Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
575
February 2014
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Should you have any comments on the attached revision, please send these to Dr S. Kopp, Group
Lead, Medicines Quality Assurance, Technologies, Standards and Norms (kopps@who.int) with a
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MarchApril 2014
Compilation of feedback
May 2014
June 2014
July 2014
Compilation of feedback
September 2014
Contents
page
1.
2.
3.
4.
5.
Introduction ...
1.1
Objectives .
1.2
Scope and application of the guideline .
Glossary .
General considerations ..
3.1
Reporting types .
3.1.1 Notification
3.1.2 Minor variation ..
3.1.3 Major variation ..
3.2
New applications and extension applications
3.3
Labelling information
3.4
Conditions to be fulfilled ..
3.5
Documentation required
General stability considerations
Comparative studies ..
5.1
Comparative in vivo studies ..
5.2
Comparative in vitro studies ..
5.3
Variations (changes) to pharmaceutical aspects of registered products which
may be made without prior approval
5.3.1 Annual notification .
5.3.2 Immediate notification Do and tell ..
5.4
Variations (changes) to pharmaceutical aspects of registered products which
require prior approval before implementation
5.4.1 Minor variation ...
5.4.2 Major variation
1.
INTRODUCTION
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authorization holder or applicant is responsible for the safety, efficacy and quality of a
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medicinal product that is placed on the market throughout its life-cycle. As such, changes are
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required or necessary for an approved or registered product to account for technical and
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scientific progress, to improve the quality of the medicinal product, to meet market
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information (e.g. updates to information on adverse reactions). The common areas for change
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are pharmaceutical aspects (quality control, source of raw materials, manufacturing, shelf-life
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etc.) and product information. Such changes, regardless of the nature of the change, are
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referred to as variations and may require the approval of national medicines regulatory
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Technical requirements for the different types of variations are set out in these guidelines in
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assessment by NMRAs.
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1.1
Objectives
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This guidance document is intended to assist applicants with the classification of changes
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guidance on the technical and other general data requirements to support changes to the
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quality attributes of the active pharmaceutical ingredient (API) or FPP. Variation applications
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are categorized into major variation, minor variation (prior approval) and minor variation
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(notification).
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1.2
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These guidelines can be used by both NMRAs and applicants with respect to changes to the
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quality sections of product dossiers for an API or an FPP. This guidance should be read in
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conjunction with the Guidelines on submission of documentation for a multisource finished product
(1) and Guidance on variations (2) as well as other related WHO guidelines or applicable
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national guidelines.
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The NMRAs reserve the rights to request for additional information where necessary, in line
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This guidance document is applicable only to APIs and excipients manufactured by chemical
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synthesis or semisynthetic processes and FPPs containing such APIs and excipients. APIs
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produced by fermentation and APIs of biological, biotechnological or herbal origin are treated
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as special cases.
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similar quality changes that occur during the development of the product and that the
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recommended supporting data be included with the initial application for registration of a
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medicinal product.
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When a variation leads to a revision of the package insert, the patient information leaflet
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(PIL) and labelling, 1 the updated product information should be submitted as part of the
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application.
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For variations that require generation of stability data on the API or FPP, the stability studies
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required, including commitment batches, should always be continued to cover the currently
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accepted retest or shelf-life period. The NMRAs should be informed immediately if any
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problems with the stability of APIs or FPPs occur during storage, e.g. if found to be outside
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Applicants should be aware that some variations might require the submission of additional
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consequential variations. Therefore for any given change the applicant should consider
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If changes to the dossier only concern editorial changes, such changes need not be submitted
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Different regions/countries use different terminology for product information. In this document package insert,
PIL and label are used to refer to product information.
variation concerning that part of the dossier. In such a case a declaration should be provided
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that the contents of the associated sections of the dossier have not been changed by the
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2.
GLOSSARY
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The definitions provided below apply to the terms used in this guidance. They may have
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have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to
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beings.
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A raw material, intermediate, or an API that is used in the production of an API and that is
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incorporated as a significant structural fragment into the structure of the API. An API starting
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material can be an article of commerce, a material purchased from one or more suppliers
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applicant
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For the purposes of this document, the term applicant refers to any person or entity that holds
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the legal responsibility for the product on the market by submission of the required
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documentation on a product that has been listed after evaluation as registered or approved.
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biobatch
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final intermediate
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Product formed in the last reaction in the synthetic pathway that undergoes synthetic
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transformation to the API or the crude API. Purification is not considered to be a synthetic
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transformation.
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A finished dosage form of a pharmaceutical product, which has undergone all stages of
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in-process control
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Check performed during manufacture to monitor or to adjust the process in order to ensure
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manufacturer
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A company that carries out operations such as production, packaging, repackaging, labelling
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the national regulatory agencies (e.g. national pharmacopoeia (if applicable), The
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Pharmacopoeia (BP), the Japanese Pharmacopoeia (JP) and the United States Pharmacopeia
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(USP)).
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pilot-scale batch
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that to be applied to a full production-scale batch. For example, for solid oral dosage forms, a
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pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100 000
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production batch
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register
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A list of all the pharmaceutical products authorized for marketing in a particular country. The
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the medicines regulatory authority in a country which is: (a) a member of the
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International Conference on Harmonisation (ICH) (European Union (EU), Japan and the
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United States of America); or (b) an ICH Observer, being the European Free Trade
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Association (EFTA) as represented by Swiss Medic and Health Canada (as may be
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updated from time to time); or (c) a regulatory authority associated with an ICH member
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validation
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The demonstration, with documentary evidence, that any procedure, process, equipment,
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variation
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A change to any aspect of a pharmaceutical product, including but not limited to a change to
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formulation, method and site of manufacture, specifications for the finished product and
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3. GENERAL CONSIDERATIONS
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3.1
Reporting types
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The definitions outlined in the following reporting types are intended to provide guidance
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with respect to the classification of quality-related changes. Specific examples of changes are
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provided in these guidelines. However, it should be noted that a change not covered by these
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unclear about the classification of a particular change, the respective NMRA should be
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justify that the change will not have a negative impact on the quality of the product.
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when variations are consequential to each other, e.g. introduction of a new impurity
when the same change affects multiple FPPs, e.g. addition of a new API
manufacturing site for multiple FPPs;
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Applicants are also advised to exercise caution whenever several changes to the same FPP are
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envisaged. Although each of the individual changes may be classified as a particular reporting
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composite effect of these changes. In all such cases, applicants are advised to contact the
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NMRA prior to submission of the variation application to obtain guidance on classifying such
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changes.
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3.1.1 Notifications
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Notifications are changes that could have minimal or no adverse effects on the overall safety,
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efficacy and quality of the FPP. Such notifications may not require prior acceptance, but must
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be notified to the NMRA immediately after implementation, i.e. immediate notification (IN),
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Minor variations are changes that may have minor effects on the overall safety, efficacy and
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quality of the FPP. Applicants must satisfy themselves that they meet all of the prescribed
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conditions for the change and submit all required documentation with the variation
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application.
Prior approval by the NMRA may be required, before the changes can be implemented. The
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timeline and implementation of the variation are subject to the NMRAs specific
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Major variations are changes that could have major effects on the overall safety, efficacy and
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quality of the FPP. In general, a change that is supported by extensive documentation and/or
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variation, e.g. a change supported by in vivo studies. Prior approval by the NMRA is required
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before the changes can be implemented. The timeline and implementation of the
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The NMRA reserves the right to recategorize the application type, where deemed appropriate.
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Subject to country specific procedure, recategorization may require the applicant to resubmit
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3.2
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Certain changes are so fundamental that they alter the terms of the accepted dossier and
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submitted in line with applicable national requirements for applications for registration of
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medicines.
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1.
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2.
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3.
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4.
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5.
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vice versa.
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Labelling information
3.3
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For any change to labelling information (package insert, PIL, labels), the NMRA must be
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notified and submission of the revised labelling information is expected as per country
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3.4
Conditions to be fulfilled
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For each variation, attempts have been made to identify particular circumstances where lower
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reporting requirements, e.g. notifications, are possible. A change that does not meet all of the
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conditions stipulated under general and specific circumstances for the notifications are
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automatically considered at the next higher level of change, i.e. require prior approval before
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implementation.
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3.5
Documentation required
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All data recommended to support a change should be provided with the submission.
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provided. Regardless of the documents specified, applicants should ensure that they have
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provided all relevant information to support the variation. Additional documentation may be
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required. For all changes it remains the responsibility of the applicant to provide all necessary
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documents to demonstrate that the change does not have a negative impact on the safety,
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Where applicable, the following should be included in the application for variations requiring
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prior approval:
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a covering letter (including a list of changes describing each in sufficient detail to allow for a
quick assessment as to whether the appropriate reporting category has been used);
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where relevant, a side-by-side comparison of the previously approved and the proposed
information;
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replacement of the relevant sections of the dossier as per acceptable dossier format for the
respective NMRAs with the proposed changes clearly annotated;
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registration status and date of the proposed change(s) in other countries/agencies that had
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approved the variation(s), especially the country of origin and the reference agencies.
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It should be noted that the NMRA reserves the right to request further information not
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Alternative approaches to the principles and practices described in this document may be
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acceptable provided they are supported by adequate scientific justification. It is also important
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to note that the NMRA may request information or material, or defines conditions not
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specifically described in this guidance, in order to adequately assess the safety, efficacy and
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quality of an FPP.
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The effect of the changes on an approved medicinal product on the stability of the medicinal
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product should be evaluated. For general guidance on conducting stability studies, applicants
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are referred to the WHO Guideline on Stability Studies [3]. For variation submissions, the
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In most cases (except those involving scale up), stability data from pilot scale batches will be
acceptable to support the proposed change.
Where stability data show a trend toward potency loss or degradant increase under accelerated
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pre-change batch be submitted for comparison. It is also recommended that under these
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circumstances, all available long-term data on test batches from ongoing studies be provided
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in the supplement. Submission of historical accelerated and available long-term data would
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expiration-dating period, according to the approved protocol, on the first or first three
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5.
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5.1
COMPARATIVE STUDIES
Comparative in vivo studies
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Applicants should consult the ICH Q5E guideline and applicable WHO guidance documents
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5.2
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to support a variation, the comparison should be made to the product manufactured according
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to the same formulation and manufacturing process used in the pivotal clinical and/or
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comparative bioavailability studies approved for the original drug submission (e.g. including
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batch formula, manufacturing process). This is referred to as the "approved product" in the
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appendices.
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For example, a comparison to an applicant's marketed product (rather than the product used in
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significant body of information has been established for the marketed drug product. For the
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purposes of this document, a significant body of information for the marketed drug product is
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likely to exist after a reasonable number of batches of the drug product will be marketed
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Applicants should refer to the General Chapters available in the current Schedule B
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pharmacopoeia for general dissolution and drug release specifications (e.g. United States
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5.3
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Changes that may be applied without prior approval but included in annual notifications (AN)
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1.
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currently accepted batch size on condition that (a) the product continues to meet specifications, (b) the
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dissolution profile is not significantly altered, (c) a stability study has been commenced on at least one
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full-scale production batch and (d) the change does not concern a sterile API.
Changes in batch size of the API or intermediate involving up to 10-fold compared to the
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2.
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do not reflect a change in processing, e.g. from a fine to microfine particle size.
Additional tests and limits for starting materials or finished products on condition that these
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3.
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4.
Alteration of the quantitative composition of a tablet or capsule coating amounting to less than
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2% of the total weight of the tablet or capsule. On condition that (a) the coating has no modified-
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release properties, (b) there is no API in the coating, (c) any new colours are permitted by the
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European Commissions List of Permitted Food Colours (4), or the United States Food and Drug
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Agencys (US-FDA) Summary of Color Additives for Use in the United States in Foods, Drugs,
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Cosmetics, and Medical Devices (5) and (d) the change is notified.
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5.
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continues to meet specifications and (b) the dissolution profile is not significantly altered.
Changes to the volume of granulating fluid of up to 15%, provided that (a) the product
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6.
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viscous. On condition that (a) it has been demonstrated that any solid material present is at least
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equally well suspended and (b) a stability study has been commenced on at least two batches of the
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altered product.
Changes to the quantitative content of agents whose only function is to make the product
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7.
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On condition that (a) multipoint in vitro dissolution profiles of the proposed version of the product
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(determined in the routine release medium on at least two batches of pilot- or production-scale) are
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similar to the dissolution profiles of the biobatch, (b) coating is not a critical factor for the release
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mechanism and (c) specifications for the FPP are updated only with respect to weight and dimensions,
Change in weight of tablet coatings or capsule shells involving immediate-release oral FPPs.
if applicable.
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8.
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product is not a slow- or otherwise modified-release product, (b) a new stability study has been
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commenced on at least two batches of the altered product, (c) no change in the specifications of the
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intermediates or the FPP, (d) the dissolution profiles are similar to those of the biobatch and (e) the
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manufacturing processes for the currently accepted and proposed products use the same principles
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(e.g. a change from wet to dry granulation, from direct compression to wet or dry granulation, or vice
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versa, would be considered a change in manufacturing principle), the same processing intermediates
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and there are no changes to any manufacturing solvent used in the process.
Alteration of methods of manufacture and manufacturing equipment on condition that (a) the
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9.
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does not affect the reproducibility and/or consistency of the product, (b) the change pertains only to
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immediate-release oral pharmaceutical forms and to non-sterile liquid forms and (c) changes to the
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manufacturing method and/or to the in-process controls are only those necessitated by the change in
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Change in the batch size of the FPP involving downscaling. On condition that (a) the change
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10.
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involving (a) tightening of in-process limits, (b) deletion of a test and (c) addition of new tests and
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limits.
Change to in-process tests or limits applied during the manufacture of the FPP or intermediate
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11.
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do not reflect a change in processing, e.g. from a fine to microfine particle size.
Additional tests and limits for starting materials or finished products on condition that these
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12.
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pharmacopoeia provided that there is no change to the specifications other than those required to
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13.
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14.
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Change in the analytical procedures for the FPP involving updating the analytical procedure
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5.3.2
Applicants must satisfy themselves that they meet all of the prescribed conditions for the
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change and submit all required documentation with the notification application. Such changes
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can be implemented immediately at the time of submission and they can be considered
501
accepted if an objection is not issued by the NMRA within a reasonable period subject to
502
country specific proposal after the date of acknowledgement of receipt of the application.
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504
505
5061.
507
Change to the marketing authorization holder (name, address and/or legal entity). On
condition that there is no change to the product, including sites of manufacture.
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5092.
510
Change in the name and/or corporate address of the supplier of the FPP on condition
that the supplier of the product remains the same legal entity.
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5123.
513
the API/FPP intermediate or API/FPP provided that at least one other site continues to
514
perform the same function(s) as the site(s) intended to be deleted and that the deletion of the
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4.
Change in the manufacturing process of the API. On condition (a) that there is no
518
change in the physical state (e.g. crystalline, amorphous) of the API, (b) for low solubility
519
APIs, there is no change in the polymorphic form and whenever particle size is critical
520
(including low solubility APIs) there is no significant change in the particle size distribution
521
compared to that of the API lot used in the preparation of the biobatch, (c) where materials of
522
human or animal origin are used in the process, the manufacturer does not use any new
523
process for which assessment of viral safety data or transmissible spongiform encephalopathy
524
(TSE) risk assessment is required, (d) no change in qualitative and quantitative impurity
525
profile or in physicochemical properties of the API, (e) the change does not affect the
526
sterilization procedures of a sterile API, (f) the change involves only steps before the final
527
intermediate and (g) the change does not require revision of the starting material, intermediate
528
or API specifications.
531
that (a) no changes to the manufacturing process other than those necessitated by changes in
532
scale (e.g. use of a different size of equipment) and (b) the change does not affect the
533
534
5356.
536
Changes to the test parameters, acceptance criteria or analytical procedures of the API
manufacturer that do not require a change to the FPP manufacturers API specifications.
537
5387.
Change to the test parameters or acceptance criteria of the API specifications of the
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540
acceptance criterion and (c) addition of test parameter. On condition that (a) for insoluble
541
APIs there is no change in the polymorphic form and whenever particle size is critical
542
543
criteria, (b) no additional impurity found over the International Conference on Harmonisation
544
545
threshold and (c) the change does not concern sterility testing.
546
5478.
Change to the analytical procedures used to control the API by the FPP manufacturer
548
549
550
551
recognized pharmacopoeia.
552
5539.
554
additional types of container-closure on condition that (a) the product is not a sterile product,
555
(b) the new system offers equal or better protection to the product, (c) stability data are
556
available on two batches of the product in the new container for at least three months under
557
accelerated conditions (as defined in relevant guidelines) or one year under non-accelerated
558
conditions, (d) a stability study has been commenced on at least two batches of the altered
559
product for the full duration of the shelf-life and (e) the change is notified. Changes may not
560
561
56210.
Reduction in the retest period or shelf-life of the API provided the change is not
564
concerns.
565
56611.
Change in the composition of a solution dosage form. On condition that (a) the
567
affected excipient(s) does/do not function to affect the solubility and/or the absorption of the
568
API, (b) the affected excipient(s) does/do not function as a preservative or preservative
569
enhancer, (c) no change in the specifications of the affected excipient(s) or the FPP, (d) no
570
change in the physical characteristics of the FPP (e.g. viscosity, osmolality, pH), (e) the
571
change does not concern a sterile FPP and (f) the excipients are qualitatively the same. The
572
change in the amount (or concentration) of each excipient is within 10% of the amount (or
573
574
57512.
Changes to flavours, perfumes or colours on condition that (a) any new colours are
576
permitted by the European Commissions List of Permitted Food Colours (4), or the United States
577
Food and Drug Agencys (US-FDA) Summary of Color Additives for Use in the United States in
578
Foods, Drugs, Cosmetics, and Medical Devices (5), (b) the change is notified, (c) stability data are
579
available on two batches of the altered product for at least three months under accelerated
580
conditions (as defined in relevant guidelines) or one year under non-accelerated conditions
581
and (d) a new stability study has been commenced on at least two batches of the altered
582
583
58413.
585
including replacement or addition of inks used for product markings and change in scoring
586
configuration. On condition that (a) these do not imply an unapproved indication or patient
587
population, (b) no unapproved colour (as defined above) is introduced, (c) any changes to
588
scoring are consistent with the dose schedules in the approved product information and (d)
589
590
59114.
592
mean mass of tablets, capsules, suppositories and pessaries. On condition that (a)
593
specifications for the FPP are updated only with respect to dimensions of the FPP and (b)
594
multipoint in vitro dissolution profiles of the current and proposed versions of the product
595
(determined in the routine release medium, on at least one batch of pilot- or production-scale)
596
are comparable.
599
process for an FPP involving (a) secondary packaging of all types of FPPs, (b) primary
600
packaging site of solid FPPs (e.g. tablets, capsules), semi-solid FPPs (e.g. ointments, creams)
601
and solution liquid FPPs and (c) primary packaging site of other liquid FPPs (suspensions,
602
emulsions). On condition that (a) satisfactory good manufacturing practices (GMP) inspection
603
in the last three years and (b) site appropriately authorized by an NMRA (to manufacture the
604
605
60616.
Change in the batch size of the FPP involving up to and including a factor of 10
607
compared to the biobatch. On condition that (a) the change does not affect the reproducibility
608
and/or consistency of the product, (b) the change pertains only to immediate-release oral
609
pharmaceutical forms and to non-sterile liquid forms, (c) changes to the manufacturing
610
method and/or to the in-process controls are only those necessitated by the change in batch
611
size, e.g. use of different-sized equipment, (d) a validation protocol is available or validation
612
613
accordance with the current validation protocol and (f) the biobatch size was at least 100 000
614
615
61617.
617
Change to in-process tests or limits applied during the manufacture of the FPP or
intermediate involving revision or replacement of a test.
618
61918.
Change in the specifications of the FPP involving test parameters and acceptance
620
621
provided that the change to the specifications does not affect the stability and the performance
622
of the product and the change does not concern sterility testing.
623
62419.
Analytical methodology for the finished product on condition that (a) validation shows
625
that the new method is equivalent to or better than the existing method and (b) major changes
626
(e.g. ultra violet assay to high-pressure liquid chromatography (HPLC)) are notified.
627
62820.
Change in the package size involving: (a) change in the number of units (e.g. tablets,
629
ampoules, etc.) in a package; and (b) change in the fill weight or fill volume of non-parenteral
630
multidose products. On condition that (a) the change is consistent with the posology and
treatment duration accepted in the package insert and (b) no change in the primary packaging
632
material.
633
63421.
635
additional types of container-closure. On condition that (a) the product is not a sterile product,
636
(b) the new system offers equal or better protection to the product, (c) stability data are
637
available on two batches of the product in the new container for at least three months under
638
accelerated conditions (as defined in relevant guidelines) or one year under non-accelerated
639
conditions, (d) a stability study has been commenced on at least two batches of the altered
640
product for the full duration of the shelf-life and (e) the change is notified. Changes may not
641
642
64322.
Change in any part of the (primary) packaging material not in contact with the FPP
644
formulation (e.g. colour of flip-off caps, colour code rings on ampoules or change of needle
645
shield), provided the change does not concern a fundamental part of the packaging material,
646
647
64823.
649
Reduction in the shelf-life of the FPP (as packaged for sale) or in the in-use period of
the FPP (after first opening or after reconstitution or dilution).
650
651
New sites of manufacture require prior approval because the NMRA should see evidence of
652
compliance with GMP, e.g. a WHO-type certificate of pharmaceutical product (6). Changes
653
or additions to pack size also require prior approval because the new size must be consistent
654
655
656
Changes may not be made to labelling without prior approval, except for changes to layout
657
without alteration of text or meaning. Pictures or diagrams may not be added without prior
658
659
660
661
662
No variations have been made other than (1) those notified herewith and (2) changes
663
which are permitted without notification or prior approval according to the guidelines of
664
5.4
666
667
668
669
670
Below is a list of variations considered minor. In addition to the general documents stated in
671
672
673
674
1.
675
API testing only provided the transfer of analytical methods has been successfully undertaken and
676
677
678
2.
3.
Change of the specification of drug substance a) specification limits are tightened and b)
679
680
681
682
683
4.
684
685
686
687
688
b) addition/deletion/replacement of pictures, diagrams, bar code, logos and/or texts that do not
689
690
691
692
693
e) deletion of indication.
694
695
5.
696
Change in batch size of the API or intermediate involving more than 10-fold increase
compared to the currently accepted batch size.
697
698
6.
699
manufacture of the API (e.g. raw materials, starting materials, reaction intermediates, solvents,
700
702
703
7.
704
Change of the specification of drug substance a) specification limits are tightened and b)
addition of new test parameter and limits.
705
706
8.
Change to the test parameters or acceptance criteria of the API specifications of the FPP
707
708
an acceptance criterion.
709
710
9.
711
Change to the analytical procedures used to control the API by the FPP manufacturer
involving modification or replacement of an analytical procedure.
712
713
10.
714
Change in the immediate packaging (primary and functional secondary components) for the
storage and shipment of the API provided the change is not due to instability issues.
715
716
11.
Change in the retest period or shelf-life of the API involving extension provided (a) no change
717
to the primary packaging in direct contact with the API or to the recommended condition of
718
storage and (b) stability data were generated in accordance with the currently accepted stability
719
protocol.
720
721
12.
722
Any change in the labelled storage conditions of the API provided (a) the stability studies
must show compliance with specification and (b) no change in shelf-life/retest period.
723
724
13.
725
addition of inks used for product markings and change in scoring configuration involving addition
726
of a score line. On condition that (a) the change does not affect the stability or performance
727
characteristics (e.g. release rate) of the FPP, (b) changes to the FPP specifications are those
728
necessitated only by the change to the appearance or to the scoring and (c) addition or deletion of
729
a score line from a generic product is consistent with a similar change in the comparator product
730
731
732
14.
733
mass of gastroresistant, modified or prolonged-release FPPs and scored tablets. On condition that
734
specifications for the FPP are updated only with respect to dimensions of the FPP and multipoint
735
in vitro dissolution profiles of the current and proposed versions of the product (determined in the
736
routine release medium, on at least one batch of pilot- or production-scale) are comparable.
737
15.
Addition or replacement of a manufacturing site for part or all of the manufacturing process
739
for an FPP involving all other manufacturing operations except batch control and/or release
740
testing. On condition that (a) no change in the batch formula, description of manufacturing
741
process and process controls, equipment class and process controls, controls of critical steps and
742
intermediates or FPP specifications, (b) satisfactory inspection in the last three years, (c) site
743
appropriately authorized by an NMRA (to manufacture the pharmaceutical form and the product
744
concerned) and (d) validation protocol is available or validation of the manufacturing process at
745
the new site has been successfully carried out on at least three production-scale batches in
746
747
748
16.
17.
749
750
751
752
753
18.
754
Replacement or addition of a primary packaging type provided the change does not concern a
sterile FPP.
755
756
19.
Change in qualitative and/or quantitative composition of the immediate packaging material for
757
semisolid and liquid FPPs. On condition that (a) the change does not concern a sterile FPP, (b) no
758
change in the packaging type and material (an example of an allowable change is blister to blister)
759
and (c) the relevant properties of the proposed packaging are at least equivalent to those of the
760
761
762
20.
Extension in the shelf-life of the FPP (as packaged for sale) provided there is no change to the
763
primary packaging type in direct contact with the FPP and to the recommended conditions of
764
storage and stability data were generated in accordance with the currently accepted stability
765
protocol.
766
767
21.
768
Extension in the in-use period of the FPP (after first opening or after reconstitution or
dilution).
769
770
771
22.
Change in the labelled storage conditions of the FPP (as packaged for sale), the product
during the in-use period or the product after reconstitution or dilution.
772
773
774
5.4.2
Major variation
Variations, which fail to fulfil the conditions for notifications or minor variations
778
automatically, become major variations. In addition, variations, which are not covered by
779
780
781
References
782
783
1.
784
pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part.
785
786
report. Geneva, World Health Organization. Technical Report Series, No. 970, 2012, Annex 4.
787
788
2.
789
790
791
792
3.
Guidelines for stability testing of active pharmaceutical ingredients and finished pharmaceutical
793
794
Forty-third report. Geneva, World Health Organization. Technical Report Series, No. 953,
795
2009, Annex 2.
796
797
4.
798
European Commission. List of permitted food colours: EC Directive 94/36/EC. Official Journal
of the European Communities 1994; L237.
799
800
5.
801
FDA. Summary of Color Additives for Use in the United States in Foods, Drugs, Cosmetics,
and Medical Devices. 2010.
802
803
6.
804
805
806
807
808
809
***