Stability Toolkit for the Appraisal of Bio/Pharmaceuticals’ Level of Endurance (STABLE) as a Framework and Software to Evaluate the Stability of Pharmaceuticals

Reviewer 1

Comment

 Response

The manuscript presents and proposes the use of a freely accessible software, STABLE, which was developed based on established forced degradation protocols, to evaluate the stability of drugs and APIs. STABLE provides a standardized and comprehensive approach to drug stability assessment, evaluating all relevant degradation pathways (acidic, basic, oxidative, thermal and photolytic) with equal emphasis. It uses a quantitative scoring system and a color-coded assessment, facilitating the interpretation of results. Its use is proposed as a complement to regulatory guidelines in stability assessments of pharmaceutical products or APIs. Five case studies were compiled, allowing the reader to use the STABLE tool and verify its ease of use, the score achieved and view the color pictogram for immediate stability assessment, easily detecting the most sensitive points.

We sincerely thank the reviewer for their thorough and insightful summary of our manuscript. We are pleased to see that the objectives and key features of the STABLE software its foundation in established forced degradation protocols, comprehensive evaluation of all relevant degradation pathways, standardized scoring system, and ease of interpretation through color-coded visuals were clearly conveyed and well-received. We also appreciate the acknowledgment of the five case studies, which were included to demonstrate the practical application and usability of the tool. We hope that STABLE will serve as a valuable complement to existing regulatory guidelines and aid researchers and formulators in making informed decisions during drug development. Thank you once again for your thoughtful evaluation.

In item 3. Case studies, the parameters used in the degradation conditions in acidic, basic, oxidative, thermal and photolytic media are mentioned and the final quantitative result (points) and the color pictogram are provided. In this way, the reader can access STABLE, whose address is also presented in the manuscript, and fill in the parameters for each degradation condition, but the degradation percentage was not presented, forcing the reader to scrutinize the references to find the values. I suggest including this information in the text as well, as this item is an invitation for the reader to use the proposed tool, check the results expressed by STABLE and appreciate the facilities of this system.

We agree that including the degradation percentages directly in the manuscript would enhance clarity and usability, The Case Studies section has been revised to include the degradation percentages used for each condition. (Line 263-266, 281-285,301-305, 319-322,336-339)

The text uses the abbreviation M for molar, which is no longer used in the chemical world, where the term mol/L is preferred, which provides greater clarity. It is up to the authors to decide whether or not to make this substitution.

The abbreviation M for molar has been replaced with mol/L as suggested by Reviewer # 1. (Lines 129, 144, 155, 165, 257, 259, 276, 278, 294, 295, 314, 316, 332 and 333)

The same text also uses M as an abbreviation for millions (for example 1.2 M Lux hours), which, although correct, is especially used in informal contexts. Since this is a scientific article, the use of 10⁶ is more appropriate (please correct on lines 260, 276, 290, 306, 319).

We agree with the reviewer. The abbreviation M has been replaced with 10⁶ (Lines 261, 280, 298, 318 and 335)

Typing errors were detected in lines 259 and 318 (e.g. 1.5 % M hydrogen peroxide) – please remove the M.

We thank the reviewer for this comment, M has been deleted from the text (Lines 260 and 316)

In lines 75, 270, 285 and 288 there is a lack of spacing between the text and the bibliographic reference, please correct it.

A space has been added between the text and the bibliographic reference (Lines 76, 274, 293)

In line 295, the sentence is missing a full stop.

A full stop has been added.

In lines 301 and 304, there are larger spaces between “DAD_____and tandem” and between “less ____than___%”. Please check and correct.

The extra spaces have been deleted.

(Lines 313 and 316)

In line 74, reference 12 appears as: GAPI [12] and then as BAGI [12]. I believe that GAPI [12] is incorrect, please check and correct if necessary.

The references have been double checked, and the necessary amendments have been made.

Reviewer 2

Comment

 Response

In this article the STABLE (Stability Toolkit for the Appraisal of Bio/pharmaceuticals’ Level of Endurance) framework is presented as a novel, standardized, and quantitative approach to evaluating the stability of active pharmaceutical ingredients (APIs) under five key forced degradation stress conditions: acid- and base-catalyzed hydrolysis, thermal degradation, oxidative degradation, and photodegradation. This described toolkit aims to address inconsistencies in traditional stability testing by introducing a color-coded scoring system and a visual pictogram for comparative assessment.

We thank the reviewer for his clear and accurate summary of the STABLE framework. We are pleased that the novel aspects of our approach have been well recognized.

The introduction of the article provides a comprehensive overview of pharmaceutical stability, outlining key degradation pathways and types of stability testing. However, the introduction tends to be overly detailed on well-known concepts, which could be streamlined to maintain focus. The innovative aspects and unique contributions of the STABLE tool are not clearly emphasized, leaving readers wanting more clarity on how it advances beyond existing methods.

We appreciate the reviewer’s comment. The introduction has been revised to emphasize innovative aspects and unique contributions of the STABLE tool.

STABLE provides a valuable, standardized framework for forced degradation testing and early-stage stability evaluation of APIs. Its quantitative scoring and visual outputs facilitate comparative analysis and informed formulation strategies. However, its current scope and methodological simplifications (assumption of linear degradation kinetics for APIs, while real-world drug degradation often follows more complex, non-linear patterns) warrant cautious interpretation, and further development is needed to extend its applicability to solid-state stability, complex formulations, and regulatory validation, which should be mentioned in a conclusion.

We agree with the reviewer. These limitations have been acknowledged in the conclusion to encourage cautious interpretation of the results.