Monograph

• Overview
  This is a summary of the scientific conclusions reached by the Committee on Herbal Medicinal Products (HMPC) on the medicinal uses of mouse-ear hawkweed.
• The HMPC conclusions are taken into account by EU Member States when evaluating applications for the licensing of herbal medicines containing mouse-ear hawkweed.
• Herbal medicines containing mouse-ear hawkweed are usually available as a herbal tea to be drunk and in solid forms to be taken by mouth.
• Key facts
  - Latin name
  - Pilosellae herba cum radice
  - English common name
  - Mouse-ear hawkweed
  - Botanical name
  Hieracium pilosella L.
  - Therapeutic area
  - Urinary tract and genital disorders
  - Status
  - F: Assessment finalised
  - Date added to the inventory
  - Date added to priority list
  - Outcome of European assessment
  - European Union herbal monograph

• 17

  Guideline on the pharmaceutical quality of inhalation and
  nasal medicinal products

  18

  Table of contents

  19

  Executive summary ..................................................................................... 3

  20

  1.

• Lifecycle management ........................................................................................ 28

  49

  Definitions ................................................................................................. 29

  16

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  Executive summary

  53

  This guideline is the first revision of the guideline on pharmaceutical quality of inhalation and nasal

  54

  products (EMEA/CHMP/QWP/49313/2005 Corr).

• Quality aspects specific to inhalation and nasal medicinal products are discussed, the need for

  66

  safety testing (e.g., for excipients and leachables) is also considered.

• 69

  Detailed guidance on pharmaceutical development study designs (e.g., priming studies) and the

  70

  analytical procedures primarily used for inhalation and nasal medicinal products (e.g., cascade

  71

  impactor analysis) is not included in this guideline.

• Scope

  74

  The guideline addresses requirements "on the quality of inhalation and nasal medicinal products" in

  75

  new marketing authorisation applications, including abridged applications.

• Liquid inhalation anaesthetics and nasal ointments, creams and gels are

  88

  excluded, however the general principles described in this guideline should be considered.

• 118

  Different polymorphic forms including any amorphous content could affect the quality or performance

  119

  of the finished medicinal product.

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  132

  The primary packaging, type of inhaler and, if necessary, the secondary packaging or other

  133

  components required for reasons of stability should be described.

• Pharmaceutical
  development study

  (a) Physical
  characterisation
  (b) Minimum fill
  justification
  (c) Extractable
  volume

  Pressurised

  Dry powder

  Preparations for

  Non-

  metered-

  inhalers (DPI)

  nebulisation

  pressurised

  dose

  metered-

  Device-

  Pre-

  Single-

  Multi-

  (pMDI)

  metered

  metered

  dose

  dose

  inhalers

  Yesa

  Yes

  Yes

  Yesa

  Yesa

  Yesa

  Yes

  Yes

  Yes

  Yes

  Yes

  Yes

  No

  No

  No

  Yes

  No

  No

  inhalers

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  dose

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  Table 4.2.1.

• The last doses delivered by

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  the inhaler as defined by the label claim, should meet the finished medicinal product specification limits

  180

  for delivered dose and fine particle dose.

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  263
  264

  4.2.2.8.

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  345

  Instructions regarding cold temperature use should be provided in the product information.

• Finished medicinal
  product

  Pressurised

  Dry powder inhalers

  Preparations for

  metered-

  (DPI)

  nebulisation

  dose

  Nonpressurised
  metered-dose

  Device-

  Pre-

  Single-

  Multi-

  (pMDI)

  metered

  metered

  dose

  dose

  inhalers

  (a) Description

  Yes

  Yes

  Yes

  Yes

  Yes

  Yes

  (b) Assay

  Yes

  Yes

  Yes

  Yes

  Yes

  Yes

  (c) Moisture content

  Yes

  Yes

  Yes

  No

  No

  No

  Yes

  Yes

  Yes

  No

  No

  Yes

  Yes

  Yes

  Yes

  No

  No

  Yes

  specification test

  (d) Mean delivered
  dose
  (e) Uniformity of
  delivered dose

  inhalers

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  Table 4.2.2.

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  4.2.5.4.

• The proposed specification limits should take into account the shelf-life performance of the
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  medicinal product.

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  All medical devices, including inhalers and nasal devices, have to fulfil the general requirements as

  587

  outlined in the Medical Device Regulation (EU) 2017/745.

• Stability (CTD 3.2.P.8)

  598

  All inhalation medicinal products should be tested on stability against the stability indicating tests

  599

  included in the finished medicinal product specification.

• Quality data requirements as

  619

  described in this guideline should be met, supplemented by appropriate comparative quality and

  620

  clinical data with respect to the chosen reference medicinal product.

• 621

  For inhalation medicinal products comparative in vitro data between the abridged application medicinal

  622

  product and the reference medicinal product must be provided.

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  670

  Nature and contents of container: The type of the device and its components should be listed.

• Nasal medicinal products

  695

  Inhalation and nasal medicinal products have many similarities and therefore, most of the

  696

  requirements specified for inhalation medicinal products in section 4 also apply for nasal medicinal

  697

  products.

• One difference between inhalation and nasal medicinal products is the desired

  698

  particle/droplet size of the finished medicinal product.

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  704

  5.2.

• Nasal liquids
  Pharmaceutical
  development
  study

  Pressurised

  Nasal

  metered-

  powders,

  dose nasal

  device-

  spray

  metered

  NonSingledose
  drops

  Multidose
  drops

  Single-

  pressurised

  dose

  multidose

  spray

  metereddose spray

  (a) Physical
  characterisation
  (b) Minimum fill
  justification
  (d) Extractables /
  leachables

  Yesa

  Yes

  Yesa

  Yesa

  Yesa

  Yesa

  Yes

  Yes

  Yes

  Yes

  Yes

  Yes

  Yes

  No

  Yes

  Yes

  Yes

  Yes

  Yes

  Yes

  No

  No

  Yes

  Yes

  Yes

  Yes

  No

  No

  No

  Yes

  Yes

  Yes

  No

  No

  Yes

  Yes

  (f) Particle /
  droplet size
  distribution
  (g) Uniformity of
  delivered dose
  through container
  life
  (j) Actuator /
  mouthpiece
  deposition

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  Table 5.2.1.

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  5.2.2.2.

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  769

  5.2.5.

• Quality data requirements as described in

  799

  this guideline should be met, supplemented by appropriate comparative quality and clinical data with

  800

  respect to the chosen reference medicinal product.

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  849

  5.5.

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  867

  Definitions
  Activation:

  The act of setting in motion the delivery device.

• Delivery device:

  The sum of component(s) of the container closure system responsible for
  delivering the active substance to the respiratory tract (inhalation medicinal
  product) or the nasal and/or pharyngeal region (nasal medicinal product).

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  Label claim:

  The amount of active substance (usually on a per actuation basis) declared
  on the label of the medicinal product.

• Nasal medicinal

  A finished medicinal product (including the delivery device, where

  product:

  applicable) whose intended site of deposition is the nasal and/or pharyngeal
  region.

• 868
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• The completed comments form should be sent to
  [email protected]
  10
  11
  Keywords

  Committee on Herbal Medicinal Products; HMPC; European Union herbal
  monographs; European Union list of herbal substances, preparations and
  combinations thereof for use in traditional herbal medicinal products; herbal
  medicinal products; traditional herbal medicinal products; traditional use;
  well-established medicinal use; benefit-risk assessment; assessment report

  12

  1
  2

  Changes introduced in section 6 Overall conclusions.

• Peer-reviewer

  If not the same peer-reviewer
  since last version, all peerreviewers should be listed, and
  the version specified in
  brackets.

• 22

  23

  
  on
  .

• It is a working

  24

  document, not yet edited, and shall be further developed after the release for consultation of the

  25

  
  .

• The principle of the template is to make clear
  distinctions between presentation of data (methodology and results)
  and the assessment of the data (?assessor?s comment?).
• likely from an article but it seems it is concluded by
  the rapporteur; ?According to the author? to be added.
• Chapters with
  a heading including the word ?conclusion? should include a summary
  of all critical assessment of the assessor for that particular
  chapter.
• If an assessor?s comment is not needed, the Rapporteur
  should delete the box inserted in the template.
• ?
  The report should be sufficiently detailed to allow for secondary
  assessment of the available data by other HMPC experts.
• Overview of available pharmacokinetic data regarding the herbal substance(s), herbal
  preparation(s) and relevant constituents thereof ........................................................... 16

  97
  98

  3.3.

• Overall conclusions on clinical pharmacology and efficacy ........................................ 27

  Assessment report on
  EMA/HMPC/418902/2005

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  119

  5.

• This sections is related to
  available quality standards and there is no need to repeat information
  on all preparations included in the monograph.
• Search and assessment methodology

  161

  The Rapporteur shall undertake a comprehensive search of relevant
  scientific literature and articles, Acts of law and regulations and
  other relevant sources.

• Cross-reference to the list of
  references in Annex, which should list separately the references
  supporting the assessment report.
• 143
  144
  145

  150
  151
  152
  153
  154

  162
  163
  164
  165
  166
  167
  168
  169
  170
  171
  172
  173
  174
  175

  Herbal substance(s)

  Herbal preparation(s)

  Relevant constituents for this assessment report

  Examples of scientific databases to be searched are Medline, PubMed,
  Cochrane Database of Systematic Reviews, EMBASE etc.

• Assessment report on
  EMA/HMPC/418902/2005

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  176
  177
  178
  179
  180
  181
  182
  183
  184
  185
  186
  187
  188
  189
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  Additional relevant references could also be retrieved from the checked
  references.

• Examples of books are Hagers Handbuch, The Complete German
  Commission E Monographs, PDR for herbal medicines etc.
• In addition, information from non-EU regulatory
  authorities for examples Health Canada monographs or WHO monographs
  could be searched, if relevant to herbal substances and preparations in
  EU.
• 221

  225
  226
  227

  232

  When the assessment report is revised, the rapporteur should briefly
  summarise the main changes under this section.

• Data are collected using the template entitled ?Document
  for information exchange for the preparation of the assessment report
  for the development of European Union monographs and for inclusion of
  herbal substance(s), preparation(s) or combinations thereof in the
  list? (EMEA/HMPC/137093/2006).
• Assessment report on
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  Herbal substance/

  Indication

  Posology and
  method of

  preparation

  administration

  Posology, age
  groups,
  pharmaceutical
  form, method of
  administration,
  duration of use
  As reported in
  the market
  overview

  As reported in
  the market
  overview

  As reported in
  the market
  overview.

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  Herbal substance/

  Indication/Medicinal

  Posology and

  preparation

  use

  method of
  administration

  Posology, age
  groups,
  pharmaceutical
  form, method of
  administration,
  duration of use

  Regulatory Status

  Type of
  regulatory
  status where
  possible, date,
  Country

  287

  This overview is not exhaustive.

• Clinical Safety/Pharmacovigilance

  836
  837
  838
  839
  840
  841

  See ?Assessment of clinical safety and efficacy in the preparation of
  EU herbal monographs for well-established and traditional herbal
  medicinal products?(EMA/HMPC/104613/2005) for further details.

• Overall conclusions on clinical safety

  1067

  1068

  In terms of structure, the conclusion should follow the presentation of
  the results above.

• Overall conclusions

  1092

  1093

  1101

  Describe key aspects only briefly, these will already have been
  described in detail in the respective sections.

• This section should
  cover all recommended ?well-established use? and ?traditional use?
  indications and conclusions shall be provided for each therapeutic
  indication and each herbal preparation.
• 1102

  Well established use monograph

  1103
  1104

  The clinical studies supporting well-established use should be
  specified for each therapeutic indication and each herbal preparation.

• The choice for the wording of traditional use indications vis-?vis existing wordings in monographs in the same therapeutic area should
  be briefly discussed/justified.
• 1153

  List entry

  1154

  The conclusions should include a statement pointing to the
  possibility/non-possibility to support a European Union list entry.

Herbal medicinal product: Cynarae foliumArray,Array, C: ongoing call for scientific data