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					                                                                                                Annex 5
                                                                to 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 of MoH Ukraine Order as 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 appli-        Conditions to     Documents to      Type of
      cant (registration certificate holder)                   be met          be submitted      change

1     Change in the name and/or address of the appli-             1             1,2,3                ІА
      cant (registration certificate holder)
      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 Documents to       Type of
                                                                       be met    be submitted      change
                                                                  1,2,3         1,2                  ІB
      Conditions
      1. No confusions with the names of existing medicinal products or with the international non-
      proprietary names (INN).
      2. The verification by 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
      1. Grounds for introducing change and new name
      2. Changes in summary of product characteristics, revised package-inserts and label samples.
3     Change in the name of active substance                      Conditions to Documents to Type of
                                                                       be met    be submitted      change
                                                                  1             1,2                  ІА
      Conditions
      1. The active substance shall remain the same
      Documentation

      1. Proof of acceptance of the INN by WHO or copy of the INN list. For herbal medicinal products, a
      statement that the name is in compliance with the established requirements or with the Note for
      Guidance on Quality of Herbal Medicinal Products.
      2. Changes in summary of product characteristics, relevant chapters of Part II of Registration Dos-
      sier or equivalent in the CTD format, revised package-insert and label samples.
                                                   2
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4   Change in the name and/or place of a                    Conditions to   Documents to be Type
    manufacturer of the active substance where no             be met            submitted       of
    European Pharmacopeia certificate of suitability                                          chang
    is available                                                                                 e
                                                           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                   Conditions to Documents to be       Type
    manufacturer of the finished product                       be met         submitted            of
                                                                                                 chang
                                                                                                    e
                                                           1                1,2,3                  ІА
     Conditions
     1. The manufacturing site shall remain the same.
     Documentation
     1.Copy of the modified manufacturing license, if necessary, or a document from a relevant compe-
     tent authority with indication of the new name and/or place/address.
     2.Changes in Part IIB or equivalent in the CTD format, if necessary.
     3. Changes in summary of product characteristics, relevant chapters of Part II of Registration Dos-
     sier or equivalent in the CTD format, revised package-insert and label samples.
6    Change in ATC Code                                      Conditions to Documents to be Type
                                                                be met           submitted          of
                                                                                                  chang
                                                                                                     e
                                                            1                1,2                    ІА
     Conditions
     1. Change following granting of or amendment to ATC Code by the WHO
     Documentation
     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          Conditions to Documents to be Type
    for part or all of the manufacturing process of the         be met           submitted          of
    finished product                                                                              chang
                                                                                                     e
    (a) Site of secondary packaging for all types of        1,2              1,2,5                  ІА
    pharmaceutical forms
    (b) Primary packaging site:
    1. Solid pharmaceutical forms, e.g. tablets and         1,2,3,5          1,2,5                  ІА
    capsules
    2. Soft or liquid pharmaceutical forms                  1,2,3,5          1,2,5                  ІB
    3. Liquid pharmaceutical forms (suspensions,            1,2,3,4,5        1,2,4,5                ІB
    emulsions)
    (c) All other manufacturing operations except for 1,2,4,5                1,3,4,5,6,7,8          ІB
    batch release
    Conditions
                                                     3
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     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 Ukraine where 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 li-
     cense, 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 manu-
     facturing 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 manu-
     facturers 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 pro-
     duction batches should be submitted on request. Also it should be stated that the Center shall be in-
     formed (with the appropriate propositions) in case of outside specifications.
     8. For soft and liquid pharmaceutical forms containing active substance in non-dissolved form, ap-
     propriate 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 organi-
zation and other relevant information. This will facilitate the work of the GMP Inspectorate of Ukraine.
8 Change in batch release arrangements and quality Conditions to Documents to Type of
     control testing of the finished product                         be met          be submitted      change
     (a) Replacement or addition of a site where batch           1,2,3              1,2                  ІА
     control/ testing takes place
     (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
                                                    4
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   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 at-
   testation certificate.
   2. The variation application shall clearly outline “present” and “proposed” finished product manu-
   facturers 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            Conditions to Documents to Type of
   substance, intermediate or finished product,                    be met          be submitted      change
   packaging site, if manufacturer is responsible for
   batch release and site where batch control takes
   place)
                                                               None               1,2                  ІА
   Conditions
   None
   Documentation
   1. The variation application shall clearly outline “present” and “proposed” finished product manu-
   facturers 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 Conditions to Documents to Type of
    active substance                                               be met          be submitted      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 Conditions to Documents to Type of
    intermediate                                                   be met          be submitted      change
    (a) Up to 10-fold compared to the original batch 1,2,3,4                      1,2                  ІА
    size approved at the grant of the registration cer-
    tificate
    (b) Down scaling                                           1,2,3,4,5          1,2                  ІА
    (c) More than 10-fold compared to the original 1,2,3,4                        1,3,4                ІБ
    batch size approved at the grant of the marketing
    authorization
    Conditions
                                                     5
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     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 manu-
     factured to both the currently approved and the proposed sizes. Batch data on the next two full pro-
     duction batches should be submitted on request. Also it should be stated that the Center shall be in-
     formed (with the appropriate propositions) in case of outside specifications.
     4. Copies of the approved specifications of the active substance (and of the intermediates, if neces-
     sary).
12   Change in the specification of an active substance Conditions to Documents to Type of
     or a starting material/intermediate/reagent used                be met        be submitted       change
     in the manufacturing process of the active
     substance
     (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 2,4                      1,2,3,4            ІB
        in the manufacturing process of the active
        substance
     Conditions
     1. The change should not result from previous assessments to review specification limits (e.g., made
     while submitting the application for the registration procedure 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 prod-
     uct 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 param-
     eters of the new specification comparing with the dissolution profile of the medicinal product con-
     taining substances tested according to the current specification (see Note to Table). For herbal me-
     dicinal 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.
                                                     6
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13   Change in test procedure of active substance or Conditions to Documents to Type of
     starting material, intermediate, or reagent used in           be met          be submitted     change
     the manufacturing process of the active substance
     (a) minor change to an approved test procedure           1,2,3,5            1                     ІА
     (b) other changes to a test procedure, including 2,3,4,5                    1,2                   ІB
     replacement or addition of a test procedure
     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 using the 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 for-
     mat (if applicable).
     2. Validation data confirm that the results obtained using approved test procedure are identical to
     those obtained using the new procedure.
14   Change in the manufacturer of the active                 Conditions to Documents to Type of
     substance or starting                                        be met           be submitted      change
     material/reagent/intermediate in the
     manufacturing process of the active substance
     where no European Pharmacopoeia certificate of
     suitability is available
     (a) Change in site of the already approved 1,2,4                            1,2,3,4,6              ІB
     manufacturer (replacement or addition)
     (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 minimiz-
     ing 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
                                                     7
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     1. Amendments to relevant sections of Part IIC and IIF or equivalent in the CTD format.
     2. A declaration from the registration certificate holder the synthetic route (or in case of herbal me-
     dicinal products, where appropriate the method of preparation procedure, geographical origin of
     starting material, production technology of active substance), quality control procedures and speci-
     fications of the active substance the starting material/reagents/intermediate used in the manufactur-
     ing 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 me-
     dicinal 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 in-
     formation 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 ac-
     ceptance.
     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 me-
     dicinal 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 ap-
     proved 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 Conditions to Documents to Type of
     Pharmacopoeia certificate of suitability for an                 be met         be submitted      change
     active           substance            or          stating
     material/reagent/intermediate              in         the
     manufacturing process of the active substance
     (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
                                                     8
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      1.Сopy of a new (revised) European Pharmacopoeia certificate of suitability.
      2. Amendments to relevant sections of Part IIC and IIF or equivalent in the CTD format, if applica-
      ble.
      3. If human or animal source material is used it shall be given an information on any materials fall-
      ing within the scope of the Note for Guidance on Minimizing the Risk of Transmitting Animal
      Spongiform Encephalopathy Agents via Medicinal Products including those used in the manufac-
      ture of the active substance. The information shall include the following: name of the manufacturer,
      animal species and tissues from which the product has been obtained, country of origin of the
      source animals, its use and the previous acceptance.
      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 new ad-
ditional 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 physio-
chemical properties. In notification № 12 on change in specification of active substance tightening of
specification limits or addition of new test parameters are allowed. One of the conditions for these
changes to qualify as a type I notification is that the change should not be the result of unexpected events
during manufacture. The conditions of these notifications should be born in mind in the fulfillment of the
conditions of notification № 15.
16 Submission of a new or updated TSE European Conditions to Documents                               Type of
      Pharmacopeia certificate of suitability for an                  be met        to be submit-    change
      active           substance           or         starting                            ted
      material/reagent/intermediate              in        the
      manufacturing process of the active substance for
      a currently approved manufacturer and currently
      approved manufacturing process
                                                                  None              1,2,3               ІА
      Conditions
      None
      Documentation
      1. Copy of the current (updated) European Pharmacopoeia TSE certificate of suitability.
      2. Changes in relevant sections of Part IIC or equivalent in the CTD format, if necessary.
      3. A document providing information of any materials falling within the scope of the Note for
      Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via
      Medicinal Products including those which are used in the manufacture of the active substance. The
      following information should be included: name of manufacturer, species and tissues from which
      the product has been obtained, country of origin of the source animals, its use and previous ac-
      ceptance.
17 Change in:                                                     Conditions to Documents to Type of
                                                                      be met         be submitted      change
      (a) the re-test period of the active substance              1,2,3             1,2                  ІB
      (b) the storage conditions for the active substance 1,2                       1,2                  ІB
      Conditions
      1. Stability studies have been done according to the currently approved protocol. The studies must
      show that the agreed relevant specifications are still met.
      2. The change should not result from unexpected events arising during manufacture or because of
      stability concerns.
      3. The active substance is not a biological substance.
      Documentation
                                                     9
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     1. Amendments to relevant sections of Part IIC, IIF or equivalent in the CTD format. Results of ap-
     propriate real time stability studies conducted in accordance with the Guidelines on Studies of the
     Stability of New Active Substances and Medicinal Products for at least two (three for biological
     medicinal products) pilot or production scale batches of the active substance in the authorised pack-
     aging material and covering the duration of the requested re-test period or requested storage condi-
     tions.
     2. Copies of approved specifications of the active substance.

18   Replacement of an excipient with a comparable Conditions to Documents to Type of
     excipient                                                     be met        be submitted       change
                                                               1,2,3,4,5,6     1,2,3,4,5,6,7,8,9      ІB
     Conditions
     1. Same functional characteristics of the excipient.
     2. The dissolution profile of the new product determined on a minimum of two pilot scale batches is
     comparable with the old one. For herbal medicinal products where dissolution testing may not be
     feasible, the comparative disintegration data may be acceptable.
     3. Any new excipient does not include the use of materials of human or animal origin for which
     assessment is required of viral safety data.
     4. Medicinal products do not contain biological active substances.
     5. Stability studies in accordance with the relevant guidelines have been started with two pilot or
     industrial batches and at least three months’ satisfactory stability data. The applicant shall also
     assure that after finalizing these studies their data will be provided immediately to the Center if
     outside specifications or potentially outside specifications within approved shelf life (with proposed
     action).
     6. No amendments to the specification of the finished medicinal product.
     Documentation
     1. Amendments to relevant sections of Part IIA, IIB, IIC, IIE and IIF or equivalent in the CTD for-
     mat.
     2. Substantiation of the change/choice of excipients must be given by appropriate development
     pharmaceutics (including stability aspects and antimicrobial preservation).
     3. For solid dosage forms, comparative dissolution profile data of at least two pilot scale batches of
     the finished product in the new and old composition (see Note to Table). For herbal medicinal
     products, comparative disintegration data may be acceptable.
     4. Substantiation for not submitting a new bioequivalence study according to the Guidance on The
     Investigation of Bioavailability and Bioequivalence 42-7.1:2005, if appropriate.
     5. Either a European Pharmacopoeia certificate of suitability for any new starting material or docu-
     mentary evidence that the specific source of the TSE risk material has been previously assessed by
     the competent authority of the manufacturing country and shown to comply with the scope of the
     Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathies via Medic-
     inal Products. The information should include the following: name of manufacturer, species and
     tissues from which the product has been obtained, country of origin of the source animals, its use
     and previous acceptance.
     6. Data to demonstrate that the new excipient does not interfere with the finished product specifica-
     tion test method (if appropriate).
     7. The batch numbers of the batches used in the stability studies should be given.
     8. Certificates of quality of the finished medicinal product (at least two batches) containing new
     excipients.
     9. Changes in summary of product characteristics, revised package-inserts and samples of labelling
     (if necessary).
19   Change in specification of an excipient                   Conditions to Documents to Type of
                                                                   be met        be submitted       change
     a) tightening of specification limits                     1,2,3            1,2                   ІА
                                                    10
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                                                             2,3              1,2                ІB
     b) addition of a new quality parameter to the           2,4,5            1,2,3,4,5,6        ІB
     specification

     Conditions
     1. The changes do not result from previous assessments to review specification limits (e.g., made
     while submitting the application for the registration procedure or type II variation procedure).
     2. The changes 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 methods do not concern a novel non-standard technique or standard technique used
     in a novel way.
     5. The change does not concern biological excipient.
     Documentation
     1. Amendments to relevant sections of Part IIC or equivalent in the CTD format.
     2. Comparative table of current and proposed specifications.
     3. Details of any new analytical method and summary of validation data.
     4. Batch analysis data on two production batches for all tests in the new specification.
     5. For solid oral dosage forms the study data confirming that no changes exist in dissolution profile
     of the changed product on at least one pilot scale batch containing the excipient tested by all param-
     eters of the new specification compared to the dissolution profile of the medicinal product contain-
     ing the excipient controlled according to the previous specification (see Note to Table). For herbal
     medicinal products, comparative disintegration data may be acceptable.
     6. Substantiation for not submitting data of a new bioequivalence study according to the Guidance
     on The Investigation of Bioavailability and Bioequivalence 42-7.1:2005, if relevant.

20   Change in test procedure for an excipient               Conditions to     Documents to be      Type
                                                               be met            submitted            of
                                                                                                    chang
                                                                                                       e
     (a) Minor change to an approved test procedure           1,2,3,5           1                     ІА
     (b) Minor change to an approved test procedure           1,2,3             1,2                   ІB
     for a biological excipient
     (c) Other changes to a test procedure, including         2,3,4,5           1,2                  ІB
     replacement of an approved test procedure by a
     new test procedure
     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 declared.
     2. Appropriate validation studies have been performed in accordance with the requirements of the
     State Pharmacopeia of Ukraine “Validation of analytical methods and tests” or Guidelines on Vali-
     dation of Analytical Procedures: Methodology (CPMP/ICH/281/95/Q2B).
     3. Results of method validation show new test procedure to be equivalent to the former procedure.
     4. Any new test method does not concern a novel non-standard technique or a standard technique
     used in a novel way.
     5. The substance is not a biological excipient.
     Documentation
     1. Amendments 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 limits for impuri-
     ties (if applicable); amendments to relevant sections of Part IIF or equivalent in the CTD format, if
     applicable.
     2. Comparative validation results showing that the current test and the proposed one are equivalent.
                                                    11
                                                                                     Продовження додатка 5
21   Submission of a new or updated European Conditions to Documents to Type of
     Pharmacopoeia certificate of suitability for an               be met          be submitted     change
     excipient
     (a) From a manufacturer currently approved               1,2,3              1,2,3                ІА
     (b) From a new manufacturer (replacement or
     addition)
     1. Exipients for manufacturing sterile medicinal 1,2,3                      1,2,3                ІB
     products
     2. Other excipients                                      1,2,3              1,2,3                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 product specific requirements (e.g. particle size profiles, polymorphic form), if
     applicable.
     3. The manufacturing process of the excipient does not include the use of materials of human or
     animal origin for which an assessment of viral safety data is required.
     Documentation
     1. Copy of the current (updated) European Pharmacopoeia certificate of suitability.
     2. Changes in relevant sections of Part IIC or equivalent in the CTD format.
     3. For excipients of animal origin a document with any materials falling within the scope of the
     Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy
     Agents via Human and Veterinary Medicinal Products including those which are used in the manu-
     facture of the excipient. The following information should be included: name of manufacturer, spe-
     cies and tissues from which the product is obtained, country of origin of the source animals, its use
     and the previous acceptance.
22   Submission of a new or updated TSE European Conditions to Documents to Type of
     Pharmacopoeia certificate of suitability for an               be met          be submitted     change
     excipient from a manufacture currently approved
     or a new manufacturer (replacement or addition)
                                                              None               1,2,3                IA
     Conditions
     None
     Documentation
     1. Copy of the current (updated) TSE European Pharmacopoeia certificate of suitability.
     2. Changes in relevant sections of Part IIC or equivalent in the CTD format.
     3. For excipients of animal origin a document providing information of any materials falling within
     the scope of the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform En-
     cephalopathy Agents via Medicinal Products including those which are used in the manufacture of
     the excipient. The following information should be included: name of manufacturer, species and
     tissues from which the material is obtained, country of origin of the source animals, its use and the
     previous acceptance.
23   Change in source of an excipient or reagent from Conditions to Documents to Type of
     a TSE risk to a vegetable or synthetic material               be met          be submitted     change

     a) Excipient or reagent used in manufacture of 1                          1,2                   ІB
     biological active substance or manufacture of a
     finished product containing biological active
     substance
     (b) Other cases                                          1                1                     IA
     Conditions
     1. Excipient and finished product specifications at release and within shelf life remain the same.
                                                   12
                                                                                    Продовження додатка 5
     Documentation
     1. Declaration from the manufacturer of the starting material that it is purely of vegetable or syn-
     thetic origin.
     2. Study of equivalence of the starting materials and the impact on production of the finished prod-
     uct.
24   Change in synthesis or recovery of a non- Conditions to Documents to Type of
     pharmacoepial (State Pharmacopoeia of Ukraine                 be met         be submitted      change
     or European Pharmacopoeia) excipient (when
     described in dossier)
                                                               1,2              1,2,3,4                ІB
     Conditions
     1. Specifications are not adversely affected: no change in qualitative and quantitative impurity
     profile or in physico-chemical properties.
     2. The excipient is not a biological substance.
     Documentation
     1. Changes in relevant sections of Part IIC or equivalent in the CTD format.
     2. Batch analysis data (in a comparative tabulated format) of at least two batches (minimum pilot
     scale) of the excipient manufactured according to the old and the new process.
     3. For solid oral dosage forms the study data confirming that no changes exist in the changed me-
     dicinal product dissolution profile for at least two pilot batches containing active substance manu-
     factured using new technology compared with the dissolution profile of the medicinal product con-
     taining active substance from the previous approved manufacturer (see Note to Table). For herbal
     medicinal products, comparative disintegration data may be acceptable.
     4. Copy of approved and new (if applicable) specifications of the excipient.
25   Change to comply with updates of the State Conditions to Documents to Type of
     Pharmacopoeia of Ukraine or with European                     be met         be submitted      change
     Pharmacopoeia
     (a) Change to comply with monograph of the
     State Pharmacopoeia of Ukraine or European
     Pharmacopoeia
     1. Active substance                                       1,2              1,2,3,4,5,6            ІB
     2. Excipient                                              1,2              1,2,3,4,5,6            ІB
     b) Change of specifications of pharmacopoeial
     substance to comply with an update of the State
     Pharmacopoeia of Ukraine or European
     Pharmacopoeia
     1. Active substance                                       1,2              1,2                    IA
     2. Excipient                                              1,2              1,2                    IA
     Conditions
     1. Change is made exclusively to comply with pharmacopoeia.
     2. Unchanged specifications (additional to the pharmacopoeia) for product specific properties (e.g.,
     particle size profiles, polymorphic form), if applicable.
     Documentation
                                                    13
                                                                                   Продовження додатка 5
     1. Changes in relevant sections of Part IIC or equivalent in the CTD format.
     2. Comparative table of current and proposed specifications.
     3. Batch analysis data on two production batches of the relevant substance for all parameters in the
     new specification.
     4. Data to demonstrate the suitability of the monograph to control the substance.
     5. Batch analysis data (in a comparative tabulated format) on two production batches of the finished
     product containing the substance complying with the current and proposed specifications. For solid
     oral dosage forms the study data confirming absence of any changes in dissolution profile on at
     least one pilot scale batch of the finished product containing the excipient complying with the pro-
     posed specification compared to the dissolution profile of the medicinal product containing the ex-
     cipient which complies with the current specification (see Note to Table). For herbal medicinal
     products, comparative disintegration data may be acceptable.
     6. For biological medicinal products, demonstration that consistency of quality and of the produc-
     tion process is maintained.
26   Change in the specifications of the immediate            Conditions to Documents to Type of
     packaging of the finished product                            be met        be submitted       change
     (a) Tightening of specification limits                   1,2,3            1,2                   IA
                                                              2,3              1,2                    ІB
     (b) Addition of a new test parameter                     2,4              1,2,3,4                IB
     Conditions
     1. The change should not result from previous assessment to review specification limits (e.g., made
     during procedure for submitting an application for the registration or a 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.
     Documentation
     1. Changes in relevant sections of Part IIC or equivalent in the CTD format.
     2. Comparative table of current and proposed specifications.
     3. Details of any new analytical method and validation data.
     4. Batch analysis certificates on two production scale batches using the proposed immediate pack-
     aging.

27   Change to a test procedure of the immediate Conditions to Documents to Type of
     packaging of the finished product                         be met        be submitted     change
     (a) minor change to an approved test procedure        1,2,3           1                    IA
     (b) other changes to a test procedure, including 2,3,4                1,2                  IB
     replacement or addition of a test procedure
     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).
     2. Appropriate validation studies were performed in accordance with the 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. Results of method validation show new test procedure to be at least equivalent to the former
     procedure.
     4. Any new method does not concern a novel standard technique or a standard technique used in a
     novel way.
     Documentation
                                                     14
                                                                                     Продовження додатка 5
     1. Amendment to relevant sections of Part IIC or equivalent in the CTD format which includes a
     description of the analytical methodology and a summary of validation data.
     2. Comparative validation results showing that the current test and the proposed one are equivalent.
28   Change in any part of the (primary) packaging               Conditions to Documents to be Type
     material not in contact with the finished product               be met           submitted            of
     formulation (such as color of flip-off caps, color                                                  chang
     code of rings on ampoules, change of needle shield                                                     e
     (different plastic used))
                                                                 1                1                        IA
     Conditions
     1. The change does not concern a fundamental part of the packaging material, which affects the
     delivery, useability, safety or stability of the finished product.
     Documentation
     Amendments to the relevant section of Part IIC or equivalent in the CTD format.
29   Change in the qualitative and/or quantitative               Conditions to Documents to Type of
     composition of the immediate packaging material                 be met         be submitted       change
     (а) soft and liquid pharmaceutical forms                    1,2,3,4          1,2,3,4,5               ІB
     (б) all other pharmaceutical forms                          1,2,3,4          1,4,5                   IA
                                                                 1,3,4            1,2,3,4,5               ІB
     Conditions
     1. The product concerned is not a biological or sterile product.
     2. The change only concerns the same packaging type and material (e.g. blister to blister)
     3. The proposed packaging material must be at least equivalent to the approved material in respect
     of its relevant properties.
     4. Stability studies in accordance with the relevant guidelines have been started with at least two
     pilot scale or industrial scale batches and satisfactory stability data obtained during at least three
     months. Also the applicant makes sure that once these studies are finalized the Center shall be in-
     formed immediately in case of outside specifications or potentially outside specifications within the
     approved shelf life (with proposed action).
     Documentation
     1. Amendments to relevant sections of Part IIA, IIC and IIF or equivalent in the CTD format.
     2. Appropriate data on the new packaging (comparative data on permeability e.g. for O2, CO2,
     moisture).
     3. Proof must be provided that no interaction between the content and the packaging material occurs
     (e.g. no migration of components of the proposed packaging material into the content of the prod-
     uct, and the quality profile of the product in the new pack remains the same).
     4. The batch numbers of batches used in the stability studies should be indicated.
     5. Comparative table of the current and proposed specifications, if applicable.
30   Change (replacement, addition or deletion) in Conditions to Documents to Type of
     supplier of packaging components or devices                     be met         be submitted       change
     (when mentioned in the dossier); spacer devices
     for metered dose inhalers are excluded
     (a) deletion of a supplier                                  1                1                       IA
     (b) replacement or addition of a supplier                   1,2,3,4          1,2,3                   ІB
     Conditions
     1. No deletion of packaging component or device.
     2. The qualitative and quantitative composition of the packaging components/device remains the
     same.
     3. The specifications and quality control method are equivalent.
     4. The sterilization method and conditions remain the same, if applicable.
     Documentation
                                                    15
                                                                                     Продовження додатка 5
      1. Amended section Part IIC or equivalent in the CTD format.
      2. For devices for administration of medicinal product, proof of CE marking (if applicable) and
      conclusion of MoH Ukraine on the device safety.
      3. Comparative table of current and proposed specifications, if applicable.
Note. CE marking – obligatory marking of certain classes of products to ensure the compliance with re-
quirements of the European Union directives on their safety for health. Marking “'CE” – an abbrevia-
tion of Conformit Europeane. In order to make CE marking to be applicable to the product the require-
ments of the European directives shall be met. In addition, the product’s conformance shall be justified
during the registration and/or trials.
31 Change to in-process tests or limits applied                 Conditions to Documents to Type of
      during the manufacture of the product                         be met         be submitted       change
      (a) tightening of in-process limits                       1,2,3            1,2                    IA
                                                                2,3              1,2                    ІB
      (b) addition of new quality parameters and limits 2,4                      1,2,3,4                ІB
      Conditions
      1. The change is not a consequence of any commitment from previous assessments caused by the
      necessity to revise the specification (e.g. made during the registration procedure or a type II
      variation procedure).
      2. The change does not result from unexpected events arising during manufacture or because of
      stability concerns.
      3. Any change should be within the range of the currently approved limits.
      4. Any new test method does not concern a novel non-standard technique or standard technique used
      in a novel way
      Documentation
      1. Amendments to relevant sections of Part IIB or equivalent in the CTD format, and IID or equiva-
      lent in the CTD format.
      2. Comparative table of current and proposed specifications.
       3. Details of any new analytical method and validation data.
      4. Batch analysis certificates on two (three for biological medicinal products) production batches
      for all parameters in the new specification.

32   Change in batch size of the finished product     Conditions to Documents to                 Type of
                                                          be met     be submitted                 change
     (a) up to 10-fold compared to the original batch 1,2,3,4,5     1,4                          IA
     size approved at the registration
     (b) up to 10-fold decrease                       1,2,3,4,5,6   1,4                          ІB
     (c) other situations                             1,2,3,4,5,6,7 1,2,3,4,5                    ІB
     Conditions
                                                    16
                                                                                    Продовження додатка 5
     1. The change does not affect the reproducibility and/or consistency of the product functional char-
     acteristics.
     2. The change relates only to standard immediate release oral pharmaceutical forms and non-sterile
     liquid forms.
     3. Any changes to the manufacturing method and/or to the in-process controls are only those
     necessitated by the change in batch size, e.g. use of different-sized equipment.
     4. Validation scheme is available or validation of manufacture has been successfully carried out
     according to the current protocol with at least three batches at the proposed new batch size in
     accordance with the relevant guidelines.
     5. It does not concern a medicinal product containing a biological active substance.
     6. The change should not be a result of unexpected events arisen during manufacture or because of
     stability concerns.
     7. Stability studies in accordance with the relevant guidelines have been started with at two pilot
     scale or industrial scale batches and satisfactory stability data obtained during at least three months.
     Also the applicant makes sure that once these studies are finalized the Center shall be informed
     immediately in case of outside specifications or potentially outside specifications within the
     approved shelf life (with proposed action).
     Documentation
     1. Amended section Part IIB or equivalent in the CTD format.
     2. Batch analysis data (in a comparative tabulated format) on a minimum of one production batch
     manufactured to both the currently approved and the proposed sizes. Batch data on the next two full
     production batches should be made available upon request and reported immediately to the Center
     in case of outside specifications (with proposed action).
     3. Copy of approved specifications at release and within shelf life.
     4. The batch numbers (≥3) used in the validation study should be indicated or validation protocol
     (scheme) be submitted.
     5. The batch numbers of batches used in the stability studies should be indicated.
     Minor change in the manufacture of the finished Conditions to Documents to Type of
33   product                                                        be met        be submitted        change
                                                                1,2,3,4,5        1,2,3,4,5,6,7,8        ІB
     Conditions
     1. The overall production technology remains the same.
     2. The new process must lead to an identical product regarding all aspects of quality, safety and
     efficacy.
     3. The medicinal product does not contain a biological active substance.
     4. In case of a change in the sterilization process, the change is to standard pharmacopoeial cycle
     only.
     5. Stability studies in accordance with the relevant guidelines have been started with two pilot scale
     or industrial scale batches and at least three months’ satisfactory stability data are available. Also
     the applicant makes sure that once these studies are finalized the Center shall be informed
     immediately in case of outside specifications or potentially outside specifications within the
     approved shelf life (with proposed action).
     Documentation
                                                    17
                                                                                    Продовження додатка 5
     1. Amended section Part IIB or equivalent in the CTD format.
     2. For soft and liquid products in which the active substance is present in non-dissolved form: ap-
     propriate validation of the change including microscopic imaging of particles to check for visible
     changes in morphology; comparative size distribution data by an appropriate method.
     3. For solid dosage forms: dissolution profile data of one representative production batch of the me-
     dicinal product the manufacture of which has been changed in comparison with other three batches
     from the previous process (see Note to the table). Data on the next two batches should be made
     available on request and declared that the Center will be informed in case of outside specifications
     (with proposed action). For herbal medicinal products, comparative disintegration data may be ac-
     ceptable.
     4. Justification for not submitting a new bioequivalence study according to the Note for Guidance
     on The Investigation of Bioavailability and Bioequivalence 42-7.1:2005.
     5. In case of a change to the sterilisation process, validation data should be provided.
     6. Copy of approved specifications at release and within shelf life.
     7. Batch analysis data (in a comparative tabulated format) on a minimum of one batch manufac-
     tured to both the currently approved and the proposed process. Data on the next two full production
     batches should be made available on request. Also it should be stated that the Center will be in-
     formed in case of an outside specification (with proposed action).
     8. The batch numbers of batches used in the stability studies should be indicated.
34   Change in the coloring system or the flavoring Conditions to Documents to Type of
     system currently used in the finished product                  be met        be submitted        change
     (a) Reduction or deletion of one or more
     components of the:
     1. coloring system                                         1,2,3,4,7        1,2,3                  IА
     2. flavoring system                                        1,2,3,4,7        1,2,3                  IА
     (b) Increase, addition or replacement of one or
     more components of the:
     1. coloring system                                         1,2,3,4,5,6,7    1,2,3,4,5              ІB
     2. flavoring system                                        1,2,3,4,5,6,7    1,2,3,4,5              ІB
     Conditions
     1. No change in functional characteristics of the pharmaceutical form, e.g. disintegration time,
     dissolution profile.
     2. Any minor adjustment to the formulation to maintain the total weight should be made by an
     excipient which currently makes up a major part of the finished product formulation.
     3. The finished product specification has only been updated in respect of appearance/odour/taste
     and if relevant, deletion or addition of an quality parameter for colouring or flavor additive .
     4. Stability studies in accordance with relevant guidelines have been started with at least two pilot
     scale or industrial batches and at least three months’ satisfactory stability data are available. Also
     the applicant makes sure that once these studies are finalized the Center shall be informed
     immediately in case of outside specifications or potentially outside specifications within the
     approved shelf life (with proposed action). In addition, where relevant, photo-stability testing
     should be performed.
     5. Any new components must comply with the relevant requirements.
     6. Any new component does not include the use of materials of animal or human origin, for which
     assessment is required of viral or spongiform encephalopathy safety data.
     7. Changes in short characteristic of product, revised package-insert and samples of labelling.
     Documentation
                                                      18
                                                                                  Продовження додатка 5
     1. Amendments to relevant sections of Part II A, II B, II C, II E or equivalent in the CTD format
     (including identification method for any new colorant, where relevant) and IIF or equivalent in the
     CTD format (if specifications have been updated within shelf life).
     2. The batch numbers of the batches used in the stability studies should be indicated.
     3. Sample of the new finished medicinal product.
     4. Either a European Pharmacopoeia certificate of suitability for any new starting material or where
     applicable, documentary evidence that the specific source of the TSE risk substance has been previ-
     ously assessed by the competent authority of the manufacturing country, and the medicinal product
     has been shown to comply with the current Note for Guidance on Minimising the Risk of Transmit-
     ting Animal Spongiform Encephalopathies via Medicinal Products. The following information
     should be included: name of manufacturer, species and tissues from which the product is a deriva-
     tive, country of origin of the source animals, its use and previous permit.
     5. Data to demonstrate that the new colouring agent or flavour additive does not interfere with the
     finished product specification test methods, if appropriate.
35   Change in coating weight of tablets or change in Conditions to Documents to Type of
     weight of capsule shells                                      be met        be submitted     change

     (a) immediate release oral pharmaceutical forms            1,3,4            1,4                     IА
     (b) gastro-resistant, modified or prolonged release 1,2,3,4                 1,2,3,4                 ІB
     pharmaceutical forms
     Conditions
     1. No changes in dissolution profile, in a minimum of two pilot scale batches of the medicinal
     product with new composition as compared to the dissolution profile of two production scale batch-
     es with new vs. approved composition. For herbal medicinal products the comparative
     disintegration data may be acceptable.
     2. The coating is not a critical factor for the release mechanism.
     3. The finished product specification has only been updated in respect of weight and dimensions, if
     applicable.
     4. Stability studies in accordance with the relevant guidelines have been started with at least two
     pilot scale or industrial scale batches, and at least three months’ satisfactory stability data are avail-
     able. Also the applicant makes sure that once these studies are finalized the Center shall be in-
     formed immediately in case of outside specifications or potentially outside specifications within the
     approved shelf life (with proposed action).
     Documentation
     1. Amended pages of Part IIA, IIB and IIE or equivalent in the CTD format.
     2. Data of studies confirming the absence of any changes in dissolution profile, in a minimum of
     two pilot scale batches of the medicinal product with new composition as compared to the dissolu-
     tion profile of two production scale batches with the new vs. approved composition (see Note to
     Table). For herbal medicinal products the comparative disintegration data may be acceptable.
     3. Justification for not submitting a new bioequivalence study according to the Note for Guidance
     on “The Investigation of Bioavailability and Bioequivalence”42-7.1:2005 .
     4. The batch numbers of the batches used in the stability studies should be indicated.
36   Change in shape or dimensions of the container Conditions to Documents to Type of
     or closure                                                     be met         be submitted       change
     (a) sterile pharmaceutical forms and biological 1,2,3                       1,2,3                   IB
     medicinal products
     (b) other pharmaceutical forms                             1,2,3            1,2,3                   IA
     Conditions
                                                    19
                                                                                    Продовження додатка 5
     1. No change in qualitative or quantitative composition of the container.
     2. The change does not concern a fundamental part of the packaging material, which affect the
     delivery, usability, safety or stability of the finished product.
     3. In case of change in the head space or change in the surface/volume ratio, stability studies in
     accordance with the relevant guidelines have been started with at least two pilot scale (three for
     biological medicinal products) or industrial scale batches and at least three months’ (six months’ for
     biological medicinal products) stability data should be at the disposal of the applicant. Also the ap-
     plicant makes sure that once these studies are finalized the Center shall be informed immediately in
     case of outside specifications or potentially outside specifications within the approved shelf life
     (with proposed action).
     Documentation
     1. Amendments to relevant sections of Part IIC or equivalent in the CTD format (including descrip-
     tion, detailed drawing and composition of the container or closure material).
     2. The batch numbers of the batches used in the stability studies should be indicated.
     3. Samples of the new container/closure.
37   Change in the specification of the finished Conditions to Documents to Type of
     product                                                         be met       be submitted     change
     (a) tightening of the specification limits                  1,2,3          1,2                  IА
                                                                 2,3            1,2                  ІB
     (b) addition of a new quality parameter                     2,4,5          1,2,3,4              ІB
     Conditions
     1. The change does not result from previous assessment to review specification limits (e.g. made
     during the registration procedure or a type II variation introduction procedure).
     2. The change should not result from unexpected events arising during manufacture or because of
     stability concerns.
     3. Any change should be within the range of currently approved limits within the specification.
     4. Any new test method does not concern a novel non-standard technique or a standard technique
     used in a novel way.
     5. The test procedure does not apply to a biological active substance or biological excipient in the
     medicinal product.
     Documentation
     1. Amendments to relevant sections of Part IIE or equivalent in the CTD format.
     2. Comparative table of current and proposed specifications.
     3. Details of any new analytical method and validation data.
     4. Batch analysis data on two production batches of the finished product for all parameters in the
     proposed specification.
38   Change in test procedure of the finished product            Conditions to Documents to Type of
                                                                     be met       be submitted     change
     (a) minor change to an approved test procedure              1,2,3,4,5      1                    IА
     (b) minor change to an approved test procedure 1,2,3,4                     1,2                  ІB
     for active substance or excipients of biological
     origin
     (c) other changes to a test procedure, including 2,3,4,5                   1,2                  ІB
     replacement or addition of a test procedure
     Conditions
                                                   20
                                                                                    Продовження додатка 5
     1. The method of analysis should remain the same (e.g. change in column length or temperature, but
     not a different type of column or method).
     2. Appropriate validation studies have been performed in accordance with the requirements of the
     State Pharmacopeia of Ukraine “Validation of analytical methods and tests” or Guideline on Vali-
     dation of Analytical Procedures: Methodology (CPMP/ICH/281/95/Q2B).
     3. Results of method validation show the results obtained using the new test procedure to be at least
     equivalent to the results obtained using the former procedure.
     4. Any new test method does not concern a novel non-standard technique or a standard technique
     used in a novel way.
     5. The test procedure does not apply to a biological active substance or biological excipient in the
     medicinal product.
     Documentation
     1. Amendments to sections of Part IIE or equivalent in the CTD format, which includes a descrip-
     tion of the analytical methodology, a summary of validation data, revised specifications for impuri-
     ties (if applicable); amendments to relevant sections of Part IIF or equivalent in the CTD format (if
     applicable).
     2. Comparative validation results showing that results obtained using the current test are equivalent
     to results obtained using the proposed test.
39   Change or addition of imprints, bossing or other Conditions to Documents to Type of
     marking (except scoring/break lines) on tablets or            be met        be submitted     change
     printing on capsules, including replacement, or
     addition of inks used for product making
                                                               1,2              1,2                  IA
     Conditions
     1. Finished product release and within shelf life specifications have not been changed (except for
     appearance).
     2. Any new ink must comply with the relevant requirements.
     Documentation
     1. Amendments to relevant sections of Part IIA, IIC (in case of new ink), IID and IIE or equivalent
     in the CTD format (including a detailed drawing or written description of the current and new ap-
     pearance).
     2. Samples of the finished medicinal product.
     3. Changes in summary of product characteristics, revised package inserts and samples of label-
     ling.
40   Change of dimensions of tablets, capsules, suppos- Conditions to Documents to Type of
     itories or pessaries without change in qualitative            be met        be submitted     change
     or quantitative composition and mean mass

     (a) gastro-resistant, modified or prolonged release 1,2                   1,2,3,4,5             ІB
     pharmaceutical forms and scored tablets
     (b) all other tablets, capsules, suppositories and 1,2                    1,2                  IA
     pessaries
     Conditions
     1. No changes in the dissolution profile of the product with new dimensions in comparison with the
     dissolution profile of the product with the old dimensions. For herbal medicinal products, where
     dissolution testing may not be feasible, the comparative disintegration data may be acceptable.
     2. Specifications of the product at release and within shelf life have not been changed (except for
     dimensions).
     Documentation
                                                    21
                                                                                    Продовження додатка 5
     1. Amendments to the relevant sections of parts IIB and IIE (including a detailed drawing of the
     current and proposed dimensions of tablets, capsules, suppositories or pessaries) or equivalent in the
     CTD format.
     2. For solid dosage forms: dissolution profile data confirming the absence of any changes in disso-
     lution profile of one pilot production batch of the medicinal product with new dimensions compared
     to the dissolution profile of the medicinal product with old dimensions (see Note to Table). For
     herbal medicinal products, comparative disintegration data may be acceptable.
     3. 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.
     4. Samples of the finished product.
     5. Where applicable, data on breakability test of tablets at release must be given and commitment to
     submit data on breakability within shelf life.
41   Change in pack size of the finished product               Conditions to Documents to be Type
                                                                   be met           submitted         of
                                                                                                   chang
                                                                                                       e
     (a) change in the number of units (e.g. tablets,
     ampoules, etc.) in a pack
     1. Change within the range of the currently approved 1,2                   1,3                   IА
     pack sizes
     2. Change outside the range of the currently              1,2              1,2,3                 ІB
     approved pack size
     (b) change in the fill weight/fill volume for non-        1,2              1,2,3,4               ІB
     parenteral multi-dose products
     Conditions
     1. New pack size should be consistent with the posology and treatment duration as approved in the
     summary of product characteristics.
     2. The primary packaging material remains the same.
     Documentation
     1. Amendments to the relevant sections of parts IIA, IIC and IIE and equivalent in the CTD format.
     2. Substantiation for the new pack-size, showing that the new size is consistent with the dosage reg-
     imen and duration of use as approved in the summary of product characteristics.
     3. Declaration that stability studies will be conducted in accordance with the Guidance on The Sta-
     bility Study of New Active Substances and Medicinal Products where stability parameters could be
     affected. Data to be reported only if outside specifications (with proposed action).
     4. Changes in summary of product characteristics, revised package inserts and samples of
     labelling.
42   Change in:                                                Conditions to Documents to be Type
                                                                   be met           submitted         of
                                                                                                   chang
                                                                                                       e
     (a) the self-life of the finished product:
     1.As packaged for sale                                    1,2,3            1,2,3                 ІB
     2. After first opening                                    1,2              1,2,3                 ІB
     3.After dilution or reconstitution                        1,2              1,2,3                 ІB
     (b) the storage conditions of the finished product or     1,2,4            1,2,3                 ІB
     the diluted/reconstituted product
     Conditions
                                                    22
                                                                                   Продовження додатка 5
     1. Stability studies have been done according to the currently approved protocol. The studies must
     show that the agreed relevant specifications are still met.
     2. The change should not be the result of unexpected events arising during manufacture or because
     of stability concerns.
     3. The shelf life does not exceed five years.
     4. The product is not a biological medicinal product.
     Documentation
     1. Amendments to relevant sections of Part IIF or equivalent in the CTD format must contain results
     of appropriate real time stability studies conducted in accordance with the Guidance on The Stabil-
     ity Study of New Active Substances and Medicinal Products on at least two production scale batches
     of the finished product in the authorised packaging material and/or after first opening or reconstitu-
     tion, as appropriate; where applicable, results of appropriate microbiological testing should be in-
     cluded.
     2. Copy of approved specifications within shelf life of the finished product and where applicable,
     specifications after dilution/reconstitution or first opening.
      3. Changes in summary of product characteristics, revised package inserts and samples of label-
     ling.
43   Addition, replacement or deletion of a measuring Conditions to Documents to Type of
     or administration device not being an integrated               be met       be submitted       change
     part of the primary packaging (spacer device for
     metered dose inhalers are excluded)
     1. Addition or replacement                                 1,2            1,2,4                   IА
     2. Deletion                                                3                                      ІB
     Conditions
     1. The proposed dose measuring device must accurately deliver the required dose for the product
     concerned in line with the approved posology and the results of such studies should be made
     available.
     2. The new device is compatible with the medicinal product.
     3. The medicinal product can still be accurately delivered and metered.
     Documentation
     1. Amended sections of Part IIA and Part IIC or equivalent in the CTD format (including descrip-
     tion, detailed drawing and composition of the device material and supplier where appropriate).
     2. Proof of CE marking, if appropriate, or relevant MoH Ukraine conclusion on the device safety.
     3. Reference to CE marking for device, where applicable, or data to demonstrate accuracy, precision
     and compatibility of the device if no CE marking is available.
     4. Samples of the new device.
44   Changes in the summary of product Conditions to Documents to Type of
     characteristics, package leaflet/insert and                    be met       be submitted       change
     labelling introduced in the context of healthcare,
     in particular, due to the results of postmarketing
     surveillance.
                                                                1              1,2                     ІB
     Conditions
     The variation concerns only the introduction of change to the summary of product characteristics,
     package leaflet/insert and labelling to take into account decisions made in the interests of healthcare
     after the results of postmarketing surveillance.
     Documentation
     1. Substantiation of changes.
     2. Changes in summary of product characteristics, revised package inserts and labelling, mock-ups
     of packaging.
                                                   23
                                                                               Продовження додатка 5
45   Deletion of:                                           Conditions to   Documents to be Type
                                                              be met            submitted      of
                                                                                             chang
                                                                                                e
     (a) pharmaceutical form                                   1            1,2,3              IА
     (b) strength                                              1            1,2,3              IА
     (c) a pack size                                           1            1,2,3              IА
     Conditions
     1. The remaining product presentation(s) must be adequate for the dosing instructions and treatment
     duration as mentioned in the summary of product characteristics.
     Documentation
     1. Deletion justification of pharmaceutical form, strength and/or package (-s) and declaration the
     safety of medicinal product shall remain the same.
     2. Declaration that after the introduction of changes the medicinal product shall comply with the
     dosage regimen and treatment duration indicated in the summary of product characteristics.
     3. Revised summary of product characteristics, package insert, packaging (if appropriate).

                                        Note to Table
         Validation of similarity of dissolution profiles for solid oral dosage forms

Testing for validation of similarity of dissolution profiles for solid oral dosage forms shall
comply with requirements of general monograph “Dissolution” of the State Pharmacopoeia
of Ukraine or the European Pharmacopoeia if there are no proofs that these requirements
are not acceptable. If these conditions of dissolution testing are not in compliance with the
pharmacopoeial ones the validation data of the indicated testing shall be provided.
Providing data on dissolution profile the following shall be indicated:
   1. Brief description of the changed product including the information on batch size,
      batch numbers, shelf life, dosing, number of tested samples.
   2. Used device/method (device with paddle or device with basket, or other device at
      justification).
   3. Agitation rate (for device with paddle – 50 rpm, for device with basket – 100 rpm or
      other values at justification).
   4. Justification of the medium composition for dissolution to provide the pH 1.2, pH
      4.5, pH 6.8 values.
   5. Volume of the dissolution medium shall be 900 ml if other is not justified.
   6. Temperature of the dissolution medium (37.0±0.5)°C.
   7. Time of sampling collection (e.g., for immediate release dosage forms – 10, 15, 30,
      45, 60 minutes and for prolonged release dosage forms – 1, 2, 3, 5, 8 hours).
   8. Analytical methods of quantitative determination of the active substance dissolved
      and the validation of these methods.
   9. Dissolution data obtained for 12 individual units of the changed product and of the
      product manufactured according to the previous technology which were obtained in
      three different media at pH range 1.2-6.8 (calculation data of the quantitative com-
      position of the active substance dissolved, mean value (in %), relative standard devi-
      ation and figures of dissolution profiles should be indicated).
   10. Data justifying the similarity of dissolution profiles of the changed product and of
      the product produced according to the previous technology (for example using
                                                             24
                                                                                    Продовження додатка 5
        method of statistical comparison of Weibull function parameters or using the simi-
        larity factor calculation). If the similarity factor is applied the calculations shall be
        performed using the following equitation
f 2  50  log{[1 ( 1 )t 1 (R t  Tt ) 2 ]-0,5  100} ,
                             n
                      n
    where
    f2 – the similarity factor;
n- number of time points
R(t) – mean value of the quantitative determination of the active substance dis-
solved/released at each time point during the investigation of the product produced accord-
ing to the previous technology (in %);
T(t) – mean value of the quantitative determination of the active substance dis-
solved/released at each time point during the investigation of the product produced accord-
ing to the previous technology (in %).
The similarity evaluation shall be validated provided that:
    - at least three time points (except for zero);
    - 12 individual values in each time point for each product;
    - not more than one mean value exceeding 85% for each composition;
    - standard deviation of the mean value for each product is not to exceed 10% starting
    from the second and to the last time point.
The value range of similarity factor (f2) from 50 to 100 justifies that two dissolution pro-
files are similar.
If over 85% of the medicinal product dissolves within 15 minutes the dissolution profiles
might be similar without further statistical evaluation.

                                             (Annex 5 in wording of MoH Ukraine Order as of 01.03.2006 № 95,
                                                      amended by MoH Ukraine Order as of 11.09.2007 № 536)

				
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