Published: 2014-12-22
Key Benefits:
Passed 17.12.2014 Annex 74
This Regulation is established on the basis of subsection 16 (8) of the Medicinal Products Act.
(1) The rules for manufacture of medicinal products (hereinafter the rules) establishes the general requirements for the manufacture of medicinal products.
(2) In addition to the requirements provided in this Regulation, the requirements established for the European Economic Area in the Good Manufacturing Practice shall be applied to the manufacture of medicinal products.
(3) These rules shall not establish requirements for occupational safety.
For the purposes of these rules, the following definitions shall be used:
1) manufacturing process - for the purposes of these rules, any activity related to the manufacture of medicinal products, including intermediate products;
2) starting material - a substance or material used in the manufacture of medicinal products, except for packaging material;
3) packaging material - material used for the packaging of medicinal products (except for transport packaging), including primary and secondary packaging material, depending on whether the packaging is in direct contact with the medicinal product;
4) intermediate product - a partially processed substance or material which must be subjected to further stages of the manufacturing process before becoming a wholesale product;
5) wholesale product - a product which has completed all stages of the manufacturing process, except for packaging and labelling required for the finished product in its final packaging;
6) validation - a documented activity, which certifies that a procedure, process, device or system ensures the desired result;
7) process-integrated testing - tests conducted in the course of the manufacturing process for continual monitoring and, if necessary, adjustment of the process with the aim of ensuring compliance of the medicinal product with the quality requirements;
8) packaging - any activity, including bottling or filling (except for sterile bottling) and labelling of the wholesale product before it becomes a finished product in its final packaging; in sterile bottling, the filled primary packaging which is not intended to serve as final packaging shall be considered the wholesale product;
9) batch - a quantity of starting material, packaging material or products manufactured in the course of a (combined) manufacturing process or series of manufacturing processes in such a way that it can be considered homogeneous;
10) rules of procedure - description of the activities, precautionary and other measures directly or indirectly related to the manufacture of medicinal products.
(1) An enterprise engaged in the manufacture of medicinal products and the work arrangement within such an enterprise shall comply with the activity licence for manufacture of medicinal products and the requirements stipulated in the Good Manufacturing Practice.
(2) The organisation of the manufacture of medicinal products within an enterprise shall comply with the terms and conditions established for the marketing authorisation. The organisation of the manufacture of investigational medicinal products shall comply with the documentation for authorisation of clinical trials.
(3) An enterprise shall update the medicinal product manufacturing process in accordance with research advances and technological improvements. An application for the amendment of the marketing authorisation or for authorisation of clinical trials shall be filed, if necessary.
An enterprise engaged in the manufacture of medicinal products shall ensure a functional quality system, involving the enterprise's management and staff members of business units.
(1) To achieve the objectives of the quality system, an enterprise engaged in the manufacture of medicinal products shall have an adequate number of employees with the required qualification and practical experience.
(2) The sphere of responsibility of each employee shall be documented and understandable to the employee. The obligations of responsible employees shall be documented in the job description. The positions of responsible employees shall be filled, and unjustifiable duplication of the employees' spheres of responsibility shall be avoided. Relationships of subordination shall be disclosed in the organisational chart. The organisational chart and the job descriptions shall be approved pursuant to internal rules.
(3) Each employee shall be familiar with the Good Manufacturing Practice within his or her sphere of responsibility, complete the introductory training in the sphere of responsibility, and regularly participate in enrichment training. The organisation of training sessions and their productivity shall be monitored.
(4) The enterprise shall establish hygiene programmes that correspond to the manufacturing process and cover procedures related to occupational health, hygiene habits and clothing.
(1) The location, design, structure, adaptation, use and maintenance of rooms and equipment shall correspond to the manufacturing activities and, to the maximum extent possible, prevent defects and damage, contamination or cross-contamination of materials or products, which could be harmful to the quality of medicinal products.
(2) Only authorised employees may have access to rooms and equipment.
(3) The equipment used in the manufacturing process shall be qualified and validated. A cleanliness category shall be designated for the rooms, and compliance therewith regularly monitored.
(1) An enterprise engaged in the manufacture of medicinal products shall prepare and manage a document system covering the quality requirements of materials and products used in the manufacturing process, manufacturing guidelines, rules of procedure, work procedure rules, contracts, protocols and reports. The documents shall be unambiguous, without error, updated and approved pursuant to internal rules.
(2) The documentation shall cover the manufacturing of each batch. Any changes in batch manufacturing shall be tracked in the documentation.
(3) Any changes in the development of investigational medicinal products and the planning of the manufacturing process shall be tracked in the documentation.
(4) Any documents related to the manufacture of the batch shall be preserved for a period of at least one year after the expiry date of the batch, or for a period of at least five years after the release (certification) of the batch, whichever period is longer. The documents on all batches of investigational medicinal products shall be preserved for a period of at least five years after completion or suspension of the clinical trial in which the batch was used. A sponsor or marketing authorisation holder shall ensure preservation of the documents and data required for the application for marketing authorisation, and present the same to the State Agency of Medicines upon demand.
(5) The documentation may be prepared on a hard copy or in electronic, photographic or other form, as long as the data presented therein can be preserved for the specified time period, and data readability is ensured. Where electronic, photographic or other data systems are used instead of written documents, these systems shall be validated. Electronic data shall be duplicated, transferred to another data system or additionally protected against destruction. Any changes in the documentation shall be tracked.
(1) All manufacturing processes shall comply with the previously approved guidelines, rules of procedure, work procedure rules and the Good Manufacturing Practice.
(2) An enterprise shall have access to suitable and operational equipment and means for carrying out process-integrated testing. Any deviation from the requisite process and any errors shall be documented and thoroughly investigated.
(3) An enterprise shall take adequate technical and organisational measures for preventing mix-up and cross-contamination of materials and products. Containers, equipment and rooms shall be labelled or otherwise clearly identified. In case of investigational medicinal products, extra measures shall be taken for the handling of medicinal products during and after blinding.
(4) Prior to the implementation of a new manufacturing process or introduction of fundamental changes in the manufacturing process, the suitability of the new process for ensuring a consistent output with the requisite quality shall be verified. Manufacturing processes affecting the quality of medicinal products shall be re-validated on a regular basis. The validation of processes shall be documented.
(5) The safety features of the packaging of medicinal products may be partially or completely removed only on the following conditions:
1) upon previous verification that the medicinal product is authentic and has not been violated;
2) the safety features are replaced with new features of equivalent safety. Safety features shall be considered equivalent, if they allow to ascertain with equivalent efficiency that the medicinal product is authentic and identical, and to verify the violation of the medicinal product, and are in line with the rules stipulated in Article 54a(2) of Directive 2001/83/EC of the European Parliament and of the Council.
(1) An enterprise engaged in the manufacture of medicinal products shall establish a quality control unit, which is separated from the manufacturing unit. An employee with a suitable qualification shall be responsible for the work of the unit, and shall have access to one or several adequately equipped testing laboratories for investigating and testing the starting material, packaging material, intermediate products and finished products.
(2) In justified cases, including in case of import of materials or products, laboratory services may be outsourced in accordance with the requirements for contract work and the marketing authorisation of the medicinal product. In case of investigational medicinal product, the sponsor of the clinical trial shall ensure compliance of the contract work with the authorisation for clinical trials. No analytical inspections are required in case of import of investigational medicinal products.
(3) Assessment of the finished product prior to release of the batch for marketing or use in clinical trials shall cover the documentation on all relevant factors, including results of analytical inspections and compliance of the finished product with the quality requirements, manufacturing conditions, results of process-integrated testing, manufacturing (including packaging) documentation and inspection of the final packaging.
(4) Samples of batches of finished products shall be preserved for a period of at least one year after the batch expiry date. In case of investigational medicinal products, an adequate quantity of reference standards of wholesale batches and significant packaging materials used for each batch of finished products shall be preserved. Reference standards of investigational medicinal products shall be preserved for a period of at least one year after batch expiry date or for a period of at least two years after completion or suspension of the clinical trial, whichever period is longer.
(5) Reference samples of starting materials used in the manufacturing process (except for solvent, gas and water samples) shall be preserved for a period of at least two years after release of the batch. The period of preservation may be shorter, if the expiry date set forth in the product specification is shorter.
(6) Reference standards and reference samples shall be made available to the State Agency of Medicines. Upon previous coordination with the State Agency of Medicines, other conditions may be established for the reference standards and reference samples of starting materials and certain products, if the medicinal product has been manufactured under a special contract or in small quantities, or if special conditions are required for storage thereof.
(1) A written contract shall be entered into for manufacture, analysis or other related activities performed as a part of contract work.
(2) The contract shall clearly stipulate the parties' liabilities, the contractor's obligation to adhere to the Good Manufacturing Practice, and the procedure according to which the competent person releasing the medicinal product batches fulfils his or her obligations.
(3) A contractor shall not delegate to third parties any work assigned to the contractor under the contract, unless the contracting entity has previously approved the delegation of work in writing.
(4) On the permission of the State Agency of Medicines, manufacture and inspection may be outsourced.
(5) A contractor shall adhere to the Good Manufacturing Practice and allow the exercise of supervision. The State Agency of Medicines shall have the right to inspect the contractor.
(1) An enterprise engaged in the manufacture of medicinal products shall conduct a thorough investigation into any complaints and other information regarding potential defects, and document the investigation in accordance with the rules of procedure. An enterprise shall establish a system for immediate and efficient withdrawal from the market of medicinal products with a known or suspected defect.
(2) The State Agency of Medicines shall be immediately notified of any defects leading to a withdrawal from the market or restriction of marketing. The notice shall describe, inter alia, the known or suspected causes for the defect, and specify the known countries where the medicinal product is still being marketed.
(1) An enterprise engaged in the manufacture of medicinal products shall carry out internal audits with the aim of continually monitoring the implementation of and adherence to the Good Manufacturing Practice and to make suggestions for corrective measures.
(2) The internal audits conducted and corrective measures applied shall be documented.
Ministry of Social Affairs Regulation No 55, 4 April 2005, "Rules for manufacture of medicinal products" shall be repealed.
1Directive 2001/82/EC of the European Parliament and of the Council on the Community code relating to veterinary medicinal products (OJ L 311, 28.11.2001, pp. 1–6); Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use (OJ L 311, 28.11.2001, pp. 67–128); Commission Directive 2003/94/EC laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use (OJ L 262, 14.16.2003, pp. 22–26); Commission Directive 91/412/EEC laying down the principles and guidelines of good manufacturing practice for veterinary medicinal products (OJ L 228, 17.08.1991, pp. 70–73).
Urmas Kruuse
Minister of Health and Labour
Marika Priske
Secretary General
