9 Approaches for Managing Regulatory Approval and Process Validation of Accelerated Approval Drugs


Historically, it has taken an average of 12 years and, according to a Tufts Center for the Study of Drug Development (CSDD) report, including expenditures and opportunity costs, an average of ~$2.6 billion to bring a prescription drug to market. The speed required at every point in the industry – from innovator to the FDA – to develop Fast Track, Accelerated Approval or Breakthrough drugs is having a profound impact.

Approval of a Breakthrough drug, which can be classified for Accelerated Approval, means manufacturers need to develop Chemistry, Manufacturing and Controls (CMC) data in about half the time of the traditional process. In addition, Breakthrough or other expedited designation does not mean the innovator company can do less. In order to meet these accelerated timelines, they do need to start analytical methods creation and product and process characterization sooner, and handle the process differently.

Although new approaches are required, the guiding force behind these new approaches is that despite sharply reduced timeframes, manufacturers cannot compromise patient safety or product supply.

Process Validation and Regulatory Approval Challenges within the Accelerated Drug Paradigm

  • Extensive collaboration and communication between the FDA and innovator companies is required. Given limited FDA resources and the extensive resources required by innovator drug companies, is the growth of expedited approval programs sustainable?
  • New Drug Applications (NDA) for Breakthrough Therapies include less manufacturing information and data requiring alternative risk-mitigation approaches and often nontraditional statistical models.
  • Both patient safety and product supply is at the forefront, without the data and historical knowledge traditionally used to address these concerns.
  • The primary concerns for CMC reviewers include incomplete characterization of the drug, underdeveloped analytical methods and a lack of full understanding of a product’s Critical Quality Attributes (CQA) and associated risks.
  • Process Validation will, in many cases, be incomplete at product launch.

Accelerated Approval Drugs – 9 Approaches for Managing Regulatory Approval and Validation Challenges

The approval of, and ultimate Process Validation for, Breakthrough/Accelerated Approval drugs will not look like the construct the pharmaceutical industry is familiar with. Again, all Breakthrough and Accelerated Approval drugs address very serious conditions and offer treatment where none currently exists, or offers benefits well above and beyond drug products currently on the market. Therefore, flexibility has been applied to segments of the traditional product review and approval process to speed the availability of treatments for these critical conditions.

Despite the flexibility in, and often changes to the product review and approval process, patient safety remains at the forefront, as well as the guarantee of consistent product supply. So, how can the industry best handle this?

  1. Open and transparent communication with the FDA throughout the entire approval and post-market process. The pharmaceutical company mindset of not wanting to learn certain information for fear of needing to revalidate based on those discoveries has no place in this new reality. New information will be learned pre- and post-launch, and plenty of amendments will need to be filed.
  2. Additional stability data amendments will likely need to be filed during the review process and in some cases post-market. This approach is required given that less data will be available at submission due to compressed timeframes.
  3. Launch commercial process with limited experience and optimize post-approval–the classic three runs is not the guiding force within this construct. The level of flexibility regulators will extend is determined for each specific product. Factors taken into consideration include: riskiness of product characteristics, seriousness of the condition and medical need, complexity of manufacturing processes, state of the innovator’s quality system and merits of the innovator’s risk-based quality assessment including Critical Quality Attributes (CQA).
  4. Novel statistical models and approaches will need to be applied in many cases. Representative samples and assays for these models will likely need to be acquired from sources, like prior knowledge and use of comparability protocols. Also, determination of the appropriate use of stability data from representative pilot scale lots will be required.
  5. Manufacturers should freely acknowledge where data is limited, demonstrate that the missing data pose no risk to patient safety or product supply and outline post-market strategy for acquiring the missing data. Conversations with the FDA are clearly required for successful outcomes here.
  6. Focus on patient safety and reliable supply of quality product at launch, not process optimization. In addition, begin critical product attributes and process characterization work much earlier than a typical pharmaceutical development process. In many cases, consider broader product quality ranges for non-Critical Quality Attributes until further manufacturing experience is acquired post-approval.
  7. Enhance analytical methods and understanding to offset more limited process understanding and to support future comparability work. Extremely important, involve commercial Quality Control representatives in the development assay design.
  8. Some CMC activities may be incomplete at launch. Incomplete processes could include: Process Validation, stability studies on commercial product, manufacturing scale/tech transfer data and complete control system data.
  9. A post-approval product lifecycle management plan is a must, and it needs to be included in the filing to support deferred CMC activities.

Fast Track, Breakthrough Therapy and Accelerated Approval drugs have profoundly changed the thinking and approach to Process Validation and other CMC activities. BioTechLogic has extensive experience bringing to market challenging biologics, monoclonal antibodies, recombinant proteins, vaccines, blood products, Adeno-associated virus (AAV) and many other product types often under accelerated timelines. BioTechLogic brings to its clients decades of expertise in process validation, regulatory quality systems, technology transfer and analytical method development which are key assets to be leveraged to successfully meet accelerated timelines of Fast Track, Breakthrough Therapy and Accelerated Approval drugs.

If you are challenged with bringing an Accelerated Approval drug to market, contact BioTechLogic to see if they can help.



Joseph A. DiMasia, Henry G. Grabowskib, Ronald W. Hansenc, “Innovation in the Pharmaceutical Industry: New Estimates of R&D costs,” Tufts Center for the Study of Drug Development, Tufts University

  1. Wechsler, “Breakthrough Drugs Raise Development and Production Challenges,” Pharmaceutical Technology39(7) 2015.

Earl S. Dye, PhD, “CMC/GMP Considerations for Accelerated Development and Launch of Breakthrough Therapy Products,” Roche

“Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics,” U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), May 2014 Procedural

Anthony Mire-Sluis, Michelle Frazier, Kimberly May, Emanuela Lacana, Nancy Green, Earl Dye, Stephan Krause, Emily Shacter, Ilona Reischl, Rohini Deshpande and Joe Kutza, “Accelerated Product Development: Leveraging Industry and Regulator Knowledge to Bring Products to Patients Quickly,” BioProcess International, December 2014

Daniel Alsmeyer and Ajay Pazhayattil, Apotex Inc.,A Case for Stage 3 Continued Process Verification,” Pharmaceutical Manufacturing, May 2014


BioTechLogic, Inc. provides biopharmaceutical regulatory and manufacturing consulting services with strategic and hands-on experience to assist clients in bringing their products to market quickly and successfully by augmenting and optimizing their organization’s resources.

We are a team of professionals with expertise in Process Development, Manufacturing, Process Validation, Analytical Testing/Quality Control, Quality Assurance, Regulatory Submissions, Project Management, Supply Chain Management and Combination Products.