In April 2016, in the guidance document Pharmaceutical Quality/Manufacturing Standards (CGMP) Data Integrity and Compliance With CGMP, FDA began discussing its remit with a foreboding introduction stating that, “In recent years, FDA has increasingly observed CGMP [current good manufacturing practice] violations involving data integrity during CGMP inspections. This is troubling because ensuring data integrity is an important component of industry’s responsibility to ensure the safety, efficacy, and quality of drugs, and of FDA’s ability to protect the public health. These data integrity-related CGMP violations have led to numerous regulatory actions, including warning letters, import alerts, and consent decrees” (1). The context and consequences of those warning letters was made clear in com- mentary by Peter Zipfell, product marketing manager at Thermo Fisher Scientific, who spelled out that “... based on findings from a 2019 report on drug shortages, of 163 drug shortages in the US between 2013 and 2017, 62% of supply disruptions were associated with manufacturing or product quality problems” (2).
In that FDA 2019 Drug Shortages Report (updated February 2020), the second recommendation was to “create a rating system to incentivize drug manufacturers to invest in achieving quality management system maturity... as the market does not recognize and reward mature quality management systems. This recommendation aims to rectify this failure by suggesting the development of a system to measure and rate the quality management maturity (QMM) of individual manufacturing facilities based on specific objective indicators” (3). This new framework appears near introduction as FDA issued a white paper last month (March 2022) on the QMM program and will be holding two workshops in May to gain further input from stakeholders.
The drug shortages report goes on to say that, “A rating system could be used to inform purchasers, Group Purchasing Organizations (GPO) and even consumers about the state of, and commitment to, the quality management system maturity of the facility making the drugs they are buying. Pharmaceutical companies could, at their discretion, disclose the rating of the facilities where their drugs are manufactured. GPOs and purchasers could require disclosure of the rating in their contracts with manufacturers. This effort would introduce transparency into the market, and provide firms committed to quality management maturity with a competitive advantage, potentially enabling them to obtain sustainable prices as well as grow market share” (3). So, change is coming, and with it the requirement to tighten up on how data are collected, collated, and shared.
PAT and data integrity
Because past is prologue, BioPharm International asked Edita Botonjic-Sehic, director, Global Analytics, Pall Life Sciences if the original push by FDA to promote process analytical technology (PAT) adoption was helpful in setting expectations and in creating a new tools and services ecosystem. “Yes,” Botonjic-Sehic says, “advanced technologies and computation modeling has contributed significantly to making this capability come to life. By utilizing PAT into integrated bioprocessing, better process understanding is gained, production cycle time is reduced, improvement of yield is achieved, efficiency is improved, and cost reduction is achieved by the reduction of waste and energy consumption resulting from the real-time release of a batch with improved quality.” She goes on to explain, “Biotech processes consist of several unit operations, with each unit operation serving a defined purpose. The need for appropriate control of each step and continuous evaluation of its performance is critical. To date, there are still gaps in the area of advanced analytics for the process; however, computational modeling has slowly started to contribute towards process characterization. The goal is to have both process technologies and advanced computing used in real-time for process control.” So along with the rest of the world, pharmaceutical manufacturing is becoming a digital undertaking.
When asked if increasing compliance and validation requirements lead to more processes and documentation burden, Botonjic-Sehic responded that, “Data driven frameworks and transformation to digitalization will lead to a new future state. There are still many challenges in bringing technological innovation and advancement due to lack of adoption and change in processes ... FDA has been very much involved with the industry to support the adoption of the advancements in the process. It may seem as if it is complex at this given moment; however, the ultimate goal is to make the process and filing seamless and putting in the effort upfront is a necessity in order to make the future of manufacturing much easier.”
Measuring complex product quality attributes