Continue to Read:Formulation Changes and Bridging During Formulation Development – Part 2

Prologue

Given the volume of new drugs being developed for launch as well as the effort being put into Life Cycle Management of drugs, “Formulation changes and Bridging studies during Formulation Development” is a key topic in demand and hence, I am choosing to write a two series article on this topic.

The first article provides an outline of formulations change during development, details of the kind of Formulation changes from Phase 1 clinical study to commercialization of drug, Formulation changes Post-Approval and Commercialization, types of Bridging Studies, their purpose, different types of bridging studies, considerations for bridging studies, study design and analysis of bridging studies,

The second article in the series would focus on the real-life examples of bridging studies due to formulation changes from Phase 1 clinical study to commercialization of drug and real-life examples of bridging studies due to Reformulation (formulation changes) post commercialization of drug.

Formulation Changes

Formulation changes are a critical and often inevitable part of drug development. They are made to optimize the drug product's safety, efficacy, stability, manufacturability, patient compliance, or regulatory needs. Changes could made to the drug's composition, manufacturing process, or both.

1. Optimization of Drug Efficacy and Stability

Bioavailability: Initial formulations might be adjusted to improve the drug's absorption and bioavailability (the degree to which the drug reaches circulation and its target in the body). Changes like adjusting particle size or using different excipients (inactive ingredients) can make a significant difference.

Stability: A stable formulation is crucial to ensure the drug remains effective over time. Adjustments might be needed if the drug degrades under certain conditions (e.g., temperature, light, moisture) or if interactions occur between the drug and excipients.

2. Enhancing Safety and Reducing Side Effects

Tolerability: If early testing reveals side effects, changes may be made to modify release rates, reduce peaks in drug levels, or alter absorption.

Inactive Ingredients: Sometimes certain excipients may cause allergic reactions or other adverse effects, leading to the substitution or removal of specific ingredients to enhance tolerability and safety.

3. Improving Patient Compliance and Convenience

Dosing and Administration: Formulation modifications are often made to simplify the dosing regimen or create easier methods of administration (e.g., shifting from injections to oral tablets or patches), making it more convenient and improving adherence.

Taste and Palatability: For oral or liquid formulations, especially those intended for children, taste can be a factor that requires changes. Flavoring agents or coatings may be added to improve the experience for patients.

4. Regulatory and Manufacturing Considerations

Scale-Up Feasibility: Formulations in early stages may work well in small lab-scale batches but not on an industrial scale. Adjustments are often needed to ensure the formulation can be consistently manufactured with quality control.

Regulatory Compliance: Regulatory agencies may set specific guidelines on ingredient types and levels, and formulations may need to be altered to meet these standards for safety, quality, and efficacy.

5. Intellectual Property and Market Differentiation

Patent Strategy: Changes to formulation can allow companies to extend patent protection or differentiate a drug in the market (e.g., creating an extended-release version).

Competitive Advantage: As new technology emerges, such as nano-formulations or delivery systems, companies may alter their formulations to leverage these advancements, making the drug more competitive.

6. Adaptation Based on Clinical Trial Data

Phase-Driven Changes: Clinical trials (Phases I–III) often reveal new information on how the body processes the drug. Adjustments to formulations are frequently made to reflect these findings, improve outcomes, and prepare for regulatory submission.

Each of these six factors contributes to the refinement of a drug’s formulation as it moves from initial research to becoming a safe, effective, and marketable therapy.

Types of Changes:

Quantitative Changes: Adjustments in the amount of an ingredient without altering its identity (e.g., changing the amount of an excipient).

Qualitative Changes: Introducing a new ingredient or removing an existing one, which may alter the overall drug pro?le.

Manufacturing Process Changes: Modi?cations in the process, like a switch from wet to dry granulation.

Each change requires careful impact assessment to understand its e?ect on critical quality attributes (CQAs), bioavailability, stability, and the release pro?le.

Formulation changes from Phase 1 clinical study to commercialization and post commercialization of drug

Formulation changes from Phase 1 clinical studies through to commercialization are common, as each phase of development provides new data that informs adjustments to optimize the drug's performance, safety, stability, and manufacturability.

Let us examine why and how formulations change throughout the clinical development phases:

Phase 1: Focus on Initial Safety and Tolerability

In Phase 1, the primary goal is to evaluate the safety, tolerability, and pharmacokinetics of the drug in a small group of healthy volunteers or patients. Formulation considerations in this phase include:

• Simplified Formulation: Often times, the formulations are basic, sometimes in powder or solution form, to allow rapid adjustment of doses as the pharmacokinetics are studied.

• Flexible Dosing Forms: Early-stage formulations are designed to allow quick adjustments based on findings of how the body absorbs, distributes, metabolizes, and excretes the drug.

• Short-Term Stability: Since the formulation is not yet final, stability requirements are focused on short-term conditions, and long-term stability is not yet a primary concern.

As the drug moves to Phase 2 of the clinical trials, there could be potential changes to the formulation. The data gathered on drug absorption, distribution, and early safety may indicate the need for formulation changes to optimize bioavailability or modify release profiles. Excipients might be added or modified to reduce side effects or improve tolerability.

Phase 2: Focus on Efficacy and Dose Optimization

In Phase 2, the formulation is refined to achieve an effective dose while monitoring safety in a larger group. This phase seeks to establish optimal dosing regimens.

• Dose Refinement: Dosing frequency and concentration might be adjusted to improve efficacy or reduce side effects. If the drug has a narrow therapeutic window, an extended-release form or controlled-release mechanism may be explored.

• Stability Improvements: More robust stability data is gathered, as the formulation needs to be viable for the longer trial periods and in conditions closer to what it might face in the market.

• Patient-Centric Modifications: Formulations are considered with the end user in mind (e.g., oral tablets instead of IV infusions if appropriate), as convenience can improve adherence and outcomes in trials.

As the drug moves to Phase 3 clinical trials, again, there could be changes made to formulations. Additional excipients or coating might be added to improve taste, decrease irritation, or ensure that the drug releases appropriately in the gastrointestinal tract. Changes to support consistent manufacturing at larger scales may also begin to take shape.

Phase 3: Focus Large-Scale Efficacy and Safety Testing

Phase 3 typically involves a larger, more diverse population and is designed to demonstrate efficacy and safety on a broader scale.

• Finalization of Dosage Form: The drug product’s formulation is finalized, typically as the form intended for commercial distribution. Minor adjustments are still possible, but the goal is to lock in a formulation that balances efficacy, safety, and patient adherence.

• Manufacturability Testing: The formulation is refined to ensure it can be consistently manufactured at large scales, maintaining quality, purity, and potency. Formulations may need to be adjusted for mass production to comply with Good Manufacturing Practice (GMP) standards.

• Long-Term Stability: Stability studies for long-term shelf life are conducted, often leading to packaging and preservation adjustments to maintain the drug’s effectiveness.

At this stage as the drug moves to commercialization stage, there could still be changes made to the formulation. The final drug product dosage form may be slightly modified based on regulatory  feedback or to optimize stability, quality, and packaging for distribution and long-term storage. Taste, ease of administration, or formulation changes to differentiate from competitors can also be considered.

Post-Approval and Commercialization

Once a drug reaches commercialization, changes may still occur based on feedback or market demand:

• Post-Approval Formulation Adjustments: Sometimes, after launch, companies may develop alternative forms, such as extended-release or paediatric-friendly formulations, to better meet patient needs or extend the drug’s lifecycle.

• Regulatory-Driven Changes: Occasionally, regulators may request formulation updates to improve safety, reduce impurities, or enhance manufacturing reliability.

• Market Adaptations: A drug might be reformulated for different markets (e.g., liquid versus tablet) or adapted to new delivery technologies as they become available.

These phased formulation changes are critical to optimizing the drug’s therapeutic effects while ensuring that it can be manufactured at scale, it meets the needs of regulators and patients alike as well as to meet market challengers in terms of competitors and life cycle management of the drug.

Bridging studies during formulation development

Bridging studies play a critical role in the pharmaceutical development process, especially during the transition from Phase 1 to commercialization. This transition often involves adjustments in formulation, manufacturing processes, or other parameters, which may affect the drug's bioavailability, efficacy, or safety profile. Bridging studies help ensure that these changes do not impact the drug's performance, enabling a smooth progression to later phases of clinical testing and ultimately to market.

Let us now review the purpose of these bridging studies, the different type of bridging studies, the considerations involved in these studies and finally the design and analysis of these bridging studies

Purpose of Bridging Studies

Bridging studies are designed to:

• Confirm Bioequivalence: When formulation changes occur, bridging studies confirm that the modified formulation has a similar pharmacokinetic (PK) profile to the original, ensuring consistent therapeutic efficacy.

• Evaluate Safety and Tolerability: Safety data from Phase 1 trials may not fully account for all populations or long-term use, so bridging studies can provide more comprehensive safety data in relevant populations.

• Reduce Development Time and Costs: By validating formulation changes early, bridging studies allow developers to avoid delays that could arise from unexpected efficacy or safety issues later in the process.

Types of Bridging Studies in Formulation Development

Common types of bridging studies include:

• Pharmacokinetic (PK) Studies: These are used to demonstrate bioequivalence between the new and original formulations by comparing metrics like the area under the curve (AUC), peak plasma concentration (Cmax), and time to peak concentration (Tmax).

• Comparative Dissolution Studies: Used to assess differences in dissolution profiles between the initial and new formulations, particularly for oral dosage forms. Similarity in dissolution profiles often suggests comparable bioavailability.

• Clinical Bridging Studies: If substantial changes are made to the formulation, additional clinical trials may be needed to confirm that the clinical outcomes remain consistent.

Key Considerations in Bridging Studies

Bridging studies require strategic planning, taking into account several key considerations:

• Scale-Up and Process Changes: Moving from small-scale production in Phase 1 to larger scales for commercialization often requires process adjustments, which could impact formulation stability and performance.

• Regulatory Requirements: Regulatory agencies often have specific criteria for bridging studies to ensure that new formulations meet quality, safety, and efficacy standards.

• Population and Disease Considerations: Formulation changes may have different effects in specific populations, so bridging studies often incorporate data from diverse demographic groups to address variations in drug metabolism.

• Analytical Methods: Ensuring that analytical methods are sensitive and specific enough to detect any differences between formulations is essential for accurate assessment.

Bridging Study Design and Analysis

Study designs vary depending on the formulation changes and target patient populations, with common designs including:

• Crossover Designs: Participants receive both formulations in different periods, allowing a direct comparison within the same individuals.

• Parallel Designs: Different groups receive either the original or new formulation, useful when the drug has a long half-life or carryover effects.

• Modelling and Simulation: Pharmacokinetic and pharmacodynamic models are increasingly used to predict the impact of formulation changes and optimize study designs, reducing the need for extensive clinical trials.

Bridging studies enable pharmaceutical companies to streamline the path to commercialization while ensuring quality, efficacy, and safety. By carefully planning and conducting these studies, companies can address potential formulation issues early and facilitate regulatory approval, minimizing risks as they move through the phases of development.

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.