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Annex 5to Item 4.1 of the Procedure
for Expert Evaluation of Materials
Related to Medicinal Products
Submitted for the State Registration
(Re-registration) and
Expert Evaluation of Materials
Related to Changes Introduced
to the Registration Materials
during the Validity Period
of the Registration Certificate
(in wording ofMoH Ukraine Orderas of 01.03.2006 № 95)
І. REQUIREMENTS TO DOCUMENTS SUBMITTED FOR EXPERT EVALUATION OF TYPE I CHANGES MADE IN REGISTRATION MATERIALS DURING THE VALIDITY PERIOD OF THE REGISTRATION CERTIFICATE
№ /Change in the name and/or address of the applicant (registration certificate holder)
/ Conditions to be met / Documents to be submitted / Type of change1 / Change in the name and/or address of the applicant (registration certificate holder) / 1 / 1,2,3 / ІА
Conditions
1. The marketing authorization holder shall remain the same legal entity.
Documentation
1. Document from a relevant competent authority in which the new name and/or new place/address of the applicant (registration certificate holder) is specified.
2. Letter of the applicant.
3. Changes in summary of product characteristics, revised package-inserts and label samples.
2 /
Change in the name of medicinal product
/ Conditions to be met / Documents to be submitted / Type of change1,2,3 / 1,2 / ІB
Conditions
1. No confusions with the names of existing medicinal products or with the international non-proprietary names (INN).2. The verificationby the Center of the new name acceptability should be finalized before the variation application is submitted.
3. The change does not concern the addition to a name.
Documentation
- Grounds for introducing change and new name
3 /
Change in the name of active substance
/ Conditions to be met / Documents to be submitted / Type of change1 / 1,2 / ІА
Conditions
1. The active substance shall remain the same
Documentation
- Proof of acceptance of theINNby WHOorcopyof theINNlist. For herbal medicinal products, a statement that the name is in compliance with the established requirements or with the Note for Guidanceon Quality of Herbal Medicinal Products.
4 / Change in the name and/or place of a manufacturer of the active substance where no European Pharmacopeia certificate of suitability is available / Conditions to be met / Documents to be submitted / Type of change
1 / 1,2 / ІА
Conditions
1. The manufacturing site shall remain the same.
Documentation
1. Document from a relevant competent authority with indication of the new name and/or place/address of the manufacturer of the active substance.
2. Changes in sections of Part IIC or equivalent in the CTD format
5 / Change in the name and/or address of a manufacturer of the finished product / Conditions to be met / Documents to be submitted / Type of change
1 / 1,2,3 / ІА
Conditions
1. The manufacturing site shall remain the same.Documentation
- Copy of the modified manufacturing license, if necessary, or a document from a relevant competent authority with indication of the new name and/or place/address.
- Changes in Part IIB or equivalent in the CTD format, if necessary.
6 /
Change in ATC Code
/ Conditions to be met / Documents to be submitted / Type of change1 / 1,2 / ІА
Conditions
1. Change following granting of or amendment to ATC Code by the WHODocumentation
1. Proof of acceptance by WHO or copy of the ATC Code list.2. Changes in summary of product characteristics, revised package-insert and label samples (if necessary).
7 / Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product / Conditions to be met / Documents to be submitted / Type of change
(a) Site of secondary packaging for all types of pharmaceutical forms / 1,2 / 1,2,5 /
ІА
(b) Primary packaging site:1. Solid pharmaceutical forms, e.g. tablets and capsules / 1,2,3,5 / 1,2,5 / ІА
2. Soft or liquid pharmaceutical forms / 1,2,3,5 / 1,2,5 / ІB
3. Liquid pharmaceutical forms (suspensions, emulsions) / 1,2,3,4,5 / 1,2,4,5 / ІB
(c) All other manufacturing operations except for batch release / 1,2,4,5 / 1,3,4,5,6,7,8 / ІB
Conditions
1. Satisfactory inspection results in the last three years by an inspection service of competent authorities of PIC/S countries, WHO inspection or GMP Inspectorate of Ukraine.2. Manufacturing site appropriately authorized to manufacture the pharmaceutical form or product concerned.
3. Product concerned is not a sterile product.
4. Validation scheme is available or validation of the manufacture at the new site has been successfully carried out according to the current protocol with at least three production scale batches.
5. Product concerned is not a biological medicinal product.
Documentation
1. Proof that the proposed manufacturing site is appropriately authorised for the pharmaceutical form or product concerned, i.e.:
- for manufacturing site in Ukraine – a copy of the current manufacturing license;
- for manufacturing site outside Ukrainewhere an operational GMP mutual recognition agreement exists;
- a copy of the current manufacturing license, a GMP certificate or equivalent document issued by the relevant competent authority of manufacturing country;
- for a manufacturing site outside Ukraine where no GMP mutual recognition agreement exists, a statement issued by the GMP Inspectorate of Ukraine or a copy of the current manufacturing license, GMP certificate or equivalent document issued by a competent authority of manufacturing country (if necessary).
2. Date of last satisfactory inspection of the manufacture carried out by the PIC/S state competent authorities, WHO inspection or GMP Inspectorate of Ukraine, or their authorized bodies in manufacturing country in the last three years (if necessary).
3. Date and scope of the last satisfactory inspection of the manufacture carried out by authorized bodies of the manufacturing country in the last three years (if necessary)
4. The batch numbers of batches (≥3) used in the validation study shall be indicated or validation protocol (scheme) to be submitted.
5.The variation application shall clearly outline “present” and “proposed” finished product manufacturers as listed in section 2.5 of the application form for state registration of medicinal product.
6. Copies of approved specifications during release and within the shelf life period.
7. Batch analysis data (in the form of comparative table) on one production batch and two pilot-scale batches simulating the production process (or two production batches) produced at the proposed site and comparative data on three batches produced at the previous site. Batch data on the next two production batches should be submitted on request. Also it should be stated that the Center shall be informed (with the appropriate propositions) in case of outside specifications.
8. For soft and liquid pharmaceutical forms containing active substance in non-dissolved form, appropriate validation data on validation, microscopic imaging of particle distribution and morphology shall be provided.
Note.If GMP certificate recognized in Ukraine is not available the registration certificate holders may be recommended to consult the relevant authorized bodies prior to submission of the application and to provide information on any previous manufacture inspection conducted in the last 2-3 years and/or any planned inspection including inspection dates, product dispensing category inspected, inspecting organization and other relevant information. This will facilitate the work of the GMP Inspectorate of Ukraine.
8 / Change in batch release arrangements and quality control testing of the finished product / Conditions to be met / Documents to be submitted / Type of change
(a) Replacement or addition of a site where batch control/ testing takes place / 1,2,3 / 1,2 / ІА
(b) Replacement or addition of a manufacturer responsible for batch release
1. Not including batch control/testing / 1 / 1,2,3 / ІА
2. Including batch control/testing / 1,2,3 / 1,2,3 / ІА
Conditions
Conditions:1. The site is appropriately authorized.
2. The product is not a biological medicinal product.
3. Transfer from the old to the new site or new test laboratory has been successfully completed.
Documentation
1. For a manufacturing site in Ukraine: copy of the current manufacturing license or laboratory attestation certificate.
2. The variation application shall clearly outline “present” and “proposed” finished product manufacturers as listed in section 2.5 of the application form for state registration of medicinal product.
3. Information about new authorised person responsible for recalling defective products.
9 / Deletion of any manufacturing site (for an active substance, intermediate or finished product, packaging site, if manufacturer is responsible for batch release and site where batch control takes place) / Conditions to be met / Documents to be submitted / Type of change
None / 1,2 / ІА
Conditions
NoneDocumentation
1. The variation application shall clearly outline “present” and “proposed” finished product manufacturers as listed in section 2.5 of the application form for state registration of medicinal product.2. Changes or amendments to relevant parts of registration dossier (Part II or Module 3).
10 / Minor change in the manufacturing process of the active substance / Conditions to be met / Documents to be submitted / Type of change
1,2,3 / 1,2,3 / ІB
Conditions
1. No change in qualitative and quantitative impurity profile or in physico-chemical properties of substances.2. The active substance is not a biological substance.
3. The method of synthesis remains the same, i.e. intermediates remain the same. In case of herbal medicinal products, the geographical source, production of the herbal substance and the manufacturing route remain the same.
Documentation
1. Amendment to relevant sections of part IIC or equivalent in the CTD format chapters, and of the approved Drug Master File (if applicable) as well as results of the comparison of the present and new production processes.
2. Batch analysis data (in comparative tabular format) of at least for two batches (minimum pilot scale) produced in compliance with the currently approved and proposed production process.
3. Copy of approved specifications of the active substance.
11 / Change in batch size of active substance or intermediate / Conditions to be met / Documents to be submitted / Type of change
(a) Up to 10-fold compared to the original batch size approved at the grant of the registration certificate / 1,2,3,4 / 1,2 / ІА
(b) Down scaling / 1,2,3,4,5 / 1,2 / ІА
(c) More than 10-fold compared to the original batch size approved at the grant of the marketing authorization / 1,2,3,4 / 1,3,4 / ІБ
Conditions
1. Any changes to the manufacturing process are only those necessitated by scale-up, e.g. use of different-sized equipment.2. Test results of at least two batches according to the specifications should be available for the proposed batch size.
3. The active substance is not a biological substance.
4. The change does not affect the reproducibility of the process.
5. The change should be the result of unexpected events arising during manufacture or because of stability concerns.
Documentation
1. Amended section Part IIC or equivalent in the CTD format.
2. Analysis certificates of the tested batches having the proposed batch size.
3. Batch analysis data (in a comparative tabulated format) on at least one production batch manufactured to both the currently approved and the proposed sizes. Batch data on the next two full production batches should be submitted on request. Also it should be stated that the Center shall be informed (with the appropriate propositions) in case of outside specifications.
4. Copies of the approved specifications of the active substance (and of the intermediates, if necessary).
12 / Change in the specification of an active substance or a starting material/intermediate/reagent used in the manufacturing process of the active substance / Conditions to be met / Documents to be submitted / Type of change
(a) tightening of specification limits / 1,2,3 / 1,2 / ІА
2,3 / 1,2 / ІB
(b) addition of a new test parameter to the specification of
1. an active substance / 2,4,5 / 1,2,3,4,5,6 / ІB
2. a starting material/intermediate/reagent used in the manufacturing process of the active substance / 2,4 / 1,2,3,4 / ІB
Conditions
1. The change should not result from previous assessments to review specification limits (e.g., made while submitting the application for the registrationprocedure or type II variation procedure).
2. The change should not result from unexpected events arising during manufacture.
3. Any change should be within the range of currently approved limits.
4. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
5.The active substance is not a biological substance.
Documentation
1. Amendment to relevant section of Part IIC or equivalent in the CTD format.
2. Comparative table of current and proposed specifications.
3. Description of any new analytical method and validation data.
4. Batch analysis certificates on two production batches of the proposed substance according to all parameters of the new specification.
5. For solid oral dosage forms the study data confirming the lack of changes in the medicinal product dissolution profile of at least one pilot batch (the size should be 1/10 production scale batch or 100,000 units according to what is more) produced from a substance tested/controlled by all parameters of the new specification comparing with the dissolution profile of the medicinal product containing substances tested according to the current specification (see Note to Table). For herbal medicinal products, comparative disintegration data may be acceptable.
6. Justification for not submitting a new bioequivalence study according to the current Note for Guidance on The Investigation of Bioavailability and Bioequivalence, 42-7.1:2005, if relevant.
13 / Change in test procedure of active substance or starting material, intermediate, or reagent used in the manufacturing process of the active substance / Conditions to be met / Documents to be submitted / Type of change
(a) minor change to an approved test procedure / 1,2,3,5 / 1 / ІА
(b) other changes to a test procedure, including replacement or addition of a test procedure / 2,3,4,5 / 1,2 / ІB
Conditions
1. The method of analysis should remain the same (e.g., a change in column length or temperature, but not a different type of column or method); no new impurities are detected.2. Appropriate validation studies have been performed in accordance with requirements of the State Pharmacopoeia of Ukraine “Validation of analytical methods and tests” or Guideline on Validation of Analytical Procedures: Methodology (CPMP/ICH/281/95/Q2B).
3. Validation data confirm that the results obtained using approved test procedure are identical to those obtained usingthe new procedure.
4. Any new test method does not concern a novel non-standard technique or standard technique used in a novel way.
5. The active substance, starting material, intermediate or reagent is not a biological substance.
Documentation
1. Amendment to relevant sections of Part IIC or equivalent in the CTD format, which includes a description of the analytical methodology, a summary of validation data, revised specifications for impurities (if applicable); amendment to relevant sections of Part IIF or equivalent in the CTD format (if applicable).
2. Validation data confirm that the results obtained using approved test procedure are identical to those obtained usingthe new procedure.
14 / Change in the manufacturer of the active substance or starting material/reagent/intermediate in the manufacturing process of the active substance where no European Pharmacopoeia certificate of suitability is available / Conditions to be met / Documents to be submitted / Type of change
(a) Change in site of the already approved manufacturer (replacement or addition) / 1,2,4 / 1,2,3,4,6 / ІB
(b) new manufacturer (replacement or addition) / 1,2,3,4 / 1,2,3,4,5,6 / ІB
Conditions
1. The specifications (including in-process controls, methods of analysis of all materials), method of preparation (including batch size, starting material, impurity profile etc.) and detailed route of synthesis are identical to those already approved.
2. Where materials of human or animal origin are used in the process, the manufacturer shall not use any new supplier for which the assessment has not been performed of viral safety or the compliance with the current requirements on minimizing the risk of transmitting animal spongiform encephalopathy agents via medicinal products produced in compliance with Guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via medicinal products has not been justified.
3. The current or new active substance manufacturer shall not use a drug master file.
4. The change shall not concern a medicinal product containing a biological active substance.
Documentation
1. Amendments to relevant sections of Part IIC and IIF or equivalent in the CTD format.
2. A declarationfrom the registration certificate holder the synthetic route (or in case of herbal medicinal products, where appropriate the method of preparation procedure, geographical origin of starting material, production technology of active substance), quality control procedures and specifications of the active substance the starting material/reagents/intermediate used in the manufacturing process of the active substance are the same as those already approved.
3. TSE European Pharmacopoeia certificate of suitability for any new source of material or, where applicable, documentary evidence that the specific source of the TSE risk material has previously been assessed by the competent authority of the manufacturing country has demonstrated: the medicinal product is produced in compliance with the current Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products. The information shall include the following: name of the manufacturer, species and tissues from which the preparation has been obtained, country of origin of the source animals, its use and previous acceptance.
4. Batch analysis data (in a comparative tabular format) for at least two batches (minimum pilot scale) of the active substance from the current and proposed manufacturers/sites.
5. For solid oral dosage forms the study data confirming that no changes exist in the changed medicinal product dissolution profile for at least two pilot batches or production batches compared with the dissolution profile of the medicinal product containing active substance from the previous approved manufacturer (see Note to Table).
6. The variation application form shall clearly outline the “present” and “proposed” manufacturers as listed in section 2.5 of the application form for state registration of the medicinal product.
15 / Submission of a new or updated European Pharmacopoeia certificate of suitability for an active substance or stating material/reagent/intermediate in the manufacturing process of the active substance / Conditions to be met / Documents to be submitted / Type of change
(a) From a manufacturer currently approved / 1,2,4 / 1,2,3,4 / ІА
(b) From a new manufacturer (replacement or addition)
1. Sterile substance / 1,2,3,4 / 1,2,3,4 / ІB
2. Other substance / 1,2,3,4 / 1,2,3,4 / ІА
Conditions
1. The finished product specifications at release and within shelf life remain the same.
2. Unchanged additional (to State Pharmacopoeia of Ukraine or European Pharmacopoeia) specifications for impurities and other substance requirements (e.g. particle size profiles, polymorphic form), if applicable.
3. The active substance will be tested immediately prior to use if no retest period is included in the European Pharmacopoeia certificate of suitability, or if data to support a retest period is not provided.
4. The manufacturing process of the active substance, starting material/intermediate/reagent does not include the use of materials of human or animal origin for which an assessment of viral safety data is required.
Documentation
- Сopy of a new (revised) European Pharmacopoeia certificate of suitability.
- Amendments to relevant sections of Part IIC and IIF or equivalent in the CTD format, if applicable.
4. The variation application form shall clearly outline the “present” and “proposed” manufacturers as listed in section 2.5 of the application form for state registration of the medicinal product.
Note.The reference to unchanged specifications for impurities in condition № 2 should refer to newadditional impurities.
In notification № 10 on minor change in the manufacturing process of the active substance,condition no. 1 stipulates that there is no change in the qualitative and quantitative impurity profile or in the physiochemicalproperties. In notification № 12 on change in specification of active substance tightening of specificationlimits or addition of new test parameters are allowed. One of the conditions for these changes to qualify as a type Inotification is that the change should not be the result of unexpected events during manufacture. The conditions ofthese notifications should be born in mind in the fulfillment of the conditions of notification № 15.
16 / Submission of a new or updated TSE European Pharmacopeia certificate of suitability for an active substance or starting material/reagent/intermediate in the manufacturing process of the active substance for a currently approved manufacturer and currently approved manufacturing process / Conditions to be met / Documents to be submitted / Type of change
None / 1,2,3 / ІА
Conditions