Quality Assurance of Extemporaneous Formulations in a Resource-Limited Setting: A Comparison with International Standards and an Analysis of Compounding Practices

Extemporaneous compounding is a vital pharmacy service that bridges the gap when suitable licensed medicines are unavailable, particularly for pediatric, geriatric, and patients with specific dosage requirements [1, 2]. However, unlike commercially manufactured products, EPs are not subject to rigorous pre-market regulatory review, placing the entire responsibility for their quality, stability, and safety on the compounding pharmacist and the institution [3, 4].

The risks associated with EPs are well-documented and include formulation errors, microbial contamination, chemical and physical instability, and incorrect beyond-use date (BUD) assignment [5, 6]. Internationally recognized compendia, such as the United States Pharmacopeia (USP), provide standardized formulas, compounding procedures, and stability guidelines to mitigate these risks and ensure consistent quality [7, 8]. Adherence to such standards is a cornerstone of safe compounding practice.

In resource-limited settings, the reliance on EPs is often high due to persistent drug shortages and a lack of pediatric formulations [9, 10]. However, these same settings frequently face challenges in implementing robust quality assurance systems, including a lack of equipment, reference standards, and trained personnel [11]. Studies from Africa have highlighted concerns regarding the quality of compounded products, but few have directly compared local practices against international standards [12, 13].

A previous study at Royal Care Hospital established a high volume of extemporaneous compounding [14]. Building on that foundation, this study aims to critically evaluate the quality and safety of these practices by comparing them with USP standards and analyzing the existing quality control measures, thereby identifying key areas for improvement.

2. METHODS

2.1 Study Design and Setting

This observational, cross-sectional study was conducted in the pharmaceutical manufacturing unit of Royal Care Hospital, a tertiary care facility in Khartoum, Sudan. The study period was from April to June 2022.

 2.2 Data Collection

Data were prospectively collected for all EPs prepared during the study period. A structured checklist was used to extract information on:

1. Detailed compounding methods and ingredient
2. Assigned beyond-use dates (BUD) and storage conditions
3. Sources of formulation references
4. Types of quality control (QC) and stability tests performed

2.3 Comparative Analysis with USP Standards

The local preparation methods for all EPs were reviewed. Those with a corresponding monograph in the United States Pharmacopeia (USP) 2021 were identified. A systematic, point-by-point comparison was conducted for these preparations, focusing on:

1. Active Pharmaceutical Ingredient (API) source (e.g., crushed tablet vs. pure powder).
2. Vehicles and excipients used.
3. Compounding procedure.
4. Assigned BUD and storage conditions.

2.4 Data Analysis

Descriptive statistics (frequencies and percentages) were used to summarize the data on quality control practices. The comparative analysis with USP was presented descriptively, highlighting areas of concordance and discordance.

3. RESULTS

3.1 Overview of Compounding Practices and USP Availability

During the study period, 27 different drugs were compounded extemporaneously. Only six of these (22.2%) had a dedicated compounding monograph in USP 2021: Captopril, Enalapril, Omeprazole, Sildenafil, Spironolactone, and Vancomycin.

3.2 Comparison of Local Methods with USP 2021 Standards

Substantial discrepancies were observed between local practices and USP standards for all six drugs. Key differences are summarized in Table 1.

Table 1: Comparison of Local Compounding Practices with USP 2021 Standards

The pharmacy had no formal quality control testing program for finished compounded products. The quality was presumed based on the quality of the starting materials (commercial products or APIs). As shown in Table 2, stability was assessed primarily by relying on published literature and physical examination (63.3%). Contamination testing was infrequently performed and was limited to a monthly swab test on API containers (36.7%).

This study reveals a significant misalignment between local extemporaneous compounding practices and internationally recognized USP standards, coupled with a critical lack of systematic quality assurance in a Sudanese hospital.

The most striking finding is the extensive variation in formulation ingredients. The reliance on simple syrup and purified water as universal vehicles, instead of the specialized, buffered, and preserved vehicles recommended by USP (e.g., Ora-Blend, SyrSpend), raises concerns about physical stability, microbial growth, and chemical degradation [8, 15]. For instance, using simple syrup for Enalapril, instead of a suspending agent like Ora-Plus, could lead to rapid settling and dose non-uniformity, while using distilled water for Vancomycin offers no antimicrobial protection, justifying the very short 1-day BUD but rendering the preparation highly impractical [16].

The arbitrary and widely variable assignment of BUDs is another major concern. For Sildenafil, where the local method matched the USP vehicle, the BUD still varied from 7 days to 3 months, far exceeding the USP-recommended 90 days. This inconsistency, also seen with Omeprazole and Enalapril, suggests a lack of evidence-based protocols and reliance on inconsistent references or individual judgment. Overestimating BUDs can lead to patients receiving degraded or sub-potent medication, while underestimating them increases workload and cost [17].

The absence of any finished product quality control testing is a profound patient safety gap. The assumption that quality starting materials guarantee a quality final product is flawed, as the compounding process itself can introduce errors and contamination [5]. The limited swab testing of APIs does not assess the microbiological quality of the final aqueous preparation, which is a known risk factor for microbial contamination in EPs [18].

Our findings are consistent with studies from Jordan and Ethiopia, which also reported a lack of quality testing and standardized procedures [12, 19]. The variation in excipients and APIs from different manufacturers, as highlighted in other studies, creates uncertainty and makes the application of published stability data unreliable [20].

The implications of these gaps are severe in a tropical country like Sudan, where high ambient temperatures and frequent power cuts can accelerate drug degradation [21]. Without stability-indicating assays and proper storage, the therapeutic efficacy and safety of these life-saving EPs cannot be guaranteed.

Limitations: This study was conducted in a single center. The comparative analysis was limited to only six drugs due to the lack of USP monographs for the others, which itself is a finding that reflects the challenge of compounding less common drugs.

Example of Detailed Method Comparison (Sildenafil Suspension)