This article was published online on Aug. 18, 2020
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Risk-based decision-making is impacting all aspects of manufacturing quality from raw material supply to facility inspections.
With additional safety protocols required in the manufacturing environment, gatherings of large people generally prohibited, and onsite inspections limited due to restricted travel, ensuring quality throughout the supply chain from raw material to API is more challenging. API producers have responded rapidly, implementing safety protocols, leveraging digital tools and technologies for virtual audits and inspections, and generally taking a reasoned, risk-based approach for making use of available resources.
FDA has conducted mission-critical inspections, assessed records remotely using the authority under Section 704(a)(4) of the Food Drug & Cosmetic Act, and has developed a risk assessment system to help the agency use dynamic information to qualitatively assess COVID-19 cases in a local area based on state and national data and make informed risk-based decisions on when and where to resume prioritized domestic surveillance inspections.
In a time of crisis, risk-based decision making and strong leadership take on new meaning, according to David Waddington, NSF International’s executive director of pharmaceutical services for Europe, Middle East, and Africa. “It’s simply not possible for companies to operate their pharmaceutical quality systems (PQSs) and meet all their commitments with such a drastic reduction in available resources. Forward-thinking organizations have taken a proactive approach to deciding what activities can be stopped or delayed. Stopping an activity may seem to be extreme, but taking this decision proactively, before the quality system slips out of control, is a sensible approach,” he says.
This article was published online on Aug. 18, 2020
For example, Waddington notes that change controls that have not yet been implemented could be halted without reducing validation effort, regulatory affairs work, quality control (QC) testing, and documentation updates. “Being extremely stringent with limiting change controls can free up [quality assurance] QA and QC resources,” he adds. Similarly, improvement plans such as introducing new systems could be halted, again freeing up resources. While delaying compliance activities feels wrong, Waddington says that in extreme situations it can be done using the quality system.
Activities that should be continued are those linked to batch release and testing. “It is important to ensure that there are sufficient QA/QC staff to support production activity and, if necessary, to reduce planned output. Deviations and out-of-specification/trend activities should also be performed in a timely manner to ensure product flow and also to identify any problems as early as possible,” observes Waddington. If action has been taken to stop some activities at the site and delay others, then, he comments, some staff may be re-deployed to bolster frontline staff.
“Taking a hard look at all activities that consume resources and applying a risk-assessment approach can help to free up some resources to bolster direct product fulfillment activities and thereby keep critical medicinal products flowing to patients,” Waddington concludes.
Because of the nature of pharmaceutical manufacturing and the need to ensure both operator safety and product quality, extensive systems and procedures are already in place at facilities producing pharmaceutical intermediates and APIs, including regular use of personal protective equipment (PPE) and good hygiene practices. Manufacturers, as a result, have been able to adapt quickly to new safety requirements and ensure continued supply of critical medicines according to current good manufacturing practices (CGMPs) and other regulatory requirements. This compliance is happening despite the challenges created by temporary plant shutdowns, the need for social distancing, and reduced on-site staff at a time of increasing production demands, complex supply chain challenges, and existing product shortages, according to Waddington. “It’s not uncommon for facilities to be operating with at least 30% less staff and key support functions, including QA, working remotely. Both companies and regulators are having to make some tough choices,” he says.
Fortunately, because API manufacturing is different from many other types of manufacturing, the need to exercise social distancing in these situations does not affect the nature of most processes, according to Jeff Ross, director of environmental health and safety for Cambrex Charles City.
“Outside of the need for social distancing, Cambrex was an early adopter in implementing screening protocols for anyone entering the site. Today, employees are required to undertake a daily temperature check in addition to answering a series of health questions. Any visitors to the site must also go through the same process and need to complete a formal questionnaire,” Ross says. Cambrex also performs job hazard analyses for all operational areas and makes recommendations on a variety of different elements in the typical workday, such as room capacities, the necessary frequency of sanitization, and the maximum size of any essential gathering.
Employee safety is always a priority for Thermo Fisher Scientific, and since the start of the COVID-19 pandemic the company has focused on protecting their health and safety while continuing to serve the needs of its customers, according to Vice President of Drug Substance Quality,Ben Gerlach. “Manufacturing safe APIs for medicines that can improve or save the lives of patients is both a large responsibility and a privilege. During the COVID-19 pandemic, we have continued to ensure the safety, efficacy, quality, and availability of the APIs we manufacture through a globally coordinated response, comprehensive site preparedness, employee training and communication, and robust business continuity planning,” he comments.
Thermo Fisher Scientific manufacturing sites have specifically established increased hygiene protocols and tightened visitor guidelines. Stringent preventative measures developed in line with guidance from the World Health Organization, US Centers for Disease Control and Prevention, and local government agencies include restricting employee travel, encouraging remote work, enforcing social distancing, and requiring employees to wear masks at all times, according to Gerlach. For those employees who are on-site, the company keeps contact logbooks, takes employees’ temperatures regularly, and employs a two-shift system for teams in the laboratories and on the manufacturing floor to accommodate social distancing.
“As a result of the support, flexibility, and discipline of our colleagues and supply chain partners, as well as the IT infrastructure available, all Thermo Fisher API manufacturing sites have remained operational since the start of the pandemic with continued GMP compliance,” Gerlach remarks.
Key to ongoing provision of API to pharma customers is effective management of the supply chain, including assurance that materials continue to meet the high-quality standards of the pharma industry. Prior to the COVID-19 pandemic, many API manufacturers made use of international industry conferences to meet with their vendors and customers, from raw material producers to contract research organizations, and contract development and manufacturing partners. Travel restrictions and the prohibition of large gatherings, both designed to limit spread of the SARS-CoV-2 virus, have forced API producers to find other means of keeping track of the supply chain.
Despite being unable to attend major industry conferences in-person, representatives of Thermo Fisher Scientific have joined events virtually and maintained close communication with supply-chain partners to ensure there is no change in quality or availability of raw material, according to Gerlach. In addition, the company’s regional teams continue to closely monitor the COVID-19 situation, particularly in Asia, Europe, and North America, where most of its qualified suppliers are located. “We also continue to closely track our purchase orders and have put a major focus on regional governmental restrictions that could affect manufacturing and shipping and the timely availability of raw materials and critical equipment so there is no lapse in our ability to help customers bring important medicines to market as fast as possible,” Gerlach says.
Before the pandemic ever emerged, Cambrex had prepared for various emergencies and crisis situations by undertaking strategic logistics planning and implementing response processes, according to Ross. “Over the past several months, we have been working strategically to expand the supply chain globally by evaluating suppliers across the globe, including those in the [European Union] EU or US. Expanding our footprint and ensuring supply chain redundancy has enabled us to minimize the risk of supply chain interruptions and work with partners efficiently,” he explains.
Because of the circumstances connected with COVID-19, Ross also stresses that it is extremely important to frequently engage with supply chain partners to ensure that Cambrex understands the impact of the pandemic on their businesses and any potential downstream effects on Cambrex’s unit operations that might ensue. “Video conferencing and more frequent communications have been important for our continued visibility into the supply chain,” he asserts.
Effective communication, which Waddington says involves listening more and speaking only when there is something valuable to say, has enabled NSF International to successfully transition from a training, consultancy, and auditing service provider that operated primarily face-to-face with clients to one that can now provide true virtual and blended learning, remote audits, and consultancy. “We believe we have achieved a truly remarkable transition in such a short time frame, as have many of our pharma industry clients,” he states.
That rapid transition has been made possible by leveraging a wide range of digital tools and technologies in new ways and to a much greater extent than API manufacturers and their suppliers and customers were previously accustomed to. The most obvious change, according to Waddington, is the reliance on digital meeting platforms. “We have seen a significant increase in the need and willingness for more regular video calls and sharing of documents and information through secure file handling platforms. Participants can often feel self-conscious to begin with, but soon adapt and get to grips with presenting, using whiteboards, interacting breakout rooms etc.,” he observes.
As part its digital transformation strategy, Thermo Fisher had already implemented digital tools to support many of its GMP processes, and many of these systems have proven to be highly beneficial to ensuring continued API quality, according to Gerlach. As an example, he points to the company’s SampleManager Laboratory Information Management System, which helps drive productivity, ensure compliance, streamline processes, and improve organizational efficiency.
Thermo Fisher also uses Documentum (OpenText) to store GxP documentation and manage the creation, amendment, approval, use, and retention of all documents. “This system provides traceability, ensuring data integrity and compliance to good documentation practices to meet our regulatory standards,” Gerlach notes. The company also uses tools to manage quality events and support training and virtual communication and systems for electronic process control and data analysis. Cutting-edge camera and augmented reality (AR)/mixed reality technology is also leveraged to provide safe, virtual access to Thermo Fisher facilities.
Cambrex has also invested heavily in recent years in information technology platforms and advanced technologies that have enabled the company to maintain its current quality systems while allowing remote working for staff and facilitation of virtual collaboration with internal and external stakeholders, according to Chuck Walker, director of regulatory compliance at Cambrex’s Charles City facility.
Examples include live broadcasting from Cambrex’s manufacturing sites and clients being able to remotely visit its facilities, have instant interaction with subject matter experts, and undertake live-virtual audits. “When lockdown conditions were implemented at our multiple sites, we saw immediate results from these investments in that our employees were able to operate as usual from remote locations; client visits became virtual; and we were still able to undertake internal and external audits,” Walker observes.
In fact, from an auditing perspective, NSF International has witnessed a major shift with companies allowing the use of camera technology within facilities to share images, according to Waddington. “This approach is a real game-changer as it transitions from a virtual ‘desktop’ audit to a true interactive remote audit, allowing the auditor to view operations live and assess effective implementation of the PQS including remotely observing facility design, hygiene, and even operator behaviors,” he explains.
Such digital tools have also been invaluable for regulatory agencies during a period when most onsite inspections have been halted due to the COVID-19 pandemic. Many agencies have historically conducted some form of remote risk-based review or “desktop” assessment, so in some respects their current approach is an extension of that process, according to Waddington. One additional challenge that regulatory authorities have had to face, though, is to ensure the processes they are following have legal standing in line with legislation in place in their respective countries. “A number of agencies, including the [United Kingdom’s Medicines and Healthcare products Agency] UK MHRA, have been successfully conducting very detailed remote inspections of facilities and have been able to follow up on for-cause audits and ensure remediation programs are progressing in line with company commitments,” he says.
The use of AR technology, Gerlach adds, enables Thermo Fisher to provide regulatory agencies unprecedented access to its facilities without them needing to be physically present. “Auditors can navigate through the facilities and perform factory acceptance tests. Remote assist provides the means to facilitate support both internally and externally from anywhere in the world,” he says. “Limiting onsite visits helps protect both employees and visitors without impeding operations or impacting quality,” Gerlach continues. “All of these solutions are made possible with training from the augmented execution team and tremendous collaboration from our sites, vendors, clients and regulatory agencies,” he concludes.
Cambrex deployed virtual live tour technologies throughout its facilities when lockdown and restricted access conditions became applicable. “These technologies have enabled both client audits and regulatory audits to continue,” Walker says. “Although we have not had any direct regulatory requests during this period at our Charles City [Iowa] facilities, many of our other sites in different locations have successfully undertaken virtual audits, and we are fully prepared for live virtual audits if needed here at Charles City,” he notes.
In fact, Walker believes that the API industry in the United States is innately equipped to manage the COVID-19 pandemic given the governing force behind employee protections with US Occupational Safety and Health Administration’s industrial standards. “Because safety is already so deeply engrained in our daily operations, along with engineering controls, we have been able to operate confidently knowing we are protecting our employees and product simultaneously,” he asserts.
API manufacturers have also invested in expanding capacity for specialized intermediates and APIs in recent years, which has also contributed to the ability of contract service providers to meet growing demand during the pandemic. Thermo Fisher, for instance, invested more than $800 million to increase capacity and meet rising demand for biologics, cell and gene therapies, and drug products. “These global and strategic investments have ensured that lack of capabilities, capacity, or supply is never a reason medicines are delayed in reaching patients,” Gerlach asserts. “We continue to protect our colleagues on the manufacturing floor and in our testing laboratories and warehouses by adhering to strict safety measures and requirements. At the same time, we remain flexible, creative, and vigilant to ensure API quality and supply as we continue to work to bring medicines to market as fast as possible for customers and the patients they serve,” he concludes.
As horrible as the COVID-19 pandemic has been and continues to be, it, like all crises, has presented opportunities for improvement as well. “If there is a silver lining to the current situation, it will lie with those employees who stepped forward for their colleagues and found creative ways to get things done. Or it may lie in the cross-training of employees for new or expanded roles,” Waddington states. For instance, he points out that key decisions around product quality may be delegated closer to the unit operation, which should result in efficiency gains.
Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology.
Vol. 44, No. 9
When referring to this article, please cite it as C. Challener, “Tracking API Quality During a Pandemic,” Pharmaceutical Technology 44 (9) 2020.