Documentation

Draft guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and chronic obstructive pulmonary disease (COPD)

Retrieved on:

Thursday, April 18, 2024

21

Key Points:

21
Guideline on the requirements for demonstrating
therapeutic equivalence between orally inhaled products
(OIP) for asthma and chronic obstructive pulmonary
disease (COPD)

22

Table of contents

23

Executive summary ..................................................................................... 4

24

1.
Primary PK parameters to be analysed and acceptance criteria .............................. 14
43

Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

51

6.4.
Definitions ........................................................................................... 18
56

List of Abbreviations.................................................................................. 20

57

Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

58

Executive summary

59

This guideline is the 2nd revision of the CHMP Guideline formerly called ?Guideline on the requirements

60

for clinical documentation for orally inhaled products (OIP) including the requirements for

61

demonstration of therapeutic equivalence between two inhaled products for use in the treatment of

62

asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of

63

asthma in children and adolescents?.
It addresses the requirements for demonstration of therapeutic
64

equivalence (TE) between orally inhaled products containing the same active moiety(ies).
It is generally not recommended to aim at demonstrating TE using pharmacodynamic
70

or clinical endpoints as these are deemed insensitive.
This
83

guideline is directed particularly at the requirements for demonstrating TE between OIPs containing the

84

same active moiety(ies) and used in the management and treatment of patients with asthma and/or

85

COPD.
86
The guideline was first published as points to consider in 2004 and revised for the first time and

87

became guideline in 2009.
Since then, a number of Q&A documents have been published by Quality
88

Working Party (QWP) and former Pharmacokinetic Working Party (PKWP).
Scope
93

This document provides guidance on the requirements for demonstrating TE between OIPs, including

94

both, single active substance products and combination products.
Also, in the case that there is a need
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

98

to confirm similarity to a product for which literature data is available (e.g., well-established use

99

applications), the same principles apply.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
132

4.
Products for nebulisation
177

This guideline applies also for products for nebulisation although it is acknowledged that the

178

performance of these is highly dependent on the nebuliser used.
In vitro criteria for demonstrating TE
206

The test and reference products should be compared in order to conclude on TE.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
211
212

2.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
353

6.2.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
392

6.3.
If the
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
432

different strengths of the test and the reference product are not shown to be proportional in vitro, in

433

vivo equivalence should be demonstrated with a bracketing approach.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
471

6.4.
Griffin, 1964
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

553

which both reference product-na?ve and experienced users should be included.
568
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

569

10.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
Product strength

Product strength may be either the delivered
dose or the metered dose.
570
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

571

List of Abbreviations
APSD

Aerodynamic Particle Size Distribution

AUC

Area Under the Curve

CHMP

Committee for Medicinal Products for Human
Use

CI

Confidence Interval

Cmax

Peak concentration

COPD

Chronic Obstructive Pulmonary Disease

DPI

Dry Powder Inhaler

FPD

Fine Particle Dose

GI

Gastrointestinal

ICH

International Conference on Harmonisation

IVIVC

In vitro in vivo correlation

MDI

Metered Dose Inhaler

OIP

Orally Inhaled Product

PD

Pharmacodynamic

PK

Pharmacokinetic

pMDI

Pressurised Metered Dose Inhaler

QWP

Quality Working Party

SmPC

Summary of Product Characteristics

TE

Therapeutic equivalence

tmax

Time to peak concentration

572

Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

Draft guideline on the pharmaceutical quality of inhalation and nasal medicinal products

Retrieved on:

Thursday, April 18, 2024

17

Key Points:

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

50
51

Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024

Page 2/30

52

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.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 4/30

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

Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024

dose

Page 5/30

Table 4.2.1.
The last doses delivered by
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024

Page 7/30

179

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

180

for delivered dose and fine particle dose.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 9/30

263
264

4.2.2.8.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 11/30

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

Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024

Page 15/30

Table 4.2.2.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 16/30

510

4.2.5.4.
The proposed specification limits should take into account the shelf-life performance of the
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 17/30

552

medicinal product.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 18/30

586

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.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 20/30

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.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 21/30

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

Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024

Page 22/30

Table 5.2.1.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 23/30

728

5.2.2.2.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 24/30

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.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 27/30

849

5.5.
866
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024

Page 28/30

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).
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 29/30

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
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 30/30

Draft guideline on good agricultural and collection practice (GACP) for starting materials of herbal origin - Revision 1

Retrieved on:

Thursday, April 18, 2024

Reproduction, SCOPE, Eating, Pesticide, Convention, Change control, Confusion, Alkaloid, Climate, Fungus, Directive (European Union), Ethylene oxide, Wind, Wood, Glass, European Medicines Agency, HMPS, QDG, Hygiene, Water, Marketing, Fertilizer, Legislation, Manure, Distillation, Risk, Education, Committee, Compost, Draft, Policy, Person, EMA, Seed, Polycyclic aromatic hydrocarbon, Collection, Freezing, GMP, Risk assessment, GACP, Sunlight, Fermentation, Personal protective equipment, Animal, Herbal, Herbicide, Weather, INTRODUCTION, Documentation, Regeneration, Decontamination, EudraLex, Disease, International trade, European Pharmacopoeia, Part, Livestock, Public, Inhalation, Knowledge, Seedling, Factorization of polynomials, Record, Plant, Skin, API, Irrigation, Part Two, Soil, Directive, Pharmacopoeia, Codex, Guideline, Temperature, Attention, Hydrocarbon, Pyrrolizidine alkaloid, Polychlorinated biphenyl, Growth, Rotation, Incineration, Environment, Humidity, Smell, Ventilation, Light, Bird, Mineral, Fumigation, Pyrrolizidine, SOP, Housing, Smoking, Atmosphere, Postharvest, Rain, Liver, QWP, Medicinal plants

REFERENCES ....................................................................................................................................... 14

Key Points:

REFERENCES ....................................................................................................................................... 14
29

Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005

Page 3/14

30

EXECUTIVE SUMMARY

31
32
33
34
35
36

This guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin

37

1.
Due to the inherent
complexity of medicinal plants and herbal substances the quality of these starting materials requires an
adequate quality assurance system for the collection and/or cultivation, harvest, and primary
processing.
(either outdoor, indoor or in greenhouses) should be carefully considered, since each of the mentioned
types could have several problems and advantages.
The used cultivation method may be dependent on
the final application of the herbal medicinal product.
primary processing of herbal substances that are used for the preparation of herbal medicinal products.
medicinal plants and herbal substances, ensuring that they are handled appropriately throughout all
stages of cultivation, collection, processing and storage.
their preparations are exposed to a large number of environmental contaminants of both biotic and
abiotic origin.
to existing wildlife habitats and must adhere to CITES (Convention on International Trade in
Endangered species of Wild Fauna and Flora).
https://health.ec.europa.eu/document/download/bd537ccf-9271-4230-bca1-2d...
4 https://health.ec.europa.eu/document/download/fd318dd6-2404-4e67-82b0232...
3
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005

Page 5/14

104

4.
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005
Page 6/14

147
148
149

8.
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005
Page 7/14

185

7.
Where possible, stable varieties and cultivars naturally
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005
Page 8/14

227
228

resistant or tolerant to disease should preferably be used.
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005
Page 9/14

268
269
270
271
272
273

The application should be carried out only by qualified staff using approved equipment.
The following should be noted:
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005

Page 10/14

309
310

?

311
312
313

?

314
315
316
317

?

318
319
320

?

321
322

?

323
324
325

?

326
327
328

?

Damaged plants or plant parts need to be excluded or limited in accordance with a specific
pharmacopoeia monograph, where relevant.
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005
Page 11/14

347
348

directly to the sun (except in cases where there is a specific need) and must be protected from
rainfall, insect infestation, etc.
The label must be clear, permanently fixed and made from
6

Reflection paper on the use of fumigants (EMEA/HMPC/125562/2006)

Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005

Page 12/14

386
387

non-toxic material.
Certain exudates that have not been subjected to a specific treatment are
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005

Page 13/14

425
426
427

also considered to be herbal substances.
European Pharmacopoeia General Monograph ?HERBAL DRUGS? 07/2017:1433
Are obtained by subjecting herbal substances to treatments such as
extraction, distillation, expression, fractionation, purification, concentration
or fermentation.

Draft guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and chronic obstructive pulmonary disease (COPD)

Retrieved on:

Thursday, April 18, 2024

21

Key Points:

21
Guideline on the requirements for demonstrating
therapeutic equivalence between orally inhaled products
(OIP) for asthma and chronic obstructive pulmonary
disease (COPD)

22

Table of contents

23

Executive summary ..................................................................................... 4

24

1.
Primary PK parameters to be analysed and acceptance criteria .............................. 14
43

Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

51

6.4.
Definitions ........................................................................................... 18
56

List of Abbreviations.................................................................................. 20

57

Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

58

Executive summary

59

This guideline is the 2nd revision of the CHMP Guideline formerly called ?Guideline on the requirements

60

for clinical documentation for orally inhaled products (OIP) including the requirements for

61

demonstration of therapeutic equivalence between two inhaled products for use in the treatment of

62

asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of

63

asthma in children and adolescents?.
It addresses the requirements for demonstration of therapeutic
64

equivalence (TE) between orally inhaled products containing the same active moiety(ies).
It is generally not recommended to aim at demonstrating TE using pharmacodynamic
70

or clinical endpoints as these are deemed insensitive.
This
83

guideline is directed particularly at the requirements for demonstrating TE between OIPs containing the

84

same active moiety(ies) and used in the management and treatment of patients with asthma and/or

85

COPD.
86
The guideline was first published as points to consider in 2004 and revised for the first time and

87

became guideline in 2009.
Since then, a number of Q&A documents have been published by Quality
88

Working Party (QWP) and former Pharmacokinetic Working Party (PKWP).
Scope
93

This document provides guidance on the requirements for demonstrating TE between OIPs, including

94

both, single active substance products and combination products.
Also, in the case that there is a need
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

98

to confirm similarity to a product for which literature data is available (e.g., well-established use

99

applications), the same principles apply.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
132

4.
Products for nebulisation
177

This guideline applies also for products for nebulisation although it is acknowledged that the

178

performance of these is highly dependent on the nebuliser used.
In vitro criteria for demonstrating TE
206

The test and reference products should be compared in order to conclude on TE.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
211
212

2.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
353

6.2.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
392

6.3.
If the
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
432

different strengths of the test and the reference product are not shown to be proportional in vitro, in

433

vivo equivalence should be demonstrated with a bracketing approach.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
471

6.4.
Griffin, 1964
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

553

which both reference product-na?ve and experienced users should be included.
568
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

569

10.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024
Product strength

Product strength may be either the delivered
dose or the metered dose.
570
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

571

List of Abbreviations
APSD

Aerodynamic Particle Size Distribution

AUC

Area Under the Curve

CHMP

Committee for Medicinal Products for Human
Use

CI

Confidence Interval

Cmax

Peak concentration

COPD

Chronic Obstructive Pulmonary Disease

DPI

Dry Powder Inhaler

FPD

Fine Particle Dose

GI

Gastrointestinal

ICH

International Conference on Harmonisation

IVIVC

In vitro in vivo correlation

MDI

Metered Dose Inhaler

OIP

Orally Inhaled Product

PD

Pharmacodynamic

PK

Pharmacokinetic

pMDI

Pressurised Metered Dose Inhaler

QWP

Quality Working Party

SmPC

Summary of Product Characteristics

TE

Therapeutic equivalence

tmax

Time to peak concentration

572

Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and
chronic obstructive pulmonary disease (COPD)
EMA/CHMP/101453/2024

Draft revised Heads of Medicines Agency / European Medicines Agency guidance document on the identification of personal data and commercially confidential information within the structure of the marketing authorisation application dossier

Retrieved on:

Thursday, April 18, 2024

Steps, Union, Patient, CTD, Syndrome, CCI, Local, Disclosure, Toxicity, Process validation, MAH, Clinical trial, IP, RMP, Pharmacovigilance, Cell, Legislation, Annex, Trial of the century, Escherichia coli, Safety, Pediatrics, INTRODUCTION, Documentation, Prevalence, Vital signs, Tablet, Design, Transparency, Conclusion, Pip, Analysis, European Parliament, INN, Record, Quality, Generic, Biology, CMO, Genotoxicity, Composition, CTIS, Uncontrolled, Health care, European Medicines Agency, Prejudice, Committee, Policy, HCP, Animal, Characterization, Cell bank, Fertility, IRB, CMOS, Risk management, Private law, European Pharmacopoeia, Telephone, Research, Good, Data Protection Directive, Ampere-hour, IEC, QP, Human, Personal data, Labelling, Bibliography, Figure, MAA, R4, Institutional review board, Elucidation, Marketing, M4, ChromeOS, Contract research organization, Mental, Impairment, Toxicokinetics, NCA, Independent, Metabolite, Drug, Risk, Metabolism, GMO, Organ, EMA, Common Technical Document, General Data Protection Regulation, Confidentiality, PPD, PI, Language, DRUG, Privacy, Result, Claimed, Medication, Comparison, Ethics, Drive, PD, Narrative, EEA, Developmental toxicity, Saccharomyces cerevisiae, Pharmacopoeia, PIP, MCB, HMA, Physical chemistry, Midol, Particle size, Council, GCP, European Economic Area, Draft, Fermentation, Overview, Justification, Control, Dicarboxylic acid, Pharmacology, WCB, Expert, Immunogenicity, Data, Study, Publication, European, ICH, Element, Analytical procedures (finance auditing), Name, Common, Guideline, Exceptional circumstances, ID, Liver, Chin Na, Toxicology, Protein primary structure, Immunosuppressive drug, Vaccine

See websites for contact details

Key Points:

See websites for contact details
Heads of Medicines Agencies www.hma.eu
European Medicines Agency www.ema.europa.eu
11

Table of contents

12

Abbreviations .............................................................................................. 3

13

Definitions ................................................................................................... 4

14

1.
redaction, masking,
68

hiding) in such a manner that the recipient can no longer attribute the resulting information to a data

69

subject and make it identifiable.
81
Contract Manufacturing Organisation (CMO): shall mean an arrangement under which a

82

manufacturer provides upstream manufacturing services under contract on behalf of third-party

83

pharmaceutical companies.
94
Protected Personal Data (PPD): shall mean any personal data which should be protected from

95

disclosure.
?Finalised? shall mean that the marketing
102

authorisation (MA) has been granted or refused or that the MAA has been withdrawn.
The application of the general principles laid down in this guidance is without prejudice to
106

national rules on transparency.
The guidance should be read in conjunction with the relevant applicable
107

legislation and case law on transparency and data protection.
117
This guidance document is intended to apply to information/documents on medicinal products for

118

human use, for which the procedure has been finalised under the national, mutual recognition,

119

decentralised and centralised procedures.
Third
124

parties shall be informed or consulted as needed depending on respective national and European legal

125

frameworks.
140
In the following sections, the agreed principles on PD and CCI are presented, including guidance on

141

whether such information can be disclosed.
EMA/131365/2024
Page 5/50

142

Any information identified as PD or CCI must be subject to a preliminary review by the EMA/NCA prior

143

to the possible disclosure of the information/documents.
Principles on the protection of personal data (PD)
145

The protection of PD is enshrined in EU legislation; it is a fundamental right of EU citizens.
In
146

compliance with the applicable European/national legislation, PD should be anonymised in order to

147

avoid the disclosure of the document undermining the privacy and integrity of any individual.
EMA/NCA applies a risk-based approach to assess which PD elements are to be
152

removed from the information/documents in order to limit the risk of re-identification.
are included in the MAA dossier because they have a legally
164

defined role or responsibility and it is in the public interest to disclose this data.
168
Applicants are advised that non-essential information (e.g., personal address, personal phone number)

169

should not be included in the MAA dossier.
The
183

confidentiality of records that could identify subjects should be protected, respecting the privacy and

184

confidentiality rules in accordance with the applicable regulatory requirement(s).
185
The applicant remains responsible for compliance with the relevant legislation in cases where such data

186

is inadvertently included in the MAA dossier.
188
EMA/NCA applies a risk-based approach to assess which personal data elements need to be removed

189

from the information/documents in order to limit the risk of re-identification.
194
EMA/NCA applies a risk-based approach to assess which personal data elements need to be removed

195

from the information/documents in order to limit the risk of re-identification.
205
Any proposal to consider information as commercially confidential should be properly justified by the

206

owner of the information.
In this respect, any reference(s) to the risk of that interest being
209

undermined should be foreseeable and not purely hypothetical.
210
Information that is already in the public domain is not considered to be commercially confidential.
Information on the Quality and Manufacturing of medicines
226

A general principle regarding quality and manufacturing information is that detailed information could

227

be considered commercially confidential but general information should be disclosed.
234
In general, and if not in the public domain, the names of manufacturers or suppliers of the active

235

substance or the excipients are considered commercially confidential.
248
A general description of the type of test methods used and the appropriateness of the specification is

249

not commercially confidential.
General information on the fermentation and purification process
259

is not commercially confidential, although details including operating parameters and specific material

260

requirements are commercially confidential.
273
A general description of the type of test methods used and the appropriateness of the specification is

274

not commercially confidential.
In general, the data included in clinical trial study reports is considered to be data that can be
283

disclosed once PD has been anonymised.
338
In each module, a non-exhaustive list of information that may be considered protected personal data (PPD) or commercially confidential information

332
333

339

(CCI) is included.
?
Direct contact details such as telephone

Therefore, please refer to the appropriate sub-

number, fax number, email, postal address,

modules hereafter for guidance.
?
Information that may reveal strategic
(contractual) agreements

?

Any quality information on the clinical batches

principal investigator

that might be included here (such as e.g.
?
Information that may reveal strategic
(contractual) agreements

principal investigator

Study Reports
5.3.3.3

as the evaluation of new formulation, innovative

number, fax number, email, postal

Paediatric Development Plan (PIP), etc.
This may include taking into
More Than One Study
5.3.5.4

Other Clinical Study Reports

5.3.6

Reports of Post-Marketing
Experience

5.3.7

Direct identifiers such as name,
signature, contact details, etc.

Draft guideline on the pharmaceutical quality of inhalation and nasal medicinal products

Retrieved on:

Thursday, April 18, 2024

17

Key Points:

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

50
51

Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024

Page 2/30

52

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.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 4/30

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

Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024

dose

Page 5/30

Table 4.2.1.
The last doses delivered by
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024

Page 7/30

179

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

180

for delivered dose and fine particle dose.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 9/30

263
264

4.2.2.8.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 11/30

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

Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024

Page 15/30

Table 4.2.2.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 16/30

510

4.2.5.4.
The proposed specification limits should take into account the shelf-life performance of the
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 17/30

552

medicinal product.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 18/30

586

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.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 20/30

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.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 21/30

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

Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024

Page 22/30

Table 5.2.1.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 23/30

728

5.2.2.2.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 24/30

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.
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 27/30

849

5.5.
866
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024

Page 28/30

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).
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 29/30

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
Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
EMA/CHMP/20607/2024
Page 30/30

Draft guideline on good agricultural and collection practice (GACP) for starting materials of herbal origin - Revision 1

Retrieved on:

Thursday, April 18, 2024

REFERENCES ....................................................................................................................................... 14

Key Points:

REFERENCES ....................................................................................................................................... 14
29

Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005

Page 3/14

30

EXECUTIVE SUMMARY

31
32
33
34
35
36

This guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin

37

1.
Due to the inherent
complexity of medicinal plants and herbal substances the quality of these starting materials requires an
adequate quality assurance system for the collection and/or cultivation, harvest, and primary
processing.
(either outdoor, indoor or in greenhouses) should be carefully considered, since each of the mentioned
types could have several problems and advantages.
The used cultivation method may be dependent on
the final application of the herbal medicinal product.
primary processing of herbal substances that are used for the preparation of herbal medicinal products.
medicinal plants and herbal substances, ensuring that they are handled appropriately throughout all
stages of cultivation, collection, processing and storage.
their preparations are exposed to a large number of environmental contaminants of both biotic and
abiotic origin.
to existing wildlife habitats and must adhere to CITES (Convention on International Trade in
Endangered species of Wild Fauna and Flora).
https://health.ec.europa.eu/document/download/bd537ccf-9271-4230-bca1-2d...
4 https://health.ec.europa.eu/document/download/fd318dd6-2404-4e67-82b0232...
3
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005

Page 5/14

104

4.
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005
Page 6/14

147
148
149

8.
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005
Page 7/14

185

7.
Where possible, stable varieties and cultivars naturally
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005
Page 8/14

227
228

resistant or tolerant to disease should preferably be used.
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005
Page 9/14

268
269
270
271
272
273

The application should be carried out only by qualified staff using approved equipment.
The following should be noted:
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005

Page 10/14

309
310

?

311
312
313

?

314
315
316
317

?

318
319
320

?

321
322

?

323
324
325

?

326
327
328

?

Damaged plants or plant parts need to be excluded or limited in accordance with a specific
pharmacopoeia monograph, where relevant.
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005
Page 11/14

347
348

directly to the sun (except in cases where there is a specific need) and must be protected from
rainfall, insect infestation, etc.
The label must be clear, permanently fixed and made from
6

Reflection paper on the use of fumigants (EMEA/HMPC/125562/2006)

Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005

Page 12/14

386
387

non-toxic material.
Certain exudates that have not been subjected to a specific treatment are
Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin
EMA/HMPC/246816/2005

Page 13/14

425
426
427

also considered to be herbal substances.
European Pharmacopoeia General Monograph ?HERBAL DRUGS? 07/2017:1433
Are obtained by subjecting herbal substances to treatments such as
extraction, distillation, expression, fractionation, purification, concentration
or fermentation.

Survey on credit terms and conditions in euro-denominated securities financing and OTC derivatives markets (SESFOD) - March 2024

Retrieved on:

Thursday, April 18, 2024

Survey on credit terms and

Key Points:

Survey on credit terms and
conditions in euro-denominated
securities financing and OTC
derivatives markets (SESFOD)
March 2024
The Eurosystem conducts a three-monthly qualitative survey on credit terms and
conditions in euro-denominated securities financing and over-the-counter (OTC)
derivatives markets.
The survey questions are grouped into three sections:
1.
counterparty types ? credit terms and conditions for various counterparty
types in both securities financing and OTC derivatives markets;

2.

securities financing ? financing conditions for various collateral types;

3.

non-centrally cleared OTC derivatives ? credit terms and conditions for
various derivative types.
The survey focuses on euro-denominated instruments in securities financing and
OTC derivatives markets.
For securities financing, the survey refers to the
euro-denominated securities against which financing is provided, rather than the
currency of the loan.
Reporting institutions should report on their global credit terms, so the survey is
aimed at senior credit officers responsible for maintaining an overview of the
management of credit risks.
SESFOD March 2024
2

March 2024 SESFOD results
(Review period from December 2023 to February 2024)
The March 2024 Survey on credit terms and conditions in euro-denominated
securities financing and OTC derivatives markets (SESFOD) reports qualitative
changes in credit terms between December 2023 and February 2024.
Looking at credit terms and conditions for the various types of non-centrally cleared
OTC derivative, initial margin requirements increased slightly for all derivative types.
Survey respondents reported mostly unchanged conditions as regards the maximum
amount of exposure and the maximum maturity of trades.
Moreover, they reported that the volume of valuation disputes had
declined for all derivative types except credit derivatives.
The survey asked respondents to compare credit terms
and conditions on the cut-off date for the March 2024 survey round (i.e.
Compared with the
previous year, overall terms and conditions for securities financing and OTC
derivatives transactions had eased somewhat across all counterparties, while credit
standards for funding secured against various types of collateral and non-price terms
in OTC derivatives markets were generally tighter.
Credit terms and conditions for various counterparty types in both
securities financing and OTC derivatives markets
Overall credit terms and conditions eased between December 2023 and
February 2024 (Chart A).
The overall easing of conditions masked some
heterogeneity between price and non-price terms, and across different types of
counterparty, though reported changes were relatively small.
Credit terms and conditions for various types of non-centrally
cleared OTC derivative
Initial margin requirements increased slightly for all derivative types.
Meanwhile, they reported
unchanged conditions for credit derivatives referencing sovereigns and commodities,
as well as a slight deterioration for credit derivatives referencing corporates and
structured credit products.
The survey asked respondents to compare the credit terms and conditions observed
on the cut-off date for the March 2024 survey (i.e.
Compared with the previous year, overall terms and conditions for securities
financing and OTC derivatives transactions had eased somewhat across all
counterparties.
Survey respondents reported that non-price credit terms in OTC derivatives
markets had tightened somewhat for almost all types of derivative relative to
the previous year.

Two New Apple and Google Platform Privacy Requirements Kicking In Now

Retrieved on:

Thursday, April 18, 2024

Apple?s important mandatory requirements affecting iOS apps are about to kick in, and Google’s new requirements for publishers and advertisers have just gone into effect. Accurately implementing these requirements calls for close cooperation between the legal, privacy, and ad ops teams. Apple’s Privacy Manifests At WWDC 2023, Apple announced privacy manifests, signatures for SDKs, and [?]

Key Points:

Apple?s important mandatory requirements affecting iOS apps are about to kick in, and Google’s new requirements for publishers and advertisers have just gone into effect. Accurately implementing these requirements calls for close cooperation between the legal, privacy, and ad ops teams. Apple’s Privacy Manifests At WWDC 2023, Apple announced privacy manifests, signatures for SDKs, and [?]

Fossil beetles found in a Botswana diamond mine help us to reconstruct the distant past

Retrieved on:

Wednesday, April 10, 2024

One of the few Cretaceous age deposits that’s been discovered in Africa is at Botswana’s Orapa Diamond Mine.

Key Points:

One of the few Cretaceous age deposits that’s been discovered in Africa is at Botswana’s Orapa Diamond Mine.
Recently a team I lead discovered two new species of rove beetles preserved in the sediments of the Orapa Diamond Mine.
Rove beetles are typically identified by their unique short elytra (protective wing cases) which expose the rest of the abdomen.
Our finds are the first fossil rove beetles ever discovered on the continent and in the southern hemisphere.
The fossils closely resemble today’s rove beetles, showing how successful they’ve been in adapting to various environments without significant changes to their bodies.

Identifying the fossils

We found the fossils in lacustrine sediments (deposits that accumulate in lake environments).
Afristenus orapensis belongs to the stenine rove beetle subgroup while Paleothius mckayi belongs to the subgroup staphylinine.
The stenine rove beetle was previously described in Russia, France and Myanmar while the staphylinine rove beetle was previously described in Russia, China, Myanmar and England.
So we scoured research articles about fossils of a similar age that have already been studied elsewhere for comparative purposes.

More to find

We are currently studying each specimen and preparing academic manuscripts that describe what we’ve found.
My hope is that more money will be invested in training more palaeoentomologists in South Africa and on the continent more broadly.
The study of fossil insects and plants is an important way to preserve our beloved continent’s heritage.

Sandiso Mnguni receives funding from GENUS (Centre of Excellence in Palaeosciences - UID 86073). He is affiliated with the Sophumelela Youth Development Programme (SYDP).