Fast-tracking Generic Approvals: 5 Keys to Being First to Market

Written by Michael Zhou

In the game of generics, the first to market is the winner.  At a time when many of the most successful drugs are reaching the patent cliff, opening the floodgates for generic substitutes, generic companies are rushing in to target the best candidates and enter the market first. And they are relying more heavily than ever on a qualified outsourcing partner for their development.

Competition in the generics market has never been greater. As patents on pharmaceutical products with sales of more than US$267 billion expire over the next 6 years [1] generic company worldwide are seizing the opportunity to introduce a generic alternative and rigorously competing to be first to market.

The US generic drug market is booming. Where blockbuster drugs once ruled, bioequivalent generics are replacing them as welcome lower-cost alternatives for patients and the medical community, and as part of the solution to the economic burden of healthcare in the US. In the last decade alone, generic drugs provided more than $824 billion in savings to the nation’s healthcare system [2]. Today, there are more than 7800 generic versions of approximately the 10,668 US FDA-approved pharmaceuticals [3].

Saving time and costs in developing a generic product are extremely important for a generic drug’s success. The first generic company to market wins the industry’s ‘Holy Grail’ – the 180-day exclusivity period that is critical to a generic product’s success. During that period, the manufacturer dominates the market, building the product’s market share without competition.

Outsourcing generic development

Since time largely dictates the economic profile of a generic product, generic companies today are increasingly relying on qualified contract research organizations (CROs) to provide the time and cost efficiencies needed to be first to market. With a highly qualified partner, companies gain broad expertise in development processes, advanced technology and infrastructure without capital investment – flexibility with optimal use of resources – the services they need to gain a competitive edge. Outsourcing generic drug research, development and production can significantly reduce the time required to bring a generic to market, which determines its success.

The key to successful development of a generic product goes beyond a successful bioequivalency study and regulatory approval and a successful process validation study. Developing a bioequivalent demands efficient, high-quality, regulatory-compliant analyses at every step.

Five common development challenges

Here are five of the most common challenges of developing a generic product and how a qualified CRO can help you gain valuable speed to market.

1. Preformulation and Formulation

Generic products must meet the same quality standards as brand name products. Most countries require manufacturers to prove the efficacy of their formulation compared with the designated reference product by conducting a bioequivalence/bioavailability (BE/BA) study. The FDA requires BE to be between 80% and 125% of the innovator product.

The development scientist has a demanding role, as generic forms not only need to match innovator products within tight acceptance criteria, but should also circumvent restrictive formulation patents. Before preparing trial formulations, reformulation must be done to obtain as much information about the reference product and drug substance as possible. Preformulation includes determining the active ingredient(s), compounds and excipients, as well as drug solubility, chemistry, flow and absorption, drug release and other characteristics.

Since labels for innovative drugs state only the main excipients, but not all of them, generic scientists are challenged to determine the missing ingredients. Conducting analytical testing for each likely excipient is based on experienced guesswork, which can add considerable time to the development process if the scientists lack experience. An experienced CRO will know what ingredients to test for various dosage forms and APIs and is most likely to select the right ones first time, avoiding costly delays.

During formulation, scientists compare their recipe with the innovator drug to see if it is the same or has a very close profile without impurities.

In addition to having the needed expertise, the CRO partner will typically have the advanced equipment to conduct the tests efficiently, as well as the quality systems and standard operating procedures (SOPs) in place.

2. Regulatory Expertise

BE/BA studies must comply with specific requirements for each product and with the regulatory requirements of each country where the drug is intended to be marketed. In the US, the FDA has specific requirements for an Abbreviated New Drug Application (ANDA); for marketing abroad, there are different requirements for national submission in areas such as Europe, Japan, China and India.

Your service provider must be aware of and comply with all applicable regulations. The formulation scientist must ensure that a non-patent-infringing raw material can be incorporated into a non-patent-infringing formulation that will be at least as stable as the innovator drug product and bioequivalent. Submitting accurate BE studies will expedite regulatory approval, whereas failure to comply and submitting applications without all the necessary information can result in costly delays.

3. In Vitro/In Vivo Testing

To demonstrate BE, the formulation must have the same amount of active ingredient and the same dissolution and release profiles as the reference product. In some cases, in vivo testing may be necessary – sometimes toxicology studies satisfy this requirement. A service provider knowledgeable in this area and with an onsite toxicology facility can provide the needed expertise, efficient continuity from one process to the next and more effective oversight for greatest efficiency.

For in vitro and in vivo testing, it is critical to have highly qualified medical and technical staff, both clinical and laboratory principal investigators. If human testing is necessary, the investigators must be able to efficiently recruit qualified subjects and conduct the study. The number of subjects is based on pharmacokinetic (PK) variability.

4. Quality by Design

Development of a generic product, as with any other drug, must be governed by Quality by Design (QbD) principles and incorporated into the development planning. This requires a thorough understanding of the product and development process, along with the knowledge of risks and how best to mitigate them.

Scientists must not only gather test data, but know how to interpret the data to determine whether the formulation’s PK and dissolution profiles are comparable to those of the reference drug. They should also have an understanding of the quality target product profile (QTPP).

Incorporating QbD, scientists must justify why and how the formulation was chosen through actual experimentation, including identifying the critical excipients and justifying the concentration of each excipient in the formulation. Modeling and simulation can aid generic developers in determining what drug release profile is needed to provide BE to the reference list drug/product.

Then the challenge to the generic developer becomes the selection of excipients and the design of a formulation and release mechanism that will provide the intended in vivo release profile. A mechanistic understanding of how the physical properties of a drug substance and excipients affect drug product performance can enable rational choices of excipients and reduce the number of experimental formulations that need to be produced.

Because it is usually not feasible to test every trial formulation in an in vivo study, better in vitro/in vivo correlations (IVIVC) will give better feedback in an iterative design process. When an in vitro dissolution test can be related to the in vivo dissolution of a product, a generic sponsor will have an efficient tool to evaluate different formulations and select the optimal formulation for use in the pivotal BE study.

However, the correlation of dissolution testing with in vivo performance varies from product-to-product. The FDA’s data from dissolution tests and PK studies can help external collaborators develop and test models capable of predicting the connection between dissolution and BA/BE.

In addition, companies need to quickly develop a Chemistry, Manufacturing and Controls (CMC) strategy, the part of drug development that deals with the nature of the drug substance and product, the manner in which they are made and the manufacturing process. However, many companies lack an understanding of CMC guidelines.

5. Planning

Early, thorough planning, supported by a solid understanding of generic development science and regulatory requirements, is essential for timely delivery of data for an ANDA submission. Experienced CROs can provide consultation and advice for regulatory compliance and ANDA submission, which result in considerable time and cost savings.

The key to a successfully developed generic product goes beyond a successful BE study, product approval and a successful process validation study. A truly successful generic product is one that can be made repeatedly by any trained manufacturing operator without problems. Considerable effort and careful planning during development will improve the chances of generating a robust product.

A manufacturer typically begins searching for the right product about 2 years in advance. When selected, the project needs to be scheduled and its progress closely tracked and managed with the goal of being first to market. The company then begins reformulation following guidance by the regulators (FDA).

Choosing a highly competent CRO

The following checklist is a guide to choosing the best CRO to produce a near-equivalent formulation expeditiously at the lowest cost. Thus, find out if the CRO has the following qualifications:

  • A solid knowledge of formulation, process design and development of a generic product;
  • Experience in lab-testing generics, including in vitro/in vivo testing capability;
  • Highly qualified staff who can efficiently, thoroughly and accurately carry out every step, including analytical testing and data interpretation, and support for regulatory submission;
  • Experience working with innovator drugs, particularly the one you are targeting for generic development;
  • Knowledgeable in generic regulatory requirements;
  • An exemplary regulatory compliance record;
  • Adheres to CMC guidelines and has standardized protocols for development and quality SOPS;
  • An excellent track record of speed, quality and cost efficiency;
  • Provides consultation and guidance;
  • Has the development infrastructure, capacity, technology and sites for efficient development, as well as onsite temperature- and humidity-controlled stability storage;
  • State-of-the-art technology;
  • Provide a broad array of services, from bioanalytical method development and sample analysis to ANDA submission and post-commercialization product testing;
  • History of satisfied customers.

CROs = Faster drug development

Why will a well qualified CRO get your generic product to market faster? Simple. R&D is a CRO’s core competency, the focus of its business. Outsourcing generic development offers broad expertise, the needed infrastructure and the ability to quickly solve formulation challenges, which enable generic manufacturers to achieve substantial time and cost efficiencies. In the generic race to market, companies who outsource development to a qualified CRO will gain a competitive advantage – and have the best shot at being first to market and achieving market success.


  1. Pharma 2020: Supplying the future. PriceWaterhouseCoopers Trend Report. 2011.
  2. Generic Drugs vs. Brand Name Drugs. July 21, 2010. Accessed at
  3. Drug Prescriptions: Generic vs. Brand Name. Accessed at