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6 Considerations for Developing Modified Release Versions of Immediate Release Oral Solid Dosage Forms

By Richard Sidwell, Ph.D., Senior Vice President and Chief Scientific Officer, and Wayne Wiley, RPh, Vice President, Regulatory Affairs and Pharmacovigilance

Regulatory and CMC Strategy Key for Extended and Controlled Release Products

Developing a modified release (MR) formulation of an existing immediate release (IR) oral solid dosage creates product life cycle management opportunities. MR formulations can offer greater patient convenience and, therefore, improve adherence and marketability. They can also improve efficacy and reduce side effects by sustaining drug levels within the therapeutic range. Financial incentives may include exclusivity rights or patent benefits over the IR predecessors.

It’s important to realize, though, that MR dosage forms are a challenge, and careful thought must go into their development and planning to fulfill all regulatory expectations. Here are a few points to consider when reformulating from immediate to modified release:

  1. Be Sure Your Product Makes Sense

Before you commit to the project, think about what kind of improvements you could possibly make and which, if any, would be beneficial. Understanding the immediate release product’s pharmacology and pharmacokinetics in detail is the first step. What’s the therapeutic duration? What are the side effects? Will it make any difference to the patient if the blood levels are sustained? If the therapeutic duration is long, there may be no benefit in making a modified release version. However, if side effects are an issue, lowering the peak drug levels through a controlled release format might help. In an analgesic, for example, a rapid onset, controlled release format minimizing subtherapeutic troughs would be desirable. Armed with knowledge of how the drug works and what modifications are possible, you can make sure you’re embarking on an MR project that will truly benefit patients.

  1. Understand How Regulatory Planning, Clinical Development, and Formulation Strategy Are Interconnected

All strategic decisions will stem from the desired performance of the modified release dosage form and the basic understanding of the active pharmaceutical ingredient (API) and how it works. Knowledge of the benefit you intend to build into your new MR dosage form, the type of delivery system, the dosing strategy, and whether release should be sustained or pulsatile will drive your regulatory and clinical strategy. These, in turn, will drive the formulation and process development strategy.

The most common regulatory pathways are:

  • NDA 505(b)(1)
    • Pathway available to the reference NDA sponsor; this applicant has ownership and full reference to the entire original NDA
  • NDA 505(b)(2)
    • Predominant pathway for MR formulations; (b)(2) applicants have no ownership or right of reference to the listed drug

Fortunately, the (b)(2) applicant does have the benefit of the FDA’s prior knowledge and acceptance of the established pharmacology/toxicology safety and efficacy information provided in the original NDA. This FDA awareness ultimately results in time and cost savings for the (b)(2) applicant. A (b)(2) application entitles you to the same number of regulatory meetings as a (b)(1) application. Furthermore, successful (b)(2) applications typically earn at least three years of exclusivity post-approval, which are crucial for competing in the market.

  1. Gather Key Supporting Data Beyond the Usual Immediate Release Investigations

Data gathered — or not gathered — during API characterization and preformulation can make or break a team’s efforts and impact development and approval timelines. For example, as in immediate release formulations, particle size and polymorphism are important. However, in modified release formulations, pH solubility and stability profiles in buffers that mimic various segments of the gastrointestinal (GI) tract come into play. This is because MR formulations may be designed to release API as far down the GI tract as the colon. 

  1. Focus Extra Closely on Safety

Generally, a modified release dosage form contains more API than the safe dose for immediate release. Therefore, if all the drug is released at once, patient safety could be at risk. Patient safety could also be at risk if the drug is critical to the patient and fails to release. With IR delivery in or near the stomach and MR delivery taking place along a much greater extent of the GI tract, identical total doses may not be equally bioavailable, depending upon rates and timing of absorption. Similarly, as the MR dose transits the GI tract, metabolism may occur differently, resulting in more or different, possibly active metabolites, which could affect efficacy and proper dosage.

Safety considerations for MR versus IR include:

  • Unit dose carries more than a safe IR dose
    • Dose dumping
    • Failure to release
  • Possible change in exposure
    • Example: 1 x 500 mg MR may not be equivalent to 2 x 250 mg IR
  • Possible change in rate or extent of metabolism
  1. Plan Ahead to Meet Exacting FDA Expectations for CMC and Clinical Data

Modified release dosage forms are subject to specific regulatory expectations for Chemistry, Manufacturing, and Controls (CMC) and clinical data, distinct from the expectations for IR. FDA regulation 21 CFR 320.25 is a good place to start to understand the agency mindset for what you need to do and prove during development. For example, you need to show that the drug product meets the extended release claims; you must show that dose dumping is unlikely; and you must show consistent pharmacokinetic performance between individual dosage units. For these purposes, in vitro release testing may be beneficial.

  1. Talk to the FDA as Much as Possible

In our experience, whenever you have a chance to meet with the agency, do so. NDA 505(b) affords applicants three different meeting opportunities. Always take advantage of this. Because the agency has much broader exposure to all the therapies under development, meeting with them gives you an opportunity to learn of updates or additional information that you had not considered. These meetings can be beneficial to your overall program. The more involved they are, the better the chance the agency will support you when something unexpected happens. They may even help you find answers, solve difficult challenges in product development, and give you an opportunity to correct in order to help you make a useful product.

If you learn as much as possible about the original IR product and strategize with care, developing an MR dosage form can be a useful and lucrative project. For a much more comprehensive treatment of this subject, including a discussion of dissolution profiles plus illustrative examples and perspectives gleaned over 20+ years of commercial manufacturing, click the link to listen to and view the webinar below.