HPRA 发布 MIA 变更申请指南 AUT-G0182 第 3 版
Guide to applications for a variation to a manufacturer's authorisation
HPRA 发布制造商授权（MIA）变更申请指南 AUT-G0182 第 3 版，文件内标示日期为 2026 年 9 月 29 日，官方目录列示日期为 2026 年 9 月 30 日。
指南逐项说明 MIA 变更申请的三种流程、时限与支持文件，便于核对 Annex 1 至 8 的填报要求。
HPRA 人用药品质／GMP／GDP 指南：Guide to applications for a variation to a manufacturer's authorisation
文件编号：AUT-G0182；版本：3。
官方目录列示日期：2026-09-30（原文 30/09/2026，DD/MM/YYYY）；文件内日期另行保留。
适用范围及爱尔兰监管要求以原文件为准。
文件内标示日期：2026-09-29。与目录列示日期不同，两者保留；排序仍采用目录日期。
PDF 文字版；图形和原始排版请参阅官方 PDF。
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Guide to
Applications for Variation to a
Manufacturer’s Authorisation
AUT-G0182-3
29 SEPTEMBER 2026
This guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only.
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Guide to Applications for a Variation to a Manufacturer’s Authorisation
CONTENTS
INTRODUCTION 4
OVERVIEW OF VARIATIONS TO MANUFACTURER’S AUTHORISATION 4
Structure of the standard variation application form 5
Clock stops 6
APPLICANT DETAILS 6
Guidance on addresses 7
ANNEXES OF THE EU FORMAT FOR A MANUFACTURER’S AUTHORISATION 9
ANNEX 1 AND ANNEX 2 MANUFACTURING AND IMPORTATION OPERATIONS 10
Guidance on terminology used in the MIA 10
Part 1 Manufacturing Operations 13
Part 2 Importation of medicinal products 20
ANNEX 3 CONTRACT MANUFACTURER(S) 23
Listing contract storage sites 23
Listing contract manufacturing sites 23
When are contract sites not required to be listed in Annex 3? 24
Important notes 25
Contract manufacturing site details and supporting documentation 26
Sites based in MRA territories 27
Sites based in non-MRA third country territories 28
ANNEX 4 CONTRACT LABORATORY 31
Listing contract laboratories 31
Contract laboratory details and supporting documentation 31
Sites based in MRA territories 32
New contract laboratories based in Ireland 33
ANNEX 5 QUALIFIED PERSON(S) 36
Qualifications 36
Practical experience 36
Training 37
ANNEX 6 PERSONNEL FOR PRODUCTION OPERATIONS AND QUALITY CONTROL 38
ANNEX 7 NOT USED BY THE HPRA 39
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ANNEX 8 IMPORTATION OF PRODUCTS WHICH ARE CONTRACT MANUFACTURED AT A
SITE OUTSIDE THE EEA 39
Listing entries in Annex 8 39
Details to be placed in Annex 8 Entry 40
APPENDIX 1 SUPPLY OF UNLICENSED/EXEMPT MEDICINAL PRODUCTS 43
APPENDIX 2 REMOTE BATCH CERTIFICATION BY THE QUALIFIED PERSON 44
APPENDIX 3 DECLARATIONS BY THE QUALIFIED PERSON 46
APPENDIX 4 FURTHER DETAIL ON SUPPORTING DOCUMENTATION REQUIRED FOR SITES
BASED IN MRA/ACAA PARTNER TERRITORIES 47
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Guide to Applications for a Variation to a Manufacturer’s Authorisation
INTRODUCTION
There are three types of manufacturer’s/importer’s authorisation (MIA) depending on the type
of medicinal products within scope - human medicinal products, subject to marketing
authorisation (H), veterinary medicinal products, subject to marketing authorisation (V) and
human investigational medicinal products (IMP). This document provides guidance on
applying to the HPRA to vary an existing MIA. These MIAs are required where the company
performs manufacturing or importation activities related to the category of medicinal
products.
This guide should be read in conjunction with the following relevant application forms:
- Application for variation to a manufacturer’s authorisation (AUT-F0211)
- IMP expedited assessment of variations to Annex 3 and/or 4 application form (AUT-F0791)
- IMP immediate notification of variations to Annex 3 and/or 4 application form (AUT-F0819)
The MIA is formatted into the agreed EU format included in the Compilation of Union
Procedures on Inspections and Exchange of Information published by the European Medicines
Agency on behalf of the European Commission. This guidance is located on the EMA website
at Interpretation of the Union format for Manufacturer Importer Authorisation.
OVERVIEW OF VARIATIONS TO MANUFACTURER’S AUTHORISATION
There are three processes that can be used to vary an MIA. In each case, applicants must
submit a completed application form, the required supporting documentation as detailed in
this guide, and the appropriate fee.
Details of the variation type, timeline and scope of each process are provided in Table 1.
The timelines commence following acknowledgement of receipt of the application by the
HPRA. These timelines can be suspended during periods, known as clock-stop, where further
information is required from the applicant, or where the applicant indicates that they are not
currently in a position to facilitate an inspection.
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Table 1: Types of processes to vary manufacturer’s authorisations
Variation Scope and timeline Application
process form
reference
Standard Applies to all variation types. AUT-F0211
variation The assessment timeline can vary from 30 to 90 days. In
process general, when an inspection is required, the timeline is
extended to 90 days. Refer to later sections of this document,
which outline the timelines for variations to specific Annexes,
and provide further guidance on the type of standard
variations which require inspection.
Expedited Applicable to IMP MIAs only, and only for the addition or AUT-F0791
assessment removal third country-based contract manufacturing sites and
of contract laboratories (Annex 3 and 4).
variations
This is an optional process to allow faster processing of these
to Annex 3
types of applications. The standard variation process can be
and/or 4
applied if an expedited assessment is not required.
Assessment timeline is seven days; however, the timeline is
contingent on the provision of supporting documentation.
Immediate Applicable to of IMP MIAs only, and only for the addition or AUT-F0819
notification removal of EU/EEA-based contract manufacturing sites and
of contract laboratories (Annex 3 and 4). This process is only
variations applicable to contract sites, which are appropriately authorised
to Annex 3 by an EEA competent authority for the requested
and/or 4
manufacturing operations.
This is an optional process as the standard variation process,
with the associated timeline, can also be applied. Variations
which do not meet these criteria should not be submitted
through this process.
MIA holders can commence proposed activities immediately
after submission of the variation application. Assessment
timeline is 30 days.
Structure of the standard variation application form
The application for variation to a manufacturer’s authorisation (AUT-F0211) is used for the
standard variation process. This form is divided into the following four sections, depending on
the variation type and applicable timeline. Each section consists of variations which are of the
same type (administrative or technical) and have the same timeline (30, 60, or 90 days).
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Guide to Applications for a Variation to a Manufacturer’s Authorisation
- Administrative variations, 30-day procedure
- Technical variations, 30-day procedure
- Technical variations, 60-day procedure
- Technical variations, 90-day procedure
These are described throughout this guide.
Clock stops
When the HPRA receives an MIA variation application, we consider whether or not the
application requires further supporting information and/or an inspection. Where further
information is required, the HPRA assessment time is stopped (the so-called 'clock-stop' days)
from the date the notice is given, and the clock recommences only on receipt of the
information requested.
Issues that can result in ‘clock-stop’ include the following:
- The application form is not filled out correctly.
- Adequate supporting documentation is not enclosed.
- Assessment requires an inspection and the company is not ready for inspection.
Where multiple variations are submitted in the same application form, the HPRA will progress
the approval of those variations that have adequate supporting evidence, while the
outstanding variations will remain in progress until such time when adequate supporting
evidence is provided or the company chooses to withdraw variations that cannot be
supported.
Linked variations must be processed together, e.g. the addition of a third country contract
manufacturer in Annex 3, which requires inspection (90-day timeline) and the addition of an
imported product from that manufacturer in Annex 8 (30-day timeline) must be processed
together resulting in both variations having the longer 90-day timeline.
Note: Addition of a third country manufacturer, which requires inspection due to absence of
EU GMP certification for the products/processes concerned, is required to be notified in
advance of submission of the variation application to the HPRA through a pre-submission
process.
APPLICANT DETAILS
Variations may be made to the legally registered name and/or address, or the name and/or
address of the manufacturing site of the MIA holder.
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Guidance on addresses
The Location ID (LOC-ID) of sites is required on all applications for variation to an MIA. For this,
applicants must check that the manufacturing organisation is correctly registered in the EMA
Organisation Management Service (OMS). Further information on this process is outlined on
the European Medicines Agency (EMA) website. For more information refer to the following
links.
- SPOR Data Management Service portal
- Organisation Management Service (OMS)
- Video tutorial: Overview of OMS
- Webinar for Industry: Introduction to OMS services and activities
If the manufacturing site consists of a number of separate units located in an industrial estate
which are managed under the same pharmaceutical quality system and the responsibility of
the same key personnel named on the application, then include the main contact address for
the manufacturing site.
- Provide details of other ‘units’, which will operate under the scope of this MIA below the
main contact address. The scope of operations at each address/unit should be made clear
in the application.
- A single MIA and one GMP certificate referencing all the units will be issued on the
EudraGMDP database.
If the manufacturing activities are carried out at addresses which are not adjacent or in close
proximity, then a separate ‘Scope of authorisation’ section must be completed for each
address.
- All of the manufacturing activities must be under the same pharmaceutical quality system
and under the responsibility of the same key personnel for these separate addresses to be
considered under a single MIA application.
- In the event that this application is successful then a single MIA, which includes details of
the activities at each separate address, will be issued on EudraGMDP and a separate GMP
certificate will be issued on EudraGMDP for each manufacturing address.
Further detail on timelines and supporting documentation is detailed in table 2.
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Table 2: Variations to applicant details
Variation Type, timeline and Supporting documentation
form
Minor corrections of - Admin variation None required.
typographical errors to - 30 days Note: The HPRA may request
authorisation - AUT-F0211, section 1 further information related to this
variation.
Change in the name of - Admin variation Certificate of Incorporation.
authorisation holder - 30 days A statement from a Qualified
- AUT-F0211, section 1 Person (QP) named on the MIA
outlining any implications that this
change may have on the quality
management system or its
operation at the site.
Note: When a change to the name
of the MIA holder is a result of a
proposed sale or transfer to
another company, this is not a
variation application and requires a
transfer application. please refer to
the HPRA website (MIA transfers)
for further information.
Change in the legally - Admin variation Certificate of Incorporation.
registered address of the - 30 days
MIA holder - AUT-F0211, section 1
Change in the main address - Technical variation An inspection may take place as
of the manufacturing site - 90 days part of the assessment of such a
Or - AUT-F0211, section 4 variation.
Addition of new
manufacturing address If the company is not relocating to
different premises and the address
of the current site is being updated,
Note:
the QP must submit a declaration
This refers to a new site confirming no change to the
where manufacturing/ physical location of the premises or
importing activities are the activities carried out therein.
performed by the MIA
holder, and not to the
addition of a new contract An updated version of the site
manufacturing site or master file should be submitted to
contract laboratory, which the HPRA when a variation to
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Variation Type, timeline and Supporting documentation
form
are covered in Annex 3 and change the manufacturing address
4 respectively. has been approved.
ANNEXES OF THE EU FORMAT FOR A MANUFACTURER’S AUTHORISATION
Table 3 gives an overview of the Annexes that can be completed for an MIA, which will be
reflected in the format of the authorisation. Further clarity on completion of each Annex is
given in subsequent sections.
Table 3: Summary of Annexes
Annex Annex title Notes
1 Scope of authorisation This describes the manufacturing/ importation/ testing
relating to medicinal operations/ batch certification carried out directly
products, subject to under the MIA at the company’s own address in
marketing authorisation relation to medicinal products, subject to marketing
for human and/or authorisation for human and/or veterinary use.
veterinary use Activities carried out at contract sites must not be
indicated in Annex 1. This information is published on
the EudraGMDP database.
2 Scope of authorisation This describes manufacturing, importation, testing
relating to operations or batch certification carried out directly
investigational under the MIA at the company’s own address in
medicinal products relation to IMPs. Activities carried out at contract sites
must not be indicated in Annex 2. This information is
published on the EudraGMDP database.
3 Names and addresses This includes manufacturing, storage, importation or
of contract testing operations which are carried out at contract
manufacturing site(s) manufacturing site(s). This information is not published
on the EudraGMDP database.
4 Names and addresses This includes testing operations carried out at contract
of contract laboratories laboratories. This information is not published on the
EudraGMDP database.
5 Name(s) of Qualified This information is not published on the EudraGMDP
Person(s) database.
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Annex Annex title Notes
6 Names of personnel This information is not published on the EudraGMDP
responsible for database.
production and quality
control
7 Date of inspection on This optional annex within the EU format for an MIA is
which authorisation not currently used by the HPRA. The annex
granted number/title is referenced merely for completeness.
8 Importation of products This information is not published on the EudraGMDP
which are contract database.
manufactured at a site
outside the EEA
ANNEX 1 AND ANNEX 2 MANUFACTURING AND IMPORTATION OPERATIONS
The principal operations performed at the site of a manufacturer are outlined in Annex 1 and
Annex 2. Annex 1 is selected when medicinal products, subject to marketing authorisation, are
manufactured for human and/or veterinary use. Annex 2 is selected when medicinal products
are manufactured for IMPs.
When completing Annex 1 and Annex 2, all activities proposed at the address must be
indicated separately, e.g. if the applicant proposes to manufacture bulk tablets, perform
primary and secondary packaging, quality control testing and batch certification, all these
activities must be ticked in the application form. Table 4 indicates the timelines along with
supporting evidence for variation to Annex 1 and Annex 2.
Guidance on terminology used in the MIA
Each operation carried out by the MIA holder is identified in the authorisation, as
appropriate. The scope of manufacturing operations which are authorised at the site is defined
using the unit operations listed as follows.
Processing operations
This includes any or all processing steps in the manufacture of a dosage form.
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Production of intermediates
If the site manufactures intermediates as part of the manufacturing process for bulk products,
this does not need to be indicated separately in the application. However, if a company
exclusively manufactures intermediates that contain one or more active substances, the
company must apply for authorisation of the ‘1.4.1.3 Other’ activity and indicate the
formulations (e.g. granules, powder, fluid, etc.) that are manufactured.
Primary packing
Refers to placing and sealing of the medicinal product within the finished product packaging
material, which is in direct contact with the product.
Secondary packing
Refers to placing the medicinal product, which is already sealed within its primary packaging
material, within an outer packaging material. This also includes labelling operations or the
assembly of other components which are specified in the marketing authorisation (or product
specification file in the case of an IMP) to form the finished product pack.
Repackaging
A manufacturer that repackages and certifies the repackaging of the product for release of the
product (e.g. repackaging of parallel imported product) need only list 1.5.2 ‘Secondary
Packaging’ in Annex 1 or Annex 2, as applicable.
Batch certification
Refers to the certification of a finished product batch of medicinal product by a QP before its
release into the marketplace or before a batch is exported. For an IMP, this refers to the QP
certification of the batch of IMP before release to the clinical trial sponsor.
For sites that only perform batch certification, include a statement clarifying the security
arrangements at the site address, storage arrangements for retention and reference samples
for product certified and general arrangements for access to the HPRA authorised officers to
the site on a constant basis (e.g. for sites which are leased/shared office spaces).
QP confirmation
The QP confirmation of a specific operation is inherent in the listed operation, e.g. activity 1.5.2
‘secondary packaging’ covers the confirmation of that packaging process. Where a
manufacturer also performed QP certification to allow release to the market, batch certification
operations in Annex 1 or Annex 2, as applicable, must also be selected.
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Quality control
Refers to types of laboratory testing which the MIA holder is authorised to perform.
Storage
Any site which holds an MIA and carries out processing operations or packaging of medicinal
products is also authorised for storage.
If the site carries out storage of intermediates or bulk products as a stand-alone activity, the
company must apply for authorisation for storage under ‘1.4.3 Other’ and indicate the
formulations (e.g. granules, powder, fluid, etc.) that are stored. This also applies to the storage
of unreleased medicinal products that are manufactured and packaged.
Note: All components released for the manufacture of a medicinal product are considered as
intermediates. Consequently, an MIA is required to store released raw materials and packaging
components, if such components are not released again prior to the manufacture of the
medicinal product.
Distribution
Any site, which holds an MIA, and which carries out manufacturing operations on batches of
medicinal products is also authorised to distribute those batches of medicinal products unless
there is a comment to the contrary in the clarifying remarks. Distribution activities by another
MIA holder require a wholesale distribution authorisation (WDA).
If a manufacturer has not carried out a manufacturing operation on a batch of medicinal
product which it intends to distribute (including manufacture of the dosage form, packaging
or batch certification) then the site is required to hold a separate WDA for distribution
activities in relation to those batches or products.
Real time release testing
If a manufacturer is authorised to carry out real time release testing instead of one or more
finished product tests, then identify this as a clarifying remark in relation to the processing
operations for the particular dosage form. The type of real time release testing (e.g. parametric
release) which is authorised is also to be identified in the clarifying remarks. The use of real
time release testing should reflect any relevant requirements described in a marketing
authorisation or clinical trial application.
Note: For activities included under ‘processing operations’, primary and secondary packaging,
batch certification and quality control, manufacturers should evaluate materials which are
handled at the site with regard to the risk posed in terms of their potency, toxicity or potential
for sensitisation, using the guidance described in Chapters 3 and 5 of the EU Guide to GMP.
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If a site is authorised to carry out processing operations or primary packing activities on
substances or products which are considered to be highly sensitising, highly potent or highly
toxic or have a specific hazard (e.g. radiopharmaceuticals) then this is identified in relation to
the particular dosage form using the relevant items from the list below.
List of specific hazards for a dosage form (as per dropdown menu items from EudraGMDP):
- β-Lactam antibiotics
- Other highly sensitising materials
- Live cells
- Pathogenic Organisms (Biosafety 3 or 4)
- Radiopharmaceuticals
- Ectoparasiticides
- Others (free text entry)
Any restrictions that may apply in relation to these products (e.g. if product is to be
manufactured in a dedicated facility) should be included in the clarifying remarks with
reference to the relevant dosage form.
Examples of products to be included under ‘Other’ category include:
- Highly potent products
- Highly toxic products
Note: see guidance in Appendix 1 on unlicensed/exempt medicinal products.
Part 1 Manufacturing Operations
The following section reflects the manufacturing operations available to the applicant in the
variation types related to Part 1 of Annex 1 or Annex 2 in the application form. Guidance is
provided to help select the correct options.
1.1 Sterile products
1.1.1 Aseptically prepared (processing operations for the following dosage forms)
1.1.1.1 Large volume liquids
1.1.1.2 Lyophilisates
1.1.1.3 Semi-solids
1.1.1.4 Small volume liquids
1.1.1.5 Solids and implants
1.1.1.6 Other aseptically prepared products <free text>
An example of an activity captured under 1.1.1.6 ‘Other’: ‘Manufacture of sterile active
substance’.
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1.1.2 Terminally sterilised (processing operations for the following dosage forms)
Where terminal sterilisation of a product is not carried out on site by the MIA holder but is
contracted out to another site, enter a comment such as ‘terminal sterilisation by gamma
irradiation is outsourced to another site’ in relation to that dosage form in the clarifying
remarks section.
1.1.2.1 Large volume liquids
1.1.2.2 Semi-solids
1.1.2.3 Small volume liquids
1.1.2.4 Solids and implants
1.1.2.5 Other terminally sterilised prepared products <free text>
1.1.3 Batch certification
This is understood to apply to all sterile dosage forms unless restrictions are stated in the
clarifying remarks.
Remote batch certification: See Appendix 2 regarding requirements for remote batch
certification by the Qualified Person.
1.2 Non-sterile products
1.2.1 Non-sterile products (processing operations for the following dosage forms)
1.2.1.1 Capsules, hard shell
1.2.1.2 Capsules, soft shell
1.2.1.3 Chewing gums
1.2.1.4 Impregnated matrices
1.2.1.5 Liquids for external use
1.2.1.6 Liquids for internal use
1.2.1.7 Medicinal gases
1.2.1.8 Other solid dosage forms
1.2.1.9 Pressurised preparations
‘Pressurised preparations’ are defined as preparations presented in special containers under
pressure of a gas. If, for example, a liquid aerosol is generated by mechanical pumping action
rather than a propellant then such dosage forms are categorised as ‘Liquids for external use’ or
‘Liquids for internal use’, as appropriate.
A metered dose inhaler which uses a propellant to deliver the required dose is listed as a
‘Pressurised preparation’. If the dose is delivered by other means, e.g. breath activation, then
enter processing operations relating to this dosage form under Other (1.2.1.17) ‘Breath
activated metered dose inhaler’.
1.2.1.10 Radionuclide generators
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1.2.1.11 Semi-solids
1.2.1.12 Suppositories
1.2.1.13 Tablets
1.2.1.14 Transdermal patches
1.2.1.15 Intraruminal devices
1.2.1.16 Veterinary premixes
1.2.1.17 Other non-sterile medicinal product <free text>
Examples of activities captured under 1.2.1.17 ‘Other’:
- ‘Manufacture of intermediates’ (e.g. powders for further processing)
- ‘Over-encapsulation’ (This activity is usually applicable to IMPs and controls may differ from
those used in filling a standard hard shell capsule product.)
- ‘Breath activated metered dose inhaler’
1.2.2 Batch certification
This is understood to apply to all non-sterile dosage forms unless restrictions are stated in the
clarifying remarks.
Remote batch certification: See Appendix 2 regarding requirements for remote batch
certification by the Qualified Person.
1.3 Biological medicinal products
A biological medicinal product is a medicinal product, the active substance of which is a
biological substance.
A biological substance is a substance that is produced by or extracted from a biological source
and that needs for its characterisation and the determination of its quality a combination of
physico-chemical-biological testing, together with the production process and its control.
There may be substances obtained from a biological source (e.g. extracted from a plant or
animal source) which do not require a biological test to determine appropriate quality of the
substance. Products manufactured using such substances are not generally classified as
biological medicinal products and therefore not listed under this section of the MIA.
1.3.1 Biological medicinal products
The following product categories are used to identify if a site is carrying out any processing
steps relating to the manufacture of a biological product. The manufacture of the biological
substance may be part of the continuum of processing steps in the manufacture of the
finished biological product and these operations are captured under this section, where
appropriate.
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For variations to add biological drug product manufacture, where the site produces the final
dosage form, both the category of biological medicinal product (1.3) and the dosage from (1.1
or 1.2) must be selected. e.g. a manufacturer producing 10ml filled vials of an aseptically
prepared monoclonal antibody should select 1.1.1.4 and 1.3.1.5 Biotechnology products, with
the clarifying remark ‘manufacture of the finished dosage form’, as outlined below:
- 1.1.1.4 Small volume liquids
- 1.3.1.5 Biotechnology products
Clarifying remark: 1.3.1.5 relates manufacture of the finished dosage form.
1.3.1.1 Blood products
Select this category where there are processing operations performed in relation to biological
products containing an active substance isolated from blood. Examples of such products
include albumin, plasma Factor VIII or immunoglobulins which are isolated from blood. The
processing of Factor VIII, which is manufactured using a biotechnology method, is not
included in this category. For a human medicine, the steps in the manufacture of a blood
product, which come under an MIA, are those processing steps which are not covered under
Directive 2002/98/EC.
1.3.1.2 Immunological products
Select this category where there are processing operations carried out in relation to
manufacture of biological products which have an immunological mode of action (e.g.
vaccines).
1.3.1.3 Cell therapy products
Somatic cell therapy medicinal product is defined in Part IV of Annex I to Directive 2001/83/EC.
Select this category where there are processing operations carried out in relation to the
manufacture of cell therapy products. The steps in the manufacture of cell therapy product,
which come under an MIA, are those steps which are not covered under Directive 2004/23/EC.
1.3.1.4 Gene therapy products
A gene therapy medicinal product is defined in Part IV of Annex I to Directive 2001/83/EC.
Select this category where there are processing operations carried out in relation to the
manufacture of gene therapy products. The steps in the manufacture of a gene therapy
product, which come under an MIA, are those steps which are not covered under Directive
2004/23/EC.
1.3.1.5 Biotechnology products
Biotechnology includes the use of genetically modified mammalian cells or micro-organisms,
(e.g. bacteria or yeasts), or biological substances (e.g. enzymes), in the manufacture of
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biological products. This category is selected where there are processing operations carried
out in relation to the manufacture of biological products using biotechnology.
For steps involving the manufacture of a biological product manufactured via a biotechnology
route, insert a clarifying remark relating to activities under 1.3.1.5 to specify which of the
following activities apply (multiple options may apply):
- Cell culture mammalian
- Cell culture bacterial
- Isolation/purification
- Modification (e.g. pegylation, glycosylation, etc.)
- Low bioburden bulk intermediate
- Final dosage form
Production of monoclonal antibodies (mAbs) is included as an activity under biotechnology
products.
1.3.1.6 Human or animal extracted products
Select this category where processing steps are carried out in relation to the manufacture of a
biological product containing active substances derived from human or animal sources (cells,
tissues, fluids), with the exception of blood. The steps in the manufacture of human extracted
products, which come under an MIA, are those steps which are not covered under Directive
2004/23/EC.
1.3.1.7 Tissue engineered products
A tissue engineered product is defined in Article 2(1)(b) of Regulation (EC) No 1394/2007.
Select this category where processing steps are carried out in relation to the manufacture of a
product that contains or consists of engineered cells or tissues, and is presented as having
properties for, or is used in or administered to human beings with a view to regenerating,
repairing or replacing a human tissue. The steps in the manufacture of tissue engineered
product derived from human tissue which come under an MIA are those steps which are not
covered under Directive 2004/23/EC.
1.3.1.8 Other biological medicinal products <free text>
Select this category where processing steps are carried out in relation to manufacture of a
biological product, including a biological active substance which does not fit into the
previously named categories. An example would be allergen products, which are derived from
non-animal sources such as grass-pollen.
1.3.2 Batch certification (list of product types)
Complete this section with regard to final QP certification of the finished dosage form of a
biological product. An entry should also be made under 1.1.3 or 1.2.2, as appropriate to
identify if the dosage being certified is a sterile or non-sterile product respectively. See
Appendix 2 regarding requirements for remote batch certification by the Qualified Person.
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1.3.2.1 Blood products
1.3.2.2 Immunological products
1.3.2.3 Cell therapy products
1.3.2.4 Gene therapy products
1.3.2.5 Biotechnology products
1.3.2.6 Human or animal extracted products
1.3.2.7 Tissue engineered products
1.3.2.8 Other biological medicinal products <free text>
1.4 Other products or manufacturing activity
Note: Where a manufacturer carries out processing steps in relation to herbal or
homoeopathic dosage forms (e.g. tablets) then there will be an entry for the relevant dosage
form (sections 1.1 to 1.2) in addition to the entry in this section. Where the facility is only
authorised for manufacturing operations in relation to herbal or homoeopathic products then
include a clarifying remark (‘herbal products only’ or ‘homoeopathic products only’) in relation
to the dosage forms/manufacturing operation authorised on the MIA.
1.4.1 Manufacture of other products
1.4.1.1 Herbal products
1.4.1.2 Homoeopathic products
1.4.1.3 Other <free text>
1.4.2 Sterilisation of active substances/excipients/finished product
Complete this section where these sterilisation activities are not carried out as part of the
manufacture of a dosage form, for example, where the MIA holder is a contract sterilisation
facility performing gamma irradiation of products on behalf of other manufacturers. If the site
carries out sterilisation as part of the manufacturing process for a given dosage form in section
1.1 of the MIA, this does not need to be separately indicated.
1.4.2.1 Filtration
1.4.2.2 Dry heat
1.4.2.3 Moist heat
1.4.2.4 Chemical
1.4.2.5 Gamma irradiation
1.4.2.6 Electron beam
1.4.3 Other <free text>
Example of activities to be listed under 1.4.3: ‘Storage’: where the MIA-holder only carries out
batch certification and storage of medicinal products.
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Note that an MIA-holder, which carries out processing operations or packaging of medicinal
products is also authorised for storage, without having to specifically mention ‘storage’ under
1.4.3.
1.5 Packaging
1.5.1 Primary packing
Primary packing of a sterile product is taken as being included as part of the processing
operations covered under section 1.1 and therefore this section is not required to be
completed for sterile products, unless a comment to the contrary is entered in the clarifying
remarks in relation to the particular dosage form.
1.5.1.1 Capsules, hard shell
1.5.1.2 Capsules, soft shell
1.5.1.3 Chewing gums
1.5.1.4 Impregnated matrices
1.5.1.5 Liquids for external use
1.5.1.6 Liquids for internal use
1.5.1.7 Medicinal gases
1.5.1.8 Other solid dosage forms
1.5.1.9 Pressurised preparations
1.5.1.10 Radionuclide generators
1.5.1.11 Semi-solids
1.5.1.12 Suppositories
1.5.1.13 Tablets
1.5.1.14 Transdermal patches
1.5.1.15 Intraruminal devices
1.5.1.16 Veterinary premixes
1.5.1.17 Other non-sterile medicinal products <free text>
Example of activities to be captured under 1.5.1.17 ‘Other non-sterile medicinal products’:
If the MIA holder carries out primary packing but not the actual manufacture of a dosage form
(e.g. implants), which subsequently undergoes terminal sterilisation, enter a statement under
‘Other non-sterile medicinal products’ 1.5.1.17, as follows: ‘Primary packing of (name of dosage
form), which undergoes terminal sterilisation’.
1.5.2 Secondary packing
Where secondary packaging is authorised, it is understood to apply to all dosage forms unless
otherwise specified in the clarifying remarks.
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1.6 Quality control testing
Where quality control testing is carried out at the site authorised, categories of testing should
be identified below.
1.6.1 Microbiological: sterility
1.6.2 Microbiological: non-sterility
1.6.3 Chemical/Physical
1.6.4 Biological
Endotoxin testing should be indicated under biological testing. Where endotoxin testing is the
only biological test performed, include a clarifying remark ‘1.6.4 refers to endotoxin testing
only’.
Any restrictions or clarifying remarks related to the scope of these manufacturing operations
The addition of clarifying remarks by the applicant is outlined in the guidance above.
The HPRA may also add restrictions or clarifying remarks related to the scope of these
manufacturing operations. Unless a clarifying remark is intended as a general comment
relating to activities at the site, a numerical reference, as per the item listing on the MIA
format, is included wherever a clarifying remark or restriction is applied.
Remarks may be entered as confidential or public remarks on EudraGMDP, as determined by
the HPRA. Confidential remarks may only be viewed by competent authorities (registered users
on EudraGMDP) whereas public remarks can be viewed by anyone.
Part 2 Importation of medicinal products
The following section reflects operations concerning imported medicinal products in Part 2 of
Annex 1 or Annex 2 in the application form.
2.1 Quality control testing of imported medicinal products
Where quality control testing is carried out at the site in relation to imported medicinal
products, identify the authorised categories of testing. Complete this section where applicable,
even if entries have been made under section 1.6 relating to the same testing operations on
products manufactured in the EEA. Endotoxin testing should be indicated under biological
testing. Where endotoxin testing is the only biological test performed, include a clarifying
remark ‘2.1.4 refers to endotoxin testing only’.
2.1.1 Microbiological: sterility
2.1.2 Microbiological: non-sterility
2.1.3 Chemical/Physical
2.1.4 Biological
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2.2 Batch certification of imported medicinal products
Complete this section where the site performs certification of either an imported finished
product or a bulk dosage form which undergoes packing after importation. If the MIA holder is
also the site of physical importation, then an entry is made under 2.3.1.
For IMP manufacturers (Annex 2), identify authorisation to carry out certification of imported
comparator products by a clarifying remark in relation to the relevant product category. See
Appendix 2 regarding requirements for remote batch certification by the Qualified Person.
2.2.1 Sterile Products
2.2.1.1 Aseptically prepared
2.2.1.2 Terminally sterilised
2.2.2 Non-sterile products
Identify the relevant dosage form under 2.2.1 or 2.2.2 in addition to the category of biological
product.
2.2.3 Biological medicinal products
2.2.3.1 Blood products
2.2.3.2 Immunological products
2.2.3.3 Cell therapy products
2.2.3.4 Gene therapy products
2.2.3.5 Biotechnology products
2.2.3.6 Human or animal extracted products
2.2.3.7 Tissue engineered products
2.2.3.8 Other biological medicinal products <free text>
2.3 Other importation activities (any other relevant importation activity that is not covered
above)
2.3.1 Site of physical importation
An entry here means that the site is authorised to receive and store imported product which is
awaiting QP certification. Certification is identified separately in relation to the relevant
product categories under section 2.2.
2.3.2 Importation of intermediate which undergoes further processing
When selecting this operation, also specify the type of intermediate imported, e.g. granulate,
sterile active substance, partially manufactured biological product.
2.3.3 Biological active substance
Select this operation when importing biological drug substance, either for further processing
of for storage and further distribution.
2.3.4 Other <free text>
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Any restrictions or clarifying remarks related to the scope of these importation operations
The HPRA may add restrictions or clarifying remarks related to the scope of importation
operations.
Unless a clarifying remark is intended as a general comment relating to activities at the site,
include a numerical reference, as per the item listing on the MIA format, wherever a clarifying
remark or restriction is applied.
Remarks may be entered as confidential or public remarks on EudraGMDP, as determined by
the HPRA. Confidential remarks may only be viewed by competent authorities (registered users
on EudraGMDP) whereas public remarks can be viewed by anyone.
Table 4: Variations to Part 1 and/or Part 2, Annex 1 or Annex 2
Variation Type, timeline and Supporting documentation
form
Addition to the - Technical variation An updated version of the site master file should be
currently - 90 days submitted to the HPRA when a variation to change
approved - AUT-F0211, the manufacturing operations has been approved.
operations section 4
Submit evidence of the site QPs’ training or
or These variation types experience in the new product/dosage form to be
often require an batch certified. This should include:
inspection, subject - A CV of the relevant QP(s),
Addition of
to clock stops.
new dosage - A comprehensive summary of the training
form or conducted demonstrating that the QP has
product type detailed knowledge of the product type and
production processes.
Deletion of - Admin variation None required.
currently - 30 days
approved - AUT-F0211,
operations section 1
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ANNEX 3 CONTRACT MANUFACTURER(S)
Annex 3 should be completed in relation to contract storage or contract manufacturing sites
and the requirements relating to each of these outsourced activities are described under
separate headings below.
Listing contract storage sites
Any site performing contract storage on behalf of the MIA holder should be listed in Annex 3
where the storage activity specifically relates to the following:
- Storage of intermediates/partially manufactured medicinal products.
- Storage of medicinal products which are awaiting QP certification.
- Storage of reference/retention samples.
Section 1.4.3 <Other> on the application form should be used to identify the storage activity
performed at the contracted sites. It is not necessary to specify the particular product types to
which these storage activities apply.
Listing contract manufacturing sites
The requirement to list contract manufacturing sites in Annex 3 is only applicable where the
MIA-holder acts as the site of batch certification for a product, which is intended for supply to
EU/EEA markets or a clinical trial in the EU/EEA.
- Contract manufacturers include sites involved in any part of the manufacture (including
packaging) of the medicinal product. Please see the section below for scenarios when a
contract site is not required to be listed in Annex 3.
- The operations described in Annex 3 for the contracted site should reflect the specific
activities carried out at the site in relation to the product intended for batch certification as
opposed to all the activities at the contract site listed on the relevant GMP certificate, e.g. if
a contract manufacturing site is authorised to perform multiple manufacturing operations
but will only conduct secondary packaging on behalf of the MIA holder, only secondary
packaging operations would be specified for the site in Annex 3.
- In the case of biological medicinal products, manufacturers of the biological active
substance are also required to be named in Annex 3.
- If the contract site performs testing in addition to manufacturing activities, then this testing
activity should be included in Annex 3; if the site performs only testing activities in relation
to the product, then the site must be listed in Annex 4 and not Annex 3.
- The contract site must hold a valid regulatory approval (GMP certificate or equivalent);
please see the section on supporting documentation.
- Batch certification cannot be listed as an outsourced activity in Annex 3.
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When are contract sites not required to be listed in Annex 3?
- If the MIA holder itself is contracted to perform any part of the manufacture (including
packaging) of medicinal product on behalf of another site but is not responsible for
performing batch certification, then the sites in its supply chain do not need to be added in
Annex 3.
For example:
o If the MIA holder performs secondary packaging on vials but is not responsible for
batch certification of the final product, then the sites from which it receives such vials
do not need to be listed in Annex 3.
o If the MIA holder only acts as the site of physical importation, then third country sites
in the supply chain do not need to be listed in Annex 3.
- There is no requirement to list contract storage sites which store:
o QP certified finished product
o Stability samples
o Starting materials
- Contract manufacturers involved in the generation and/or storage of Master or Working
Cell Banks are not required to be added to Annex 3.
- Storage sites located in a third country are also not required to be listed in Annex 3.
- Contract sites are not required to be named when the product supplied is to be used as a
comparator product in an ongoing clinical trial. If, however, the comparator product is
modified (e.g. primary/secondary packaging), then the site that performs such modification
is to be added in Annex 3.
- In the case of an IMP MIA: If the IMP is produced by modification to an authorised product,
then manufacturers which carry out steps up to the point of modification need not be
named in Annex 3 provided a QP has confirmed that the steps have been carried out in
accordance with the marketing authorisation.
For example: A drug substance is manufactured in line with the steps authorised in an MA
at site A, and subsequent formulation of the DS, not in line with the MA, is performed at
site B. In this scenario, site B needs to be included in Annex 3 of the IMP MIA, while site A
does not need to be included given the QP has confirmed that the steps performed at site
A are in line with the MA. Contract manufacturers involved in the generation and/or
storage of master or working cell banks are not required to be added to Annex 3.
- Contract sites that only sterilise empty containers (primary or secondary packaging) do not
need to be added.
- Sites that manufacture active substance via chemical synthesis do not need to be added in
Annex 3. Please see the note below about sterilisation of active substances.
For example:
o A site that manufactures RNA via chemical synthesis such as a solid phase
phosphoramidite method does not need to be listed as a contract site in Annex 3, while
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a site that manufactures RNA using biological methods such as the use of a polymerase
needs to be added to Annex 3.
Important notes
- Activities relating to the sterilisation of active substances/excipients/finished product (e.g.
filtration) need only be specified when these activities are not performed as part of the
manufacturing process for the finished dosage form.
For example: in circumstances where a contract sterilisation facility performs gamma
irradiation of products on behalf of a manufacturer, sterilisation activities should be
selected.
In the case of a product that contains both chemical and biological components (e.g.
antibody drug conjugates), the manufacturers of the chemical component/active do not
need to be listed in Annex 3, but the manufacturers of the biological component/active
must be listed. Also, in the example of an antibody-drug conjugate, the site that performs
the conjugation needs to be added to Annex 3.
- For contract sites that manufacture biological medicinal products manufactured using
biotechnology, applicants must specify appropriate clarification for the scope of operations
under 1.3.1.5 ‘Biotechnology products’. Activities may include the following:
o Cell culture mammalian
o Cell culture bacterial
o Fermentation
o Isolation/purification
o Low bioburden bulk intermediate
o Final dosage form
- Where proposed manufacturing operations include the manufacture of the finished dosage
form for a biological product (section 1.3), the relevant dosage form must also be selected
in section 1.1 (sterile products) or section 1.2 (non-sterile products) in Annex 3.
For example, if a site manufactures a monoclonal antibody via mammalian cell culture,
purifies it and performs aseptic fill-finish to manufacture 10 ml vials, then the application
should indicate the following to document these activities:
o 1.1.1.4 Manufacture of aseptically prepared small volume liquid
o 1.3.1.5 Biotechnology products, with a selection on cell culture mammalian,
isolation/purification, low bioburden bulk intermediate and final dosage
- Primary packaging of sterile products is inherent in the processing operations covered
under section 1.1 unless a comment to the contrary is entered in the clarifying remarks, in
relation to the dosage form. Therefore, in general, primary packaging of sterile products is
not required to be included separately in the application for manufacturers of sterile
products. In the previous example where the site aseptically manufactures 10 ml vials, there
is no need to indicate primary packaging separately.
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- Endotoxin testing should be captured under biological testing. The applicant must specify if
endotoxin testing is the only form of biological testing performed. In such cases, a
clarifying remark to this effect will be included in the MIA such as ‘Biological testing refers
to endotoxin testing only.’ It is acknowledged that endotoxin testing may be listed as non-
sterile microbiological testing on some supporting documentation. Where the supporting
GMP certificate lists non-sterile microbiological testing, a supporting statement from the
applicant is required, clarifying that endotoxin testing is within the scope of authorised
activities.
- Under QC testing, applicants should specify whether the site performs release testing,
stability testing or both. If the site performs only stability testing, applicants should also
identify the specific category of the stability tests by selecting microbiological: sterility,
microbiological: non-sterility, chemical/physical and/or biological, as appropriate.
- Where physical importation is outsourced to a contract site, this activity will be recorded
under operation 1.4.3. Where physical importation is conducted at a site located in another
Member State, the applicant should be satisfied that each site used for physical importation
is appropriately authorised by the relevant competent authority of that Member State.
Contract manufacturing site details and supporting documentation
Applicants must submit the following details relating to add contract manufacturing sites:
- Name and address of facility (as it appears on a GMP certificate issued to the site by an EEA
competent authority, if one exists, unless otherwise justified).
- Manufacturing operations performed and quality control testing, where the testing is
performed at the same site (as per guidance for Annex 1 or 2).
Required documentation for the addition of a contract manufacturing site varies depending on
the country where the site is located, as well as the type of medicinal product, i.e. human
medicinal products, veterinary medicinal products or IMPs.
Contract manufacturing site address
Before applying to add a manufacturing site, applicants should check that the manufacturing
site is registered in OMS. If the site is registered in OMS, then the site name and address
(including the LOC-ID) presented on the variation application should be aligned to the details
on OMS. Further information on the process for registration with OMS is outlined on the
European Medicines Agency (EMA) website.
Supporting evidence to add contract sites to a human or veterinary MIA
Evidence of satisfactory GMP inspection should be provided.
- The GMP certificate should be issued to the site by a relevant EEA competent authority.
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- The inspection referenced on the GMP certificate should have been conducted within the
last three years.
- The dosage form, operation details, name and address must align with the GMP certificate
(or equivalent). The scope of the certificate should include the proposed manufacturing
operations for the relevant dosage form which will be manufactured at the site.
- For example, a GMP certificate related to IMPs would not support the addition of a contract
site to an authorised human medicines MIA.
- All operations applied for must be listed on the certificate unless inherent in the activities
stated, e.g. primary packaging of sterile products is inherent in the processing operations.
- Justification should be provided if the supporting documentation does not clearly reflect
the activities included in the application.
Supporting evidence to add contract sites to an IMP MIA
A GMP certificate with specifications outlined above can be provided. In the absence of a GMP
certificate, a QP declaration can be provided as evidence. Please refer to Appendix 3 for details
on QP declarations.
Addition of contract storage sites
- In the absence of GMP certification, a declaration by a QP named on the MIA stating that
they are satisfied that the contracted site operates in accordance with EU GMP in relation to
the activities concerned is acceptable. The HPRA reserves the right to perform its own
inspection of the contracted site.
- A WDA can be used to support the addition of a storage site for products awaiting batch
certification. The WDA must include authorisation for holding of medicinal products.
- Appropriate active substance registrations may also be considered to support the addition
of a storage site.
Sites based in MRA territories
The European Union has signed mutual recognition agreements (MRAs) with several third-
country competent authorities concerning the conformity assessment of regulated products.
These countries include the United States, Australia, Canada, Japan, New Zealand, Israel and
Switzerland. The MRA with Israel is an agreement on conformity assessment and acceptance of
industrial products (ACAA). This is a specific type of MRA based on the alignment of the
legislative system and infrastructure of the country concerned with those of the EU. The scope
of these MRAs differ depending on the country. Where a product type is within the scope of
an MRA, an applicant can submit documentation confirming compliance of the contractor by
the regulator in the MRA territory or an EEA GMP certificate. Please refer to Appendix 4 for
information on MRA/ACAA countries and type of evidence provided.
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Sites based in non-MRA third country territories
For contract manufacturers based in other non-MRA third countries, a copy of the GMP
certificate issued on the EudraGMDP database by a relevant EEA competent authority should
be submitted. A copy of a GMP certificate issued by Medicines and Healthcare products
Regulatory Agency (MHRA), UK can also be submitted, as applicable. Where no certificate is
available and an inspection is required for the site, prior to including this site on an
application, the applicant should contact the HPRA.
A summary of the timelines and supporting documentation required for variations to contract
manufacturers in Annex 3 is given in Table 5.
Table 5: Variations to contract manufacturing sites, Annex 3
Variation Type, timeline and form Supporting documentation
Addition of contract Standard process: Refer to ‘Contract manufacturing site
manufacturing site - Technical variation details and supporting
- 30 days documentation’ section above.
If this variation - AUT-F0211, Section 2
requires an
inspection, the Expedited process (IMP only):
timeline can be
- Technical variation
extended to 90 days.
- 7 days
- AUT-F0791
Immediate notification (IMP only):
- Admin variation
- 30 days
- AUT-F0819
Change in the name Standard process: - A formal document from a relevant
of a contract - Technical variation official body (e.g. Companies
manufacturing site - 30 days Registration Office or Chamber of
- AUT-F0211, Section 2 Commerce or equivalent) in which
the new name is mentioned.
- A statement from a QP named on
Expedited process (IMP only): the MIA regarding any implications
- Technical variation that this change may have on the
- 7 days quality management system or its
- AUT-F0791 operation at the contracted site.
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Variation Type, timeline and form Supporting documentation
OR
Immediate notification (IMP only): A revised GMP certificate including
- Admin variation the new name may be provided.
- 30 days
- AUT-F0819
Change in the Standard process: Submit a formal document from a
address of a contract - Technical variation relevant official body (e.g. Companies
manufacturing site - 30 days Registration Office or Chamber of
- AUT-F0211, Section 2 Commerce or equivalent) in which the
new address is mentioned.
OR
Expedited process (IMP only):
If the site is moving to a different
- Technical variation
location, then refer to ‘Contract
- 7 days
manufacturing site details and
- AUT-F0791
supporting documentation’ section
above.
Immediate notification (IMP only):
- Admin variation
- 30 days
- AUT-F0819
Addition of Standard process: Refer to ‘Contract manufacturing site
production activities - Technical variation details and supporting
at approved contract - 30 days documentation’ section above.
manufacturing site - AUT-F0211, Section 2
Expedited process (IMP only):
- Technical variation
- 7 days
- AUT-F0791
Immediate notification (IMP only):
- Admin variation
- 30 days
- AUT-F0819
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Variation Type, timeline and form Supporting documentation
Deletion of Standard process: None required.
operations or - Admin variation
removal of a - 30 days
contract - AUT-F0211, section 1
manufacturer
Expedited process (IMP only):
- Admin variation
- 7 days
- AUT-F0791
Immediate notification (IMP only):
- Admin variation
- 30 days
- AUT-F0819
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ANNEX 4 CONTRACT LABORATORY
Listing contract laboratories
All sites involved in the conduct of in-process tests, finished product tests and stability tests
described in a marketing authorisation or the clinical trial application should be included in
Annex 4. This includes additional laboratories subcontracted to perform this testing.
If a contract site performs both testing activities and manufacturing activities, it should appear
in Annex 3 and not be duplicated in Annex 4.
Testing operations are identified for each contract laboratory using the following categories:
Table 6: Testing categories
Test categories Category obligatory for these tests
Microbiology Sterility
Sterility
Microbiology non- Testing involves culturing, enumeration and identification of micro-
sterility organisms, preservative efficacy testing
Chemical/physical Testing of quality attributes by physical or chemical means, e.g. physical
testing measurements, wet chemistry, chromatographic techniques
Biological testing Tests involving use of live cultured animal cells or animals and tests utilising
materials of biological origin (e.g. antibodies, antigens). For example, rabbit
pyrogen, ELISA, Monocyte Activation Test & qPCR, Endotoxin testing (e.g.
gel clot, turbidimetric or chromogenic methods)
In the application form, testing activities are differentiated into the following types.
- Stability testing
- Release testing
Contract laboratory details and supporting documentation
Applicants must submit the following details relating to contract laboratories:
- Name and address of facility (as it appears on a GMP certificate issued to the site by an EEA
competent authority, if one exists, unless otherwise justified).
- Testing operations performed and quality control testing, where the testing is performed at
the same site (as per guidance for Annex 1 or 2).
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Required documentation for the addition of a contract manufacturing site varies depending on
the country where the site is located, as well as the type of testing performed at the site.
Contract laboratory address
Before applying to add a testing site, applicants should check that the laboratory is registered
in OMS. If the site is registered in OMS, then the site name and address (including the LOC-ID)
should be aligned to those on OMS. Further information on this process is outlined on the
European Medicines Agency (EMA) website.
Supporting evidence to add contract sites to a human or veterinary MIA
Evidence of satisfactory GMP inspection should be provided.
- The GMP certificate should be issued to the site by a relevant EEA competent authority.
- The inspection referenced on the GMP certificate should have been conducted within the
last three years.
- The testing activities, name and address must align with the GMP certificate (or equivalent).
The scope of the certificate should include the proposed testing operations, For example, a
GMP certificate related to IMPs would not support the addition of a contract site to an
authorised human medicines MIA.
Addition of contract sites to IMP MIA
A GMP certificate with specifications outlined above can be provided. In the absence of a GMP
certificate, a QP declaration can be provided as evidence. Please refer to Appendix 3 for details
on QP declarations.
Addition of contract sites performing stability testing
Contract laboratories which perform only stability testing of authorised medicines can be
added to the MIA on the basis of a declaration by a QP named on the MIA, regarding GMP
compliance of the contracted site in relation to the stability testing. The HPRA reserves the
right to perform its own inspection if deemed necessary or request another relevant authority
to inspect where appropriate.
Sites based in MRA territories
The information provided regarding MRA or ACAA sites in Annex 3 is also applicable for the
addition of contract laboratories based in those territories. Applicants should refer to Appendix
4 of this document.
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New contract laboratories based in Ireland
If a manufacturer is intending to use a contract laboratory located in Ireland that does not
currently hold a GMP certificate, the HPRA should be notified in advance of submitting a
variation through a pre-submission process.
- The HPRA will make arrangements for inspection directly with the contract laboratory
and fees associated with the inspection will be charged to the contract laboratory.
- Pending a satisfactory inspection, the resultant GMP certificate will be used as
supporting documentation and a variation application to the contract-giver’s MIA can
be submitted.
Note: Under regulation 2019/6, testing of veterinary medicines requires the testing facility to
hold a veterinary MIA.
The supporting documentation required for variations to contract laboratories in Annex 4 is
detailed in Table 6.
Table 6: Variations to contract laboratories, Annex 4
Variation Type, timeline and form Supporting documentation
Addition of a new Standard process: Refer to ‘Contract laboratory
contract laboratory - Technical variation details and supporting
- 30 days documentation’ section above.
- AUT-F0211, section 2
Expedited process (IMP only):
- Technical variation
- 7 days
- AUT-F0791
Immediate notification (IMP only):
- Admin variation
- 30 days
- AUT-F0819
If this variation requires an
inspection, the timeline can be
extended to 90 days.
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Variation Type, timeline and form Supporting documentation
Change in the name Standard process: - A formal document from a
of a contract - Technical variation relevant official body (e.g.
laboratory - 30 days Companies Registration Office
- AUT-F0211, section 2 or Chamber of Commerce or
equivalent) in which the new
name is mentioned.
Expedited process (IMP only): - A statement from a QP named
- Technical variation on the MIA regarding any
- 7 days implications that this change
- AUT-F0791 may have on the quality
management system or its
Immediate notification (IMP only): operation at the contracted
site.
- Admin variation
- 30 days OR
- AUT-F0819 A revised GMP certificate including
the new name may be provided.
Change in the Standard process: - A formal document from a
address of a contract - Technical variation relevant official body (e.g.
laboratory Companies Registration Office
- 30 days
or Chamber of Commerce) in
- AUT-F0211, section 2
which the new address is
mentioned.
Expedited process (IMP only): - Submit a statement from a QP
- Technical variation named on the MIA regarding
- 7 days any implications that this
- AUT-F0791 change may have on the
quality management system
or its operation at the
Immediate notification (IMP only):
contracted site.
- Admin variation
OR
- 30 days
- AUT-F0819 A revised GMP certificate including
the new name of the contract
laboratory.
Note: The HPRA reserves the right
to perform an inspection or
request another relevant authority
to inspect where appropriate.
Addition of activities Standard process: Refer to ‘Contract manufacturing
at an approved - Technical variation site details and supporting
contract laboratory - 30 days documentation’ section above.
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Variation Type, timeline and form Supporting documentation
- AUT-F0211, section 2
Note: The HPRA reserves the right
Expedited process (IMP only): to perform an inspection or
request another relevant authority
- Technical variation
to inspect where appropriate.
- 7 days
- AUT-F0791
Immediate notification (IMP only):
- Admin variation
- 30 days
- AUT-F0819
Deletion of testing Standard process: No supporting documentation
activities carried out - Admin variation required.
at a contract - 30 days
laboratory or - AUT-F0211, section 1
deletion of a
contract laboratory
Expedited process (IMP only):
- Admin variation
- 7 days
- AUT-F0791
Immediate notification (IMP only):
- Admin variation
- 30 days
- AUT-F0819
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ANNEX 5 QUALIFIED PERSON(S)
This section must be read alongside the HPRA ‘Guide to Attainment of Qualified Person Status
in Ireland: Educational Requirements, Training and Licensing’ (AUT-G0080). In order to
progress the addition of a Qualified Person (QP) to the MIA, three key pieces of supporting
documentation must be provided: qualification, evidence of practical experience and training.
Qualifications
To fulfil the qualification requirements, the following documents must be submitted:
- Certificates of the primary degree and the QP-qualifying course of the proposed QP
- A university-issued letter confirming successful course completion if the formal
qualification is pending
For candidates who completed a pharmacy or QP course outside of Ireland, please provide
either:
- Proof of registration with the Pharmaceutical Society of Ireland (PSI) for Pharmacy
graduates,
- A letter from the EEA competent authority in the country where the pharmacy or QP-
qualifying degree was obtained. confirming that the candidate's qualifications satisfy the
educational requirements outlined in Article 49 of EU Directive 2001/83/EC and Article 97
of EU Regulation 2019/6. The candidate must also have fulfilled any other requirement set
out under the framework in the relevant Member State, or
- A copy of the MIA issued by the relevant EEA authority listing the candidate as the QP.
All documents must be provided in English or accompanied by certified English translations.
Practical experience
A copy of the proposed QP’s CV, clearly indicate the name and address of the site(s) at which
the proposed QP has had relevant experience should be provided.
Please refer to the HPRA ‘Guide to Attainment of Qualified Person Status in Ireland:
Educational Requirements, Training and Licensing’ for further information on relevant work
experience.
If the proposed QP has relevant experience in an EEA country outside of Ireland, applicants are
required to submit proof of this experience. Acceptable forms of evidence may include:
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- A letter issued by the relevant competent authority confirming the site's MIA status during
the applicant’s employment,
- A signed statement from the previous employer confirming that the proposed QP
candidate was employed at the site during the period when the site held an MIA, in a
relevant role,
- If the proposed QP has previously worked as QP, the MIA issued to the site with the
proposed QP named on it.
Candidates acting as QPs for manufacturing sites based in Northern Ireland may be accepted
where the training, experience and qualification requirements outlined in this section are met.
For other UK candidates, those candidates must have been deemed eligible as qualified
persons prior to Brexit (i.e. prior to 31 January 2020).
Training
A training summary for the proposed QP must be submitted. This is a summary of training,
relevant to the role of QP, conducted at the specific manufacturing site. The training summary
can include prior experience and training to demonstrate that the QP candidate has gained the
requisite knowledge and experience for the types of products they will be certifying. The
training plan and the summary must be signed and dated by the proposed QP, and the
relevant trainer/manager/supervisor.
The proposed QP should have completed training in all key elements of the company’s
pharmaceutical quality system to enable them to effectively carry out the routine duties of a
QP (e.g. key company QMS systems, quality technical agreements, supplier audits, batch
certification activities, regulatory compliance systems, product/dosage forms, authorisation(s)
held by the company, manufacturing processes, product types and dosage forms, among
others).
It is not expected that all training is completed prior to the application. The training plan may
include the training status up to the time of the application submission (for instance, by dating
each completed training).
In the event that training is ongoing at time of application, a statement affirming that all
necessary training will be concluded prior to commencement of batch certification activity by
the proposed QP can be accepted. This statement should be signed by the proposed QP, and
trainer/manager/supervisor, as appropriate.
If the proposed QP is designated to certify batches of a specific product type exclusively, this
limitation must be clearly stated in either the training summary or the application. The
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company's Pharmaceutical Quality System, including the site master file, should clearly reflect
the types of dosage forms each QP is authorised to certify, when applicable.
The supporting documentation required for variations to Qualified Person(s) in Annex 5 is
detailed in Table 7.
Table 7: Variations to Qualified Person(s), Annex 5
Variation Type, timeline and Supporting documentation
form
Addition of Qualified - Technical variation Refer to the guidance provided in the
Person - 60 days Qualifications, Experience and Training
- AUT-F0211, section 3 sections.
Removal of Qualified - Admin variation None required.
Person - 30 days
- AUT-F0211, section 1
ANNEX 6 PERSONNEL FOR PRODUCTION OPERATIONS AND QUALITY CONTROL
Personnel responsible for production and quality control are required to be named when the
MIA includes operations at the site for the corresponding activity.
For example, when an MIA is granted in relation to batch certification only, no personnel for
production or quality control should be named. In line with the requirements of Chapter 2 of
the EU GMP guidelines, the person responsible for production may not be the same as the
person responsible for quality control.
The supporting documentation required for variations to persons responsible for quality
control/production in Annex 6 is detailed in Table 8.
Table 8: Variations to Responsible Person(s), Annex 6
Variation Type, timeline and Supporting documentation
form
Addition of a person - Technical variation A copy of the candidate’s CV outlining the
responsible for - 60 days job responsibilities of the role.
production/quality - AUT-F0211, section Note: The candidate must have
control 3 appropriate qualifications and practical
experience relevant to the site activities, as
well as adequate authority to carry out
their responsibilities.
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Variation Type, timeline and Supporting documentation
form
The responsibilities of the persons
responsible for production and quality
control are outlined in Chapter 2 of the EU
Guide to GMP.
Removal of a person - Admin variation None required.
responsible for - 30 days
production/quality - AUT-F0211, section
control 1
ANNEX 7 NOT USED BY THE HPRA
This is an optional annex which includes details relating to the last inspection. It is not used by
the HPRA.
ANNEX 8 IMPORTATION OF PRODUCTS WHICH ARE CONTRACT MANUFACTURED
AT A SITE OUTSIDE THE EEA
Listing entries in Annex 8
Annex 8 is required when the MIA holder performs batch certification of imported products
which are imported either as a bulk dosage form (e.g. bulk tablets or bulk nude vials) or
finished packed product.
Please complete a separate Annex 8 for each site from which products are imported (i.e. last
third country site in the manufacturing chain).
Note: Third country sites involved in storage only prior to importation should not be listed in
Annex 8.
Annex 8 is not required in the following cases:
- Annex 8 entries are not required for IMP MIAs.
- Where site of physical importation is the only activity performed under Annex 1 of the MIA
- For importation of product intermediates (where this activity is performed it should be
listed under section 2.3.2 of Annex 1 of the MIA.)
- Third country sites involved in storage only prior to importation
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The third country site listed in Annex 8 should also be included in Annex 3, with appropriate
operations for the manufacture and packaging of the product specified. The name and address
of this site must accurately reflect the Annex 3 details and the supporting documentation for
the manufacturer. These table entries in Annex 8 are specific to a single contract manufacturer,
product type and dosage form. A separate Annex 8 table is required for each contract
manufacturer.
Details to be placed in Annex 8 Entry
Product type
The ‘product type’ field of the table refers to whether the products are non-sterile products,
aseptically prepared products or terminally sterilised products. Applicants should choose the
appropriate product type from the drop-down in the field for this value.
Dosage form
The ‘dosage form’ field must correspond to the description of the manufacturing operation for
the dosage form at the relevant contract manufacturing site as specified in Annex 3, e.g. ‘Small
volume liquids’, ‘Hard shell capsules’, ‘Tablets’, etc. Applicants should choose the appropriate
dosage form from the drop-down in the field for this value.
In instances where both the ‘product type’ field and ‘dosage form’ field are the same for a
group of products imported from the same contract manufacturer, they will be included in the
same table (see the example provided below). Where this information is not the same for the
products, separate tables are required, e.g. where tablets and capsules are imported from the
same contract manufacturer separate tables are required, as the ‘dosage form’ fields will be
different.
Product description
This description should complement the basic information on the dosage form as necessary.
Where the products are imported as bulk dosage forms this information should be included in
this section.
The trade name of the product should not be included in this description. Examples of what
may be considered appropriate entries under ‘Product Description’ for a number of dosage
forms are suggested in the table below:
Dosage form Product description
Aseptically prepared small volume Vials
liquid Pre-filled syringe
Autoinjector
Vial containing concentrate for solution for infusion
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Dosage form Product description
Aseptically prepared lyophilisate Vial containing powder for solution for infusion
Non-sterile tablets Enteric coated tablets
Sustained release tablets
Tablets
Non-sterile semisolid Ointment
Cream
Gel
Paste
Non-sterile liquid for internal use Oral suspension
Oral liquid
Activities by MIA holder
This refers to the activities which are intended to be carried out by the applicant under the
MIA in relation to the specific product.
Example of a completed table
The below table outlines an example of the type of information to be included in each field. As
outlined above, where the ‘product type’ fields and ‘dosage form’ fields are the same for the
products they may be included in the one table. In the event that these fields are different,
separate tables would be required.
Product type Dosage form
Terminally sterilised products Small volume liquids
If other: N/A
Product Strength Active ingredient Activities by MIA holder
description
☒ Batch certification
Prefilled syringe 150 mcg Adrenaline
☐ Site of physical importation
Single-dose eye ☒ Batch certification
2% Pilocarpine
drops ☐ Site of physical importation
☒ Batch certification
Bulk Ampoules 50 mg/ml Haloperidol
☐ Site of physical importation
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Note: Acceptance of a product entry in Annex 8 does not infer that the product is approved
for any particular market. The QP should ensure that the product has received relevant market
approvals prior to certification of batches.
The supporting documentation required for variations to Annex 8 is detailed in Table 10.
Table 10: Variations to imported products, Annex 8
Variation Type, timeline Supporting documentation
and form
Addition of imported products - Technical See guidance for variation to
resulting from a new contract variation manufacturing operations in
manufacturer located outside the EEA - 30 days Annex 3.
OR - AUT-F0211, No additional supporting
section 2 documents required for entries
Addition of a new product type
and/or dosage form to the list of in Annex 8 as the manufacturing
imported products for a contract details should reflect those for
manufacturer which is already the relevant manufacturing site
approved on the authorisation, e.g. which is listed in Annex 3.
tablets already listed but sterile small
volume liquids to be added
Addition to the list of imported - Technical None required.
products where the manufacturer is variation
already approved on authorisation - 30 days
for manufacture of the same dosage - AUT-F0211,
form, e.g. addition of another tablet section 2
product sourced from a contract
manufacturer which has already been
authorised for supply of tablets
Deletion of an imported product - Admin None required.
variation
- 30 days
- AUT-F0211,
section 1
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APPENDIX 1 SUPPLY OF UNLICENSED/EXEMPT MEDICINAL PRODUCTS
Article 5 of Directive 2001/83/EC outlines circumstances when a medicinal product without a
marketing authorisation may be supplied. In Ireland these medicines are referred to as exempt
medicines and the relevant exemptions are described in the Medicinal Products (Control of
Placing on the Market) Regulations 2007.
The guidance provided relates solely to the authorisation requirements for the import and
supply of such medicines within Ireland. Applicants intending to supply (export) medicines
under Article 5 of Directive 2001/83/EC to other countries should ensure compliance with any
local requirements applicable in that country.
For the Irish market, the import and supply of these medicines may take place under an MIA or
a WDA. The import and supply of these medicines may be performed under an MIA provided
that the holder conducts manufacturing or importation operations for the products as
described in part 1 or part 2 of the MIA. When these activities take place under an MIA, the
following clarifying remark will be inserted on the MIA to authorise the activities:
‘This site is authorised to supply medicinal products in accordance with the provisions of Article 5
of Directive 2001/83/EC providing that it would normally conduct a manufacturing activity, as
listed above, for the product concerned.’
MIA holders wishing to supply products meeting these criteria under Article 5 of Directive
2001/83/EC should apply for the addition of such clarifying remarks to the MIA.
In all other circumstances the import and supply of exempt medicines is to be conducted
under a WDA. Further information and guidance in relation to applications and variations to
WDAs can be found on the HPRA website.
Applicants should also refer to the HPRA ‘Guide to The Notification System for Exempt
Medicinal Products’ and any other national requirements, which may be applicable for the
supply of these products in Ireland.
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APPENDIX 2 REMOTE BATCH CERTIFICATION BY THE QUALIFIED PERSON
Manufacturing operations which are detailed on the MIA should only be performed at the
authorised site address. Batch certification is an operation which is specified on the MIA, and it
is expected that the QP is present at the authorised site when performing batch certification
unless otherwise approved on the MIA by the HPRA.
A pre-requisite for HPRA approval of remote batch certification on an MIA is a satisfactory
inspection following on-site batch certification activities being undertaken. This would
normally occur one to three years post the first inspection at the site. Where approved, a
clarifying remark is added to the MIA stating ‘Authorised operations include remote batch
certification by a Qualified Person when operating within the EEA or Northern Ireland’.
MIA holders applying for a variation to include remote batch certification by QPs should
submit the following supporting documents:
- Signed declaration on behalf of the MIA holder to confirm that certification, when
performed remotely, will only be performed by QPs when operating within the EEA (or
Northern Ireland).
- Summary of the means by which the QP will maintain familiarity and current knowledge in
relation to the products, manufacturing process(es), the pharmaceutical quality system at
the manufacturing site and its effectiveness in relation to the products concerned. This
should include details of when QPs who are operating remotely will be required to attend
the authorised manufacturing site. The time spent on the site should be commensurate
with the nature and frequency of manufacturing operations conducted at the site.
- Details of how the MIA holder will facilitate the QPs to perform their duties remotely and in
a secure manner including:
o Summary description of how it will be ensured that the QPs can access the same
information concerning the manufacture and control of batches as would be provided if
carrying out the duties at the authorised manufacturing site.
o Summary of the remote certification process and means by which the QP will complete
the batch register (or equivalent), including reference to relevant procedures in the
pharmaceutical quality system. The declaration should clearly state the means by which
batch certification will be communicated to the authorised site and what
documentation, if applicable, will be forwarded in this regard.
o In circumstances where GMP documentation is stored remotely from the site for periods
of time, it is considered that risks associated with this practice are assessed and
documented, e.g. controls to ensure the integrity of the records, protection from loss,
damage, etc. Summary details of how it will be ensured that the HPRA will have access,
in real time, at the authorised manufacturing site, to all relevant information relating to
activities by QPs operating remotely and the concerned batches of medicinal product.
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QP duties at a manufacturing site may also include providing QP confirmation, as defined in
Annex 16 of the EU GMP guide. No variation to the MIA is required to perform the QP
confirmation activity remotely; however, it is expected that the same principles, as outlined
above, would be applied and this will be reviewed during GMP inspections.
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APPENDIX 3 DECLARATIONS BY THE QUALIFIED PERSON
Where declarations by the QP are being provided to support activities (e.g. addition of
contract manufactures in Annex 3 or contract laboratories in Annex 4), the following should be
noted and considered:
- Applicants are encouraged to utilise the European Commission’s QP declaration template.
- The basis of the QP declaration should be clearly stated and encompass the proposed
activities at the contract site.
- When an applicant provides multiple product-specific QP declarations to facilitate the
addition of a contract manufacturing site(s), written guidance should be provided outlining
which QP declaration supports each of the manufacturing operations to be performed at
the site.
- Sufficient detail must be provided on the scope of the audit referenced in the QP
declaration, e.g. if the scope of the audit was ‘aseptically prepared small volume liquids and
microbiological sterility testing’ then this must clearly be stated on QP declaration, as
opposed to general remarks such as ‘manufacturing’ or ‘testing’.
It is expected that the following is accounted for on the declaration provided by the QP:
- The scope of the declaration should clearly cover the operations to be included for the
contract manufacturer in Annex 3.
- The basis of the declaration should be clearly outlined within the declaration. If the
declaration is based on an audit the declaration should outline:
o When the audit was performed
o Sufficient detail on the scope of this audit
o Who performed this audit, and what their relationship is to the party being audited
- The name and address of any sites specified on the QP declaration should fully align to
what is proposed to be added to the MIA.
- Justification should be provided if the QP declaration does not clearly reflect the activities
included in the application.
- The declaration should be signed and dated by a QP named on the MIA.
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APPENDIX 4 FURTHER DETAIL ON SUPPORTING DOCUMENTATION REQUIRED FOR
SITES BASED IN MRA/ACAA PARTNER TERRITORIES
General guidance for the inclusion of contract sites based in MRA/ACAA partner territories is
outlined in the Annex 3 guidance. Applicants should refer to this general guidance and provide
the supporting documentation outlined below for sites covered within the scope of an MRA
with the EU. Please note that in certain circumstances, it may be necessary for the HPRA to
request further information from the relevant MRA partner. In these instances, it will not be
possible to approve the addition of the contract facility until the information is provided by the
MRA partner.
There are four different scenarios when a contract site located in an MRA/ACAA partner
country is required to be included in an MIA:
- Addition of a contract site to a commercial MIA where the product concerned is covered by
the scope of the MRA/ACAA: The MIA holder is required to provide evidence of appropriate
GMP certification, as detailed below under each country. This should be provided in
addition to any QP declaration for the site concerned.
- Addition of a contract site to a commercial MIA where the product concerned is not
covered by the scope of the MRA: The MIA holder is required to provide a GMP certificate
issued by an EU regulatory authority that covers the dosage form.
Addition of a contract site to an IMP MIA where the product concerned is covered by the
scope of the MRA: The MIA holder is required to provide evidence of appropriate GMP
certification or equivalent, as detailed below under each country.
- Addition of a contract site to an IMP MIA where the product concerned is not covered by
the scope of the MRA: The MIA holder is required to provide a QP declaration to support
the activities to be included in Annex 3 or Annex 4 of the MIA.
Australia
Applicants should provide a GMP certificate issued by the Therapeutic Goods Administration
(TGA) of Australia, which includes within the scope of the certificate the operations to be
conducted on behalf of the applicant. The inspection referenced on the certificate should
preferably have been conducted within the last three years.
Canada
Applicants should, at minimum, provide evidence of compliant status of the Canadian site with
regard to the relevant category of manufacturing activity (e.g. as available on the Health
Canada website under Drug and Health Product Inspections). Applicants should also submit a
copy of the inspection exit notice issued by Health Canada for the site in question, which
assists in demonstrating that the site has been appropriately authorised for the product type
and dosage form concerned.
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Israel
Applicants should provide a GMP certificate issued on EudraGMDP by the Institute for
Standardization and Control of Pharmaceuticals of Israel which includes within the scope of
the certificate the operations to be conducted on behalf of the applicant. The inspection
referenced on the certificate should preferably have been conducted within the last three
years.
Japan
Applicants should provide a GMP certificate issued by the Ministry of Health, Labour and
Welfare (MHLW) of Japan; an English language version of this document should be provided,
or the document should be accompanied by an English translation. The certificate should
preferably have been issued within the last three years. When issuing GMP certificates on the
EudraGMDP database, the MHLW certifies pharmaceutical manufacturing operations with
respect to specific products. The applicant should confirm if the imported product is the same
as that referenced on the MHLW certificate.
New Zealand
Applicants should provide a copy of the GMP certificate issued by Medsafe. The inspection
referenced on the certificate should preferably have been conducted within the last three
years.
Switzerland
Applicants should provide a GMP certificate issued by Swissmedic which includes within the
scope of the certificate the operations to be conducted on behalf of the applicant. The
inspection referenced on the certificate should preferably have been conducted within the last
three years.
United States
Applicants should provide the Food and Drug Administration (FDA) Establishment Identifier
(FEI) number for the site in the section indicated on the application form. Applicants should
also indicate in the relevant section the date of the most recent pharmaceutical inspection
conducted by the FDA.
Please note the FDA may conduct other inspections such as food or cosmetic inspections so
applicants should ensure the date of the most recent pharmaceutical inspection is provided.
Information provided by the FDA will then be reviewed to determine if the addition of the
requested site is acceptable.
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来源：HPRA 人用药品质与 GMP 指南 · assets.hpra.ie