Regulation on marketing authorization of medicinal products of

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					                                                                              Annex N 4 to the Order
                                                                             of the Ministry of Health
                                                                            Nr. 344 from 18.11.2004

            REGULATIONS ON THE EVALUATION PROCEDURE FOR
    TYPE I VARIATIONS APPLICATIONS TO A REGISTRATION CERTIFICATE


1. Introduction
The present Regulations on the evaluation procedure for type I variations applications to a
Registration Certificate (further on Regulations) represent a transposition of the relevant parts
regarding type I variations from the Commission Regulation (EC) No. 541/95 from March 10 th,
1995 concerning the examination of variations to the terms of a Marketing Authorization granted
by a competent authority of a Member State and No. 542/95 from March 10th, 1995 concerning
the examination of variations to the terms of a Marketing Authorization falling within the scope
of the Council Regulation (EEC) No. 2309/93 from July 22nd, 1993 laying down Community
procedures for authorization and supervision of medicinal products for human and veterinary use
and establishing a European Agency for the Evaluation of Medicinal Products and from Volume
2A Notice to Applicants – Rules governing the medicinal products in EU, Chapter 5, Variations.

2. Definitions
Type I variations (minor) = changes which do not lead to a fundamental modification from the
point of view of the quality, safety and efficacy of the medicinal product and require only
updated information about the product.

3. Scope
The present Regulations apply for changes included in Annex II.

4. The evaluation procedure for type I variations applications to a Marketing
    Authorization
4.1. Regarding the approval of a type I variation, the Registration Certificate Holder will submit
    to the Medicines Agency the variation application in the format presented in Annex I having
    completed all sections and having annexed the supporting documentation mentioned in
    column III of Annex II.
         Where necessary, samples will be submitted.
4.2. The application completed as per paragraph 1 is concluded individually for each medicinal
    product for which the respective change applies, with the indication of the proposed type
    variation and with the comparative data presentation regarding to the change.
         When more type I variations for the same medicinal product exist, these will be included
    in a single type I variation application form.
4.3. The evaluation of the variation application will start after the payment confirmation by the
    Accountancy, in accordance with the regulations of the Medicines Agency .
4.4. The necessary timeframe for approval of a type I variation is maximum 4 months from the
    payment confirmation.
         For type I variations for products under renewal procedure, no tariff for variation
    application is requested.
4.5 In the case of a favorable opinion, the Medicines Agency informs through an official
    notification the Registration Certificate holder about the variation approval.
4.6. If the approved variation changes the terms of the Registration Certificate the Medicines
    Agency grants a “Change to the Registration Certificate”.
4.7. In the case a completion of supporting documentation is needed, the Medicines Agency will
    send a single notification with the request of completions to which the applicant should
    respond in maximum 3 months from the date of receiving it.
        A single application for completion of the initial documentation is admitted following the
    requests of the Medicines Agency.
        The finalization period is prolonged with the timeframe to which the Medicines Agency
    receives the requested completions. If the applicant does not respond to the requests within 3
    months, the Medicines Agency can interrupt the evaluation procedure of variation
    application.
4.8. In the case the submitted documentation does not support the variation application, the
    Registration Certificate holder is informed about the rejection of the variation.
4.9. The variation rejection does not prejudice the right of the Registration Certificate holder to
    resubmit the variation application, case in which the evaluation procedure of the application
    for type I variation is resumed.




                                                2
                      APPLICATION FOR TYPE I VARIATIONS TO A
                            REGISTRATION CERTIFICATE




Product trade name


Product trade name:


Active substance(s) (qualitative and quantitative data)




Pharmaceutical form, strength, route of administration


Pharmaceutical form:
Strength:
Route of administration:


Marketing Authorization holder


Name:
Address:
City:
Country:
Telephone:
Fax:
E-mail:


Authorization procedure type


National:
Centralized:
Mutual recognition:

                                             3
Product status


Authorized:
-RC no…/date of granting
Under renewal procedure:
- submission notice of the renewal
application (no, date)

NOTE
For foreign products, identification data on the variation approval by competent authority (as the
case is, based on authorization procedure) will be included.


Payer


Name:
Address:
City:
Country:
Telephone:
Fax:
E-mail:


Payment proposal


ML:          ‫ڤ‬
Dollars :    ‫ڤ‬


Contact person/Representative office for Republic of Moldova


Name:
Address:
City:
Country:
Telephone:
Fax:
E-mail:

The undersigned assumes the responsibility on the information in this application and in the
annexed variation documentation are in accordance with the provisions of Medicines Agency
regarding type I variations.
Date……………….

                                                              Signature
                 Registration Certificate holder/Representative office for Republic of Moldova
                                                 4
                                                                                  ANNEX I

                                    Type I variations

                                  CHANGE TYPE
   (in accordance with the Regulations regarding the evaluation procedure for type I
                 variations applications to a Registration Certificate)

1                ‫ٱٱٱ‬                      18        ‫ٱ‬
2                ‫ٱ‬                        19        ‫ٱ‬
3                ‫ٱ‬                        20, 20a   ‫ٱٱ‬
4                ‫ٱ‬                        21        ‫ٱ‬
5                ‫ٱ‬                        22        ‫ٱ‬
6                ‫ٱ‬                        23        ‫ٱ‬
7                ‫ٱ‬                        24, 24a   ‫ٱٱ‬
8                ‫ٱ‬                        25        ‫ٱ‬
9                ‫ٱ‬                        26        ‫ٱ‬
10, 10a          ‫ٱٱ‬                       27        ‫ٱ‬
11, 11a, 11b     ‫ٱٱٱ‬                      28        ‫ٱ‬
12, 12a          ‫ٱٱ‬                       29        ‫ٱ‬
13               ‫ٱ‬                        30        ‫ٱ‬
14               ‫ٱ‬                        31        ‫ٱ‬
15, 15a          ‫ٱٱ‬                       32        ‫ٱ‬
16               ‫ٱ‬                        33        ‫ٱ‬
17               ‫ٱ‬                        34        ‫ٱٱٱ‬




               Comparative presentation
                         Present                          Proposed




                                              5
                                                                                                                                Annex II
         Guideline on requested documentation to support the application for type I variations to the Registration Certificate of
                                                           medicinal products
          Type of change              Conditions / remarks                                  Documentation requirements
                 I                              II                                                       III
1. Changes of the Registration
Certificate
 Change of the name of the        The manufacturing place  Signed statement showing that the change of the name of the manufacturer
   medicinal product               remains the same.              does not imply a change of the manufacturing place;
   manufacturer                                                 Revised drafts of the package leaflet, labeling, where the case, incorporating
                                                                  the variation applied for;
                                                                Statement as to when the change will be implemented in future production
                                                                  batches.
 Change of manufacturing place There are no changes in the  Proof that the proposed place has appropriate authorization for the respective
   for a part or the entire manufacturing process or              pharmaceutical form: GMP certificate issued by competent authorities;
   manufacturing process of the specifications       including  Manufacturing contract between the Registration Certificate holder and the
   respective medicinal product testing methods.                  proposed manufacturer (other than Registration Certificate holder)
   (Note 1)                                                     Written statement that the manufacturing process and release and end-of-shelf
                                                                  life specifications are the same as those already approved;
                                                                Copy of approved release and end of shelf-life specifications;
                                                                Data on analysis results on an production batch and two pilot batches (or two
                                                                  production batches) and comparative data on the last three production batches
                                                                  at the previous place; analysis data on the next two production batches should
                                                                  be available on request or reported if there are outside specifications (proposed
                                                                  limits).
                                                                If the change refers to a new responsible for batch release or a new place where
                                                                  only batches release is employed or if the change refers to a new packager
                                                                  (secondary packaging or labeling), the submitance of batch analysis data is not
                                                                  necessary;
                                                                Validation data of the manufacturing process at the new place for products like
                                                                  vaccines, toxins, serums and allergens, derivates of human blood or plasma
                                                                  and products derived from biotechnology;
                                                                Revised drafts of the package leaflet, labeling, where the case, incorporating
                                                                  the variation applied for;
                                                                Statement as to when the change will be effective.
 Renunciation to Registration                                  Revised drafts of the package leaflet, labeling, where the case, incorporating

                                                                                                                                        6
    Certificate for a manufacturing                                 the variation applied for;
    place                                                          Statement as to when the change will be effective.
2. Name of the medicinal product Confusion with names of           Revised drafts of the SPC, package leaflet and labeling incorporating the
(either invented name or common other existing medicinal            variation applied for;
name)                               products or INNs names         Statement as to when the product will be marketed under the new name;
                                    must be avoided.
                                    When the name is a            Note: If the Registration Certificate holder wishes to amend the presentation of
                                    common name, the change       the entire name of the product in the product information in the form: name
                                    has to be made in the         (commercial) – strength – pharmaceutical form – these may be treated as a type I
                                    following order: from         variation.
                                    common        name       to
                                    pharmacopoeial name or to
                                    INN.
3. Name and/or address of the The                  Registration    Signed statement that the Registration Certificate holder remains the same
Registration Certificate holder     Certificate holder should       legal entity;
                                    remain the same legal          Revised drafts of the SPC, package leaflet and labeling incorporating the
                                    person.                         variation applied for;
                                                                   Statement as to when the change will be effective.
4. Replacement of an excipient      No change in dissolution       Amendments to relevant sections of Parts IIA, IIB, IIC and IIE;
with a comparable excipient         profile for solid dosage       Justification for the change/choice of excipients must be given by appropriate
(excluding adjuvants for vaccines   forms.                          pharmaceutical development data (including stability aspect and antimicrobial
and       biologically    derived                                   preservation where appropriate);
excipients)                         Same             functional    Comparative dissolution profile data of at least one representative batch
                                    characteristics (excipients     (pilot/production) of the finished product in the new and old composition for
                                    with the same role in           solid dosage forms (Note 2);
                                    formulation).                  Justification for not submitting a new bioequivalence study according to the
                                                                    norms in force;
                                                                   Commitment that appropriate stability studies have been already started in
                                                                    accordance with the norms in force and that the applicant has stability data for
                                                                    at least three months (on at least two pilot or production batches, indicating the
                                                                    batch numbers) and that relevant stability studies will be finished; data should
                                                                    be provided for outside specifications only (with proposed limits);
                                                                      Note: Stability data for at least six months should be submitted for vaccines,
                                                                      toxins, serums and allergens, derivates of human blood or plasma and
                                                                      products derived from biotechnology in which the manufacturing process is
                                                                      intrinsic part of the product quality.
                                                                   Revised drafts of the SPC, package leaflet and labeling, where applicable,
                                                                                                                                           7
                                                                      incorporating the variation applied for;
                                                                     Declaration that the release and end of shelf-life specifications of the finished
                                                                      product have not been changed;
                                                                     Copy of approved release and end of shelf-life specifications;
                                                                     Data to demonstrate that the “new” excipient does not interfere with the
                                                                      finished product specification testing methods (if appropriate).
5. Change in the product colouring Functional characteristics        Amendments to relevant sections of Parts IIA, IIB, IIC and IIE and should
system (addition, deletion or are the same without any                include identification method for the new colorant;
replacement of a colorant(s))      change in the dissolution         Revised drafts of the SPC, package leaflet and labeling, where applicable,
                                   profile for solid dosage           incorporating the variation applied for;
                                   forms.      Any       minor       Sample of new product, where applicable;
                                   adjustment of the formula         Commitment that appropriate stability studies have already been started in
                                   in order to maintain the           accordance with the norms in force and that the applicant has stability data for
                                   total weight must be made          at least three months (on at least two pilot or production batches, indicating the
                                   with an excipient present in       batch numbers) and that relevant stability studies will be finished; data should
                                   major proportion in the            be provided for outside specifications only (with proposed limits);
                                   formulation.                      Declaration that the release and end of shelf-life specifications have not been
                                                                      changed following the variation (except for appearance);
                                                                     Data to demonstrate that the “new” excipient does not interfere with the
                                                                      finished product specification testing methods (if appropriate).
6. Change in the product            Proposed flavour must be         Amendments to relevant sections of Part IIA, IIB, IIC and IIE;
flavouring  system   (addition,     in accordance with Council       Amendments to sections of part IIC must contain details of qualitative
deletion or replacement of a        Directive 88/388/EEC.             composition of the flavour, demonstration of composition consistency (e.g.,
flavour(s))                         Any minor adjustment of           through GLC data for three batches) and any new specifications for the
                                    the formula in order to           flavour. In case data on the flavour are submitted directly by the supplier of the
                                    maintain the total weight         flavour this data must be in the possession of the competent authority before
                                    must be made with an              the procedure can be started; name of supplier and the date of the submission
                                    excipient present in major        of the data must be stated in the annex to the application;
                                    proportion      in     the       Revised drafts of the SPC, package leaflet and labeling, where applicable,
                                    formulation.                      incorporating the variation applied for;
                                                                     Declaration that the release and end of shelf-life specifications of the product
                                                                      have not been changed (except for flavour);
                                                                     Commitment that appropriate stability studies have already been started in
                                                                      accordance with the norms in force and that the applicant has stability data for
                                                                      at least three months (on at least two pilot or production batches, indicating the
                                                                      batch numbers) and that relevant stability studies will be finished; data should
                                                                      be provided for outside specifications only (with proposed limits);
                                                                                                                                             8
                                                                    Data to demonstrate that the “new” excipient does not interfere with the
                                                                     finished product specification testing methods (if appropriate).
7. Change in coating weight of No change in dissolution             Amendments to relevant sections of Parts IIA, IIB and IIE;
tablets or change in weight of profile.                             Comparative dissolution profile data of at least one batch (pilot/production) of
capsule shells                                                       the finished product in the new and old composition (for modified release
                                                                     products in vitro data correlated with in vivo data will be used) (Note 2);
                                                                    Justification for not submitting a new bioequivalence study according to the
                                                                     norms in force;
                                                                    Declaration that the release and end of shelf-life specifications of the finished
                                                                     product have not been changed (except for average weight).
8.   Change      of       qualitative The proposed packaging        Amendments to relevant section of Part IIA and IIC;
composition     of        immediate material must be at least       Justification for the change in packaging material and appropriate scientific
packaging material                    equivalent to the approved     studies on the new packaging (comparative data regarding permeability, e.g.,
                                      material in respect of its     for O2, CO2, humidity);
                                      relevant properties.          For semisolid and liquid forms, proof must be provided that no interaction
                                      The change does not relate     between the content and the packaging material occurs (e.g., no migration of
                                      to sterile products.           components of the proposed material into the content and no loss of
                                                                     components of the product into the package);
                                                                    Validation data for all new analytical methods of the packaging material;
                                                                    Commitment that appropriate stability studies have already been started
                                                                     according to the norms in force and that the applicant has stability data for at
                                                                     least three months (on at least two pilot or production batches, indicating the
                                                                     batch numbers) and that relevant stability studies will be finished; data should
                                                                     be provided for outside specifications only (with proposed limits);
                                                                    Declaration that the product will still meet the release and end of shelf-life
                                                                     specifications of the product;
                                                                    Revised drafts of the SPC, package leaflet and labeling, where applicable,
                                                                     incorporating the variation applied for;
9. Deletion of an indication         The safety in use of the       The reasons for deletion of indication and declaration that no safety concerns
                                     medicinal product has not       exist for the product;
                                     been subject of concern        Revised drafts of the SPC, package leaflet and labeling, where applicable,
                                     from pharmacovigilance,         incorporating the variation applied for;
                                     preclinical safety or quality  Statement as to when the change will be effective.
                                     data.
                                     Justification must be given.
10. Deletion     of   a   route   of The safety in use of the  The reasons for deletion of route of administration and declaration that no
administration                       medicinal product has not     safety concerns exist for the product;
                                                                                                                                 9
                                  been subject of concern            Revised drafts of the SPC, package leaflet and labeling, where applicable,
                                  from pharmacovigilance,             incorporating the variation applied for;
                                  preclinical safety or quality      Statement as to when the change will be effective.
                                  data.
                                  Justification must be given.
10a. Addition or replacement of Size and, where applicable,          Amendments to relevant sections of Parts IIA and IIC;
measuring devices for oral liquid exactity     of    proposed        Description of devices (including a detail drawing) and the name of the
dosed forms or for other dosed measuring devices must be              supplier, where applicable;
forms (Note 3)                    compatible with approved           Samples of new measuring devices, where applicable;
                                  posology.                          Justification that the size and exactity of measuring devices are adequate to the
                                                                      posology approved in SPC;
                                                                     Revised drafts of the SPC, package leaflet and labeling, where applicable,
                                                                      incorporating the variation applied for;
                                                                     The composition of device material. Where applicable, materials must comply
                                                                      with the provision of the European Pharmacopoeia;
                                                                     Stability/compatibility data between the measuring device material and the
                                                                      medicinal product, where applicable;
                                                                     References on CE marking of the measuring device, if relevant.
11. Manufacturer or manufacturers   The           specifications,    Amendments to relevant sections of Part II C;
of active substance                 synthetic route and quality      Batch analysis data of at least two batches (minimum pilot scale);
                                    control procedures are the       Stability data for at least six months should be submitted for vaccines, toxins,
                                    same as those already             serums and allergens, medicinal products derived from human blood or plasma
                                    approved or an European           and products derived from biotechnology in which the manufacturing process
                                    Pharmacopoeia certificate         is intrinsic part of the product quality, according to the norms in force for the
                                    of suitability for the active     active substance and for the product manufactured with this substance.
                                    substance is submitted.           Statement that relevant real time stability studies will be finished should be
                                                                      submitted; data should be provided for outside specifications only (with
                                                                      proposed limits);
                                                                     A certificate of conformity issued by the European Pharmacopoeia or a
                                                                      revision of the certificate submitted in Part IIC, where applicable, or a
                                                                      declaration from the Registration Certificate holder that the synthetic route (or,
                                                                      where applicable, preparation method, e.g., for phytoterapeutic products),
                                                                      quality control procedures and specifications аге the same as those already
                                                                      approved including а statement that the Registration Certificate holder has
                                                                      access to adequate information (this may include а new Drug Master File
                                                                      (DMF) with all requirements, if the conditions аге fulfilled).
11a. Change of the name of active The manufacturer of the            Amendments to relevant sections of Part II C;
                                                                                                                                           10
substance manufacturer              active substance remains  Signed statement that the manufacturing place remains the same;
                                    the same.                      A revision of the certificate of conformity issued by the European
                                                                    Pharmacopoeia submitted in Part IIC, where applicable;
                                                                   Statement as to when the change will become effective.
11b. Change of the supplier of an   The specifications,            Amendments to relevant sections of Part II C;
intermediate component used in      synthetic route and quality  Data on analysis results for at least two batches (minimum pilot scale) of the
the manufacture of active           control procedures are the      intermediate compound and of active substance;
substance                           same as those already          A certificate of conformity issued by the European Pharmacopoeia or a
                                    approved.                       revision of the certificate submitted in Part IIC, where applicable, or a
                                                                    declaration from the Registration Certificate holder that the synthetic route (or,
                                                                    where applicable, preparation method, e.g., for phytoterapeutic products),
                                                                    quality control procedures and specifications for the intermediate compound
                                                                    and for the active substance are the same as those already approved including a
                                                                    statement that the Registration Certificate holder has access to adequate
                                                                    information (this may include an update of an existing Drug Master File
                                                                    (DMF), where applicable).
12.      Minor      change       of Specifications are not  Amendments to relevant section of Part IIC including a direct comparison of
manufacturing process of the adversely affected.                    the present process and the new process;
active substance                                                   Batch analysis data of at least two batches (minimum pilot scale);
                                    No change in the physical  Stability data for at least six months should be submitted for vaccines, toxins,
                                    properties.                     serums and allergens, medicinal products derived from human blood or plasma
                                    No new impurities or            and products derived from biotechnology in which the manufacturing process
                                    change      in    level    of   is intrinsic part of the product quality, according to the norms in force for the
                                    impurities     that    would    active substance and for the product manufactured with this substance.
                                    require               further   Statement that relevant real time stability studies will be finished should be
                                    qualifications in safety        submitted; data should be provided for outside specifications only (with
                                    studies.                        proposed limits);
                                                                   A certificate of conformity issued by the European Pharmacopoeia or a
                                    Alternative conditions: a       revision of the certificate submitted in Part IIC, where applicable,
                                    certificate of conformity       or
                                    issued by the European The following data that may also include an update of the approved Drug Master
                                    Pharmacopoeia may be File (DMF), where applicable:
                                    submitted.                     evidence that any potential new impurities are detectable at an acceptable limit
                                                                    of detection; declaration that no new impurities have been introduced at or
                                                                    over the level accepted for impurity qualification or that there is no increase in
                                                                    the level of impurities, which require further safety studies;
                                                                   validation data for all new analytical methods (where applicable) (see also
                                                                                                                                          11
                                                               variation 24);
                                                              declaration that the specifications of the active substance have not been
                                                               changed (see also variation 14) or if there is any change to the specifications,
                                                               (e.g., an extension of these) the texts of the current and proposed specifications
                                                               should be provided (side by side comparison where possible);
                                                              copy of the specifications of the active substance (approved).
12a. Change in specification of Specification must be  Amendments to relevant section of Part IIC;
starting or intermediate material extended or a new test and  A certificate of conformity issued by the European Pharmacopoeia or a
used in manufacture of active limits must be added.            revision of the certificate submitted in Part IIC, where applicable,
substance                                                      or
                                                             A description of analytic methods and a summary of validation data should be
                                                             submitted for all new analytic methods (where applicable) (see also variation
                                                             24a).




                                                                                                                                     12
13. Batch size of active substance                           Amendments to relevant sections of Part IIC;
                                     Batch data must show that
                                                             Batch analysis data (in a comparative tabulated format) on a minimum of one
                                     the change does not affect
                                     consistency of production production batch manufactured to both the currently approved and the
                                     or physical properties.   proposed sizes. Analysis results on the next two production batches should be
                                                               available on request and reported by the Registration Certificate holder if
                                                               outside specification (with proposed limits) as a post-approval commitment;
                                                             Stability data for at least six months should be submitted for vaccines, toxins,
                                                               serums and allergens, medicinal products derived from human blood or plasma
                                                               and products derived from biotechnology in which the manufacturing process
                                                               is intrinsic part of the product quality, according to the norms in force for the
                                                               active substance and for the product manufactured with this substance.
                                                               Statement that relevant real time stability studies will be finished should be
                                                               submitted; data should be provided for outside specifications only (with
                                                               proposed limits);
                                                             A certificate of conformity issued by the European Pharmacopoeia or a
                                                               revision of the certificate submitted in Part IIC, where applicable,
                                                               or
                                                            The following data that may also include an update of the approved Drug Master
                                                            File (DMF), where applicable:
                                                             declaration that the specifications of the active substance have not been
                                                               changed;
                                                             copy of the specifications of the active substance (approved);
                                                             evidence that any additional potential impurities are detectable at an acceptable
                                                               limit of detection.
14. Change in specifications of Specifications must be  Amendments to relevant sections of Part IIC;
active substance                tightened or a new test and  Comparative data on analysis results for at least two pilot/production batches
                                limits must be added.          covering all tests from specifications;
                                                             A certificate of conformity issued by the European Pharmacopoeia or a
                                                               revision of the certificate submitted in Part IIC, where applicable,
                                                               or
                                                            The following data:
                                                             validation data for all new analytical methods (where applicable) (see also
                                                               variation 24);
                                                             comparative dissolution profile data for the finished product (if appropriate) on
                                                               at least one pilot production batch manufactured with the active substance
                                                               complying with the current and proposed specifications (Note 2);
                                                             comparative list of current and proposed specifications of active substance.
                                                                                                                                    13
15. Minor changes in manufacture Medicinal           product   Amendments to relevant sections of Part IIB which contains:
of the medicinal product         specifications    are   not  - for semisolid and liquid products in which the active substance is present in
                                 adversely affected.            non dissolved form:
                                 New process must lead to      appropriate validation of the change including microscopic images of particles
                                 an     identical    product    to check for visible changes in morphology; comparative data on distribution
                                 regarding quality, safety      size by an appropriate method;
                                 and efficacy aspects.        - for solid forms:
                                                               dissolution profile data of one representative production batch and comparative
                                                                data of the last three batches from the previous process; analysis data on the
                                                                next two production batches should be available on request or reported if
                                                                outside specification (with proposed limits);
                                                               declaration that the release and end of shelf-life specifications of the finished
                                                                product have not been changed or if there is any change to the specifications
                                                                (e.g., tightened), the texts of the current and proposed specifications should be
                                                                provided (side by side comparison where possible);
                                                               justification for not submitting a new bioequivalence study according to the
                                                                norms in force;
                                                               copy of approved release and end of shelf-life specifications;
                                                               in case of change to a sterilization process, justification and validation data
                                                                should be provided.
15a. Change in interphasic control Specifications must be  Amendments to relevant sections of Part IIB and IID;
applied during the product tightened or a new test and  Description of the analytical methods and summary of the validation data must
manufacturing                      limits must be added.        be provided for all new analytical methods (where appropriate).
16. Size of finished product batch The change does not affect  Amendments to relevant sections of Part IIB;
                                   consistency of production.  Batch analysis data (in a comparative tabulated format) on a minimum of one
                                                                production batch manufactured to both the currently approved and the
                                                                proposed batch sizes. Batch data on the next two production batches should be
                                                                available on request or reported if outside specifications (with proposed
                                                                limits);
                                                               For the products for which a content uniformity test is mandatory, data on
                                                                homogenous distribution of active substance inside the batch should be added;
                                                               Declaration that the release and end of shelf-life specifications of the finished
                                                                product have not been changed;
                                                               Copy of approved release and end of shelf-life specifications.


                                                                                                                                     14
17. Change in specification of the Specifications must be  Amendments to relevant sections of Part IIE and IIF;
medicinal product                  tightened or a new test and  Description of the analytical methods and summary of the validation data must
                                   limits must be added.          be provided for all new analytical methods (where appropriate);
                                                                 Comparative dissolution profile, where appropriate (Note 2);
                                                                 Comparative batch analysis data covering all tests in the specification for at
                                                                  least two production scale batches;
                                                                 Comparative listing of current and proposed release and end of-shelf life
                                                                  specifications of the finished product.
18. Changes in synthesis/recovery Specifications are not  Amendments to relevant sections of Part IIC which contain appropriate
of non- pharmacopoeial excipients adversely affected.             validation data;
which had been described in the                                  Comparative batch analysis data of at least two batches;
original dossier                   No new impurities or  Declaration that the specifications of excipients have not been changed or if
                                   change      in   level    of   there is any change to the excipient specifications (e.g., tightened), the texts of
                                   impurities which would         the current and proposed specifications should be provided (side by side
                                   require              further   comparison where possible);
                                   qualification in safety  Declaration that no new impurities have been introduced or that there is no
                                   studies exists.                increase in the level of impurities, which require further safety studies.

                                     No change in physical-
                                     chemical properties exists.

19. Change in specification of Specifications must be  Amendments to relevant section of Part IIC;
excipients in the medicinal product extended or a new test and  Description of the analytical methods and summary of the validation data must
(excluding adjuvants for vaccines) limits must be added.         be provided for all new analytical methods (where appropriate) (see also
                                                                 variation 27);
                                                                Comparative dissolution profile data of at least one pilot/production batch of
                                                                 the finished product, if appropriate (Note 2);
                                                                Justification for not submitting a new bioequivalence study according to the
                                                                 norms in force;
                                                                Comparative batch analysis data covering all tests in the specification for at
                                                                 least two pilot/production batches of the finished product;
                                                                Comparative list of current and proposed specifications of the excipients.




                                                                                                                                        15
20. Extension of shelf life foreseen Stability studies have been  Amendments to relevant sections of Part IIF that contain results of appropriate
at the time of authorization         done to the protocol that        real time stability studies (tabulated format; at least two pilot or production
                                     was approved at the time of      batch scale) of the product in the authorized packaging material, covering the
                                     the issue of Registration        proposed shelf-life period; studies will be performed in accordance with the
                                     Certificate. The studies         stability guidelines;
                                     must show that the agreed  Declaration that the stability studies have continued according to the protocol
                                     end         of      shelf-life   which was approved at the time of issue of the Registration Certificate and that
                                     specifications are still met.    the agreed end of shelf-life specifications are still met;
                                     The shelf-life period does  Revised drafts of the SPC, package leaflet and labeling, where applicable,
                                     not exceed five years.           incorporating the variation applied for;
                                                                     Copy of approved agreed end of shelf-life specifications.
20a. Extension of shelf-life or of Stability studies have been  Amendments to relevant sections of Part IIF;
the period of retesting the active done to the protocol that  A certificate of conformity issued by the European Pharmacopoeia or a
substance                            was approved at the time of      revision of the certificate submitted in Part IIC, where applicable (acceptable
                                     the      issue     of     the    only if the retesting period is mentioned in the certificate of European
                                     Registration     Certificate;    Pharmacopoeia),
                                     the studies must show that       or
                                     the agreed end of shelf-life The following data:
                                     specifications are still met.  declaration that additional stability studies complying to the protocol which
                                                                      was approved at the time of issue of the Registration Certificate and the agreed
                                                                      end of shelf-life specifications are still met;
                                                                     stability studies presented for at least two pilot/production batches in the
                                                                      authorized packaging material, covering the duration of requested shelf-life
                                                                      (real time data);
                                                                     copy of the approved end of shell-life specifications of the active substance;

21. Change in the shelf-life after Studies must show that the  Amendments to relevant sections of Part IIF must contain results of
first opening                      agreed end of shelf-life        appropriate real time stability studies on at least two production batch of the
                                   specifications are still met.   product in the authorized packaging material, after the first opening; studies
                                                                   will be performed in accordance with the stability guidelines; where
                                                                   applicable, results of appropriate microbiological testing should be included;
                                                                  Declaration that the additional real time stability studies show that the
                                                                   approved end of shelf-life specifications after the first opening are still met;
                                                                  Revised drafts of the SPC, package leaflet and labeling, where applicable,
                                                                   incorporating the variation applied for;
                                                                  Copy of approved end of shelf-life specification.

                                                                                                                                         16
22. Change in the shelf-life after Studies must show that the  Amendments to relevant sections of Part IIF that must contain appropriate
reconstitution                      agreed end of shelf-life        results of the real time stability studies on at least two production batch of the
                                    specifications are still met    reconstituted product in accordance with the stability guidelines; where
                                    for     the    reconstituted    applicable, results of appropriate microbiological testing should be included;
                                    product.                       Declaration that the additional real time stability studies show that the
                                                                    approved end of shelf-life specifications after reconstitution are still met for the
                                                                    reconstituted product;
                                                                   Revised drafts of the SPC, package leaflet and labeling, where applicable,
                                                                    incorporating the variation applied for;
                                                                   Copy of approved end of shelf life specification;
23. Storage conditions              Stability studies have been  Amendments to relevant sections of Part IIF that must contain appropriate
                                    done according to the           results of real time stability studies on at least two pilot/production batch of the
                                    protocol that was approved      product in the authorized packaging material in accordance with the stability
                                    at the time of issue of the     guidelines;
                                    Registration Certificate.      Declaration that the real time stability studies have been done according to the
                                    The studies must show that      protocol which was approved at the time of issue of the Registration Certificate
                                    the agreed end-of-shelf life    and that the approved end of shelf-life specifications are still met;
                                    specifications are still met.  Revised drafts of the SPC, package leaflet and labeling, where applicable,
                                                                    incorporating the variation applied for;
                                                                   Copy of approved end of shelf-life specifications.
24. Change in test procedure of the Results     of     validation  Amendments to relevant sections of Part IIC which include a description of
active substance                    method show new test            analytical methods, a summary of the validation data and comparative
                                    procedure to be at least        analytical results between the current testing procedures and the proposed one,
                                    equivalent to the former        if appropriate;
                                    procedure.                     Amendments to relevant sections of Part IIF, if appropriate;
                                                                   A certificate of conformity issued by the European Pharmacopoeia or a
                                                                    revision of the certificate submitted in Part IIC, where applicable (Note 4),
                                                                    or
                                                                  The following data:
                                                                   declaration that the specifications of the active substance have not been
                                                                    changed (see also variation 14);
                                                                   copy of the approved specifications;
                                                                   if a new impurity is detected with new testing procedure, a justification that the
                                                                    new detected impurity is acceptable from toxicological point of view should be
                                                                    provided.


                                                                                                                                           17
24a. Change in the testing          Results     of    validation  Amendments to relevant sections of Part IIC which include a description of
procedure     of    starting   or   method show new test           analytical methods, a summary of the validation data and comparative
intermediate material used in       procedure to be at least       analytical results between the current testing procedures and the proposed one,
active substance manufacturing      equivalent to the former       if appropriate; amendments to relevant sections of Part IIF, if appropriate;
                                    procedure.                    A certificate of conformity issued by the European Pharmacopoeia or a
                                    Specifications are not         revision of the certificate submitted in Part IIC, where applicable (Note 4),
                                    adversely affected.            or
                                                                 The following data:
                                                                  declaration that the specifications of the starting or intermediate material have
                                                                   not been changed (see also variation 12a);
                                                                  if a new impurity is detected with new testing procedure, a justification that the
                                                                   new detected impurity is acceptable from toxicological point of view should be
                                                                   provided.
25. Change in testing procedures    Medicinal           product  Amendments to relevant sections of Part IIE and/or Part IIF which include a
of the medicinal product            specifications   are     not   description of analytical methods, appropriate validation data and comparative
                                    adversely affected.            analytical results between the current testing procedure and the proposed one,
                                    Results of the method          if appropriate;
                                    validation show new test  Declaration that the release and end of shelf-life specifications of the finished
                                    procedure to be at least       product have not been changed or if there is any change to the specifications,
                                    equivalent to the former       the texts of current and proposed specifications should be provided (side by
                                    procedure.                     side comparison where possible) (see 17);
                                                                  Copy of the approved release and end of shelf-life specifications.
26. Changes to comply with          Change is made                Amendments to appropriate chapters of Part IIC1 and C2 and Part IIE;
supplements to pharmacopoeias       exclusively to implement      Active substances: when changing from a non-EU pharmacopoeia or from
(in cases where the Registration    the new provisions of the      company specifications, documentation should be provided to demonstrate the
Certificate refers to the current   supplement.                    suitability of the new monograph in the European Pharmacopoeia or national
edition of the pharmacopoeia, no                                   pharmacopoeia to control the substance from that particular manufacturer.
variation application is required                                  For substances described in European Pharmacopoeia, this may be done for
provided the change is introduced                                  example by:
within six months of adoption of                                  Comparing the list of potential impurities in the substance with the
the revised monograph)                                             pharmacopoeia’s monograph, from impurities point of view
                                                                   or
                                                                  a certificate of conformity issued by the European Pharmacopoeia or a revision
                                                                   of the certificate submitted in Part IIC, if appropriate (Note 4);
                                                                  excipients/active substances: In case the new specifications of European
                                                                   Pharmacopoeia or national pharmacopoeia of active substances or excipients
                                                                   may affect the quality of the finished product, comparative analysis data
                                                                                                                                         18
                                                                  covering all tests in the finished product specification for at least two
                                                                  production batches should be provided together with comparative dissolution
                                                                  profile, where appropriate;

                                                                  Note (finished products): In case of a new general monograph (on dosage
                                                                  form) or a new general requirement, a single application may be submitted for
                                                                  a list of products covered by the new monograph/requirement, unless the new
                                                                  requirement calls for product specific validation.
27. Testing procedures of non- Results of the method             Amendments to relevant sections of Part IIC which include a description of
pharmacopoeial excipients        validation    show     new       analytical methods, a summary of validation data and comparative analytical
                                 testing procedure to be at       validation results between the current testing procedure and the proposed one;
                                 least equivalent to the         Declaration that the specifications of the excipients have not been changed (see
                                 former testing procedure.        also variation 19).
28. Testing procedure of primary Results of the method           Amendments to relevant sections of Part IIC which include a description of
(immediate) packaging            validation    show     new       analytical methods, appropriate validation data and comparative analytical
                                 testing procedure to be at       results between the current testing method and the proposed one, where
                                 least equivalent to the          appropriate;
                                 former testing procedure.       Declaration that the specifications of the immediate packaging have not been
                                                                  changed.
29. Testing         procedure   of Results of the method         Amendments to relevant sections of Part IIC which include a description of
administration device              validation    show    new      analytical methods, appropriate validation data and comparative analytical
                                   testing procedure to be at     results between the current testing method and the proposed one, where
                                   least equivalent to the        appropriate;
                                   former procedure.             Reference to CE marking for device, where applicable;
                                                                 Declaration that the specifications of the administration device have not been
                                                                  changed.
30. Change in pack size of the Specifications     of    the      Amendments to relevant sections of Part IIA, IIC and IIE, where appropriate;
medicinal product              medicinal product are not         Declaration that the specifications of the medicinal product are not affected;
                               affected, the new pack size       Justification that the new pack size is consistent with the dosage regimen and
                               is consistent with the             that the duration of use as approved in the SPC;
                               dosage      regimen      and      Revised drafts of the SPC, package insert and labeling incorporating the
                               duration of use as approved        variation applied for;
                               in the SPC.                       Declaration that the primary packaging and closure mechanism (system) are
                               The change does not relate         unchanged and in the case of plastics, an assurance that the polymer wall
                               to parenteral preparations.        thickness is at least as thick as the current packs;
                               Packaging           material      Declaration that stability studies will be conducted for products where stability
                               remains the same.                  parameters could be affected. Data will be reported if outside specifications
                                                                                                                                       19
                                                                       only (with proposed limits).

                                                                       Note: In case of a parenteral use product and if the change refers to number of
                                                                       units in external packaging only, then the change can be consider a type I
                                                                       variation.
31. Change in container shape No change in the quality                Amendments to relevant sections of Part IIA and IIC3 (including a detailed
(primary packaging)                  and in the stability of the       drawing of the current and proposed forms) if applicable;
                                     product in the primary           Samples of old and new packaging, if appropriate;
                                     packaging.                       Declaration that the specifications of the container (except for shape) have not
                                     No change in the primary          been changed;
                                     packaging-product                Declaration that the release and end of shelf-life specifications of the product
                                     interactions.                     have not been changed.
                                     Change does not imply a
                                     fundamental component of
                                     the packaging material that
                                     would affect the release or
                                     the use of the product.
32. Change of imprints or other New markings do not             Amendments to relevant sections of Part IIA, IIB, IIC (for new proposed inks,
markings (except scoring) on cause confusion with other          the colorants should be in accordance with the Directive 78/25/EEC) and IIE
tablets or printing of certain signs tablets or capsules.        (including a detailed drawing or description of the current situation and
on capsules including addition or                                proposed one);
changing of inks used for marking                               Samples of the finished product, if appropriate;
the product                                                     Declaration that the release and end of shelf-life specifications of the finished
                                                                 product have not been changed (except for appearance);
                                                                Revised drafts of the SPC (where applicable), package leaflet and labeling
                                                                 incorporating the variation applied for.
33. Change of dimensions of           No change in dissolution  Amendments to relevant sections of Part IIB and IIE (including a detailed
tablets, capsules, suppositories or   profile.                   drawing of the current situation and proposed one);
pessaries without change of                                     Comparative dissolution data on at least one pilot/production batch of the
quantitative composition and mean                                current and proposed dimensions;
weight                                                          Declaration that the release and end of shelf-life specifications of the finished
                                                                 product have not been changed (except for dimensions);
                                                                Revised drafts of the SPC (where applicable), package leaflet and labeling
                                                                 incorporating the variation applied for;
                                                                Samples of the finished product, if appropriate;
                                                                Data of breakability test of tablets at release must be given and commitment to
                                                                 submit data of breakability at the end of shelf-life.
                                                                                                                                      20
34. Change in the manufacturing
process      of     a   non-proteic
component       due    to    further
introduction       of     a     new
biotechnological step.                     Specifications,   physical-  Data on analysis results for at least two batches (minimum pilot scale);
 Change in the manufacturing              chemical properties and all  A certificate of conformity issued by the European Pharmacopoeia or a
    process      for    components         characteristics   of    the   revision of the certificate submitted in Part IIC, if appropriate (Note 4);
    conforming to a monograph of           component remain the
    European Pharmacopoeia and             same.
    checked through a certificate of
    conformity from the European
    Pharmacopoeia.
 Change in the manufacturing              Specifications,    physical-  Data on analysis results for at least two batches (minimum pilot scale).
    process for components                 chemical properties and all  A certificate of conformity issued by the European Pharmacopoeia or a
    requiring a new impurity               characteristics    of     the  revision of the certificate submitted in Part IIC, if appropriate (Note 4).
    testing procedure.                     component remain the
                                           same. The manufacturing
                                           method may generate
                                           uncontrollable impurities
                                           by the monograph of
                                           Pharmacopoeia.        These
                                           impurities must be declared
                                           and an adequate testing
                                           procedure       must       be
                                           described.            These
                                           supplementary tests must
                                           be specified in a certificate
                                           of conformity from the
                                           European Pharmacopoeia.

    NOTES:
    1. The addition or replacement of a manufacturing place enters under the incidence of this variation. It is recommended that problem about inspection to be solved
    before submitance of the variation dossier.
    2. For the phytoterapeutic products, comparative data on disagregation time are acceptable.
    3. Variation 10a does not include measuring devices that forms a unique product, integrated with the medicinal product. Therefore, changes as those of
    components of valves/pumps of inhalation are not subjects of the provisions of this variation.
    4. In case that the new certificates of conformity mentioned do not include the retesting period, the shelf-life should be mentioned.


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