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Kyrgyzstan Drug Product Registration

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Kyrgyzstan Drug Product Registration

Eurasian Economic Union (EAEU) Drug Registration Requirements

General Requirements for Registration Dossier Modules:

Requirements for Module 1 – Administrative Information:

  • Covering Letter:
    • Include a covering letter with necessary attachments.
    • A “Note to Experts” document may be attached for improved navigation.
  • Content:
    • Submit complete contents of modules 1 – 5 of the registration dossier.
  • General Documentation:
    • Application for registration of a medicinal product.
    • Documents confirming payment for expert work and/or registration fee.
    • Duly certified copy of the certificate for the medicinal product.
    • Translation and certified copy of the expert report.
    • Conclusion/recommendation of the authorized bodies.

General Characteristics, Instructions, and Labelling (Module 1.3):

  • Draft SmPC and IMP in Russian.
  • Layouts of packaging and labelling.
  • Results of user testing of the IMP text.
  • Copies of SmPC and IMP approved by the manufacturing country.

Information on Regulatory Status (Module 1.4):

  • List of countries where the product was registered, refused, or suspended.

Quality Documents (Module 1.5):

  • Certificate of compliance with pharmacopoeia standards.
  • Letters related to the master file of the active pharmaceutical substance.
  • Draft regulatory document on quality.

Production Documents (Module 1.6):

  • Certified documents related to GMP compliance.
  • Copy of the permit/license for production.
  • Reports of GMP inspections.
  • Contracts related to production.
  • Information on regulatory measures taken.

Information about Specialists (Module 1.7):

  • Information about specialists involved in quality, preclinical, and clinical data.

Specific Requirements for Different Applications (Module 1.8):

  • Additional trade name letter.
  • Clinical trial documents.
  • Summary for registration application.
  • Table listing clinical studies.
  • Compliance letter for clinical studies.

Assessment of Potential Hazards to the Environment (Module 1.9):

  • Documents related to potential hazards to the environment (if available).

Pharmacovigilance Information (Module 1.10):

  • Master file of pharmacovigilance system (for the first application).
  • Brief description for subsequent applications.
  • Risk management plan.
  • Documents confirming interaction between legal entities.

Trademark Registration (Module 1.11):

  • Copies of documents confirming trademark registration.

Module 2: Summary of the General Technical Document (CTD) – Eurasian Economic Union (EAEU) Drug Registration

This module encompasses summaries of chemical and biological documentation, preclinical and clinical studies found in modules 3 – 5 of the medicinal product’s registration dossier. The opinions of specialists who prepared summaries on quality, preclinical, and clinical studies are also included. Summarized factual data, including tables, cross-references the main documentation in Module 3 (Quality), Module 4 (Non-clinical Study Reports), and Module 5 (Clinical Trial Reports).

2.1. Contents of Modules 2 – 5: This section presents the content of documentation on the quality, safety, and effectiveness of the medicinal product included in modules 2 – 5.

2.2. Introduction to OTD: Information on the pharmacological group, mechanism of action, and proposed clinical use of the drug must be provided.

2.3. General Summary of Quality: The overall quality summary offers an overview of information related to chemical, pharmaceutical, and biological data. Critical parameters and quality-related issues should be addressed, justifying any deviations from requirements.

2.4. Review of Preclinical Data: Provide a generalized and critical assessment of preclinical in vitro and animal studies. Assess impurities and degradation products, especially for non-biological drugs. Consider differences in chirality, chemical form, and purity. For herbal and biological products, assess comparability.

2.5. Review of Clinical Data: The Clinical Data Review should critically analyse clinical data, study design, decisions made, and study progress. Provide a brief overview of clinical trial data, assessing the benefit-risk ratio, justifying the proposed dose and indications for use.

2.6. Summary of Preclinical Studies: Present a summary of pharmacological, pharmacokinetic, and toxicological studies in both text and tabular formats. Include an introductory part.

2.6.1. Summary of pharmacological studies in text format.

2.6.2. Summary of pharmacological studies in tabular form.

2.6.3. Summary of pharmacokinetic studies in text format.

2.6.4. Summary of pharmacokinetic studies in tabular form.

2.6.5. Summary of toxicological studies in text format.

2.6.6. Summary of toxicological studies in tabular form.

2.7. Summary of Clinical Studies: Provide a detailed, evidence-based summary of clinical information from Module 5, including biopharmaceutical studies, clinical pharmacology studies, and clinical efficacy and safety studies.

2.7.1. Summary of biopharmaceutical research and associated analytical methods.

2.7.2. Summary of clinical pharmacology research.

2.7.3. Summary of clinical effectiveness.

2.7.4. Summary of clinical safety.

2.7.5. A copy of the used literary sources.

2.7.6. Brief overview of individual studies

Module 3: Quality – Requirements for Registration Dossier Documents

3.1. Contents of Module 3: This section outlines the requirements for the quality module, encompassing chemical, pharmaceutical, and biological data on active pharmaceutical substances and medicinal products. It includes information on development, production processes, characteristics, properties, quality control methods, stability, and packaging of the medicinal product.

3.2. Basic Information Required for Submission:

  1. a) Chemical, pharmaceutical, and biological data on active pharmaceutical substances and medicinal products, including production process details, characteristics, properties, quality control methods, stability, and packaging.
  2. b) Basic information about the active pharmaceutical substance and medicinal product.
  3. c) Detailed information on starting materials, raw materials, and excipients used in production.
  4. d) Clear and detailed presentation of all methods and test methods used in production and quality control, complying with current scientific standards and validation requirements. References to pharmacopoeias should be provided.
  5. e) For pharmaceutical substances in pharmacopoeias, provide references. If impurities not controlled by the pharmacopoeias may arise, specify and provide a methodology for their determination.
  6. f) If materials are not described in relevant pharmacopoeias, reference to another state’s pharmacopoeia may be applicable, requiring validation of analytical methods.
  7. g) For substances in the European Pharmacopoeia, a certificate of conformity may replace substantive data. The manufacturer must confirm no changes to the manufacturing process.
  8. h) For well-studied active substances, a separate document (master file) containing production process details, quality control, and validation may be submitted. The manufacturer can send this file to the authorized body.
  9. i) Describe measures to prevent animal spongiform encephalopathies transmission and provide evidence of compliance.
  10. j) Provide information on the assessment of the risk of contamination by extraneous agents.
  11. k) Detail the special devices and equipment used in the production process and medicinal product control.
  12. l) If applicable, submit documents confirming the registration of the medical device.

3.2.S. Active Pharmaceutical Substance:

3.2.S.1. General Information about Starting Materials and Raw Materials:

  • Provide the name of the active pharmaceutical substance, including INN, pharmacopoeia name, and chemical name.
  • For biological products, provide a list of physicochemical properties.

3.2.S.2. Process of Production of Active Pharmaceutical Substance:

  • Describe the manufacturing process, including raw materials used, their quality, and control.
  • For biological products, provide details on the origin and history of source materials, measures to prevent pathogen transmission, and confirmation of cell characteristics.

3.2.S.3. Description of the Characteristics of the Active Pharmaceutical Substance:

  • Provide data on the structure and characteristics, confirming the structure through modern methods.

3.2.S.4. Quality Control of the Active Pharmaceutical Substance:

  • Provide information on specifications, rationale for selection, and validation of test methods.
  • Present results of quality control for batches produced during development.

3.2.S.5. Standard Samples or Materials:

  • Identify and describe reference materials.

3.2.S.6. Packaging (Capping) System:

  • Describe the primary packaging and closure system.

3.2.S.7. Stability:

  • Provide a summary of research plans and results.
  • Present detailed results of stability studies and a plan for post-registration stability research.

3.2.P. Medicine:

3.2.P.1. Description and Composition of the Medicinal Product:

  • Provide a description of the dosage form, composition, and components.
  • Use accepted terminology for component descriptions.
  • Specify quantitative composition for active pharmaceutical substances.

3.2.P.2. Pharmaceutical Development:

  • Detail studies demonstrating appropriateness for the intended use.
  • Identify critical formulation parameters and process characteristics affecting reproducibility and quality. 

Module 4: Preclinical Study Reports

This module focuses on justifying the compatibility of the active pharmaceutical substance with excipients and considering physicochemical properties affecting the medicinal product. The following aspects need to be addressed:

Compatibility and Physicochemical Properties:

  • Justify the compatibility of the active pharmaceutical substance with excipients.
  • Consider basic physicochemical properties affecting the medicinal product.
  • Provide information on compatibility of different active pharmaceutical substances in combined medicinal products.

Excipient Selection:

  • Justify the choice of excipients, especially concerning their functional characteristics and content.
  • Describe the development of the medicinal product, considering the proposed route of administration and method of use.
  • Justify any excess in the composition.

Physicochemical and Biological Properties:

  • Indicate and justify any physicochemical and biological properties affecting the medicinal product.

Production Process Optimization:

  • Provide information on the selection and optimization of the production process.
  • Address differences between the production processes used in clinical trial phases and the planned industrial process.

Primary Packaging and Closure System:

  • Justify the suitability of the primary packaging and closure system.
  • Describe potential interactions between the medicinal product and the primary packaging material.

Microbiological Characteristics:

  • For both non-sterile and sterile medicinal products, present microbiological characteristics according to the Pharmacopoeia of the Eurasian Economic Union.

Solvents or Dispensers:

  • Provide additional information on the use of solvents or a dispenser, justifying their compatibility with the medicinal product.

Module 5: Clinical Study Reports

Drug Production Process:

  • Describe the production method specified in the application, including various stages, in-process controls, and acceptance criteria.
  • Include measures to ensure the uniformity of the medicinal product and validation studies for non-standard or critical production methods.
  • Provide a detailed production recipe per batch.

Analytical Methods:

  • Describe analytical methods for monitoring the quality of the medicinal product at intermediate stages.
  • Address cases where the applicant proposes analytical methods that do not quantitate all active pharmaceutical substances or excipients.

Module 6: Quality Control of Excipients

Starting Materials for Excipients:

  • Provide a list of all starting materials used in excipient production, indicating at what stage each is used.
  • Include information on quality and quality control of starting materials.

Specifications for Excipients:

  • Provide specifications and rationale for each excipient.
  • Describe and validate analytical procedures for quality control.

Excipients of Human or Animal Origin:

  • Pay special attention to excipients of human or animal origin.
  • Confirm compliance with measures to prevent transmission of pathogens, presenting certificates of conformity if necessary.

New Excipients:

  • For new excipients, provide a complete description of production, properties, and control.
  • Submit preclinical and clinical safety data in the format specified in Module 3 for active pharmaceutical substances.

Module 7: Quality Control of Medicinal Product

Medicinal Product Batches:

  • Define a series of a medicinal product and provide detailed information on specifications at release and during shelf life.
  • Justify the selection of quality indicators and provide validation information for test methods.

Module 8: Stability of the Drug

Stability Studies:

  • Summarize types of research, plans, and results obtained.
  • Provide detailed results of stability studies in an appropriate format, including analytical methods and validation.

Modules 9 to 13 (Additional Information):

  • Cover various aspects such as production premises and equipment, assessing safety regarding extraneous agents, and the validation plan for manufacturing processes. 

Module 4: Reports on Preclinical (Non-Clinical) Studies

4.1. Contents of Module 4:

Module 4 focuses on providing comprehensive information on preclinical (non-clinical) studies. The section emphasizes the need for justifying the potential toxicity of the medicinal product and detailing harmful or undesirable toxic reactions under proposed conditions of use. Additionally, it requires a thorough exploration of pharmacological properties in both qualitative and quantitative terms. The dossier must also inform medical professionals about the therapeutic and toxicological potential of the drug.

For biological medicinal products, the applicant should adapt the requirements to the specific product and provide justification for the research program used.

4.2. Reports on Preclinical (Non-Clinical) Studies:

4.2.1. Pharmacology:

  • Study and describe the pharmacodynamic activity of the drug intended for therapeutic use.
  • Use recognized and validated assays, presenting results quantitatively.
  • Evaluate potential adverse pharmacodynamic effects, especially concerning physiological functions in living organisms.
  • For fixed combinations of active substances, base the pharmacodynamic interaction studies on pharmacological premises or indications.

4.2.2. Pharmacokinetics:

  • Include results analysing all processes involving the active substance and its metabolites.
  • Cover absorption, distribution, biotransformation, and excretion.
  • Preferably use in vitro studies with human-derived test systems.
  • Compare pharmacokinetic data obtained in animals and humans, providing extrapolation.

4.2.3. Toxicology:

4.2.3.1. Toxicity after Single Administration:

  • Provide a qualitative and quantitative analysis of toxic manifestations after a single administration.
  • Conduct single-dose toxicity studies following relevant guidelines.

4.2.3.2. Toxicity after Repeated (Multiple) Administration:

  • Document physiological and/or pathological changes from repeated administration.
  • Preferably provide information from short-term and long-term studies, with the duration aligned with clinical use.

4.2.3.3. Genotoxicity:

  • Include information on the mutagenic and clastogenic potential of the medicinal product.
  • Mandatory for all new active substances.

4.2.3.4. Carcinogenicity:

  • Provide information on studies of the drug’s carcinogenic potential.
  • Considerations include intended duration of use, identified changes in toxicity studies, and chemical structure.

4.2.3.5. Reproductive and Developmental Toxicity:

  • Include studies on reproductive dysfunctions and negative effects on offspring.
  • Cover effects from conception to puberty, latent effects, and embryofetal and perinatal studies.

4.2.3.6. Local Tolerance:

  • Include information on local tolerability.
  • Differentiate mechanical effects and physicochemical properties from toxic or pharmacodynamic effects.
  • Use a study design aligned with clinical use and consider in vitro methods if comparable to animal studies.

 

 

Module 5: Clinical Trial Reports

5.1. Contents of Module 5: Module 5 of the registration dossier focuses on clinical trial reports. The dossier should include comprehensive information to support the safety, efficacy, and quality of the medicinal product. This includes data from clinical trials, pharmacokinetic and pharmacodynamic studies, biopharmaceutical research, and post-registration experience.

5.2. List of All Clinical Studies: a) Submit clinical information to allow scientifically reliable conclusions about the medicinal product’s registration conditions. Include results from all clinical trials, both favorable and unfavorable. b) Ensure clinical trials are preceded by appropriate pharmacological and toxicological studies, with investigators having access to relevant information. c) Mandate retention of main clinical trial documentation for specified periods after completion, termination, or marketing authorization. d) Describe each clinical trial comprehensively, including protocols, audit completion certificates, investigator details, location, patient information, and final reports. e) Submit clinical trial data promptly to regulatory bodies. The clinical trial report should reflect the researcher’s opinion on safety, tolerability, effectiveness, indications, contraindications, dosage regimen, and precautions. f) Generalize clinical observations, including subject numbers, age distribution, dropout reasons, adverse reactions, high-risk group information, effectiveness criteria, and statistical evaluations. g) Provide observations on habituation, dependence, drug interactions, criteria for patient exclusion, and deaths during or after the study. h) Information on new combinations of active substances must mirror data on new drugs, justifying safety and effectiveness. i) If data are partially or completely absent, provide an explanation. Unexpected results should trigger additional nonclinical studies. j) For long-term use, describe changes in pharmacological action due to repeated use and justify chosen dosages.

5.3. Reports on Clinical Studies:

5.3.1. Biopharmaceutical Research Reports:

  • Include reports on bioavailability, comparative bioavailability, bioequivalence, in vitro-in vivo correlation, and analytical methods.
  • For biowaivers, submit in vitro study reports.

5.3.2. Reports of Pharmacokinetic Studies Using Human Biomaterials:

  • Submit reports on binding to plasma proteins, liver metabolism, and interaction studies using human-derived biomaterials.

5.3.3. Reports of Pharmacokinetic Studies in Humans:

  • Describe absorption, distribution, metabolism, and excretion characteristics.
  • Include information on standard pharmacokinetic studies, population pharmacokinetics, and studies evaluating intrinsic and extrinsic factors. 

5.3.4. Reports of Pharmacodynamic Studies in Humans:

  • Confirm correlation between pharmacodynamic action and effectiveness.
  • Include information on dose-effect relationships, dosage justification, and mechanism of action.
  • Address pharmacodynamic interactions with other drugs or substances.

5.3.5. Efficacy and Safety Study Reports: 5.3.5.1. Reports of Controlled Clinical Studies:

  • Provide information on randomized, controlled trials comparing the investigational medicinal product with placebo or drugs with proven efficacy.
  • Ensure unbiased estimates through randomization and blinding techniques.
  • Pay attention to safety data, adjustments in dosage regimen, serious adverse events, and patient exclusion.

5.3.5.2. Reports of Uncontrolled Clinical Studies:

  • Include reports of uncontrolled clinical studies, data analyses from multiple studies, and reports of other clinical studies.

5.3.6. Reports on Post-Registration Experience:

  • Include information on adverse reactions from the medicinal product and similar products if registered in other countries.

5.3.7. Individual Registration Cards and Lists of Patients:

  • Submit individual registration cards and patient lists indexed by study while maintaining patient confidentiality.
  • Include data from laboratory and instrumental research methods, as well as statistical processing of clinical study results.

List of Documents Required for Obtaining a License for Pharmaceutical Activities in Kyrgyzstan

Obtaining a license for pharmaceutical activities in Kyrgyzstan involves submitting specific documents to the Department of Medicines and Medical Devices (DLO&MT). Here’s a list of the required documents:

  1. Application Form:
  • Download and fill out the official application form for a pharmaceutical activity license.
  1. Payment Receipt:
  • Pay the relevant license issuance fee:
    • 1,000 Kyrgyzstani soms (KGS) for legal entities
    • 500 KGS for individuals
  • Make the payment to the Pervomaisky ROK-1 settlement account with the details provided:
    • Account number: 4402011001000140
    • BIC: 440001
  1. Identity Documents:
  • For legal entities:
    • Provide a copy of the certificate of state registration from the state statistics bodies.
    • Submit a copy of the company charter.
  • For individuals:
    • Provide a copy of the individual’s identity document (passport, ID card, etc.).
    • Submit a copy of the certificate of state registration for individuals, if applicable.
  1. Taxpayer Identification Number (TIN) Card:
  • Provide a copy of your TIN card.
  1. Cash Register Registration:
  • Submit a registration card for your cash registers confirming their online data transfer function to the Kyrgyz Republic tax authorities.
  1. Professional Qualifications:

Notarized copies of the following documents:

  • Diploma of graduation from a higher (secondary for pharmacy and kiosk) medical educational institution.
  • Specialist’s certificate.
  • Employment record book.
  1. Premises Documents:

Copies of documents confirming ownership or lease agreement for the premises:

  • Land ownership title deed, purchase agreement, etc.
  • Lease agreement (if applicable).

Copy of the technical passport for the premises:

  • This document should clearly indicate the location of services within the premises.
  1. List of Manufactured Products:
  • Provide a list of all pharmaceutical products you will be manufacturing or distributing under the license.
  1. DLO&MT Facility License Examination Protocol:
  • Submit the protocol from the DLO&MT facility license examination.

Additional Notes:

  • When submitting your application, include a 1-plastic binder in the corresponding colour for your region:
    • Bishkek city, Chui region: Red
    • Issyk-Kul region: Blue
    • Talas region: Black
    • Naryn region: Gray
    • Osh, Jalalabad, Batken region: Green

The information provided outlines the national registration procedure for medicinal products in Kyrgyzstan. Here are the key points:

  • Applicability of Registration:
    • Import and sale of medicinal products in Kyrgyzstan are permitted only after state registration or renewal of registration.
    • Registration can be performed either under the “national” procedure until December 31, 2020, or under the “uniform” Eurasian Economic Union (EAEU) procedure; after December 31, 2020, registration is only allowed under the “uniform” EAEU procedure.
  • Competent Authority:
    • The competent authority responsible for the expert evaluation of registration materials for finished medicinal products is the Department of Pharmaceutical Supply and Medical Equipment of the Ministry of Health of the Kyrgyz Republic.
    • Website: Department of Pharmaceutical Supply and Medical Equipment
  • National Registration Procedure:
    • The procedure for national state registration of medicinal products was approved by Resolution of the Government of the Kyrgyz Republic No. 405 dated August 28, 2018.
    • Provisions of the Technical Regulation “On the Safety of Medicinal Products for Medical Use,” approved by Resolution of the Government of the Kyrgyz Republic No. 137 dated April 6, 2011 (updated December 6, 2018), should also be considered.
  • Registration Dossier:
    • The registration dossier is accepted in the Common Technical Document (CTD) format.
    • Components of a complete registration dossier include:
      • Application form
      • Normative Document (ND) – includes composition, specifications, quality control methods, storage conditions, and manufacturer information.
      • Instructions for medical use (package insert)
      • Colour artworks (mock-ups) of primary and secondary packaging.
    • Part of the documentation must be submitted with translations into Russian.
    • For orphan drugs, a summary of preclinical and clinical data, with a rationale for the benefit-risk ratio, can be submitted instead of the full preclinical and clinical materials.
  • Submission Format:
    • The registration dossier is submitted in electronic form, with some documents exempted from electronic submission.
  • Documentation Required:
    • Module 1 (administrative data)
    • Normative document (ND)
    • Instructions for medical use of a medicinal product (package leaflet)
    • Application form and registration materials
  • International Legalization of Documents:
    • Module 1 must be submitted considering the requirements for international legalization of documents.
  • Language and Labelling:
    • Package labelling must be submitted and approved in Russian and/or Kyrgyz.
    • Instructions for medical use should be submitted in Russian and approved in Russian and Kyrgyz.
  • Stages of the Registration Procedure:
    • Filling the Application form and registration materials
    • Submission of documentation and samples to the competent authority
    • Payment of state fees
    • Expert evaluation (primary and secondary) of registration materials
    • Addressing deficiency letters, corrections, and reconciliation of instructions, normative document, and package labelling
    • Laboratory control of samples
    • Positive conclusion of specialized assessment
    • Ministry of Health issues an Order on state registration of the medicinal product
    • Registration certificate is granted to the Marketing Authorization Holder (MAH)
  • Timeline of Registration:
    • 180 calendar days from submission of the Application and registration dossier.
    • Excludes time for MAH to pay state fees, laboratory analysis, and responses to questions (observations).
    • Inspection of manufacturing site and quality assurance system may be required in some cases.
  • Inspection of Manufacturing Site:
    • Carried out at newly introduced manufacturing sites and in case of transfer of manufacturing technologies (for generic medicinal products).
  • Laboratory Quality Control:
    • MAH should provide samples and reference standards sufficient for laboratory quality control in 3 parallels.
  • Registration Certificate:
    • Consists of Registration Certificate itself, approved text of instructions for medical use, approved colour artworks of primary and secondary packaging, and approved normative document on quality control of medicinal product.
    • Validity period is 5 years.
    • Issued in the name of the Applicant (MAH) of the registration, whether resident or non-resident of Kyrgyz Republic.
  • Regulatory Standards:
    • Kyrgyzstan has high standards for regulation of marketed medicinal products.
    • Inconsistencies between approved and actual packaging layouts, instructions for use, and quality certificates may lead to rejection or temporary/permanent prohibition of sales.

Changes and Variations to the Registration Certificate in Kyrgyzstan:

Basis: Variations are carried out based on the Technical Regulation “On the safety of medicinal products for medical use” approved by Resolution No. 137 dated April 6, 2011, and the Procedure for state registration of medicinal products approved by Resolution No. 405 dated August 28, 2018.

Obligation: The Marketing Authorization Holder (MAH) is obligated to inform the competent state authority of any changes to the authorized medicinal product data submitted during registration. Comprehensive information about the reasons for changes and their potential impact on efficacy, safety, and quality must be provided.

Changes that Do Not Require New Registration:

  • Change in name without changing the composition.
  • Change in the name of the manufacturer.
  • Change in the legal address or details of the manufacturer or holder of the registration certificate without changing the manufacturing site.
  • Change in the composition and quantity of excipients (except for components of vaccines and biological medicinal products) to improve the quality parameters of the medicinal product.
  • Change in the qualitative composition of the primary (immediate) packaging of the medicinal product.
  • Addition of new warnings or limitations to therapeutic indicators in the instruction for medical use.
  • Change in the prescription status of the medicinal product.
  • Addition or replacement of a measuring device for oral liquid dosage forms and other dosage forms.
  • Change of organization of the manufacturer(s) of the active substance or addition of a new manufacturer organization(s) of the active substance.
  • Change of the Normative document on the quality of the medicinal product.
  • Change in the shelf life of the medicinal product.
  • Change in the shelf life of the medicinal product after the packaging has been opened for the first time.
  • Change of dimensions of tablets, capsules, suppositories, or pessaries without change in qualitative composition of ingredients and mean mass.
  • Changes in the manufacturing process for components requiring a test procedure for new impurities.

Specialized Expert Evaluation Period for Variations: 60 business days, excluding the time for responses to observations (deficiencies).

Renewal of Registration (Confirmation of Registration):

Timeline: The application for renewal must be submitted no earlier than 180 calendar days before the expiration of the Registration Certificate but no later than the last day of its validity.

Sale of Medicinal Products: Medicinal products can be sold in Kyrgyzstan until the expiration date if placed on the market within the validity of the Registration Certificate.

Documentation Required for Renewal:

  • Module 1
  • Module 2
  • PSUR (Periodic Safety Update Report)
  • Normative document on quality
  • Copy of the valid Registration certificate

Specialized Expert Evaluation Period for Renewal: 50 business days, excluding the time for responses to observations (deficiencies).

Decision on Renewal: A positive decision on renewal results in the issuance of a Registration Certificate without expiry.

Professional Services: Cratia provides professional services for state registration (renewals, variations) of medicinal products in Kyrgyzstan, possessing in-depth knowledge of national legislation, requisite experience, and necessary resources.

Requirements for Documents of the Registration Dossier of Generic Medicinal Products

The registration dossier for a generic medicinal product must adhere to the regulations outlined in this section, considering the guidelines for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, as approved by the Commission.

The choice of a reference drug in bioequivalence studies aligns with the guidelines, and the bioequivalence of the generic medicinal product to the original must be established through relevant bioavailability studies.

The general characteristics and medical use instructions of the generic medicinal product should correspond to those of the original. If variations exist, supported by clinical studies, these should be presented in the generic product’s medical use instructions.

Module 1

In section 1.8.2 of the registration dossier, the applicant must provide a concise summary (up to 5 pages) demonstrating that the medicinal product is a generic version of the corresponding original. The summary should encompass information on the drug, its qualitative and quantitative composition, dosage form, and safety and/or effectiveness of its active substance compared to the original. If necessary, details about bioavailability and bioequivalence should be included. In certain cases, a risk management plan may be required. Any absence of elements in the summary requires justification in the relevant dossier section.

Module 2

The review of preclinical and clinical data in Module 2 should include:

  • A summary of the active substance’s impurity profile and possible degradation products in batches intended for the pharmaceutical market.
  • Assessment of bioequivalence studies or a justification for their absence.
  • Updates on literary publications related to the active substance, fulfilling this requirement through links to peer-reviewed journals.
  • Identification of points in the general characteristics of the medicinal product necessitating analysis in preclinical and clinical reviews, supported by scientific literature and/or evidence from additional studies.
  • Additional information demonstrating that the safety and/or effectiveness profiles of the declared drug align with the reference drug, even in cases of differences in the chemical forms of the active substance.

Module 3

Module 3 of the registration dossier for the medicinal product should be submitted in its entirety.

Module 4 and Module 5

As per the new edition of Decision 9 (January 30, 2020) of the EEC Council:

  • Results of bioequivalence studies, if conducted, should be included in section 5.3.1 of the registration dossier.
  • Results of biowaiver equivalence proof must be presented in subsection 5.3.1.2.
  • Submission of a bioanalytical method validation report is mandatory.
  • Data on concentration, pharmacokinetics, and statistical analysis should also be provided.

Report on Bioequivalence Studies for Generic Medicinal Products

The report on bioequivalence studies for generic medicinal products must contain the following information:

  • Researcher Information:
    • Name and workplace of the researcher conducting the studies.
    • Organization where the studies were conducted.
    • Period during which the studies took place.
  • Audit Certificates:
    • Attach audit certificates, if available, to the bioequivalence study report.
  • Confirmation of Reference Medicinal Product Selection:
    • Specify the reference medicinal product in accordance with the rules for conducting bioequivalence studies within the Eurasian Economic Union.
    • Include the following information about the reference product:
      • Trade name.
      •  
      • Dosage form.
      • Marketing authorization holder.
      • Date of registration.
      • Registration certificate number.
      • Member State where the reference product is registered.
      • Series number.
      • Manufacturer’s name.
      • Best before date.
      • Country of purchase.
    • Provide the recommendation of the Expert Committee on Medicines on the selection of the reference product, if available.
  • Details of the Tested Drug:
    • Name and composition of the drug being tested.
    • Batch size.
    • Production date.
    • Expiration date if available.
  • Certificates of Analysis:
    • Include certificates of analysis for the reference and test product series used in the bioequivalence study.
  • Confirmation of Identical Composition:
    • Submit an official letter signed by the manufacturer’s quality authority confirming that the quantitative composition and production of the investigational drug are identical to the reference product.
  • Additional Information on Safety and Effectiveness:
    • Provide additional information, following the structure of the general technical document of the registration dossier, proving that the safety and/or effectiveness profiles of the declared medicinal product do not differ from those of the reference drug, especially in case of differences in the chemical forms of the active substance (salts, esters, isomers, mixtures of isomers, complexes, or derivatives).
  • Results of Preclinical and Clinical Studies:
    • Include results of preclinical and clinical studies conducted for the generic medicinal product, if necessary. Place these results in the relevant sections of Module 4 and Module 5.
  • Exemption from Bioavailability Studies:
    • Clarify if bioavailability studies are exempted based on compliance with the criteria specified in the rules for conducting bioequivalence studies within the Eurasian Economic Union.
  • Different Forms of Active Substance:
    • If the active substance of the generic medicinal product is a different salt, ester, or derivative of the registered drug’s active substance, provide additional information such as bibliographic reviews or reports of relevant preclinical and/or clinical studies (comparative bioavailability studies) demonstrating the absence of changes in pharmacokinetics, pharmacodynamics, and/or toxicity. If such evidence is not provided, the substance is considered a new active substance.

 

  1. Requirements for Documents in the Registration Dossier of a Hybrid Medicinal Product

The registration dossier for a hybrid medicinal product must include additional data from both preclinical and clinical studies. The requirements for different sections of the dossier are outlined below: 

Module 1: In section 1.8.2, provide a concise summary (up to 5 pages) demonstrating that the medicinal product is a hybrid drug concerning the corresponding original drug. The summary should include information about:

  • The drug.
  • Active pharmaceutical substance.
  • Dosage form.
  •  
  • Indications for use.
  • Method of use compared to the original drug. Include information about bioavailability and bioequivalence if necessary. In certain cases, a risk management plan may be required. If elements are missing, provide justifications for their absence.

Module 2: In reviewing preclinical and clinical data, pay special attention to the following elements:

  • A summary of the impurity profile of the active substance, including possible degradation products in batches intended for the pharmaceutical market.
  • Updated literature publications about the active substance.
  • Unknown or derived characteristics of the drug and/or its therapeutic group. Analyse these in preclinical and clinical reviews, supported by evidence from scientific literature or additional research.
  • Additional information proving that the safety and/or effectiveness profiles of the declared drug are consistent with the reference drug, even in cases of differences in the chemical forms of the active substance.

Module 3: Submit Module 3 of the registration dossier in full.

Module 4 and Module 5: Include the results of preclinical and/or clinical studies of the hybrid medicinal product in the relevant sections of Module 4 and Module 5.

Procedure for Conducting Additional Studies: For generic and hybrid medicinal products or those with extended requirements, additional studies may be required based on certain characteristics or registration applications. The characteristics and additional data required include:

  • Various salts, esters, complexes, or derivatives: Provide evidence of no significant changes in pharmacokinetics, pharmacodynamics, and/or toxicity. Otherwise, consider the active substance as new.
  • Different route of administration or dosage form: Submit clinical data, including safety and efficacy, pharmacokinetics, and relevant nonclinical data.
  • Different dosage for the same route of administration: Include comparative bioavailability data following the rules for conducting bioequivalence studies.
  • Ultra-bioavailable drugs with a reduced dose: In some cases, comparative bioavailability studies, as per the approved rules, may be sufficient.

 

Biological Drugs:

Plasma-Derived Drugs:

General Principles for the Formation of a Registration Dossier:

  • A master file for blood plasma is a separate document containing detailed information about human blood plasma used in the production of medicinal products.
  • Each center processing human plasma must maintain detailed information in a blood plasma master file.
  • The master file must be submitted to the authorized body and is the responsibility of the applicant or marketing authorization holder.
  • The plasma master file is necessary for components derived from plasma, and reference should be made to the owner’s master file.

Additional Requirements for the Content of the Master File:

  • Information about plasma origin, collection centers, monitoring centers, and criteria for donor selection.
  • Description of the system tracking the path of each donation.
  • Plasma quality compliance with Pharmacopoeia standards.
  • Control of infectious agents in collected blood/plasma.
  • Technical characteristics of containers for blood/plasma collection.
  • Conditions for storing and transporting plasma.
  • Characteristics of the plasma pool.
  • Description of the interaction system between the manufacturer and plasma-related centers.

Examination and Issuance of Opinion:

  • Unregistered medicinal products require a complete registration dossier accompanied by a master file for plasma.
  • The master file undergoes examination as part of the registration process.
  • A positive examination results in a Union conclusion/certificate, valid throughout the Union.
  • The plasma master file is subject to annual updating and re-examination. 

Vaccines:

General Principles:

  • The vaccine antigen master file contains biological, pharmaceutical, and chemical information for each active substance in the vaccine.
  • Different vaccines may share a common master file.
  • Combination vaccines may contain multiple antigens for preventing infectious diseases.

Additional Requirements for the Master File:

  • Information on the active substance, manufacturer, production process, safety measures, and quality control.
  • Stability of the active substance.

Examination and Issuance of Opinions:

  • New vaccines or those with new antigen combinations require a complete registration dossier and vaccine antigen master files.
  • Positive examination results in a Union conclusion/certificate, applicable across the Union.
  • Changes to the master file undergo examination.

Simplified Registration Dossier for Vaccines Produced Before 2000:

  • For well-studied vaccines produced before 2000, Module 3 complies with Part I and Section 12.2.
  • Modules 4 and 5 present scientific review bibliographies instead of preclinical and clinical study reports.

Requirements for the Registration Dossier of a Biosimilar Medicinal Product

To register a biosimilar medicinal product, the following requirements must be met, and the registration dossier is submitted in accordance with the outlined sections:

Module 1:

  • In Section 1.8.2 of Module 1, the applicant must provide a summary demonstrating that the medicinal product seeking registration is biosimilar to the original medicinal product. The summary should include information about the drug, active substance, dosage form, dosage, indications for use, and method of use in comparison with the original drug.
  • In Section 1.10 of Module 1, along with brief information about the pharmacovigilance system of the marketing authorization holder, present a risk management plan for the biosimilar medicinal product applied for registration.
  • If certain elements are missing from the registration dossier, a justification for their absence should be provided in the appropriate section of Module 1.

Module 2:

  • In the review of quality data, preclinical, and clinical data, provide additional comparative information about the claimed medicinal product and the reference medicinal product. Also, include criteria for selecting the reference medicinal product and provide justification for these criteria.
  • The study report or a separate official letter must confirm the choice of the reference medicinal product, following the rules for conducting studies of biological medicinal products within the Eurasian Economic Union. Information about the reference drug should include:
  1. Trade name
  2. Dosage and dosage form
  3. Name of the marketing authorization holder
  4. Registration date and registration certificate number(s)
  5. Member States in which the reference product is registered
  6. Batch number of the reference drug used for research and pharmaceutical development
  7. Manufacturer’s name
  8. Best before date
  9. Country of purchase
  • If available, provide the recommendation of the Expert Committee on Medicines on the selection of the reference drug. Include the name and composition of the study drug(s), batch size, production date, and, if possible, the expiration date. Justify the scope of comparative preclinical and/or clinical studies based on the requirements of the rules for conducting research on biological medicinal products within the Eurasian Economic Union. Append certificates of analysis for batches of reference and study drugs used in the study to the study report.

Module 3:

  • In Module 3 of the registration dossier of a biosimilar medicinal product, provide the following additional data, adhering to the rules for conducting research on biological medicinal products within the Eurasian Economic Union:
  1. a) Confirm the similarity of the molecular and biological characteristics of the active substances of the biosimilar medicinal product and the reference biological medicinal product. This includes data on the primary structure, higher-order structures, post-translational modifications (including glycoforms), biological activity, purity, and impurities.
  2. b) Confirm the similarity of the characteristics of the medicinal product (dosage form, composition, dosage, route of administration, storage conditions, shelf life, stability, impurity profile) of the biosimilar and the reference biological medicinal product.
  3. c) If there are differences in impurities and excipients, assess their potential impact on the clinical safety and efficacy profile of the biosimilar. Provide justification for the acceptability of these differences based on research or data from the scientific literature. If there are clinically significant unknown differences, additional studies are required in the pre- and post-registration period.
  4. d) Provide a complete description and data on the production process, from the development of expression constructs to storage.
  5. e) Include data on studies conducted during the pharmaceutical development of a biosimilar medicinal product to determine and justify its dosage form, composition, and packaging.
  6. f) Specify the biosimilar medicinal product’s quality indicators, regulating crucial aspects established for the reference biological medicinal product, such as identification, purity, activity, molecular heterogeneity, degree of sialylation, and impurities.
  7. g) Include stability studies.

Module 4:

In Module 4, present the results of preclinical (non-clinical) studies of a biosimilar medicinal product compared to a reference biological medicinal product, following the rules for conducting research on biological medicinal products within the Eurasian Economic Union.

Module 5:

Module 5 should contain documents and data as per the rules for conducting research on biological medicinal products within the Eurasian Economic Union. This includes:

  1. a) Results of clinical studies comparing the biosimilar medicinal product with the reference medicinal product, covering pharmacokinetic studies, pharmacodynamic studies, and data from comparative clinical studies.
  2. b) A risk management plan, incorporating a safety specification describing identified and potential negative safety aspects, along with a pharmacovigilance plan for the biosimilar medicinal product in the post-registration period, outlining planned post-registration activities and risk minimization measures.

 

Requirements for the Registration Dossier of Combination Medicinal Products

For new medicinal products that combine two or more previously known active substances in one dosage form, the registration dossier must adhere to the following requirements:

  • Complete Registration Dossier (Modules 1-5):
    • Submit a comprehensive registration dossier encompassing Modules 1 through 5, as outlined in Part I of the Requirements.
  • Module 3:
    • Include information related to the production, quality control, and manufacturer of each active substance present in the combination medicinal product.
    • Note that single-component medicinal products presented in combination packaging are not considered combination medicinal products.
  • Modules 4 and 5:
    • Provide detailed results of preclinical and clinical studies conducted on the combinations of active substances applied for registration.

These requirements ensure that combination medicinal products, which consist of known active substances previously registered as part of single-component drugs, are thoroughly documented and assessed for their safety, efficacy, and quality.