Cell Culture
for Regulatory Filings to the FDA

How CellPort Reduced Audit Duration by 50%


In 2000, the U.S. Food and Drug Administration announced final guidance for the Biopharmaceutics Classification Sys­tem (BCS) [1], which permits human testing to be replaced by cell-based in vitro testing for determining the bioequiv­alence of generic drugs to their non-generic counterparts. This white paper describes the use of a Software-as-a-Ser­vice (SaaS) platform focused on cell culture, cell banking, and cell manufacturing to digitalize paper lab notebooks used in BCS biowaiver submissions to the FDA and the corresponding benefits that were realized during the routine FDA audits related to the BCS biowaivers in which in vitro testing predicts outcomes in humans.

Background–FDA BCS Biowaivers

In the late 1980’s, Borchardt, Hidalgo, et al. [2] characterized the human colon carcinoma cell line Caco-2 and worked out the assay conditions and demonstrated the utility of Caco-2 cells as an in vitro model system for intestinal epi­thelial permeability capable of predicting oral absorption in humans. The Caco-2 cell line was adopted by the phar­maceutical industry in the 1990’s as a part of routine screening for the “drugability” of New Chemical Entities (NCEs).

In 2000, the FDA announced the Biopharmaceutics Classification System (BCS), which provided initial guidance on the use of in vitro testing as a substitute for human testing. From a regulatory perspective, there was recognition that in vitro data from the Caco-2 cell-based assay could reliably predict in vivo outcomes in humans. Beginning in 2001, Absorption Systems, a Contract Research Organization that is the world leader in Caco-2 in vitro testing, used the as­say to provide the FDA with permeability classifications for Abbreviated New Drug Application (ANDA) and New Drug Application (NDA) submissions.

Specifically, generic drug companies were able to receive biowaivers permitting them to be awarded ANDAs on BCS Class I compounds without submitting clinical bioequivalence data measured in humans.

FDA BCS Class 1 Drug Products

  • The drug substance is highly soluble

  • The drug product (test and reference) is rapidly dissolving

  • The drug product (test and reference) is rapidly dissolving

  • The product does not contain any excipients that will affect the rate or extent of absorption of the drug

FDA Audits with Paper Lab Notebooks

In the early 2000’s, Absorption Systems performed in vitro intestinal permeability studies using Caco-2 cells for a generic version of the antianxiety drug fluoxetine. As a part of a routine FDA audit, the auditor requested all the relevant validation material for the in vitro testing. At the time, the validation materials were in paper laboratory notebooks and emails that had been printed, initialed, signed, and cataloged in binders. At the time, the company was also halfway through a project of switching all computer systems from Macs to PCs. In the end, the audit was successful, but the traceability and transparency of the information in paper format was limited, and the audit pro­cess took many days to complete.

FDA Audits with Excel

In the mid 2000’s, the FDA performed another audit. Absorption Systems was still using paper laboratory notebooks, binders of printed, initialed, and signed emails, and paper logbooks for equipment maintenance and repair records. The FDA audits were no less time consuming the second time around, so a decision was made to track information electronically in Excel spreadsheets.

The experience with Excel proved to be cumbersome and lacked the transparency, traceability, and transferability that was required in a high-volume research, GLP, and GMP setting.

50% Drop in FDA
Audit Time with

To address the issues of transparency, traceability, and transferability that hampered both paper laboratory note­book and Excel-based electronic attempts to manage the cell manufacturing process, Absorption Systems began a months-long search to find a software platform that could support their unique workflows, concluding that the type of software they needed did not exist.

To fill the market void, CellPort Software created a software platform for Absorption Systems focused on cell culture, cell banking, and cell manufacturing. The fully validated platform was then used for subsequent BCS biowaiver appli­cations at Absorption Systems. The platform converts paper-based standard operating procedures (SOPs) or proto­cols into executable, reusable, version-controlled workflows. Each time a workflow is executed in the platform, the version of the workflow used and the data it collected is stored as part of a persistent audit trail. Barcodes are utilized to allow full traceability of equipment and materials and reduce transcription errors. By the time Absorption started using the new software, the FDA had updated their BCS biowaiver guidance, a devel­opment that could have meant more time and stress in preparation for the next routine FDA audit. However, by that time Absorption Systems was entirely digital with the CellPort Software system, and because the application has a full audit trail, all changes to data were traced. With this new, singular source of truth where every detail of the laboratory procedures were almost effortlessly traceable, automatically organized and easily searchable, the audit took half the time of the earlier audits. Given the well-known, unwritten rule that the longer an FDA audit takes, the worse it looks, this was a notable feat. After years of lab-tested trial and error, Absorption Systems was ready to use CellPort Software for their next FDA audit. The result?

Flexibility in an
Inflexible Environment

The case studies of the impact of the CellPort Software-as-a-Service (SaaS) platform on FDA submissions for both BCS biowaivers and GMP gene therapy potency assays underscore the importance of flexibility in an inflexible en­vironment. Submissions to the FDA require extreme rigor, and the software systems in which the related data are stored must be fully validated—a most inflexible environment. By contrast, the rapid and iterative nature of Process Analytical Development demands flexibility. In a regulated environment, software has historically been rigid, and compliance and flexibility do not go hand-in-hand. The CellPort Software platform successfully bridges this gap through the creation of core platform that allows easy adaptation of the flow, the look and feel, and the data models of specific customers and situations, all without changing any source code.

The software platform adapts to individual customer and situational needs through trans­parent configuration without the need to revalidate the core platform.

The FDA’s Technology Modernization Action Plan (TMAP) stresses “communication and collaboration with stakeholders to drive technological progress that is interoperable across the system and delivers value to consumers and patients. The TMAP provides a sturdy technological foundation for development of FDA’s ongoing strategy around data itself—a strategy for the stewardship, security, quality control, analysis, and real-time use of data—that will accelerate the path to better therapeutic and diagnostic options for patients and clinical care providers, and better tools to enhance and promote public health.” [3]  In the world of cell culture, cell manufacturing, and cell banking and all the downstream products that are touched by cells, an integrated cloud-based platform like CellPort Software represents a critical leap towards the FDA’s plan to drive technological change across the biomedical ecosystem that is not only interoperable, but is also transparent, traceable, and transferable.


In complex assays for small molecule FDA BCS biowaiver approvals, CellPort Software provided traceability, transparency, and transferability to the cell manufacturing process that dramatically reduced the time of routine FDA audits and as a result expedited the FDA ANDA and NDA approval process. The CellPort Software low code SaaS platform provided a flexible and extensible framework that spanned research, GLP, and GMP settings.