Establishment and integration of quality management systems

The modern world pharmaceutical market is dynamically developing, which leads to increased competition and the emergence of new requirements for the organization of enterprise management. The results of the analysis of enterprises of this sector in the leading countries of the world economy show that the achievement of the strategic goal in management is provided by using European methods of quality management and certification of management systems in accordance with ISO 9001, ISO 13485, GMP, GLP, GCP, GDP, etc.

GMP – (Good Manufacturing Practice) – is a part of the quality management system in the company, which guarantees that medicinal products are constantly produced and controlled in accordance with the quality standards that correspond to the intended use of the medicinal product, as well as with the requirements of the registration dossier, the dossier for clinical trials or the specification of such products.

Simply put, it is an international standard that establishes requirements for the production and quality control of human and animal medicines, as well as specific requirements for the production of active pharmaceutical ingredients and certain types of medicines. GMP standard is the quality assurance at all stages of production – from the receipt of raw materials and packaging materials to the shipment of finished products to the warehouse. At the same time, an important element of the system remains the confirmation by the Authorized Person that each series of released drugs has been produced and controlled in accordance with the requirements of the registration dossier.

The official document confirming the compliance of medicinal products manufacturing conditions with the GMP requirements is the certificate of compliance of manufacturing conditions, issued by the authorized body of PIC/S member state, conclusion on the basis of such certificate or license for manufacturing of medicinal products in case when the authorized body of PIC/S member state does not provide the certificate of compliance of medicinal products manufacturing conditions with the GMP requirements. Such document is issued by an authorized body – the State Administration of Ukraine on Medicinal Products, which is a confirmation of manufacturing compliance with GMP requirements.

PIC/S (Pharmaceutical Inspection Convention Co-operation Scheme) is an international instrument of cooperation between countries and regulatory authorities in the field of quality control of medicinal products (national pharmaceutical inspectorates) for constructive collaboration in the field of Good Manufacturing Practice (GMP), inspection and licensing. PIC/S will eliminate barriers to international trade in medicines through mutual recognition of pharmaceutical inspections by national regulatory authorities.

List of countries participating in PIC/S.

When registering medicines in Ukraine, an Applicant or an Applicant’s representative should provide a certificate or opinion regarding the confirmation of manufacturing compliance with Good Manufacturing Practice requirements.

Manufacturing companies must carry out their manufacturing activities in accordance with the principles and rules given in the guidance ST-H MOZU 42-4.0:2015 – “Medicinal Products. Good Manufacturing Practices.” This guide-standard is used to organize the production of medicines in accordance with the principles and rules of GMP, as well as for audit, inspection, certification of production sites for compliance with GMP, scheduled and unscheduled inspections of drug production facilities, as the requirements of good manufacturing practices are introduced in the Licensing conditions of economic activity in the production of medicines, wholesale and retail trade in medicines.

The system of quality assurance of medicinal products, must ensure that:

• products are designed to meet all requirements and standards;
• for all manufacturing and control operations are clearly documented in accordance with the rules of the standard;
• responsibilities and authorities are strictly defined;
• measures for the production, supply and use of appropriate raw materials and packaging material are implemented;
• intermediate products and process control and validation are carried out;
• control and inspection of finished products is carried out in accordance with the requirements of the Standard and legislation;
• the procedure of self-inspection and/or quality audit is performed, according to which the effectiveness and suitability of the quality assurance system is regularly evaluated.
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The Ukrainian GMP certificate is issued for a period of validity of the production license, but no more than for 3 years.

Recognition of a valid GMP certificate issued by an authorized body of a PIC/S member state is carried out according to the procedure for confirmation of compliance of medicinal products manufacturing conditions with Good Manufacturing Practice requirements, which involves issuance of a conclusion by the State Administration of Ukraine on Medicinal Products based on the results of a specialized examination of the submitted documents.

For resident manufacturers confirmation of compliance of medicinal products manufacturing conditions with GMP requirements is performed by the State Administration of Ukraine on the basis of the results of a routine inspection of compliance with the relevant license conditions.

If there are no critical violations in the act of a routine inspection of compliance with the relevant license conditions, the State Administration of Ukraine on Medicinal Products issues a certificate to the licensee. If there are critical violations identified during the last scheduled audit of compliance with license conditions, the State Administration of Ukraine on Medicinal Products takes a decision to refuse to issue a certificate. However, after the elimination of critical violations and the applicant has the necessary documents that confirm it, the re-inspection of the production site. State Service of Ukraine issues a certificate within 30 days of receiving a letter from the licensee with a general list of nomenclature of products.

For non-residents that have no official documents on compliance of medicinal products manufacturing conditions with GMP requirements, issued by an authorized body of PIC/S member state, or if the manufacturing of medicinal products is performed in a country with which Ukraine has no international treaty on mutual recognition of inspection results, the manufacturing site is inspected in addition to documentation review. During the confirmation of compliance of manufacturing conditions of production with GMP requirements must be specified all intermediate production sites involved in the production of finished medicines, including contract manufacturing sites with a certificate of confirmation of compliance with GMP requirements.

The examination of documents on compliance of medicinal products production with Good Manufacturing Practice requirements in force in Ukraine, which are not submitted for registration (re-registration), is not carried out if the manufacturer has a document issued by the State Service of Ukraine, which confirms compliance of manufacturing conditions with Good Manufacturing Practice requirements.

Thus, according to the requirements of the legislation, during the examination of registration dossier for new registration and re-registration it is necessary to have GMP certificate issued or recognized by the State Service of Ukraine on Medicinal Products.

In other cases (i.e. when the manufacturer does not have a PIC/S GMP certificate) a mandatory inspection of the manufacturing site with a site visit is conducted.

The scheme of GMP certificate recognition has the following order (briefly):

• Preparation of the dossier, entering the necessary information in the Application and Annexes;
• Translation of necessary parts of the dossier into Ukrainian or English for non-PIC/S countries (if necessary);
• Submission of copies of production site dossier to state authorities (State Service on Medicinal Products of Ukraine);
• Initial and specialized expertise of materials;
• For sites of production sites that do not have PIC/S country certificate) it is necessary to perform plant inspection;
• Issuance of Conclusion on recognition of GMP certificate (for inspected sites – issuance of Ukrainian GMP certificate);
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To confirm compliance of production conditions with the requirements of GMP certification, the following documents must be submitted:

• Application, Appendix #1 – for issuance of Certificate or Appendix 2 – for issuance of Conclusion;
• PIC/S GMP certificate (if available), which is issued by the state body of the country, where the production is located; it should be legalized;
• any available GMP certificates, issued by the authorized bodies of the PIC/S member countries; legalized;
• Production license, legalized;
• Annex 5, a certificate of the quality of the manufactured products;
• Annex 6, the certificate of the results of inspections of the production site, conducted by the state control bodies;
• Appendix 7, a general list of the nomenclature of products;
• Site Master File, a copy of the production site file and the most recent site inspection report conducted by a PIC/S authority whose production facilities are located outside of PIC/S countries);
• A Letter of Assurance of Significant Changes regarding a manufacturing site that has passed GMP compliance certification for drug manufacturing conditions;
• Copy of the Application for state registration (reregistration) of a medicinal product, or respective changes, which was submitted to the Ministry of Health of Ukraine,

Power of attorney for representation before state authorities (legalized).

In case any documents from the above mentioned list, which were submitted to the State Administration of Ukraine on Medicinal Products in order to obtain a certificate or a report, contain confidential information that the manufacturer cannot disclose to the applicant (the applicant’s representative) in Ukraine, the manufacturer may send such documents directly to the State Administration of Ukraine on Medicinal Products. After receiving such documents, the State Administration of Ukraine on Medicinal Products shall immediately inform the Applicant (or the Applicant’s representative) by a letter about their receipt and consideration of the Application for Issuance of Certificate or Application for Issuance of Conclusion and the documents attached thereto.

The State Administration of Medicinal Products carries out confirmation of compliance of medicinal products manufacturing conditions with GMP requirements in a stepwise manner and within certain time limits:

• Primary examination of the submitted documents in order to check their completeness, compliance of their form with the legislation, – no more than 5 working days after registration of the Application for the Certificate or Conclusion.

Exception: For medicinal products that have undergone the WHO re-qualification procedure and are included in the WHO list of re-qualified medicinal products – no more than 2 working days after registration of the Application. The same terms are established for the primary expert review of submitted documents for medicines for treatment of tuberculosis, HIV/AIDS, viral hepatitis, oncological and rare (orphan) diseases, and which are registered as a medicinal product by the competent authorities of the United States of America, Switzerland, Japan, Australia, Canada or the European Union.

The period of specialized expertise of the submitted documents for the above-mentioned drugs will be no more than 3 working days after registration of the Application for the Certificate or Application for the Opinion.

• The specialized expertise, subject to submission of an official document on compliance of the conditions of drug production with GMP requirements, issued by the authorized body of the PIC/S member state, shall take no more than 10 working days after the initial expertise.
• For resident manufacturers, confirmation of compliance of medicinal products manufacturing conditions with GMP requirements is performed by the State Administration of Ukraine on the basis of the results of a scheduled inspection of compliance with the relevant license conditions. State Administration of Ukraine on Medicinal Products issues a certificate to the licensee within 30 working days from the date of receipt of a letter from him containing a general list of products in paper form and in electronic format for the issuance of the certificate. The letter shall be submitted by the licensee to the State Service of Ukraine for 15 working days after the scheduled inspection of compliance with license conditions. In all other cases, a specialized expertise is conducted no more than 15 business days after the initial examination.

Cratia offers you assistance in organizing the procedure of GMP certificate recognition. We have the necessary knowledge, experience and skills to carry out all the necessary work. We will undertake management and organization of the process, help to form documentation and conduct the procedure in a short time.