How Granular Can a Dose Form Be Described? Considering EDQM Standard Terms for a Global Terminology

Round 1

Reviewer 1 Report

I recommend that the goal be formulated more clearly (in one sentence). The three goals formulated in this manuscript can be the tasks set to achieve the goal. Also be a separate part of the manuscript.

1. The abstract summarizes the article well.
2. The parts Introduction, Material and Methods, Discussion and Conclusion are good.
3. In the Results section there is a duplication of the subheading numbers (line 142 and line 204).
4. I recommend that the aim be formulated more clearly (in one aim). The three aims (line 84-87) in the manuscript can be transformed into tasks to achieve the aim.
5. I also recommend that the aim be in a separate part of the manuscript.

Author Response

We thank the reviewer for his positive appreciation of our manuscript. 

We will respond to the points : 

1. The abstract summarizes the article well.
2. The parts Introduction, Material and Methods, Discussion and Conclusions are good

We thank the reviewer for the positive appreciation. 

1. In the Results section there is a duplication of the subheading numbers (line 142 and line 204).

We have corrected that duplication 

1. I recommend that the aim be formulated more clearly (in one aim). The three aims (line 84-87) in the manuscript can be transformed into tasks to achieve the aim.

We agree with the reviewer and have followed the advice. 

1. I also recommend that the aim be in a separate part of the manuscript.

We provided the aim at the end of the introduction (as is customary in many manuscripts) and changed it to : 

The aim of this study is to propose recommendations for improvements to the current EDQM in the light of its use as a global terminology in the identification of medicinal products by describing and analyzing the features of the EDQM terminology; by formulating  possible minor changes, and by creating a small ontology of dose forms, based on the basic attributes of dose forms in EDQM, and suitable for alignment with other dose form terminologies.

Reviewer 2 Report

1) The Authors performed an interesting manuscript entitled "How granular can dose form be described? Considering EDQM Standard Terms for a global terminology". The article aimed to provide recommendations for minor improvements and a simple ontology for dose forms was proposed.
2) Although the Authors worked hard, I have some questions/comments about the article. Please answer in detail to the following observations:
a) In relation to release characteristics (4 values: conventional, prolonged, delayed, and modified), I think this terminology should be revised, that is, modified-release dosage forms include prolonged-release, delayed-release and pulsatile-release dosage forms. Thus, prolonged and delayed releases are a type of modified release. Please explain your criteria and indicate the meaning of modified release.

b) The term "pharmaceutical dose form" should be replaced by "pharmaceutical dosage form".

c) I think that sometimes the terminology presented in Table 2 is not the most appropriate. For example, "oral drops dose form" is a form of "oral liquid dose form". In addition, an "Oral solid dose form" can be an "Oral effervescent or dispersible dose form", "Oral Gastroresistant dose form", "Oral Prolonged release dose form", and "Oral Modified release dose form". Please explain your criteria. 

d) I think that types of dosage form should be introduced into the terminology. For example, there are different types of tablets (uncoated tablets; coated tablets; effervescent tablets; orodispersible tablets; oral lyophilisates, etc.). Thus, I think the type of dosage form should be introduced into the terminology, as well as the route of administration (for example: oral tablet versus sublingual tablet versus vaginal tablet). Please explain your point of view.

e) "Vaginal dose form" (Table 2) is a very broad term as it can be a "vaginal ring", "vaginal soft capsule", "vaginal tablet", "vaginal cream", "vaginal foam", "vaginal gel", "powder for vaginal solution" , "vaginal ointment" and "vaginal solution". Please indicate your opinion on this topic.

f) Lines 175 and 176: Please replace "the dose form in which the medicinal product is shipped from pharmaceutical company production to the pharmacy" by "the dosage form in which the medicinal product is shipped by the pharmaceutical distribution from industrial manufacturing company to community and hospital pharmacies".

g) Please check the used abbreviations. That is, sometimes you use the abbreviation and sometimes you use the full name (for example, see EDQM in lines 315 and 325/326).

Author Response

We thank the reviewer 2 for his overall postive appreciation of our manuscript and will respond here to the different points raised: 

1) The Authors performed an interesting manuscript entitled "How granular can dose form be described? Considering EDQM Standard Terms for a global terminology". The article aimed to provide recommendations for minor improvements and a simple ontology for dose forms was proposed.

Thank you fo this reformulation of our aims. 

2) Although the Authors worked hard, I have some questions/comments about the article. Please answer in detail to the following observations:

a) In relation to release characteristics (4 values: conventional, prolonged, delayed, and modified), I think this terminology should be revised, that is, modified-release dosage forms include prolonged-release, delayed-release and pulsatile-release dosage forms. Thus, prolonged and delayed releases are a type of modified release. Please explain your criteria and indicate the meaning of modified release.

We thank the reviewer to highlight this important issue. The European Directorate and the WHO use the terms conventional release and modified release as two classes, for which the last class would encompass the gastro-resistant dose forms (syn. enteric-coated) and prolonged release dose forms. Modified release characteristics are then kept for all dose forms that can not be characterized by gastro-resistant or prolonged dose forms. 

This is obvious from the definitions of the dose form to which these attributes are assigned.  It is also repeated in the monograph "REVISION OF MONOGRAPH ON TABLETS. Final text for addition to The International Pharmacopoeia".
as adopted by the Forty-fourth WHO Expert Committee on Specifications for Pharmaceutical Preparations in October 2009 for addition to The
International Pharmacopoeia.  

https://pdf4pro.com/amp/view/revision-of-monograph-on-tablets-2f011.html

The remark of the reviewer triggered us to slighly change the ontology proposed, however, while remaining close to the directions of the EDQM. 

b) The term "pharmaceutical dose form" should be replaced by "pharmaceutical dosage form".

EDQM and the ISO IDMP standard on dose forms explictly use the term "dose form" in a consistent way in the text and the terms "pharmaceutical dose form" and "adminstrable dose form". 

Therefore we prefer to stick to this terminology. 

c) I think that sometimes the terminology presented in Table 2 is not the most appropriate. For example, "oral drops dose form" is a form of "oral liquid dose form". In addition, an "Oral solid dose form" can be an "Oral effervescent or dispersible dose form", "Oral Gastroresistant dose form", "Oral Prolonged release dose form", and "Oral Modified release dose form". Please explain your criteria. 

For the concept "oral solid dose form" we stick to the oral forms that do not require a transformation.  Hence, we put oral effervesent or dispersable tablets in a seperate class.  For the oral forms with a release method other than conventional we applied the approach as dictated by EDQM (see supra). 

We seperated "oral liquid dose forms" from "oral drops dose forms" as the methods of formulation of the strength  and of specifying the dose instructions are different. 

d) I think that types of dosage form should be introduced into the terminology. For example, there are different types of tablets (uncoated tablets; coated tablets; effervescent tablets; orodispersible tablets; oral lyophilisates, etc.). Thus, I think the type of dosage form should be introduced into the terminology, as well as the route of administration (for example: oral tablet versus sublingual tablet versus vaginal tablet). Please explain your point of view.

All these more specific dose form terms exist at the granular level of EDQM (with 428 values).   We have just proposed classes for a higher level of aggregation for granular with identical or very similar attributes. 

e) "Vaginal dose form" (Table 2) is a very broad term as it can be a "vaginal ring", "vaginal soft capsule", "vaginal tablet", "vaginal cream", "vaginal foam", "vaginal gel", "powder for vaginal solution" , "vaginal ointment" and "vaginal solution". Please indicate your opinion on this topic.

Idem as for point d)

f) Lines 175 and 176: Please replace "the dose form in which the medicinal product is shipped from pharmaceutical company production to the pharmacy" by "the dosage form in which the medicinal product is shipped by the pharmaceutical distribution from industrial manufacturing company to community and hospital pharmacies".

We agree with the reviewer and have changed the text accordingly.

g) Please check the used abbreviations. That is, sometimes you use the abbreviation and sometimes you use the full name (for example, see EDQM in lines 315 and 325/326).

We have checked the use of abbreviations and full text across the manuscript and changed this as suggested by the reviewer