The adoption of the order is related to the changes that have taken place in the legislation regulating the circulation of medicinal products in the European Union.

Instruction ST-N of the Ministry of Health 42‑4.0:2015 “Medical products. Proper production practice”, which was approved by the order of the Ministry of Health of Ukraine “On Amendments to the Order of the Ministry of Health of Ukraine dated February 16, 2009 No. 95” dated July 30, 2015 No. 478 (hereinafter – the order).

The adoption of the order is related to the changes that have taken place in the legislation regulating the circulation of medicinal products in the European Union, namely the entry into force of some sections of the document “The Rules Governing Medicinal Products in the European Union. Volume 4. EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use.”

This instruction replaces Instruction ST-N MOZU 42-4.0:2014 “Medical products. Good Manufacturing Practice”. To the Instruction ST-N of the Ministry of Health 42‑4.0:2015 “Medical products. Good Manufacturing Practice” has been amended:

 – Section 3 “Premises and Equipment” (“Premises and Equipment”) of Part I, which has been implemented in the European Union since March 1, 2015. In Section 3, Clause 3.6 has been updated in order to improve measures to prevent cross-contamination, which also concerns Section 5 of Part I;

 – Chapter 5 “Production” (“Technological Process”) of Part I, which came into force in the European Union on March 1, 2015. In Chapter 5, paragraphs 17-21 were amended, including the addition of a new paragraph, to improve the guidance on prevention cross-contamination, as well as regarding toxicological assessment. Amendments have also been made to paragraphs 27-30, including the addition of a new paragraph, regarding the qualifications of suppliers to reflect the statutory obligations of manufacturing license holders to ensure that active substances are manufactured in accordance with GMP. Changes include supply chain traceability. Clauses 35 and 36 are added to clarify and align manufacturers’ expectations regarding testing of raw materials, while clause 71 introduces a requirement to notify supply restrictions;

– Chapter 6 “Quality Control” (“Quality Control”) of Part I, which entered into force in the European Union on October 1, 2014. The main reasons for making changes in Chapter 6 are related to the introduction of a new subsection on the technical transfer of test methods and other aspects such as results outside the limits set in the specification;

– Section 8 “Complaints, Quality Defects and Product Recalls” of Part I, which came into effect in the European Union on March 1, 2015. Significant changes were made to Section 8; it now clarifies in depth and detail that the principles of quality risk management should be applied when investigating quality defects or complaints, and when deciding on product recalls or other risk mitigation actions. It emphasizes the need to investigate and determine the cause(s) of quality defects or complaints, as well as the use of preventive measures to protect against the recurrence of such cases; section 8 specifies expectations and obligations regarding notification of quality defects to competent authorities. In fact, section 8 has been completely updated;

– Part II “Basic Requirements for Active Substances used as Starting Materials” (“Basic Requirements for Active Substances used as Starting Materials”), which, with changes, entered into force in the European Union on September 1, 2014. Subsection 1.2 was revised to take into account the revision of the various annexes to the EU GMP Directive has been completed and due to the fact that the provisions of Part I can no longer apply to active substances used as raw materials. Moreover, in subsection 1.2, a clarification of the relationship between section 17 of part II of the EU GMP Directive and the following rules on good practice for the distribution of active substances for medicinal products for human use was added. A new clause 2.19 has been introduced regarding the development and implementation of a quality system, which includes good manufacturing practice, quality control and quality risk management, and additionally subsection 2.2 “Quality Risk Management” has been introduced. In point 2.21, a relevant reference to Part III of the EU GMP Guidelines was given.

Thus, in comparison with the previous version, the following changes were made to the Instruction ST-N of the MoZU 42‑4.0:2015:

– section 3 “Premises and equipment” of part 1 of the Guidelines ST-N MOZU 42-4.0:2015 was harmonized with the updated section 3 “Premises and Equipment” of part I of the EC GMP Guidelines;

– section 5 “Technological process” of part 1 of the Guidelines ST-N MOZU 42-4.0:2015 was harmonized with the updated section 5 “Production” of part I of the EC GMP Guidelines;

– Section 6 “Quality Control” of Part 1 of the Guidelines ST-N MOZU 42‑4.0:2015 was harmonized with the updated Section 6 “Quality Control” of Part I of the EC GMP Guidelines;

– Section 8 “Complaints, Quality Defects and Product Recalls” of Part 1 of the Instructions ST-N MOZU 42‑4.0:2015 was harmonized with the updated Section 8 “Complaints, Quality Defects and Product Recalls” of Part I of the EC GMP Guidelines.

– part 2 “Basic requirements for active substances used as starting materials” of this instruction takes into account the changes that were made to part II “Basic Requirements for ActiveSubstances used as Starting Materials” of the EC GMP Guidelines approved on August 13, 2014 relative to the previous version part II, approved on October 3, 2005;

– in the section “Regulatory references” an additional bibliographic description of two draft guidelines of the European Commission “Guidelines on the formalized risk assessment for ascertaining the appropriate Good Manufacturing Practice for recipients of medicinal products for human use” and “Guidelines on the principles of Good Distribution Practices for active substances for medicinal products forhuman use”, which are referenced in the updated sections of part 1 (clause 5.29) and part 2 (clause 1.2), respectively.

Some editorial changes and additions have been made to the updated sections of this guideline relative to the relevant sections of the EU GMP Guidelines, due to legal requirements adopted by harmonized regulatory documents and specific needs of the pharmaceutical industry of Ukraine. These changes and additions are listed and explained in the national annex “List of editorial changes and additions” to this guideline.

Previous editorial changes, additions and technical deviations in relation to the EC GMP Guideline concerning other sections, parts and annexes are also listed in the national annex “List of editorial changes and additions” to this guide. They are generally explained in the “National introduction” section of the previous versions of this normative document – Guidelines ST-N MOZU 42‑4.0:2013 and Guidelines ST-N MOZU 42‑4.0:2014.

This instruction is suitable for the organization of the production of medicinal products in accordance with the principles and rules of GMP, as well as for the audit, inspection, certification of production sites for compliance with GMP and scheduled and unscheduled inspections of the production of medicinal products, since the requirements of good manufacturing practice are included in the Licensing conditions for conducting economic activities with production of medicinal products, wholesale and retail trade of medicinal products approved by order of the Ministry of Health of Ukraine dated 31.10.2011 No. 723, registered in the Ministry of Justice of Ukraine on December 7, 2011 under No. 1420/20158. Manufacturing enterprises must carry out their production activities in accordance with the principles and rules specified in this instruction.

Published based on the materials of www.diklz.gov.ua