Formulation Changes and Bridging During Formulation Development – Part 2

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ABSTRACT: The second article in the series focuses on real life examples of bridging studies due to formulation changes from Phase 1 clinical study to commercialization of drug and finally real-life examples of bridging studies due to reformulation (formulation changes) post commercialization of drug

Real life examples of Bridging studies due to formulation changes from Phase 1 clinical study to commercialization of drug

The six real-life examples below illustrate the use of bridging studies due to formulation changes during drug development. These cases illustrate how the companies navigated formulation changes and conducted bridging studies to demonstrate equivalence between early-phase and final commercial formulations.

1. Abilify Maintena® (Aripiprazole)

Drug Background: Abilify Maintena® is a long-acting injectable form of aripiprazole, used for schizophrenia and bipolar disorder.

Formulation Change: The transition from oral tablets to a long-acting injectable formulation required substantial changes to the drug’s formulation to enable a controlled, steady release over an extended period.

Bridging Studies: Bridging studies were conducted to confirm that the extended-release injectable form produced plasma concentrations comparable to the daily oral doses in terms of safety, efficacy, and therapeutic outcome. Pharmacokinetic and pharmacodynamic studies confirmed bioequivalence, and clinical bridging studies ensured the new formulation met therapeutic goals over time.

Result: The bridging studies successfully demonstrated therapeutic equivalence, allowing the injectable form to reach the market as a suitable long-term alternative to the daily oral regimen.

2. Nexium® (Esomeprazole Magnesium)

Drug Background: Nexium® is a proton pump inhibitor used for acid-related disorders. Initially developed as a delayed-release capsule, formulation changes were introduced to improve patient convenience and adapt to various patient needs.

Formulation Change: To accommodate different patient populations (e.g., those who cannot swallow capsules), new formulations such as oral suspension and tablets were developed. The tablet formulation required a change in excipients and coating materials.

Bridging Studies: Pharmacokinetic studies were conducted to confirm that the new tablet and oral suspension formulations were bioequivalent to the original delayed-release capsules. Dissolution studies also ensured the delayed-release characteristics were consistent across formulations.

Result: The bridging studies confirmed bioequivalence, allowing the new formulations to be marketed alongside the original. This increased accessibility for patients requiring alternative forms.

3. Concerta® (Methylphenidate)

Drug Background: Concerta® is an extended-release form of methylphenidate used to treat ADHD. The drug uses an osmotic-release oral system (OROS) to provide a controlled release of methylphenidate throughout the day.

Formulation Change: In developing the final OROS form for commercialization, adjustments were made to optimize the drug release profile, improve manufacturing consistency, and scale up production.

Bridging Studies: Pharmacokinetic studies were essential to confirm that the final commercial OROS formulation provided similar release rates and therapeutic plasma concentrations as seen in earlier formulations. These studies compared parameters like Cmax and AUC to ensure consistent efficacy and safety.

Result: The bridging studies validated that the final OROS formulation would offer the intended controlled-release profile, enabling a once-daily dosing regimen that improved adherence and efficacy for ADHD patients.

4. Zydelig® (Idelalisib)

Drug Background: Zydelig® is an oral medication used for certain types of leukemia and lymphoma. It was initially tested in Phase 1 clinical trials using a powder-in-capsule formulation.

Formulation Change: To improve manufacturability and patient adherence, a tablet form was developed for commercialization. Tablets offer better stability, ease of use, and are more suitable for mass production.

Bridging Studies: Bridging studies, including pharmacokinetic testing, compared the bioavailability of the capsule and tablet forms. Additional in vitro studies confirmed that the dissolution profiles were similar, supporting that the tablet form would have the same therapeutic effect.

Result: Bridging studies successfully demonstrated bioequivalence between the capsule and tablet forms, allowing the tablet formulation to be commercialized.

5. Tecfidera® (Dimethyl Fumarate)

Drug Background: Tecfidera® is an oral therapy for multiple sclerosis (MS). Early-phase studies used a formulation that required improvements to stability and bioavailability.

Formulation Change: After early clinical trials, Tecfidera® was reformulated to an enteric-coated, delayed-release capsule to improve gastrointestinal tolerability and protect the active ingredient until it reached the small intestine.

Bridging Studies: Bridging pharmacokinetic studies were conducted to ensure the new formulation achieved bioequivalent systemic exposure compared to the original formulation. Additionally, clinical studies verified the improved tolerability in patients.

Result: The new formulation with an enteric coating proved both bioequivalent and more tolerable, leading to successful regulatory approval and market launch.

6. Gleevec® (Imatinib)

Drug Background: Gleevec® is used to treat chronic myeloid leukemia and other cancers. During development, initial studies were conducted with a simple oral solution formulation.

Formulation Change: For patient convenience and manufacturing scalability, the final commercial product was developed as a tablet.

Bridging Studies: Pharmacokinetic studies were performed to compare the solution and tablet formulations, assessing parameters like Cmax, AUC, and Tmax to confirm bioequivalence.

Result: Bridging studies successfully demonstrated that the tablet form had comparable pharmacokinetics to the solution, allowing the tablet form to be marketed as the primary option for patients.

Learnings from real life examples of Bridging studies due to formulation changes from Phase 1 clinical study to commercialization of drug

These examples demonstrate how bridging studies are essential when moving from early-phase formulations to final commercial products. The studies confirm that changes in formulation do not compromise the drug's therapeutic benefits, ensuring that patients receive a consistent, safe, and effective product, while also facilitating regulatory approval.

Real life examples in Reformulation (Formulation Change) and Bridging post commercialization

Real-life examples of formulation changes and bridging studies post commercialization for life cycle management are abundant in the pharmaceutical industry. These case studies showcase how companies navigate formulation modifications while maintaining product quality, efficacy, and regulatory compliance.

1.Reformulation of Humira® (Adalimumab) – AbbVie

Background:Humira is one of the best-selling biologics, used to treat autoimmune diseases like rheumatoid arthritis, Crohn’s disease, and psoriasis. Humira was initially formulated as a subcutaneous injectable solution, and its patent expiration led to an opportunity for both reformulation and the introduction of biosimilars.

Formulation Change:AbbVie sought to reformulate Humira as a low-volume, high-concentration injection to reduce injection site pain and improve patient compliance. The new formulation was designed to inject fewer milliliters, delivering the same dose of the drug.

Bridging Studies:

• Stability Studies: Extensive stability testing was carried out to ensure the new formulation would remain stable over time, given that the concentration of the active ingredient was higher.

• PK and Pharmacodynamics (PD): Bioequivalence and pharmacodynamics studies were conducted to ensure the reformulation would not alter the therapeutic effect or patient response. These studies measured the PK profile of the original formulation versus the new high-concentration version.

• Clinical Trials: Clinical bridging trials were needed to show that the high-concentration version had similar safety and efficacy profiles as the original formulation. The clinical trials were designed to assess both immunogenicity and long-term safety, crucial for biologics.

Result:AbbVie received approval for the new high-concentration formulation of Humira in multiple regions. This reformulation offered patients a more convenient and less painful administration method, thereby improving patient adherence and satisfaction. The company also used this formulation as a bridge to transition to their next-generation anti-TNF therapy, Rinvoq (Upadacitinib).

2. Reformulation of Seroquel® (Quetiapine) – AstraZeneca

Background:Seroquel (quetiapine) is an atypical antipsychotic used to treat schizophrenia, bipolar disorder, and other psychiatric conditions. After the patent for Seroquel expired, generic versions entered the market. AstraZeneca sought to reformulate Seroquel to extend its market life and differentiate it from generics.

Formulation Change:The reformulation involved developing a Seroquel XR (extended-release) version to improve patient compliance by reducing dosing frequency from twice a day to once a day.

Bridging Studies:

• In Vitro and In Vivo Studies: Extensive in vitro dissolution testing was performed to compare the release profile of the original immediate-release (IR) tablet and the new extended-release (XR) formulation. Pharmacokinetic studies were conducted to evaluate how the drug’s absorption would differ between the two formulations.

• Bioequivalence Trials: Clinical trials were conducted to ensure that the XR formulation delivered the same overall drug exposure (AUC) as the original IR formulation, but over a longer period. This was crucial to demonstrate that the extended-release version would not compromise the drug’s therapeutic effect.

• Clinical Efficacy: A clinical trial was performed to demonstrate that the XR formulation was as effective and safe as the IR formulation. This included assessing both the efficacy in managing symptoms and the side-effect profile.

Result:The Seroquel XR formulation was approved by regulatory agencies and helped AstraZeneca maintain market share in a post-patent environment, offering patients a more convenient dosing regimen and improving medication adherence.

3.Reformulation of Lipitor® (Atorvastatin) – Pfizer

Background:Atorvastatin, marketed as Lipitor, is a blockbuster cholesterol-lowering medication that was originally formulated as an oral tablet. After the patent expired, the pharmaceutical industry and regulators focused on providing an alternative formulation that could compete with generic versions while still offering distinct patient benefits.

Formulation Change:Pfizer introduced a new formulation of Lipitor as a dispersible tablet for patients who had difficulty swallowing pills, particularly the elderly. The reformulation aimed to provide a more user-friendly option while maintaining the same efficacy and bioavailability as the original tablet.

Bridging Studies:

• In Vitro Studies: To ensure that the bioavailability of the new dispersible formulation was consistent with the original tablet, extensive dissolution studies were performed to compare the     two formulations.

• Bioequivalence Trials: Clinical studies were conducted to demonstrate bioequivalence between the original tablet and the new dispersible tablet. The pharmacokinetic (PK) profiles of both formulations were compared in healthy volunteers to ensure similar absorption and efficacy.

• Regulatory Approval: Bridging data from the clinical trials and in vitro testing supported the approval of the new formulation. The reformulation was approved by the FDA and other international regulatory bodies without additional extensive clinical trials, as the new formulation demonstrated bioequivalence to the original.

Result:The dispersible formulation of Lipitor was approved and successfully marketed. It helped maintain the product's competitive edge even after generic versions entered the market, offering a more patient-friendly version of the drug.

4.Reformulation of Dulcolax® (Bisacodyl) – Boehringer Ingelheim

Background:Dulcolax, a widely used over-the-counter (OTC) laxative, was originally formulated as oral tablets and suppositories. The company sought to expand its market by introducing a new formulation that could provide faster relief, targeting consumers looking for quicker solutions for constipation.

Formulation Change:The reformulation introduced Dulcolax® Liquid (oral solution), designed to work faster than the traditional tablet form. The formulation change required new excipients and a different delivery mechanism to achieve faster onset of action.

Bridging Studies:

• Dissolution and Release Testing: Since the liquid form had a faster onset of action, dissolution testing was used to compare the rate of release between the oral liquid and the tablet form.

• Pharmacokinetic Comparison: Studies were conducted to measure how the two formulations were absorbed in the body. The PK profiles were evaluated to demonstrate that the liquid formulation would have a similar or improved bioavailability compared to the tablet, which is crucial for regulatory approval.

• Clinical Studies: A clinical bridging study was conducted with healthy volunteers to compare the time to effect between the oral liquid and tablet forms. The study found that the liquid form provided faster relief while maintaining safety and efficacy.

Result:The new liquid formulation was successfully launched in markets where it became a preferred option for those seeking quicker relief. It contributed to expanding the product's reach by offering a more immediate option to consumers.

5. Reformulation of Prozac® (Fluoxetine) – Eli Lilly

Background:Fluoxetine, sold under the brand name Prozac, was a widely used antidepressant. Following patent expiration, generic versions of fluoxetine were introduced to the market, prompting Eli Lilly to explore ways to differentiate the product.

Formulation Change:Eli Lilly introduced Prozac Weekly, a once-weekly formulation of fluoxetine, as a way to improve patient adherence to treatment.

Bridging Studies:

• Dissolution and Release Testing: To ensure the once-weekly formulation provided consistent drug release over a longer duration, dissolution studies were carried out to compare the new formulation with the original daily tablet form.

• Bioequivalence Studies: Clinical studies were conducted to demonstrate that the once-weekly formulation was bioequivalent to the daily version in terms of overall drug exposure and therapeutic effect.

• Clinical Trials: A clinical bridging study in depressed patients confirmed that the weekly dose of Prozac was as effective as the daily dosage, with comparable safety profiles.

Result:Prozac Weekly was successfully marketed as a more convenient alternative to the original daily dosage form. This reformulation provided a competitive edge over generic versions of daily fluoxetine, helping to retain market share.

Learnings from real-Life cases on reformulation (Formulation Change) and Bridging post commercialization:

1. Formulation Changes Must Ensure Bioequivalence: Reformulations that change the dosage form (e.g., tablet to liquid, immediate-release to extended-release) require rigorous testing to demonstrate that the new product is bioequivalent to the original.

2.Bridging Studies are Critical: For any formulation change, bridging studies are essential to demonstrate that the modified product retains the same safety, efficacy, and pharmacokinetic properties as the original.

3.Patient-Centered Innovation: Many formulation changes are aimed at improving patient compliance, such as reducing dosing frequency or making the product easier to administer (e.g., oral liquids, dispersible tablets, and less painful injections).

4.Regulatory Challenges: Companies must navigate regulatory pathways to ensure that their reformulations meet the necessary approval standards. For biologics, additional studies may be needed to assess immunogenicity, while for generics, bioequivalence is a primary concern.

Conclusion

Changes in formulation do not compromise the drug's therapeutic benefits, ensuring that patients receive a consistent, safe, and effective product, while also facilitating regulatory approval. Bridging studies are essential when moving from early-phase formulations to final commercial products. The real-life examples highlight the importance of thoughtful formulation changes and rigorous bridging studies in ensuring continued market success and patient benefit, particularly when dealing with product lifecycle management and post-patent strategies.

About the author

Deepak Hegde

Ph.D., M.F.M, is an industrial pharmacist by training. He has a been involved in development and commercialization of both innovative and generic drugs from a very early phase of development to technical transfers for commercial manufacturing sites, for the past 27 years. During his career, he has worked at Rhone Poulenc, Novartis (Sandoz), USV Ltd., WuXi AppTec, GSK & EOC Pharma. and Shenzhen Pharmacin Co. Ltd. He is currently working with as Cipla (Jiangsu) Pharmaceutical Company Ltd as General Manager & China Site Head.