white paper

505(b)(2) Regulatory Pathway

In this White Paper Follows along with the sponsor through the 505(b)(2) pathway process. This pathway will help avoid unnecessary duplication of studies already performed on the previously listed drug. This pathway gives the sponsor and FDA express permission to rely on data not developed by the New Drug Application (NDA) applicant (Camargo Pharmaceutical Services, 2017). This allows for a faster, less expensive route of approval.

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Regulatory Compliance Associates® Inc. (RCA) provides worldwide services to the pharmaceutical, biologic, sterile compounding, biotechnology, and medical device industries for resolution of compliance and regulatory challenges.

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505(b)(2) Regulatory Pathway

The industry’s recent innovations in oral drug delivery have given rise to increased controlled release dosage forms. As a sponsor, the 505(b)(2) pathway (“505b2”) can help avoid unnecessary duplication of 505b2 requirements or studies already performed. This 505b2 pathway gives the sponsor and FDA express permission to rely on data not developed by the New Drug Application (NDA) applicant. This allows for a faster, less expensive route of FDA approved drugs.

Candidate Identification

For example, let’s examine a sponsor who has conducted thorough research into a FDA approved drug. If they identify a potential novel extended-release oral dosage form, they can resubmit under the 505b2 pathway. The sponsor must identify the new Active Pharmaceutical Ingredient (API) formulation associated with the immediate-release drug for FDA approval.

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FDA Orange Book

The Orange Book will provide safety and efficacy data for which the immediate-release drug was approved. The sponsor should use this information to determine the next steps of the 505b2 pathway and create an underlying basis of additional clinical data. This new criteria is needed to ensure the drug candidate’s product quality and performance characteristics are therapeutically equivalent.

Novel Drugs

The 505b2 NDA will require full safety and effectiveness reports for your novel drug candidate. However, some of the drug safety and efficacy information required for NDA approval can come from studies not conducted by the applicant. The sponsor must only create a bridge between known clinical data in the FDA approved immediate-release tablet, and the novel extended-release tablet.

NDA Submission

For any sponsor, there comes a long list of risks associated with developing a novel drug. The success of the NDA preparation and submission depends on the entire drug development process. Drug development depends heavily on up-front planning, research, and meeting FDA expectations throughout the phases of drug development.

Pharmaceutical Research

If a sponsor wishes to seek approval for a new dosage, they must complete the necessary FDA accelerated approval research. This includes clinical trials with completed research into the immediate-release API formulation. Finally, all clinical research would include safety and efficacy data available to prepare for the Pre-Investigational New Drug (IND) meeting with the FDA.

CMC Manufacturing

The sponsor uses pharma market research based on requirements needed to prove safety and efficacy throughout the 505b2 pathway. Additionally, the sponsor will have researched methods involving Chemistry, Manufacturing and Controls (CMC) needed to manufacture the pill capsules. It is important to note some of these steps can be started simultaneously and developed in parallel.

Candidate Assessment

Once clinical research has been compiled, the sponsor can assess the drug efficacy of the extended-release tablet. Additionally, the sponsor will consider the following to build clinical evidence of the commercial value:

  • Scientific Viability: Is the formulation stable and readily prepared? Is the manufacturing scalable? Are active and inactive ingredients available and affordable?
  • Medical Viability: Does the product have a clear niche in the medical specialty? Is there clinical evidence the product would be appealing to the patient?
  • Regulatory Viability: What regulatory data will be required to gain approval? What distinguishing clinical outcomes can be presented for labeling and promotion?
  • Commercial Viability: Is there a viable market for the product? What is the optimal drug pricing?

During this product planning stage, all data available and FDA’s previous findings should be used to establish value. Additionally, a product roadmap is helpful in determining the team alignment around future product development strategy. 


The 505(b)(2) pathway begins with the pre-IND meeting with the FDA. The goal of the pre-IND meeting for a 505b2 product development strategy is to gain FDA input. Moreover, the sponsor team should leave the FDA meeting with alignment on the following:

  • Nonclinical studies
  • CMS manufacturing
  • Control plan
  • Control strategy

The objective is to agree on a research plan that minimizes the number of new studies required.

Therapeutic Equivalence

The Pre-IND meeting with the FDA will provide insight into additional data needed to successfully prove therapeutic equivalence. When managed successfully, this step in the process can accelerate the drug approval timeline. Further, approval will be granted if previous research is presented to prove the extended-release drug product safety and efficacy. Moreover, the sponsor will need to study bioavailability and bioequivalence in the extended-release drug product.

Formulation Development

The chemistry, manufacturing and controls strategy is paramount in a 505b2 submission because the formulation and the active pharmaceutical ingredient may be altered compared with the reference product, and the effect of these changes must be evaluated to assess any effects on the safety and efficacy.

CMC Strategy

As a result, a good deal of the CMC work must be invested prior to initiating Phase I studies. The change of formulation will result in new methods, technology, analytics, dosage form,s and procedures. Previously conducted research into test methods and metabolic studies will help determine the formulation. Subsequently, the systems need to prove the extended-release product meets safety and effectiveness requirements will be considered.

Matrix Systems

Matrix systems are very popular for extended-release formulations. These systems will also provide the sponsor with the detailed CMC methods needed to support the quality of the proposed drug product for marketing.

The current USP monograph for the extended release version lists five different test methods that may be used to measure drug release from a developmental formulation to match the USP specification.

Hydrophilic matrices have been extensively reviewed in literature. The current USP monograph for the extended release version lists five different test methods that may be used to measure drug release from a developmental formulation to match the USP specification.

Tablet Testing

A tablet test differs in media composition and pH, dissolution apparatus and presence of sinkers. Additionally, the number of different media to which the delivery device is exposed is considered. USP specification ER formulation based on a hypromellose (HPMC) is widely used in an extended release matrix system.


During tablet preparation, a hydrophilic matrix formulation is used and lactose, and other excipients are blended with the API. The tablets are tested for hardness, weight uniformity and friability. Drug release is measured according to the USP methods 1,2 and 3 using an automated dissolution bath.

Extended Release

The percent of drug release is measured depending on the dosage desired by the sponsor. Additionally, different USP delivery technologies can be used utilized to set a method criterion. In addition, expected bioavailability characteristics for an extended-release product use the concept of in vitro/in vivo correlation (IVIVC). It is recommended the bioequivalence studies are performed during development with dissolution profiles at the upper and lower dissolution specifications.


In some cases the information established through these studies can permit certain formulation and manufacturing changes without an in vivo bioequivalence study. After developing, testing and manufacture of the drug, the sponsor will need to provide specific CMC information to comply with regulations:

  • “21 CFR 314.50(d)(1) – the application is required to contain a full description of the chemistry, manufacturing, and controls information. Drug substance: physical and chemical characteristics, manufacturer, method of synthesis and purification, process controls, specifications, and stability.”
  • “21 CFR 314.54 – procedures for submission of an application requiring investigations for approval of a new indication for, or other change form, a listed drug – refers to information required under 314.50 that must be submitted for 505b2 applications”.

It is important to compare the new proposed formulation with the reference drug via bridging studies. For example, explain the rationale for the change and establish the new drug product is safe. By the same token, potency forms some the basis for pharmaceutical development of a 505(b)(2) NDA.

Quality Control

However, complete CMC information must be submitted for the drug substance(s) and the drug product to support the quality of the extended-release product. In some cases the dissolution test can not only serve as a quality control for the manufacturing process but also as an indicator of how the formulation will perform.

Manufacturing Process

The clinical trial materials for Phase I studies (often demonstrations of clinical bio-equivalence) must be representative of the commercial manufacturing process. To clarify, establishing the drug is safe, pure and potent will drive the basis for the pharmaceutical development section of the 505(b)(2). Further, it will also mark a very large achievement as the sponsor has completed 1-3 years of discovery.


Because the extended-release candidate has known safety profiles and previous demonstrations of efficacy, nonclinical studies and safety and efficacy tests may not be necessary to achieve 505(b)(2) approval. (Camargo Pharmaceutical Services, 2017)

Phase I

In some cases, the 505(b)(2) pathway enables the Phase I process to be reduced to a single study. Known as Phase I bridging study, is used to compare the human pharmacokinetic profiled of the extended-release tablet with that of the reference immediate-release tablet. Undoubtedly, the extended-release tablet will reference the established safety information to the immediate-release tablet.

Dissolution Test

In the meantime, the sponsor should consider a dissolution method to prove bioavailability and efficacy over a course of time. Because the immediate-release tablet dosage form will have peaks and troughs of API, the sponsor must carefully equate previous clinical trials. Equally important, active concentration requirements must be met in the blood steam for a longer period of time.


According to the Guidance for Industry, human data should be supplied for regulatory review of an IVIVC. In similar fashion, Bioavailability studies for IVIVC should be performed to characterize the performance of the extended-release tablet.


One approach is generally based on the performance of the bioavailability lots, a minimum of three time points is recommended to reach specifications. Afterwards, the extended-release product will be compared with the referenced product using pharmacokinetic analysis. This end of this phase will account for 1-2 years of non-clinical research.

Phase II & Phase III

505b2 development programs require no Phase II of Phase II studies. As a result, dosage form and formulation changes may rely on Phase I pharmacokinetic studies alone. For instance, data previously accepted by the FDA as part of a marketing application or clinical trial may be accepted.

NDA Submission & Overall Recommendation

To enhance the quality, organization and completeness of an NDA submission, it is vital the sponsor is aware of all relevant FDA and ICH guidelines. The final 505b2 NDA submission will contain full reports of investigations of safety and effectiveness. Consequently, at least some of the information required for approval comes from studies not conducted by the sponsor.

Furthermore, the 505b2 process is relatively quick and can reach FDA approval in as little as 30 months. Lastly, emphasis must be put focused on achievements in chemistry, manufacturing and controls. Formulation development and Phase I studies must prove any extended-release tablet or pill capsule is safe, effective and therapeutically equivalent.


About RCA

Regulatory Compliance Associates® (RCA) provides FDA inspection consulting services to the following industries for resolution of compliance and regulatory challenges:

We understand the complexities of running a life science business and possess areas of expertise that include every facet of R&D, operations, regulatory affairs, quality, and manufacturing. We are used to working on the front lines and thriving in the scrutiny of FDA, Health Canada, MHRA and globally-regulated companies.

As your partners, we can negotiate the potential minefield of regulatory compliance and regulatory due diligence with insight, hindsight, and the clear advantage of our unique expertise and experience.

  • Founded in 2000
  • Headquartered in Wisconsin (USA)
  • Expertise backed by over 500 industry subject matter experts
  • Acquired by Sotera Health in 2021


About Sotera Health

The name Sotera Health was inspired by Soteria, the Greek goddess of safety, and reflects the Company’s unwavering commitment to its mission, Safeguarding Global Health®.

Sotera Health Company, along with its three best-in-class businesses – Sterigenics®Nordion® and Nelson Labs®, is a leading global provider of mission-critical end-to-end sterilization solutions and lab testing and advisory services for the healthcare industry. With a combined tenure across our businesses of nearly 200 years and our industry-recognized scientific and technological expertise, we help to ensure the safety of over 190 million patients and healthcare practitioners around the world every year.

We are a trusted partner to more than 5,800 customers in over 50 countries, including 40 of the top 50 medical device companies and 8 of the top 10 pharmaceutical companies.


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