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Supplier vetting and monitoring-plus comprehensive testing-ensure quality of raw materials.
The threats posed by counterfeit drug products entering the healthcare system and reaching patients have been well documented. The World Health Organization estimates that 1 in 10 medical products in low- and middle-income countries is substandard or falsified (1). A report based on 2013 data identified prescription drugs as the leading type of counterfeited products worldwide, exceeding fraudulent sales of electronics, food, auto parts, toys, clothing, and shoes (2).
Chances are, the inexpensive handbag or watch sold by a street vendor is not the authentic brand product; however, a knock-off fashion accessory will not cause the buyer physical harm. Substandard or falsified drugs can have serious health implications for patients, especially when fake drugs look like the real thing.
Regulators routinely warn consumers against buying drugs from unknown sources and have worked to shut down fraudulent online pharmacies. The Falsified Medicines Directive introduced by the European Commission and the Drug Supply Chain Security Act in the United States set standards for product identification and traceability for finished prescription drug products. Drug companies and contract manufacturers have made significant investments in packaging, labeling, software, and electronic monitoring systems to track drug packages throughout the supply chain. Materials such as edible taggants are proposed as options to track the drug product itself.
While these anticounterfeiting efforts are directed at the final drug product, bio/pharma companies must be vigilant for fraudulent or substandard materials at the other end of the supply chain: the raw materials used to make the drug.
Contaminated or substandard ingredients pose serious safety threats. Two examples, one from more than a decade ago and one that is ongoing, illustrate the vulnerability of the raw materials supply chain, shortcomings in quality control processes at drug companies, good manufacturing practice failures, flaws in regulatory oversight, and the need for improved test methods.
Following reports in 2007 and 2008 of adverse reactions, including deaths, to the commonly prescribed blood thinner heparin, an investigation revealed that the patients received contaminated doses of the drug containing over-sulfated chondroitin sulfate (OSCS), an inexpensive synthetic adulterant. Regulators suspected that the OSCS was added to offset a shortage of heparin, which was in short supply due to a disease outbreak in pigs, the animal species used to source the material.
Regulators traced a complicated supply chain from a US-based firm to an affiliated China-based manufacturer, and the crude heparin supply chain in China. The supplier argued that existing GMPs and pharmacopeial testing standards could not detect, identify, or remove the substance (3). In response to the heparin crisis, the US and European pharmacopeias made extensive revisions to their respective heparin monographs.
The current contaminant case, which involves recalls of generic angiotensin II receptor blocker (ARB) drug products, began in mid-2018 when a generic drug manufacturer identified N-nitrosodimethylamine (NDMA), a probable human carcinogen, in an API supplied by China-based Zhejiang Huahai Pharmaceutical Co., Ltd. (ZHP). Subsequent testing found N-nitrosodiethylamine (NDEA) in valsartan products and some irbesartan and losartan products; in March 2019, N-nitroso-N-methyl-4-aminobutyric acid (NMBA) was identified in losartan potassium products.
The agency suspects the impurity may have been generated by chemical reactions during the API manufacturing process, or from the reuse of materials, such as solvents.
While admitting that neither the industry or agency understood how NDMA or NDEA could form during the API manufacturing process, FDA clearly established that the responsibility for quality control is with the API manufacturer, stating: “It is the manufacturer’s responsibility to understand and assess their manufacturing process, assess any changes to that process, and based on that assessment and understanding, ensure test methods utilized can detect impurities expected to develop during the manufacturing process” (4).
The agency reinforced that message in a warning letter to ZHP in November 2018: “Your response states that predicting NDMA formation during the valsartan manufacturing process required an extra dimension over current industry practice, and that your process development study was adequate. We disagree. We remind you that common industry practice may not always be consistent with CGMP [current good manufacturing practice] requirements and that you are responsible for the quality of drugs you produce” (5).
“The global nature of drug supply chains and manufacturing practices has evolved dramatically in recent decades,” says Jaap Venema, chief science officer at the US Pharmacopeia (USP). “This has made it necessary for all stakeholders involved in drug manufacturing to explore emerging areas of risk and identify where medicine quality may be vulnerable to being compromised.” FDA, USP, and other stakeholders must work together to develop best practices and appropriate predictive tools for understanding and addressing these risks, he says.
“Recent industry disruptions around recalls and adulteration drive home the importance of knowing your suppliers and understanding their sources and suppliers of materials,” says Maxine Fritz, executive vice-president, Pharma BioTech, NSF International. “It’s essential to have a process that traces raw materials to origin and verifies the integrity of the system at every point along the way.”
The supplier must have product requirements that include the composition of the materials, as well as any product/process and/or material degradants or variability. In addition, manufacturers that rely on sole source suppliers are at the mercy of that supplier’s ability to deliver the materials as needed, says Fritz.
“Because of the complexity of the global excipient supply chain, it is often difficult for a pharmaceutical manufacturer to know the actual source of materials, or to have complete faith in the testing of critical quality attributes of a material, even from trusted suppliers,” says Catherine Sheehan, senior director, excipients, USP. Over time, suppliers may change production processes, organizational structures, distribution chains, or lab services. “Routine identity testing of incoming materials and periodic supplier validation may help reduce risks,” she says.
The global scale and variety of suppliers for pharmaceutical raw materials creates complications for vetting suppliers, says Frederic Prulliere, Raman ID products manager, Agilent Technologies. “This leaves room for low purity, adulterated, counterfeited, or even harmful products to enter the drug manufacturing supply chain. Limited governmental oversight, multiple industry suppliers, and geopolitical events can all add to the challenge of supplying raw materials in the pharmaceutical industry,” he says.
The potential to receive counterfeit materials is greater for high value excipients, says Sheehan. “Some materials, like glycerin, have shown a high risk of economic adulteration. More than 800 deaths have been attributed to multiple glycerin adulteration events within the past century,” she reports. “Without proper testing, substandard or even poisonous substances can then enter the pharmaceutical supply chain.”
It is imperative that pharma companies follow 21 Code of Federal Regulations 211.84(d)(1) (2), which mandates full identity testing for all incoming lots of drug product components, Sheehan recommends. If a supplier’s certificate of analysis (CoA) is used in lieu of analysis of other attributes, that supplier’s test results should be regularly validated by the pharma company.
While the potential for introducing adulterated materials in the pharmaceutical supply chain is real, companies with a risk-based approach to incoming raw materials inspection are unlikely to use counterfeit or adulterated products, says Prulliere. “Controlling the quality of the raw material before it enters production, qualifying and vetting suppliers, assessing and managing risks, and tolerance for these risks are the quality pillars that pharmaceutical companies should implement to deal with this potential,” he says.
Current standards should help pharma companies identify counterfeit materials before they enter production, says Sheehan; however, not all pharma companies are applying this standard consistently and performing identity testing on each lot of incoming raw materials, including excipient raw materials. “Occasional or skip lot testing or reliance on a supplier’s CoA is inadequate,” she says, noting that FDA cited 20 different firms in 2018 for failure to adequately test incoming raw materials.
Many, but not all, drug manufacturers are testing for substandard materials, which is concerning from a public health standard, says Fritz.
“A certificate of analysis is a strong reassurance, but a certificate is only as good as the testing performed, the quality oversight, and the quality systems that the supplier has in place,” says Fritz.
“A company can’t watch raw materials being produced, load them in a truck, and transport them to their factory. Using a robust supplier qualification that includes routine inspection and verification will help to lower risk and increase confidence in the quality of incoming raw materials,” says Sheehan. “However, routine material analytical testing of each incoming lot using a USP documentary standard and associated reference standard, if available, provides a final quality check and safeguard to help ensure only acceptable materials are released into production.”
Ideally, pharma manufacturers should test for critical quality attributes, but at a minimum they must perform a full identity test for all incoming lots of components, she says.
“Using PIC/S [Pharmaceutical Inspection Co-operation Scheme] guidance, quality control labs are only required to identify raw materials provided a supplier evaluation program is in place. If not, a full analysis is usually conducted,” says Prulliere.
Mid-infrared, near infrared, or Raman spectroscopy are typically effective for verifying incoming raw materials due to probing the vibrational modes of a material providing a structure specific spectrum, he says. “Spatially offset Raman spectroscopy (SORS) is gaining popularity. SORS extends the depth of penetration to eliminate container contribution to the measurement and permit analysis through non-transparent containers.”
A third-party supplier verification service can be used to ensure suppliers are adhering to a culture of quality, follow appropriate CGMP regulations, and produce materials that pass random lot analytical testing at regular intervals, says Sheehan. “Incorporating this verification plan within a quality standard operating procedure may help pharma manufacturers comply with FDA supplier validation requirements for using CoA data,” she says.
1. World Health Organization, “Substandard and Falsified Medical Products.”
2. P. Behner, M-L Hecht, and F. Wahl, Fighting Counterfeit Pharmaceuticals: New Defenses for an Underestimated-and Growing-Menace, PriceWaterhouseCoopers (2017).
3. D. G. Strunce, Statement, Scientific Protein Laboratories–Subcommittee on Oversight & Investigations Committee on Energy & Commerce US House of Representatives, April 29, 2008.
4. FDA, Q&A on Angiotensin II Receptor Blocker (ARB) Medication Class Investigation.
5. FDA, Zhejiang Huahai Pharmaceutical, Warning Letter, Nov. 29, 2018.
Vol. 43, No. 4
When referring to this article, please cite it as R. Peters, “Locking Fraudulent Materials Out of the Supply Chain," Pharmaceutical Technology 43 (4) 2019.