There’s no question that pharmaceutical and medical device production has become more complex, especially with the growing number of biologics and combination products. These products come with their own set of complicated production challenges and supply chain risks. As life sciences companies outsource to better scale and contain costs, complexity only increases. With more manufacturing functions externalized — and outside of direct oversight — ensuring continuity of processes, regulatory compliance, and accurate, high-quality data from start to finish is difficult.
“It used to be that if a company did any outsourcing, it was primarily limited to sourcing raw materials,” said Daniel Matlis, founder and president of Axendia, a life sciences industry analyst firm. “But as a compounding number of companies began to go outside their four walls, they discovered opportunities to reduce cost and shed non-core competencies. Now, many aspects of manufacturing are handled by contract organizations.”
Demand for manufacturing outsourcing has grown steadily, from $800 million in 1998, to $2.5 billion in 2014 and is expected to reach $4.1 billion by 2019, according to a recent survey on contract manufacturing from High Tech Business Decisions. Today, the U.S. is the largest market for contract manufacturing worldwide. In total, 80 percent of the active pharmaceutical ingredients consumed in the U.S. originate in India and China, and about 40 percent of the finished products come from outside the U.S. Europe lags slightly behind, but growth is expected from developing regions such as Asia Pacific, with the Japanese market projected to register a compounded annual growth rate of 13 percent.1
That’s the good news, but increased outsourcing also adds several degrees of complexity to an already complicated process. As life sciences companies relinquish a level of control over the manufacturing process in return for lower costs, they open the door to diminished transparency. Without worldwide supply chain visibility, quality can suffer. In fact, a number of popular prescription drug products manufactured in India were recently banned from U.S. importation due to quality concerns — these include acne treatment Accutane and the antibiotic Cipro. These issues continue to grow, driving the U.S. Food and Drug Administration to increase its local presence throughout the world.
“We now have offices and inspectors in New Delhi and Mumbai, India, as well as China, Latin America, South Africa and a growing cadre of international inspectors elsewhere,” said Dr. Margaret Hamburg, former commissioner of the FDA, during a 2014 interview. “We’re trying to achieve the same levels of inspection, enforcement and compliance that we would expect of any company manufacturing drugs for consumption by the American public,” Hamburg said.2
“Unfortunately for the life sciences industry, there have been a number of challenges associated with contract organizations, which has put a finer focus on the need for control and visibility into what happens at suppliers,” said Matlis. “Regulators are well aware of this situation.” In fact, of the 20 warning letters issued by the FDA Center for Drug Evaluation and Research Office (CDER) of Manufacturing Quality in 2015 — more than half were related to cGMP.
Despite the government effort, manufacturers are still dealing with tragic manufacturing errors that are not always discovered until it’s too late. For example, Heparin, a popular blood thinner manufactured in China, was contaminated by someone upstream in the supply chain. A cheaper, incorrect active ingredient that tested just like the right active ingredient was substituted in the manufacturing process. The drug made it into the U.S. supply chain, causing a large number of patients to become ill.4
Vigilant supply chain visibility is the key. It provides the crucial system of checks and balances that often go missing when a company moves critical stages of its manufacturing process to outside vendors. As the supply chain becomes more complex and thus more risky, companies are finding that they need to adapt their quality systems to address these risks.
TROUBLE WITHOUT TRANSPARENCY
For life sciences companies, transparency means visibility into the manufacturing process, timely access to data and content, and an accurate audit trail of all activities. Often, companies do not learn about issues that can hinder the delivery of a finished product until it is too late either because the supplier is trying to resolve the problem on its own or the manufacturer is never made aware. Life sciences companies try to prevent problems by maintaining frequent communications with contracted organizations, often via phone or email, but this is not practical, sustainable or secure.3 When exchanges of vital information between companies and CMOs rely on paper-based and manual processes that involve many people reading and transcribing emails and faxes — errors are bound to occur. As problematic, there is no consolidated audit trial of these exchanges, making it nearly impossible to confirm and manage.
The troubling reality is that process gaps and inaccurate or incomplete data can lead to products that do not meet health authority standards for safety, purity or efficacy. In addition to threatening the safety of medications, poor data quality can create costly, time-consuming bottlenecks in the drug development process…and, ultimately, dangerous drug shortages.
The negative consequences of fragmented quality processes, poor data quality and lack of transparency are even more acute when a healthcare authority sends a warning letter to a company stating that its manufacturing processes, or those of its CMO, do not meet regulatory requirements. From 2007 to 2013, the number of warning letters issued by the FDA increased by 78 percent, with this number expected to increase in the coming years.4 After receiving an FDA Form 483 at the conclusion of an inspection, a company can continue manufacturing, but it is given specific instructions on steps it must take to correct problems. The FDA’s more severe Consent Decree letter can order a company to stop manufacturing altogether or order it to shut down a particular facility. Either notification usually requires that a manufacturer evaluate and revamp processes, resulting in devastating cost and time losses. In the end, it delays time to market — which can cost companies up to $8 million a day, according to various sources.
Not only can these warnings cause serious financial losses for life sciences companies, but also can dramatically erode public trust, impacting the brand and corporate reputation in confounding ways.
OUTSOURCE MANUFACTURING, NOT RESPONSIBILITY
Life sciences companies can outsource their processes, but not responsibility for quality. According to the International Council for Harmonization (ICH), “The pharmaceutical company is ultimately responsible to ensure processes are in place to assure the control of outsourced activities and quality of purchased materials.”5
The EU legislation for the pharmaceutical section, guidance contained within EudraLex, reaffirms this standpoint: “The contract giver is ultimately responsible to ensure processes are in place to assure the control of outsourced activities.”6 And, in the U.S., the FDA regards contract facilities “as an extension of the manufacturer’s own facility and therefore expects a company’s supplier network to perform as an extension of its own quality system. The FDA also states that “the owner’s quality unit is ultimately responsible for approving and rejecting drug product manufactured by the contract manufacturer.”7
The FDA is proposing to standardize quality metrics — defined as “objective measures of the quality of a product or process” — as a tool to evaluate drug manufacturers and compare quality results between similar companies and products. The FDA plans to capture data from manufacturers over a one-year period for lots attempted, lots rejected, lots with out-of-specification results, stability tests conducted, and the number of quality complaints. After the data is compiled, the FDA says that it will use this aggregated data to generate metrics to arrive at an objective measure of quality.⁸
“Now that companies are dealing with a global and outsourced environment, they need to truly characterize their products uniformly and to scientifically understand what are the critical-to-quality (CTQ) attributes essential to producing the desired outcomes. Just as important is the master data, which needs to be properly defined, curated and managed. Finally, everything — the documents, the data, the SOPs — needs to be totally transparent. This is the direction of regulators as well,” said Matlis.
Visibility is possible with the right technology. It starts with a hyper-connective network that links multiple partners in a fluid, cloud environment. Having continuous processes and timely access to data all along the supply chain fosters collaboration and transparency among the company, outsourced manufacturers and suppliers globally. This opens up the ability to measure processes, ensure compliance standards are met and quality standards are exceeded. Companies can then reduce risk, find anomalies or opportunities for improvement, and act upon them quickly.
Yet, while 90 percent of companies have implemented at least one quality management system, they often reside within and are only accessible within a company’s internal network.9 Such on-premise solutions do not easily allow appropriate levels of access to those who need it most, including most especially, contract partners. As companies outsource more, everyone — brand owners, suppliers and CMOs — need complete access and, therefore, visibility to the most current, accurate information available. This is data transparency, and it is the key to quality.
THE CLOUD MAKES QUALITY CLEAR
Using cloud-based technology to orchestrate drug development and manufacturing enables seamless processes and provides all stakeholders with access to accurate data and content in a single, authoritative system. It also enables partners to be a part of the process — offering input, contributing data and improving the entire operation. Most crucially, the cloud solution should extend enterprise-wide, from end to end, to ensure that all relevant data is captured reliably across the organization because there is just one source of truth.
The cloud gives life sciences companies the ability to extend visibility across all parts of the value chain, while at the same time enabling partners to access information they need to provide valuable services. Raw materials suppliers, CROs, CMOs, brokers and distributors can interact simultaneously under very controlled conditions that ensure up-to-date information is always available to those that need it — whenever, wherever, however they need it.
“Providing our partners with direct access to our validated, cloud-based quality system ensures we maintain a clear chain-of-custody on manufacturing documents such as batch records and audit reports,” explained Craig Gassman, associate director of regulatory operations at Karyopharm Therapeutics — a clinical-stage pharmaceutical company focused on discovery and development and subsequent commercialization of novel first-in-class drugs directed against nuclear transport and related targets for the treatment of cancer and other major diseases.
Modern solutions also enable life sciences companies to gain real-time visibility into the status of quality processes. Workflows can be set up to allow both internal staff and outsourced partners to view important data or content uploaded by either party all in one place — again, for a single source of truth. Seamless processes and comprehensive views prevent breaks in the audit trail that cause mistakes, quality control issues and even FDA observations. For example, the operations team can set alerts for people in the workflow and the entire team can see who performed tasks and when. This close collaboration is essential for efficiency and quality. In clinical trials, for instance, cloud applications speed the collection of all trial-related content, providing status updates throughout a study’s start-up, execution and close.
MANAGING PROCESSES, DATA
In manufacturing, with greater outsourcing of critical functions, companies are starting to rely on cloud solutions to manage quality processes and keep track of data received from contract test labs, manufacturers and other specialty partners. Key people can easily review executed batch records from anywhere before acceptance and release of product. Deviations and subsequent communications are also centrally tracked and visible to all parties. Increasing efficiency while improving compliance and quality results in fewer inspections, faster inspections and significant reduction in risk of receiving warning letters or forcing dreaded plant shutdowns.
“In this outsourced environment, it becomes very difficult to manage operations using ‘tribal knowledge,’ that is, bringing in a person or a group of people who really understand a step or process or molecule and getting their opinion to address an issue,” said Matlis. “Once a life sciences company establishes quality attributes critical for each product and the requisite data that needs to be managed, it must implement solutions that not only manage quality, but even more important, improve quality.8
The key to solving these challenges is a shift in the underpinnings of the life sciences supply chain. It’s time to operate the business as a broader network that allows suppliers and partners to become directly tied into the central nervous system of the life sciences company. To do so effectively, organizations are making the cloud the heart of that network — and, with greater visibility, successfully retaking full responsibility for the quality of their products.
1. “Achieving Global Supply Chain Visibility, Control & Collaboration in Life Sciences: Regulatory Necessity, Business Imperative,” Axendia, 2010. p.7
2. “The Safety of Prescription Drugs Made Outside the U.S.,” The Diane Rehme Show, February 20, 2014.
3. “Measuring the Business Value of Data Quality,” Gartner, 2011.
4. “FDA Warning Letters Rise 78% Over Six Years with Increase Expected in 2015,” The Pharma Letter, 2014.
5. “ICH Harmonised Tripartite Guideline: Pharmaceutical Quality System Q10,” International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2008.
6. Eudralex Volume 4 Chapter 7, Outsourced Activities
7. 21 CFR 200.10
8. “Quality Metrics: What Does It Really Mean?” Contract Pharma, 2016.
9. FY17-Mfg-Managing External Quality