatory Authorities?

SMF having clear information on the manufacturer’s good manufacturing practices (GMP)-related activities, can be useful in general supervision and in the efficient planning and undertaking of GMP inspections. Even Aide-Memoir or inspection checklist includes a check regarding availability of SMF.

All regulators viz. EU, MHRA, WHO, PIC/S, CDSCO etc. requires SMF except USFDA. None of the provisions of CFR requires submission or maintenance of SMF.

What shall be the length of a Site Master File?

Although different regulators have different expectations from a SMF w.r.t. chronology and description. However, in general the contents are similar. As a thumb rule an SMF shall not exceed 25–30 pages plus appendices. Simple plans, outline drawings or schematic layouts are preferred instead of long narratives. The SMF, including appendices, should be readable when printed on A4 paper sheets.

What are the contents of a Site Master File?

The SMF contains 9 chapters as shown below:

Chapter number

 Title

1

 General Information
2

Quality Management

3

 Personnel

4

Premises and Equipment
5

Documentation

6

Production

7

Quality Control
8

Distribution, Complaints, and Product Recall
9

Self-Inspection
  1. General Information:

A. Contact Information:

i. name and official address of the manufacturer: This includes a brief description of the company, relation to other sites, and any information relevant to understanding the manufacturing operations.

ii. names and street addresses of the site, buildings and production units located on the site;

iii. contact information of the manufacturer including 24-hour telephone number of the contact personnel in the case of product defects or recalls; and

iv. identification number of the site as e.g. global positioning system (GPS) details, D-U-N-S (Data Universal Numbering System) number (a unique identification number provided by Dun & Bradstreet) of the site or any other geographical location system

B. Authorized pharmaceutical manufacturing activities of the site:

i. copy of the valid manufacturing license/authorization issued by the relevant competent authority. If the competent authority does not issue manufacturing authorizations, this should be stated. Validity of license/ authorization shall also be stated;

ii. brief description of manufacture, import, export, distribution and other activities as authorized by the relevant competent authorities including foreign authorities with authorized dosage forms/activities, respectively; where not covered by the manufacturing authorization;

iii. type of products currently manufactured on-site: Lists the types of products manufactured at the site and provides information about specific toxic or hazardous substances handled, including their manufacturing. This section provides information on whether the products are manufactured in a dedicated facility or on a campaign basis and states whether both human and veterinary products are manufactured on the site. For contract manufacturing or analytical sites, this section defines whether the firm is the contract giver or acceptor; and

iv. list of GMP inspections of the site within the last five years; including dates and name/country of the competent authority having performed the inspection. A copy of the current GMP certificate or reference to the EudraGMP database should be included, if available

C. Any other manufacturing activities carried out on the site: description of non-pharmaceutical activities on site, if any.

  1. Quality Management:

A. The quality management system of the manufacturer:

i. brief description of the quality management systems run by the company and reference to the standards used;

ii. responsibilities related to the maintaining of the quality system including senior management; and

iii. information on activities for which the site is accredited and certified, including dates and contents of accreditations, and names of accrediting bodies.

B. Release procedure of finished products:

i. detailed description of qualification requirements (education and work experience) of the authorized person(s)/qualified person(s) responsible for batch certification and releasing procedures;

ii. general description of batch certification and releasing procedure;

iii. role of authorized person/qualified person in quarantine and release of finished products and in assessment of compliance with the marketing authorization;

iv. the arrangements between authorized persons/qualified persons when several authorized persons/qualified persons are involved; and

v. statement on whether the control strategy employs process analytical technology (PAT) and/or real-time release or parametric release.

C. Management of suppliers and contractors:

i. a brief summary of the establishment/knowledge of supply chain and the external audit programme;

ii. a brief description of the qualification system of contractors, manufacturers of APIs and other critical materials suppliers;

iii. measures taken to ensure that products manufactured are compliant with transmitting animal spongiform encephalopathy (TSE) guidance;

iv. measures adopted where substandard/spurious/falsely-labelled/falsified/ counterfeit medical products, bulk products (i.e. unpacked tablets), APIs or excipients are suspected or identified;

v. use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis;

vi. list of contract manufacturers and laboratories including the addresses and contact information and flowcharts of supply chains for outsourced manufacturing and QC activities, e.g. sterilization of primary packaging material for aseptic processes, testing of starting raw materials, etc. and

vii. brief overview of the responsibility sharing between the contract giver and acceptor with respect to compliance with the marketing authorization

D. Quality risk management:

i. brief description of quality risk management (QRM) methodologies used by the manufacturer; and

ii. scope and focus of QRM including brief description of any activities which are performed at corporate level, and those which are performed locally. Any application of the QRM system to assess continuity of supply should be mentioned.

E. Product quality reviews: brief description of methodologies used.

3. Personnel:

i. organization chart showing the arrangements for quality management, production and quality control positions/titles including senior management and authorized person(s)/qualified person(s);

ii. number of employees engaged in the quality management, production, quality control, storage and distribution, respectively;

iii. Qualifications, experience, and responsibilities of key personnel;

iv. Training Programme: describing the training need identification, new employee training, regular GMP training, job related skills training, external training, training evaluation, retraining etc.

v. Medical checkup and health requirements: Describe requirements for pre-employment medical examinations and how employees are checked depending on the nature of their work. Describes the system for reporting sickness or contact with sick people before working in a critical area. Provides information on any system of reporting back to work after illness, and the requirements for personnel who work in sterile areas and any additional monitoring to which they may be subjected.

vi. Personnel hygiene and clothing requirements: States the washing, changing, and rest areas and the clothing/growing requirements for the production areas. Gives instruction on how clothing should be used and when it should be changed. Describes gowning room/change room procedures. States the rules on eating, drinking, smoking, and use of chewing gum or tobacco.

4. Premises and equipment:

A. Premises:

i. short description of plant: size of the site and list of buildings. If the production for different markets, i.e. for local country or regional economic areas, takes place in different buildings on the site, the buildings should be listed with destined markets identified;

ii. simple plan or description of manufacturing areas with indication of scale (architectural or engineering drawings are not required). For sterile product area, indicates room and area classification(s) and pressure differentials between adjoining areas of different classifications.;

iii. layouts and flowcharts of the production areas showing the room classification and pressure differentials between adjoining areas and indicating the production activities (i.e. compounding, filling, storage, packaging, etc.) in the rooms;

iv. Nature of construction and finishes: Describes wall construction, nature of finishes, floors, ceiling, doors and windows, lighting, piping, and drainage system(s)

v. layouts of warehouses and storage areas, with special areas for the storage and handling of highly toxic, hazardous and sensitizing materials indicated, if applicable; and

vi. brief description of specific storage conditions if applicable, but not indicated on the layouts.

vii. Brief description of heating, ventilation and air-conditioning (HVAC) systems: principles for defining the air supply, temperature, humidity, pressure differentials and air-change rates, policy of air recirculation (%).

viii. Brief description of water systems: quality references of water produced; and schematic drawings of the systems

ix. Brief description of other relevant utilities such as steam, compressed air, nitrogen, etc.

B. Equipment:

i. Listing of major production and control laboratory equipment with critical pieces of equipment identified should be provided

ii. Cleaning and sanitation: brief description of cleaning and sanitation methods of product contact surfaces (i.e. manual cleaning, automatic clean-in-place, etc.).

iii. Good manufacturing practices critical computerized systems: description of GMP critical computerized systems (excluding equipment specific programmable logic controllers (PLCs)).

iv. Planned preventive maintenance programme

v. Validation, qualification and critical equipment and instruments. Also, their requalification schedule/planner shall be described.

5. Documentation:

i. description of documentation system (i.e. electronic, manual) including person responsible for the preparation, revision, and distribution of documents; and

ii. when documents and records are stored or archived off-site (including pharmacovigilance data, when applicable): list of types of documents/ records; name and address of storage site; and an estimate of time required to retrieve documents from the off-site archive. The firm shall have well defined documentation retention policy.

6. Production:

i. type of products manufactured including: list of dosage forms of both human and veterinary products which are manufactured on the site, list of dosage forms of investigational medicinal products (IMP) manufactured for any clinical trials on the site, and when different from the commercial manufacturing, information on production areas and personnel; toxic or hazardous substances handled (e.g. with high pharmacological activity and/or with sensitizing properties); product types manufactured in a dedicated facility or on a campaign basis, if applicable;

ii. Arrangements for the handling of starting materials, packaging materials, bulk and finished products, including sampling, quarantine, release, and storage: Purchasing procedures and material requisition procedures from stores to manufacturing plant and vice versa, including sampling, quarantine, release, and storage, are all described in this section. Identification of the supplier’s lot number with the company’s lot number is provided, along with sampling plans. Other details to be included are status labeling, issue of materials to manufacture and package, control of weighing, checking methods, and how materials being used for manufacture are identified and confirmed. Information for the control of bulk manufacturing and packing is provided.

iii. Process validation: brief description of general policy for process validation;

iv. Policy for reprocessing or reworking; and

v. Material management and warehousing: arrangements for the handling of starting materials, packaging materials, bulk and finished products including sampling, quarantine, release and storage; and arrangements for the handling of rejected materials and products.

 7. Quality control:

i. description of the QC activities carried out on the site in terms of physical, chemical and microbiological and biological, particularly the procedures for the release of finished products. The information includes procedure for analytical testing, packaging, component testing, and microbiological testing. It shall also briefly explain the arrangements for the preparation, revision, and distribution of documents for specification test methods and release criteria.

8. Distribution, complaints, product defects and recalls:

A. Distribution:

i. types (wholesale licence holders, manufacturing licence holders, etc.) and locations (countries or regional economic areas) of the companies to which the products are shipped from the site;

ii. description of the system used to verify that each customer/recipient is legally entitled to receive medicinal products from the manufacturer;

iii. brief description of the system to ensure appropriate environmental conditions during transit, e.g. temperature monitoring/control;

iv. arrangements for product distribution and methods by which product traceability is maintained; and

v. measures taken to prevent manufacturers’ products entering into the illegal supply chain.

vi. storage of rejected material

B. Complaints, product defects and recalls: brief description of the system for handling complaints, product defects and recalls.

9. Self-inspections:

i. short description of the self-inspection system with focus on criteria used for selection of the areas to be covered during planned inspections, practical arrangements and follow-up activities

What are the various annexures to a Site Master File?

Although number and type of annexures depend on the information provided by the manufacturer in their SMF. However, in general following are the bare minimum annexure which are required to be the part of SMF:

Annexure

 Title

I

Copy of valid manufacturing authorization
II

List of dosage forms manufactured including the International Nonproprietary Names (INN) or common name (as available) of APIs used

III

Copy of valid GMP certificate

IV

 List of contract manufacturers and laboratories including the addresses and contact information, and flowcharts of the supply chains for these outsourced activities
V

Organizational charts

VI

Layouts of production areas including material and personnel flows, general flowcharts of manufacturing processes of each product type (dosage form)

VII

Schematic drawings of water systems
VIII

List of major production and laboratory equipment

What are the formatting requirements of a Site Master File?

  1. The SMF should have an edition number, the date it becomes effective and the date by which it has to be reviewed.
  2. Each page shall be loose and individually numbered.
  3. The format and headings follow those given in the guidance notes.
  4. Wherever possible, simple plans, outline drawings, or schematic layouts are used instead of a narrative. These plans, drawings, or layouts must fit on A4 sheets of paper.
  5. If narrative or page limitations are not included in a section, information may be included in a table, tabular list, or bulleted format.

Reference: Annex 14 of WHO TRS 961 entitled “WHO guidelines for drafting a site master file“