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Q: How can we include orally disintegrating tablets in our portfolio cost-effectively and also be FDA compliant?
 
 
imageWhether you're taking advantage of the ANDA regulatory pathway to adapt a conventional tablet or you're developing a new product, you'll face unique challenges in developing a commercially approved, orally disintegrating tablet (ODT).
 
For one thing, the requirements for an ODT's taste and texture differ from those of a traditional tablet, because ODTs disintegrate and dissolve in the mouth. This limits your choice of excipients. You need ingredients that can mask an active pharmaceutical ingredient's (API's) bitter taste while also reducing chalkiness or other unpleasant sensory experiences.
 
Those ingredients must also promote rapid solubility; to receive FDA approval, tablets must dissolve in under 30 seconds. Some developers focus their attention on that criteria to the exclusion of other important product attributes, resulting in tablets that are adequately soluble but very fragile, which can cause significant headaches down the line. If a patient or physician opens a bottle of your ODTs and finds them broken in pieces, it won't matter how good your formulation is.
 
You could solve such problems with complex manufacturing technology or specialized packaging, but you'll pay a price for that, quite literally. To better control your ODT's quality and integrity while lowering your costs and improving your regulatory outcome, you need a proactive approach that balances three key elements: your regulatory submission strategy, your formulation and tablet design, and your manufacturing and packaging process.
 
Regulatory submission strategy
Approved ODTs offer a variety of advantages. They're convenient for consumers who have difficulty swallowing, such as geriatric patients with diminished muscular strength or patients suffering from nausea or dysphasia. They're also ideal for young children who are prone to refusing or spitting out a conventional tablet. In a postpandemic world, ODTs' hygienic delivery mechanism is also attractive—no need to touch shared surfaces or hold a water glass to a patient's lips.
 
These advantages have led to increased demand for ODTs. To help drug manufacturers meet that demand while protecting the quality of new products and ensuring a good experience for those who rely on them, the FDA has established strict guidelines for ODT manufacturers [1]. This includes testing across a variety of product attributes, such as meeting protocol requirements and testing weight:
  • Disintegration protocol. Tablets must fully disintegrate in fewer than 30 seconds.
  • Functional score protocol. Tablets must meet an established standard for breakage along their score lines [2]. This means that the tablet's functional score for depth must be high enough for patients and physicians to break it easily, with or without a pill cutter, and that the cutting must reproducibly deliver equally weighted half-tablets.
  • Hardness and friability protocol. Tablets must be sufficiently robust to survive the packaging process and the bumping and shaking involved in transportation.
  • Weight. Whole tablets can't exceed 500 milligrams.
 
With a robust regulatory strategy, you'll be positioned to not only meet those criteria but also to adequately demonstrate how you met them. A rigorous quality-by-design (QbD) approach based on abundant, data-driven evidence can help your submission move through the regulatory process without costly delays and with a successful outcome [3].
 
Formulation and tablet design
To develop a product that satisfies the FDA's criteria and is durable enough to withstand the manufacturing and distribution process, formulators need to understand their materials extremely well.
 
So much comes down to choosing the right excipients, which impacts everything from your ODT's solubility, bioavailability, and stability to its taste and texture. Many binders, disintegrants, and other excipients used in typical tablet formulations aren't suitable for ODTs. Cellulose, for example, is popular in conventional tablet manufacturing, but formulators who use it to strengthen their fragile ODTs will soon discover that it prevents the tablets from dissolving fully and quickly.
 
Experienced formulators should also experiment with an ODT's physical design. Tweaking its shape—from oval to round, for example—can have a significant impact on its structural integrity during the manufacturing, packaging, and shipping process.
 
Manufacturing and packaging
When your ODT is ready to move from the lab into commercial manufacturing, you need to have the right technology in place, which can depend on your formulation's composition. If you've formulated and designed a sufficiently durable tablet, then your manufacturing process can more than likely proceed using the technology you already have in place.
 
For example, in some manufacturing centers, drug products must withstand high column pressure along the conveying system as well as a six- to twelve-inch drop into prepared bottles. A well-formulated ODT shouldn't break apart under such conditions. Also, testing bottled tablets on the road can ensure that they will survive the jolts and vibrations of cross-country transportation.
 
It takes time to arrive at a formulation and tablet design that works within an existing manufacturing environment, and it shouldn't require specialized protective packaging. More fragile formulations may require smaller sizes of bulk drums to reduce the column pressure, for example, or a unit-dose blister to prevent the product from collapsing in transit.
 
The bottom line
Developing a cost-effective ODT that meets the FDA's criteria and is durable enough to withstand manufacturing, bulk packaging, and transportation requires a strong formulation and process development strategy from day one. Pairing that strategy with a well-considered regulatory approach can help you lay the groundwork for a successful pipeline of commercial ODT products.
 
 

 
Deepak Thassu is vice-president of R&D and regulatory submission at LGM Pharma, Boca Raton, FL. The company is a US-based contract development and manufacturing organization (CDMO) and provider of APIs.
 
Do you have a question for our experts? Send your questions to pwright@cscpub.com, and we'll have an expert answer them.
 
 
June 28, 2021
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