David Edwards- Chief Revenue Officer (CRO), MasterControl.
People undergoing treatment for attention deficit/hyperactivity disorder (ADHD), certain cancers, various infectious diseases, and pain management may find themselves on a medication waiting list due to a worldwide drug shortage. Various drugs such as Adderall, often prescribed for those with ADHD, as well as cisplatin and carboplatin, used in chemotherapy for several different cancers, are all in short supply. Because there are no alternatives for many of the drugs on the shortage list, patients need to either skip treatments or take lower dosages of the medications. In some cases, there are alternative treatments, but most are either not as effective or can lead to adverse outcomes.1,2
The U.S. Food and Drug Administration (FDA) has a mandate to protect public health by ensuring the safety, efficacy, and security of human and veterinary drugs and biological products by enforcing current regulations through product surveillance programs and by performing regular compliance inspections. This poses challenges for the regulatory watchdog because the agency also bares the responsibility of ensuring that there are enough medications and therapies to go around. Despite the efforts of the FDA and other global regulatory agencies to ensure the ample supply of safe and effective medications, there are still alarming numbers of public health concerns stemming from drug shortages.
Dissecting the Drug Shortage Issue
Pharmaceutical product development is one of the most innovative sectors. Companies in this industry continue to push more breakthrough products and advanced therapeutics into mainstream health care. But these medical advancements don’t offer much value until they get manufactured into the products that improve patients’ lives. The shortfall in drugs has been an ongoing concern for decades. That said, mitigating the shortages and the resulting impact of not having a sufficient supply of the medications necessary for patient care is a high priority for the FDA. In the 2020 report “Drug Shortages: Root Causes and Potential Solutions,” the FDA cited that drug shortages continue to pose a real challenge to public health, particularly when the shortage involves critical drugs that have no alternatives.3
When it comes to drug shortages, fingers tend to point in various directions in an attempt to identify root cause. For example, COVID-19 was menacing in a lot of ways, making it an easy target of blame for many societal infirmities. Most of the limitations of medical supplies can largely be attributed to the pandemic. During the global lockdown, factories shut down in order to prevent the spread of the virus. Also, regulatory agency employees were tethered to their home offices due to travel restrictions and concerns for the health and safety of the inspectors. This made it more difficult for regulators to keep up with inspection and approval timelines.
Another culprit could be the profitability, or rather lack of, in producing generic medications. With generic products, manufacturers can only compete on price. Due to the high cost of manufacturing generics, companies have little incentive to produce the less-profitable products, so they either discontinue production or opt out of launching the product lines altogether. Manufacturers of generic drugs face intense price competition, uncertain revenue streams, and high investment requirements, all of which limit potential returns.4
As with Adderall, there has been a substantial increase in demand for many pharmaceutical products. Some cancer drugs are prescribed to over 500,000 new patients per year. Manufacturing drugs requires raw materials from suppliers that are often located in a variety of countries, which can create another supply chain bottleneck. Multiple companies that produce the same products may all get their raw materials from the same supplier. When supply shortages or supply chain obstacles occur for any reason, it impacts all manufacturers of the product.
The Root Cause of Drug Shortages
While there may be a number of factors involved in the deficit in drug inventories, according to the FDA, the main contributors to the drug shortages are quality and manufacturing issues. For a 2020 report on drug shortages published by the FDA, the organization assembled a team of economists that examined a sample of 163 drugs in the agency’s database that first went into shortage between calendar years 2013 and 2017. The results revealed that of the 163 drugs in shortage, 62% went into shortage after supply disruptions occurred due to manufacturing or product quality problems.5
Pharmaceutical manufacturing firms inherently focus their efforts on compliance with current good manufacturing practices (cGMPs), which include standards for material systems, equipment and facilities, production, laboratory, packaging and labeling, and a quality system. These standards are foundational and set only a minimum threshold that companies must achieve to be compliant with regulatory guidelines. While this approach is usually sufficient for approvals, it does not incorporate the more advanced levels of quality or manufacturing management needed for public health products.
In a typical manufacturing environment, employees are still creating and expediting reports and documents on paper. This poses a number of issues and delays. Depending on the purpose of the documents they may need to be treated to be used in a laboratory or clean room. Paper documents also need to be scanned to create electronic versions for audit purposes. During document review cycles, quality personnel or other stakeholders often discover problems, deviations, or data entry errors that should have been identified much earlier or should not even exist, resulting in the product having to be reworked or scrapped. The issues that go unnoticed usually get flagged by inspectors.
In June 2022, the FDA issued a Form 483 containing six observations to a pharmaceutical company. The observations cited that the company did not evaluate the operating ranges for critical process parameters, such as temperature and packaging process/filling configuration. A non-assessment during a validation led to the distribution of products manufactured with non-validated equipment configuration and operational parameters. The list of infractions also pointed out that “procedures applicable to the quality control unit are not in writing and fully followed. Some standard operating procedures (SOPs) relating to the use and cleaning of storage vessels and sampling and testing were not followed and/or no documentary evidence was kept.”6
In July 2022, an inspection of an antibiotics manufacturer revealed lapses in the company’s drug ingredients production processes. The resulting Form 483 called out the facility’s quality unit for failing to ensure that the company’s active pharmaceutical ingredients (APIs) were up to par. The reprimand also cited that the company’s “quality unit dropped the ball when it came to document control and electronic records plus management of its computer systems.”7
Most of the bottlenecks, production errors, missing or incomplete documents, and other mishaps along the supply chain stem from using paper in production processes. To get products developed and delivered, companies implement systems and processes designed to catch errors and prevent defective products from going out the door. They have teams that perform extensive testing of materials at all stages of production. Then there are teams that review records multiple times to catch and resolve errors. A typical batch record used in a biotech company’s manufacturing operation can contain up to 45,000 manual entries — each entry is an opportunity for an error. The amount of oversight companies put into document reviews is necessary for compliance and to ensure the quality, safety, and efficacy of all products. But a significant amount of time goes into the duplicated efforts. Data from a 2021 McKinsey report states that in pharmaceutical manufacturing approximately 30% of the staff ’s time is spent on documentation-related activities.8
Human errors are a costly burden on companies as they often result in a product rejection or recall. Even in cases where the error is considered minor, it still requires an investigation and follow-up testing to confirm the identification and resolution of the root cause. Pharmaceutical products are complex, often involving multiple sites, so additional testing is often not feasible. And as medicines become more costly, the value of the material wasted increases. The financial impact of production errors is measured in the costs of materials and other manufacturing resources, lost sales, and monetary penalties, which ultimately lead to product shortages.
Taking Steps to Resolve Drug Shortages
It’s important to have an understanding of the various contributors and causes of drug shortages. Still, the situation will persist until the pharmaceutical industry is on board with a resolution. To mitigate drug shortages, there is a need for more advanced strategies and technologies in manufacturing management.
Speed, quality, and patient safety are high priorities in an industry where there is little to no margin for error. Using manual, paper-based processes, companies forfeit the necessary agility and computing power needed to effectively oversee critical aspects of manufacturing, such as collecting data, creating reports, and delivering manufacturing instructions to the shop floor for timely product releases.
The real benefits of a digital transformation are manifest in how it supports workers. A digitized manufacturing operation connects people, processes, and systems. This fosters faster and more confident decisions and provides companies with more leverage in operations, quality, and regulatory compliance. A digital transformation can be completed in a progressive process called the Digital Maturity Model (Figure 1 illustrated below), where each phase advances the company toward a fully optimized manufacturing operation.
The basic principle is that connecting machines and systems creates intelligent networks along the value chain. For instance, machines would be able to predict failures and trigger maintenance processes autonomously. Companies improve efficiency, enhance quality, and ensure compliance with regulatory requirements.
The overarching impetus of digitizing manufacturing operations is to get paper out of production in order to mitigate errors, achieve compliance, and move products out the door faster. But many companies in pharma manufacturing are lagging behind in modernizing their operations. Recent research on the implementation of technology in life sciences product manufacturing revealed that 57% of companies have a digital manufacturing solution in place; however, only 9% have it functioning on all lines and in all sites. In the same survey, respondents said their manufacturing operations struggle with process inefficiency (64%), compliance issues (64%), preventable human errors (63%), excessive rework or scrap (59%), and delayed review and release (57%). Digital transformation has become a strategic imperative. Companies not pursuing the transition risk facing increased operating costs, falling behind competitors, and losing their market position.9
How Digitization Is Improving Drug Availability
Efficient processes are a prerequisite for any company to continue achieving its growth and scalability goals. When data is spread across disconnected systems, it’s next to impossible to analyze and operationalize it in context with other cross-functional data. Digitizing operations bridges these gaps by fully integrating the organization’s quality management system (QMS), enterprise resource planning (ERP), manufacturing execution system (MES), etc. Stakeholders can automatically transfer data to other systems and functional areas and make real-time line adjustments to minimize misallocation of resources and streamline production processes. By integrating the disparate enterprise applications in your manufacturing IT ecosystem with a fully digital production record system, manufacturers glean truly actionable, data-driven performance insights to achieve significant productivity improvements.
It’s essential to seek out ways to improve processes and reduce lead times. Digitized batch record processes and modern cloud-based batch record systems are transforming the pharma landscape and offering pharma manufacturers new opportunities to dramatically improve operations. A digital transformation typically boosts productivity by between 50% to 100%. Average-performing labs could achieve an even larger productivity improvement of 150% to 200% percent of their current rates. In some cases, digitization and automation have resulted in a more than 65% reduction in overall deviations and over 90% faster closure times. They can also prevent major compliance issues, which can in themselves be worth millions in cost savings.10
Today more than ever pharmaceutical manufacturers are striving to expand their contributions to the value chain. The sheer size of the pharmaceutical industry makes it important to stay up to date with pharmaceutical industry trends. Manufacturing companies are feeling the pressure to determine how advanced technology fits into their business models and the right ways to leverage its possibilities. It’s critical to evolve faster in order to stay current with the new trends driving the industry. The implementation of advanced technologies and best practices that improve efficiency, speed, and adaptability gives enterprises a competitive edge and ensures their long-term relevance in the industry.
References
1. “The Adderall Shortage: Why It’s Still Happening and What to Do if You Can’t Get Your Meds,” Fran Kritz, Everyday Health, May 4, 2023.
2. “A National Drug Shortage Creates Care Challenges in Oncology,” Killian Meara, Drug Topics (Voice of the Pharmacist), May 25, 2023. 3. “Drug Shortages: Root Causes and Potential Solutions,” A Report by the Drug Shortages Task Force, U.S. Food and Drug Administration (FDA), 2020.
4. “Factors Involved in U.S. Drug Shortages,” Elsen C. Jacob, U.S. Pharmacist, June 18, 2020.
5. Supra Note 3.
6. “Exclusive: U.S. FDA Flags Quality Lapses At Glenmark Pharma’s Baddi Facility,” Monal Sanghvi, BQ Prime, July 26, 2022.
7. “Antibiotics Pro Centrient Runs Afoul of FDA at Indian Manufacturing Plant,” Fraiser Kansteiner, Fierce Pharma, Dec. 14, 2022.
8. “Operations Can Launch the Next Blockbuster in Pharma,” Ulf Schrader, McKinsey & Company, Feb. 16, 2021.
9. “The State of Digital Maturity in Pharma and Medtech Manufacturing,” MasterControl, 2023.
10. “Digitization, Automation, and Online Testing: Embracing Smart Quality Control,” Norman Carra, Evgeniya Makarova, et al., McKinsey & Company, April 14, 2021.
Author Biography
Dave Edwards brings more than two decades of manufacturing, general business management, sales, and customer service experience to MasterControl, a global provider of software solutions that enable life sciences and other regulated companies to deliver life-changing products to more people sooner. Edwards most recently served as the Chief Operating Officer at 3form, a leading manufacturer of translucent building materials in the architecture and design industry. Prior to 3form, he worked at Danaher Corp., a Fortune 500 manufacturing conglomerate, and at TenFold Corp., an enterprise software company. Edwards holds an MBA from Harvard Business School and a bachelor’s degree in economics from the University of Utah.
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special
offers from American Pharmaceutical Review delivered to your inbox!
Sign up now!