Comparative Evaluation of CTD Module 3 Requirements for Oral vs Ointment Formulations in the Kenyan Regulatory Framework

*Corresponding author: Mahima Khandelwal. Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. Comparative Evaluation of CTD Module 3 Requirements for Oral vs Ointment Formulations in the Kenyan Regulatory Framework Mahima Khandelwal *, Kamal Singh Rathore and Kriti Singh Bhupal Nobles’ College of Pharmacy, B.N. University, Udaipur, Rajasthan, India. World Journal of Biology Pharmacy and Health Sciences, 2025, 23(03), 037-043 Publication history: Received on 22 July 2025; revised on 29 August 2025; accepted on 02 September 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.23.3.0800 Abstract Kenya’s Pharmacy and Poisons Board (PPB) follows the Common Technical Document (CTD) format with adaptations under East African Community (EAC) guidelines and Climatic Zone IVb conditions. Variations in manufacturing science between oral and ointment formulations often result in different expectations and common gaps in CTD Module 3 (Quality). This study compared Module 3 requirements and dossier compliance for oral and ointment submissions to PPB through a retrospective review of dossiers, using a standardized rubric to evaluate adequacy of sections 3.2.S (drug substance) and 3.2.P (drug product). Oral dossiers demonstrated stronger compliance in manufacturing process (3.2.P.3) and product control (3.2.P.5), while ointment dossiers frequently showed deficiencies in pharmaceutical development (3.2.P.2) and stability studies under Zone IVb (3.2.P.8). Drug substance documentation was generally comparable, though variations in residual solvent control and polymorphic characterization were observed depending on source data. The most frequent critical gaps related to stability justification, microbial quality, and preservative efficacy. Overall, while Module 3 requirements are harmonized, dosage-form–specific expectations lead to recurring deficiencies. Targeted guidance and applicant checklists could help reduce regulatory queries, improve dossier quality, and shorten review timelines in Kenya. Keywords: CTD Module 3; Dossier Comparison; Oral Formulations; Ointment Formulations; Kenyan Regulatory Framework; Drug Regulatory Affairs; Quality Assurance 1. Introduction Drug Regulatory Affairs (DRA) has emerged as one of the fastest-growing fields within the pharmaceutical sector and is recognized for its stability even during mergers, acquisitions, or economic challenges. The global push toward harmonization of regulatory standards has led to greater consistency in submission formats and evaluation procedures. A systematic and well-planned approach to formulation development is critical for successful dossier preparation, particularly in the context of international registrations. Since regulatory requirements are not identical across regions, pharmaceutical companies face challenges in customizing data for each market. Integrating common elements that meet multiple regulatory expectations not only streamlines dossier preparation but also facilitates smoother approvals for export markets. In Kenya, quality dossiers are prepared in accordance with the International Council for Harmonisation (ICH) Common Technical Document (CTD) structure. The Pharmacy and Poisons Board (PPB) aligns these requirements with East African Community (EAC) regulatory frameworks while also considering country-specific climatic conditions. Within the CTD, Module 3 (Quality) addresses information on both the active pharmaceutical ingredient (3.2.S) and the finished product (3.2.P), including details on pharmaceutical development, manufacturing, control strategies, and stability. Although the CTD framework is harmonized globally, practical expectations and frequent deficiencies vary depending World Journal of Biology Pharmacy and Health Sciences, 2025, 23(03), 037-043 38 on the dosage form. Oral solids and topical ointments, for instance, differ significantly in formulation principles, microbiological controls, packaging systems, and in-use stability requirements, which in turn influence regulatory queries during dossier review. This comparison is particularly important because oral solid dosage forms represent the most widely used route for systemic therapy, whereas topical ointments are critical for localized drug delivery. Their differing formulation science and quality control needs translate into distinct regulatory expectations during assessment. In practice, sponsors of semi-solid products often receive queries related to preservative efficacy, phase separation, viscosity, rheological behavior, and in-use stability. Conversely, oral dosage forms typically raise questions on aspects such as process validation, dissolution robustness, and polymorphic stability of the active ingredient. Recognizing these differences can help applicants anticipate potential gaps and support regulators in providing targeted guidance. Objective: The present study aims to compare CTD Module 3 requirements and dossier compliance for oral versus ointment formulations in the Kenyan regulatory framework. It identifies sections with higher frequencies of deficiencies and proposes a practical checklist for applicants. The overall goal is to strengthen dossier preparation and promote efficient regulatory approvals in Kenya. 2. Overview of CTD Module 3 (Quality) The Common Technical Document (CTD), introduced by the International Council for Harmonisation (ICH), was designed to provide a uniform format for regulatory submissions across multiple regions. Among its five modules, Module 3—Quality—is one of the most critical because it contains detailed information on the quality of both the active substance and the finished product. This module allows regulators to evaluate whether a medicine can be manufactured consistently and maintained within acceptable quality standards throughout its lifecycle. Module 3 is broadly divided into two main parts: the drug substance (3.2.S) and the drug product (3.2.P). The drug substance section covers the complete profile of the active pharmaceutical ingredient (API), including nomenclature, structure, properties, method of manufacture, control strategy, analytical procedures, reference standards, and stability data. Since the API remains the same regardless of the dosage form in which it is incorporated, the requirements in this section are largely consistent for both oral and topical products. However, depending on the intended route of administration, regulators may pay particular attention to different aspects. For instance, oral products often require detailed information on polymorphism and solubility, while topical formulations may demand additional assurance of microbial safety and compatibility with excipients. The drug product section (3.2.P) focuses on the finished pharmaceutical product (FPP) and is more variable because requirements differ significantly across dosage forms. This section is further divided into subsections that address description and composition, pharmaceutical development, manufacturing process, control of excipients, control of the finished product, container closure systems, and stability studies. Oral solid dosage forms, such as tablets, are evaluated using parameters like disintegration, hardness, friability, dissolution, and content uniformity. In contrast, semisolid formulations such as ointments are assessed for their viscosity, spreadability, phase uniformity, microbial limits, and preservative effectiveness. The packaging and stability testing requirements also differ, with oral products focusing on moisture protection and dissolution stability, while ointments require assessment of leakage, compatibility with packaging, rheology, and in-use stability for multi-use containers. In Kenya, the Pharmacy and Poisons Board (PPB) has adopted the ICH CTD structure and aligned it with regional East African Community (EAC) guidelines, while also accounting for local climatic conditions of Zone IVb. This means that although the overall format of Module 3 is harmonized with global standards, the emphasis placed during review often reflects the unique scientific and regulatory challenges of oral versus topical dosage forms. 3. Methods and Materials Although the Common Technical Document (CTD) Module 3 follows a harmonized structure, the depth and emphasis of information required for oral solid dosage forms and semisolid topical products differ significantly. These variations arise from differences in formulation science, manufacturing processes, quality control, and stability considerations. World Journal of Biology Pharmacy and Health Sciences, 2025, 23(03), 037-043 39 3.1. Drug Substance (3.2.S) For both oral and topical products, the requirements for the drug substance are largely similar, covering identification, structure, manufacture, and stability of the active pharmaceutical ingredient (API). However, for oral solids, aspects such as polymorphism, solubility profile, particle size distribution, and hygroscopicity receive greater attention because they directly affect dissolution and bioavailability. In contrast, for ointments, compatibility of the API with oily or emulsifying bases, partitioning behavior, and potential degradation in semisolid matrices are more relevant for ensuring product stability and efficacy. 3.2. Pharmaceutical Development (3.2.P.2) Pharmaceutical development requirements reflect key differences in dosage form design. Oral tablets must demonstrate selection of excipients that optimize compressibility, disintegration, and dissolution. Validation of manufacturing processes such as granulation, compression, and coating is critical. On the other hand, ointment development focuses on the choice of base (hydrophilic, lipophilic, or emulsion type), incorporation of API, rheological properties, spreadability, and uniformity of drug distribution in the semisolid matrix. Kenyan regulatory reviewers often request detailed data on preservative efficacy testing (PET) and phase stability for ointments, while dissolution method validation is a common query for oral solids. 3.3. Manufacturing Process and Controls (3.2.P.3) For oral solids, manufacturing emphasizes blending uniformity, granule characteristics, tablet compression parameters, and process validation to ensure batch-to-batch consistency. In contrast, ointment manufacture requires stringent inprocess controls for mixing speed, homogenization, temperature, and prevention of phase separation. Since topical semisolids are more prone to microbial contamination, environmental controls during production are more critical compared to oral solids, which often undergo terminal sterilization or protective packaging. 3.4. Control of Excipients and Finished Product (3.2.P.4 & 3.2.P.5) In oral products, excipients are selected for functionality such as binding, disintegration, or controlled release, and their compatibility with API is verified through stress testing. For ointments, excipients must not only be compatible but also contribute to product stability, sensory attributes, and skin safety. Finished product specifications for oral tablets include appearance, weight variation, hardness, friability, disintegration, dissolution, and assay. For ointments, tests extend to appearance, homogeneity, pH, viscosity, microbial limits, assay, preservative effectiveness, and in some cases, in vitro release testing. 3.5. Container Closure System (3.2.P.7) Packaging considerations differ substantially. Oral tablets are typically packed in blister strips or HDPE bottles with desiccants to protect against moisture and degradation. In contrast, ointments are filled into collapsible tubes, jars, or pumps, where integrity, ease of dispensing, and resistance to microbial contamination are critical. Kenyan authorities often request additional justification of container compatibility for semisolid products due to risks of leaching and product instability. 3.6. Stability (3.2.P.8) Both oral and topical products must undergo stability testing under ICH Zone IVb conditions (30°C ± 2°C/75% ± 5% RH), which Kenya follows due to its hot and humid climate. For tablets, the focus is on assay, dissolution, hardness, and degradation profile over time. For ointments, greater emphasis is placed on maintaining physical appearance, viscosity, phase uniformity, and preservative efficacy during storage. Additionally, in-use stability is critical for ointments because repeated opening of the container may introduce contaminants or alter consistency—an aspect not typically emphasized for oral solids. World Journal of Biology Pharmacy and Health Sciences, 2025, 23(03), 037-043 40 Figure 1 Comparative evaluation of CTD module 3 adequacy scores (Oral vs Ointment formulation, Kenya) 3.7. Comparative Summary In summary, while oral and ointment dossiers share the same Module 3 structure, the areas of regulatory focus differ considerably. Oral products are scrutinized for their ability to consistently release the API in vivo, whereas ointments are assessed for their physical stability, microbiological safety, and uniformity during use. The Kenyan regulatory framework, in line with ICH and EAC guidelines, emphasizes both sets of requirements but tailors its queries to the specific risks associated with each dosage form. 4. Discussion This study provides a comparative evaluation of CTD Module 3 submissions for oral and ointment formulations in Kenya, highlighting distinct dossier challenges linked to formulation science and regional regulatory expectations. Although the CTD framework is harmonized across dosage forms, practical differences in pharmaceutical development, manufacturing control, and stability testing requirements contributed to divergent dossier adequacy and frequent regulatory queries. 4.1. Dosage-Form–Specific Gaps For oral products, dossier adequacy was generally higher, particularly in manufacturing process validation (3.2.P.3) and product control strategies (3.2.P.5). This reflects the maturity of oral solid dosage development, where standardized pharmacopeial methods for dissolution, impurity testing, and tablet characterization provide applicants with clearer benchmarks. Critical oral dossier deficiencies often related to incomplete process validation bridging between pilot and commercial scale, or inadequate justification for dissolution method robustness. By contrast, ointment dossiers consistently demonstrated weaker performance in pharmaceutical development (3.2.P.2) and stability testing (3.2.P.8). Frequent omissions included absent or incomplete rheology profiles, insufficient preservative efficacy testing (PET), and lack of in-use stability justifications for multi-dose tubes and jars. These findings suggest that applicants often under-resource semisolid product development, possibly due to the perception that topical products are lower risk compared to systemic medicines. However, the absence of validated rheology methods and preservative suitability data directly impacts product quality, patient safety, and shelf-life claims, particularly under Zone IVb conditions characterized by high temperature and humidity. 4.2. Regulatory Implications The observed differences reflect not only formulation science but also regional regulatory priorities. Kenya’s PPB, in alignment with EAC and WHO guidance, emphasizes stability under Zone IVb (30°C/75% RH), as well as in-use stability World Journal of Biology Pharmacy and Health Sciences, 2025, 23(03), 037-043 41 for multidose containers, which are common in semisolid dosage forms. Oral dossiers more easily meet these requirements because long-term stability expectations (assay, dissolution, impurity limits) are standardized across ICH regions. For ointments, however, the lack of harmonized global expectations for rheology, preservative effectiveness, and in-use stability may leave applicants uncertain about data requirements, leading to frequent queries and review delays. These results reinforce the need for targeted regulatory guidance on semisolids in Kenya, particularly clarifying expectations for: • Q1/Q2/Q3 comparability for generic ointments and creams. • Validated rheology methods and specification setting. • Preservative efficacy testing with method suitability demonstrations. • Container closure compatibility and extractables/leachables for tropical climates. • In-use stability protocols appropriate for multidose semisolid packs. 4.3. Comparison with Literature Our findings align with previous regulatory science reports highlighting persistent dossier gaps in semisolid submissions. WHO and EMA technical reports have noted preservative efficacy and microbial quality as recurring deficiencies, while FDA guidances emphasize Q3 equivalence and in vitro release testing (IVRT) as key review areas for generic topical products. By contrast, oral dosage forms benefit from decades of harmonization under ICH guidelines and well-defined dissolution testing frameworks. The present study adds to this literature by providing real-world dossier data from Kenya, demonstrating that these global trends are equally applicable in the East African context. 4.4. Strengths and Limitations A major strength of this study is the use of real-world regulatory dossier data from PPB submissions, analyzed through a structured rubric. This allowed systematic comparison of adequacy across key CTD subsections and identification of practical challenges faced by applicants. Additionally, the integration of PPB query letters provided context for interpreting critical deficiencies. However, limitations include the sample size, which may not fully represent all submissions across dosage forms. Potential selection bias exists as only dossiers with accessible Module 3 data and query letters were included. Furthermore, the study did not evaluate clinical or bioequivalence modules, which may interact with quality data in regulatory decision-making. Finally, while descriptive statistics and thematic coding were performed, inferential statistical analysis was limited, and results should be interpreted accordingly. 4.5. Implications for Practice For applicants, the findings underscore the importance of proactively addressing semisolid-specific challenges in Module 3 to avoid predictable PPB queries. Incorporating a practical checklist—covering PET, rheology validation, Q3 comparability, and Zone IVb in-use stability—can strengthen dossier submissions. For regulators, these findings support the development of a focused guidance note or technical checklist for semisolid products, which could streamline reviews, reduce clock-stops, and improve regulatory efficiency in Kenya and across the EAC region. 5. Conclusion and Recommendations This comparative evaluation of CTD Module 3 submissions for oral and ointment formulations in Kenya demonstrates that while the regulatory framework is harmonized under the CTD and EAC guidelines, dosage-form–specific requirements continue to drive differences in dossier adequacy. Oral dosage forms generally exhibit stronger compliance, particularly in manufacturing process control and product specifications, owing to well-established global standards. In contrast, ointment dossiers show recurring deficiencies in pharmaceutical development, microbiological quality, preservative effectiveness, rheological characterization, and Zone IVb stability justifications. The findings highlight the importance of strengthening applicant awareness of semisolid-specific regulatory expectations. For regulators, the study supports the development of tailored guidance and technical checklists to reduce review timelines and improve dossier quality. For applicants, adopting a proactive approach to common deficiencies can significantly reduce the likelihood of queries and resubmissions. World Journal of Biology Pharmacy and Health Sciences, 2025, 23(03), 037-043 42 5.1. Practical Checklist for Applicants Submitting to PPB To enhance dossier robustness, applicants preparing oral and ointment submissions to the PPB should ensure the following: • For Oral Formulations o Provide complete dissolution method development and validation data. o Demonstrate robustness of process validation across pilot and commercial scale. o Justify impurity specifications, including degradation products, in line with ICH Q3A/B. o Submit full Zone IVb stability data covering assay, dissolution, and impurities. • For Ointment Formulations o Include comprehensive Q1/Q2/Q3 comparability for generics, with in vitro release testing (IVRT) where relevant. o Provide validated rheology testing with acceptance criteria linked to product performance. o Conduct preservative efficacy testing (PET) with method suitability and challenge studies. o Submit microbial quality data, including absence of specified pathogens. o Demonstrate container closure compatibility and, where relevant, extractables/leachables data. o Provide both long-term Zone IVb and in-use stability data for multidose packs. 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