Reconciling sprinkle administration information in approved NDA labeling with sprinkle bioequivalence study recommendations in FDA product-specific guidances for generic drug development

INTRODUCTION

Due to their ease of administration and high acceptability by patients, most drug products are administered through the oral route as solid dosage forms, mainly in the form of tablets and capsules. It is estimated that 50% of the population, including children and the elderly, have problems swallowing tablets.^[1] In recent years, novel solid oral dosage forms, such as mini-tablets, chewable tablets, orally disintegrating tablets, orally disintegrating strips, orally disintegrating films, and sprinkle formulations, have been introduced to ease medication administration in patients with dysphagia.^[2-6] Sprinkle formulations allow sprinkling of multi-particulate beads, pellets, granules, and crushable tablets on soft foods (commonly applesauce) before oral administration.

For sprinkle instructions to be included in the reference listed drug (RLD) labeling, the new drug application (NDA) applicant needs to demonstrate the absence of impact of food vehicles on bioavailability (BA) through an in vivo fasting sprinkle bioequivalence (BE) study. If the labeling of a modified-release (MR) RLD product states that the product can be administered by sprinkling, Food and Drug Administration (FDA) also recommends that the abbreviated new drug application (ANDA) applicant conducts an in vivo sprinkle BE study.^[7,8] Sprinkle BE study is generally not recommended for an immediate-release (IR) solid oral dosage form since the formulation differences between IR generic and RLD products are not expected to impact administration with food vehicle.

During formulation development stage, NDA and ANDA applicants are recommended to perform in vitro and in vivo testing methods for selection and qualification of food, drug product, and food-drug mixture.^[7-9] Sprinkle administration of drug product with foods should not significantly alter its potency and stability. The use of inappropriate food vehicles may affect the BA and stability of drugs. For example, sprinkling acid-sensitive drugs on acidic foods (e.g., applesauce, apple juice, and orange juice) may cause drug degradation or premature drug release. On the other hand, MR products with specialized coating designed to dissolve rapidly in the intestine should not be sprinkled on alkaline foods.^[10,11]

Since 2007, FDA has implemented the product-specific guidance (PSG) program which reflects the regulatory agency’s current thinking on the type of studies and information to support the development and approval of a generic drug product therapeutically equivalent to RLD product^[12] [Figures 1 and 2]. The FDA recommends that ANDA applicants routinely access published PSGs when considering the appropriate BE study for a proposed drug product [Figure 3]. As of the third quarter (September) of 2022, FDA has published 2038 PSGs for individual products on its public webpage. For additional information on sprinkle administration of drug product, ANDA applicants should consult the “Dosing and Administration” section of the approved label of RLD.

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Figure 1:

Product-specific guidance development process.

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Figure 2:

Food and Drug Administration product-specific guidances webpage (Adapted from https://www.accessdata.fda.gov/scripts/cder/psg/index.cfm).

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Figure 3:

Illustration of steps for accessing individual product-specific guidances.

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FDALabel is a web-based application designed to allow users to perform customizable searches of thousands of “in use” labeling for human prescription drug, non-prescription drug (OTC), and biological products [Figure 4]. FDALabel database is updated weekly and contains the most recent labeling documents. Using FDALabel, one can perform: (1) full-text searches of the entire labeling or specific sections/ subsections of the labeling; (2) narrow searches by application type (e.g., NDA, ANDA), by route(s) of administration, and to retrieve only RLD labeling; and (3) locate RLD labeling for most ANDA original holders.

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Figure 4:

FDALabel database webpage (Adapted from https://nctrcrs.fda.gov/fdalabel/ui/search).

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The aim of this study was to investigate whether all MR NDAs approved for sprinkle administration have sprinkle BE study recommendations in their respective PSGs and to confirm that the food vehicle selected in the PSG is one of those mentioned in the approved RLD label.

MATERIALS AND METHODS

The external database, FDALabel (version 2.7), was used to search for current NDAs with sprinkle labeling.^[13] We conducted the search up to October 2022. To capture all variations of administration instructions, a labeling full-text search was conducted for the root words “sprinkle” and “mix,” using the Boolean operator $ (“$sprinkle OR $mix”). Labeling type was limited to human prescription drugs, and application type confined to NDAs. Query results were further filtered to include solid oral dosage forms (powders, granules, pellets, capsules, and tablets) with RLD labeling that mentions instructions for sprinkle administration on soft food or liquid. NDAs were excluded if they were non-solid oral dosage forms (e.g., intravenous solutions); required chewing, crushing, or dissolving in the vehicle; added to water only for nasogastric or enteral tube administration; labeling text specified “not to sprinkle or mix;” and discontinued products. Among NDAs with sprinkle administration labeling, only MR NDAs were included in the final evaluation since sprinkle BE study is exclusively recommended in PSGs of MR products. We, then, searched the FDA external PSG database for availability of respective PSGs containing in vivo sprinkle study recommendations for those MR products with approved NDA labeling for sprinkle administration. We used standardized data extraction sheets made by Microsoft Excel 2019 for data extraction. All the data generated and analyzed during the present study are publicly available.

RESULTS

FDALabel database search for human prescription NDAs containing iterations of the words “sprinkle” or “mix” returned 1114 results [Figure 5]. The list was further narrowed to 57 approved NDAs with sprinkle administration information in the label. Of the 57, 45 NDAs were MR (extended release [ER] and delayed release) [Table 1] and 12 NDAs were IR products [Table 2]. Out of the 45 MR NDAs, 42 had sprinkle BE study recommendations in their respective PSGs. The remaining 3 NDAs, including a recently approved drug (ranolazine [Aspruzyo Sprinkle]), may have their PSGs under development.

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Figure 5:

Flowchart of the search, selection, and inclusion of modified-release new drug applications approved for sprinkle administration.

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Among the 45 MR sprinkle formulation NDAs, 28 NDAs (62%) were ER capsules [Figure 6]. In PSG sprinkle BE study recommendations for MR sprinkle formulations, applesauce was the most used vehicle (89%), with a minority of study recommendations listing applesauce or yogurt (2%), or fruit juice (7%). One (2%) sprinkle BE study for carvedilol (Coreg CR) did not list a vehicle [Figure 7].

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Figure 6:

Types of solid oral dosage forms approved for sprinkle administration.

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Figure 7:

Commonly used soft foods and liquids for sprinkle administration.

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DISCUSSION

The “Dosage and Administration” section of approved RLD labeling includes directions for administering the drug using the recommended liquid or soft food vehicle. For sprinkle instructions to be included in “Dosage and Administration” section of RLD labeling, the NDA applicant needs to demonstrate the absence of impact of food vehicles on BA, typically through a fasting sprinkle BE study to compare the pharmacokinetics of the drug given as intact product to that of the dosage contents sprinkled on soft foods. If BA is comparable between the two ways of drug administration, the innovator may add instructions in the product label describing the drug product administration through sprinkling on the soft food used in the BE study. If a liquid or soft food is qualified as a vehicle(s) and recommended for the administration of a drug, the labeling should include: (1) recommended type(s) of soft food or liquid vehicle(s); and (2) recommended critical manipulations, such as emptying capsule contents or crushing a tablet for ease of administration. If the labeling of a MR RLD product states that the product can be administered sprinkled, FDA also recommends that an ANDA applicant conducts an in vivo sprinkle BE study.^[8]

A food vehicle is considered suitable for drug product administration when it has no appreciable effect on drug product stability or potency [Figure 8]. For instance, for drug products with an intact enteric protective coating suitable for an acidic environment with pH values 5 or below, the proposed vehicle should not have a pH value higher than 5, since exposing the coating to higher pH values will disrupt and remove the coating from the drug product. The types of food commonly used for sprinkle administration with their pH ranges are summarized in [Figure 8]. Applesauce, yogurt, fruit juice (apple juice, orange juice, etc.), pudding, jelly/jam, ice cream, syrup, mashed potato, puree, cheese, and baby food/infant formula/nutritional supplement have all been mentioned in MR products labeled for sprinkle administration.^[9] Sovaldi (Sofosbuvir) is the only drug that is indicated to be used with non-acidic soft foods (pudding, chocolate syrup, mashed potato, and ice cream), according to the applicant. Applesauce, yogurt, and fruit juice are commonly used foods for sprinkle administration.

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Figure 8:

Food vehicles used in sprinkle administration and approximate pH ranges (Adapted from Ref. No. 9).

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A generic applicant referencing the same RLD is recommended to conduct an in vivo fasting sprinkle BE study to demonstrate that their generic product is bioequivalent to RLD when sprinkled on one of the soft foods or liquids mentioned in RLD labeling, normally applesauce. For ANDAs, recommendations for in vivo BE studies involving administration with liquids or soft foods are communicated to applicants through the respective PSG.

The only limitation of our study is that we did not have information on the PSG development status for the three NDAs with no published PSGs since all the data utilized in the study were extracted from the public domain.

CONCLUSION

In this analysis, we found that almost all MR RLD products approved for sprinkle administration have recommendations for sprinkle BE study in their current PSGs. These findings suggest that prospective applicants who plan to develop MR generic products should (1) explore the FDA public web page for the availability of the product-specific BE recommendations for the proposed products and (2) understand the recommended study design and follow the recommended study procedure. Using the recommendations in the PSGs, applicants can submit more complete ANDAs that will clearly demonstrate that their generic product has no significant differences from the RLD product in all labeled routes of administration. The current PSGs should make ANDA assessments more efficient by providing more clarity to industry on study design and how to conduct in vivo BE studies including those involving sprinkle administration. FDA publishes new and revised PSGs describing the Agency’s current recommendations on demonstrating BE. For awareness of the agency’s current recommendations to demonstrate BE, applicants should monitor the regular release of new and revised PSGs in the Federal Register and on FDA Web site.