Microbiological Attributes of Chewable Gels (Gummies)

Introduction

Chewable gels (Gummies) are a long-standing confectionary product that due to their composition, processing, and physicochemical attributes e.g., low water activity (0.51 to 0.76) and pH (<4.5), are not associated with foodborne illness, and if stored to protect them from high humidity will not support microbial growth. More recently chewable gels are being widely used as dosage forms for dietary supplements, cannabis edibles, and some OTC drug products. The ease of chewing and swallowing, appealing look, and delectable flavors of gummies make them popular, especially with the young and old, which makes them particularly attractive to individuals who may find it challenging to swallow pills (Rai and Dubey, 2023).

The reader will be surprised to learn of the estimated sales of these products. The global gummy market size is expected to grow from $22.8B in 2023 to $66.6B by 2033, at a Compound Annual Growth Rate (CAGR) of 11.8% during the forecast period (https://www. grandviewresearch.com/industry-analysis/gummy-market-report). In a 2018 USP presentation, it was estimated that the narrower 2025 vitamin and dietary supplement gummy market would reach $4.2B (https://www.usp.org/sites/default/files/usp/document/stakeholder forum/chewable-gels.pdf).

Microbial Contamination Risk Analysis

Factors that should be included in the risk analyses are the microbiological quality of the ingredients, formulation, manufacturing process, physiochemical attributes, microbiological specifications and testing program, packaging and storage conditions, microbial stability, and targeted product recipients (Cundell, 2020).

Microbiological Quality of the Ingredients

The microbiological quality of the ingredients is important. Whenever possible, use USP-grade materials within your formulation. See the Handbook of Pharmaceutical Excipients for additional details (Rowe et al, 2006). Table 1 provides a risk assessment for the probable impact of the ingredients on the chewable gels.

The impact of the active ingredient in a chewable gel would require a separate microbial contamination risk assessment. Animal or plant-derived material would be subject to microbial testing with emphasis on tests for Salmonella as this bacterium is known to persist in food with low water activity (Beuchat et al, 2013).

Manufacturing Process

Typically, the gelling agent and solvent are heated to an elevated temperature, e.g., 90°C for 90 minutes, mixed, cooled to the above gelling temperature, and the other ingredients are added, mixed, poured into molds, cooled, and dried (Baydin et al, 2022). Exposure to elevated temperatures will kill vegetative microorganisms reducing the microbial contamination risk. Recent innovations using semi-synthetic gelling agents and hot-melt extrusion to produce chewable gels should further reduce this risk.

Shelf-Life Stability

Under standard storage conditions, i.e., 20-25°C at 50-60% relative humidity, gummies may have a one-to-two-year shelf life. They may lose or gain moisture depending on the difference in their water activity and the humidity of their surroundings.

Water Activity Measurement and Specification Setting

Although water activity was a widely used measurement in the food industry, its value was only relatively recently recognized in the pharmaceutical industry with the publication of USP chapters <1112> and <922>.

Perhaps the most critical quality attribute in hurdle technology (Leistner, 1994), a concept developed to control microorganisms in food products that work equally well in drug products, is water activity (Cundell and Fontana 2009, Hussong, 2009). In general, drug products with water activities < 0.75 do not support the growth of microorganisms likely to be found in drug products and may be self-preserving. Furthermore, microorganisms cannot develop resistance to low water activities as with antimicrobial agents. Additional generalizations that can be made about water activity, and that are important to the pharmaceutical microbiologist include:

• At high a_w, i.e., >0.95, bacteria out-compete fungi.
• Gram-negative bacteria require higher aw than Gram-positive bacteria.
• Below 0.85 most bacteria found in pharmaceutical products will not grow.
• Below 0.75 most yeasts and molds found in pharmaceutical products do not grow.
• Between 0.75 and 0.60 only highly specialized microorganisms, not usually found in drug products, will grow.
• Below 0.6, microorganisms cannot grow in the material.

See Table 2 for details of the water activity requirements of microorganisms of interest to pharmaceutical manufacturers.

Role of Water Activity Determination in Product Development, Specification setting, and Release and Stability Testing

During the development of non-sterile drug products, it is recommended that an experienced microbiologist conduct a microbial contamination risk assessment. The microbiology laboratory should have access to water activity instrumentation to evaluate pharmaceutical ingredients and finished products as to microbial stability. After the completion of the risk assessment, chewable gels with a_w <0.6 and pH <4.5 would be candidates for significantly reduced routine release testing or even eliminated microbial specifications. The justification for this latter decision may be found in ICH Q6 Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products Decision Tree No. 6 and 8, USP <1112> Application of Water Activity Determination to Non-sterile Pharmaceutical Products and Cundell (2020).

With low water activity and pH products like chewable gels, the elimination of routine microbial tests for release and in a long-term stability program can be justified. As a measure of the microbial stability of a chewable gel, the ability of the packaging to protect the product, and water activity measurement within your stability program has more utility than microbial testing. (Cundell, 2015)

Existing USP Chapters and Product Monographs

The USP first introduced the concept of water activity with the publication of <1112> Application of Water Activity Determination to Non-sterile Pharmaceutical Products, which recommended the measurement of water activity by AOAC chilled mirror official method 978.18.

The USP general test chapter <922> Water Activity, which became official May 1, 2021, outlines the recommended methods to qualify, calibrate, and use water activity instruments to accurately measure the aw of raw materials and products. It states:

“Measurements of a_w are made by allowing a sample to equilibrate with the moisture in the headspace above the sample at an ambient or a standardized temperature and then measuring the RH_eq of the headspace. At equilibrium, the RH_eq is also a function of the law in the sample. Most water activity meters measure the relative humidity with a moisture-dependent resistor or capacitor or may use psychrometry (wet bulb temperature) or dew point depression. Regardless of the principle of measurement, water activity meters can be calibrated and qualified using saturated salt reference solutions that provide a known and constant RH_eq .“

“The instrumentation most frequently to determine water activity includes:

• Dew Point Temperature—Chilled Mirror
• Electronic Hygrometers—Resistive (Electrolytic) Hygrometer
• Electronic Hygrometers—Capacitive Hygrometer
• Near-Infrared Spectroscopy
• Frequency Modulation Spectroscopy Using a Tunable Diode Laser “

Since the publication of <922>, the expert committees responsible for dietary supplements recommended the use of water activity as a quality attribute in USP <2800> Multi-ingredient Dietary Supplement Products – Product Quality Tests, which will be official December 2024 and proposed water activity in chewable gel monographs citing <922> for water activity measurement. The earlier dietary supplement monograph for Oil- and Water-soluble Vitamins with Minerals Chewable Gel that was official in May 2021 contained a water activity requirement citing the AOAC oofficialmethod 978.18. The monograph states:

“Water Activity

Procedure:

Measure water activity by AOAC official method 978.18. [Note— Make sure that the sample being measured is homogeneous. If the sample is crushed, ground, or sliced, the procedure used must be consistent to obtain reproducible results. Prepare fresh every time.]

Acceptance criteria:

NMT 0.75”

<2800> Multi-ingredient dietary supplement products – product quality tests state in a section entitled Water Activity (chewable gels) the following:

“Chewable gels are formulated with one or more gelling agents (e.g., gelatin, pectin, or starch), nutritive sweeteners (e.g., sucrose, fructose, or corn syrup), flavoring agents, non-nutritive sweeteners, colorants, and water. Determination of the optimum water activity specification is a critical quality attribute necessary to ensure that the product is shelf stable. Water activity can be used to predict and resolve problems with moisture migration, can identify whether microbial growth will be a concern (i.e., surface mold grown), and may be a predictor of shelf stability. It also can be used to select appropriate packaging. In general, the chemical stability of the chewable gel matrix can be compromised if the chewable gels are not properly prepared to the proper equilibrium; sometimes the disaccharides that are present can invert, causing the chewable gels to become soft and sticky. Water Activity <922> outlines the recommended methods to qualify, calibrate, and use water activity meters to accurately measure water activity. The effects of water activity should be combined with pH to control microorganisms more effectively. Water activity and pH simultaneously can provide effective microbial control at levels that would typically be considered unsafe for either one alone.”

The author expects that future chewable gel monographs will cite <922> and continue to set the specification at NMT 0.75.

Conclusions

Chewable gels due to their ingredient microbiological quality, manufacturing process, and attributes such as low water activity and low pH, when stored to protect them from elevated temperature and humidity, have a low risk of microbial contamination, so forgoing routine microbiological testing can be justified. 

References

1. Baydin, T. S., W. Arntsen et al 2022 Physical and functional properties of plant-based pre-emulsified chewable gels for the oral delivery of nutraceuticals. Appl. Food Res. 2: 100225
2. Beuchat, L. R., E. Komitopoulou et al 2013 Low-water Activity Foods: Increased Concern as Vehicles of Foodborne Pathogens. J. Food Prot. 76(1): 150-172
3. Cundell, A.M. 2009, Effects of water activity on microorganisms. In A.M Cundell and A. J. Fontana, Jr Water Activity Applications in the Pharmaceutical Industry pp 175-204 PDA/ DHI
4. Cundell, T. 2015 The role of water activity in the microbial stability of non-sterile pharmaceutical products. Eur. Pharm. Rev. 20:58-63 
5. Cundell, T. 2020 Chapter 2 - Microbial Contamination Risk Assessment in Non-sterile Drug Product Manufacturing and Risk Mitigation in Pharmaceutical Microbiological Quality Assurance and Control – A Practical Guide for Non-Sterile Manufacturing. D. Roesti and M. Goverde (editors) J. Wiley & Sons 2020
6. Food and Drug Administration 2014 Water activity (aw ) in foods
7. https://www.fda.gov/inspections-compliance-enforcement-and-criminal investigations/inspection-technical-guides/water-activity-aw-foods
8. Hussong, D. 2009 Water activity and pharmaceutical manufacturing; a regulatory microbiology perspective. In Water Activity Applications in the Pharmaceutical Industry, Davis Healthcare International Publishing, LLC. River Grove, IL, USA, pp. 253-257
9. Leistner, L., 1994 Further developments in the utilization of hurdle technology for food preservation., J Food Eng., 22:421-432.
10. Rai, S. and N. Dubey 2023 Regulatory control over chewable gels and current challenges Ann. Phytomed. 12(1): 212-219
11. Scott, V.N., R.S. Clavero and J.A. Troller 2001 Measurement of Water Activity, Acidity and Brix pp649-657 Compendium of Methods for the Microbiological Examination of Food Downes, F. P and J. Ito (editors) American Public Health Association.

Author Details

Tony Cundell, PhD, Pharmaceutical Consulting, LLC- Rye, New York

Publication Details 

This article appeared in American Pharmaceutical Review:

 Vol. 27, No. 5

July/Aug 2024

Pages: 8-12

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