Packaging
device using three different solvents: dimethyl sulphoxide, ethanol-water and phosphate buffer. Each solvent pulled a different subset of compounds, requiring three separate toxicology reports. “It took over 100 hours of work,” he says. “But in the end, none of the compounds posed a toxicological concern.” In another case, however, the story was different. A known mutagen and carcinogen, alpha-methylstyrene, was detected in a product intended for intravenous delivery. The level detected exceeded the 1.5mg/day threshold set by the regulators for mutagenic impurities. “We had to classify that risk as ‘minimal’ rather than ‘negligible’,” Erexson says. “There’s no such thing as zero risk. But we quantified it and put it in perspective.”
Perhaps the most dramatic example came from a neonatal product called Survanta, a synthetic surfactant used to treat premature infants with respiratory distress by replacing the missing natural fluid in a baby’s lungs. Several extractables were identified in the packaging, and due to the tiny body weight of the patients (as low as 0.5kg) every compound exceeded the calculated permitted daily exposure. “By the numbers, everything failed,” Erexson says. “But this is a life-saving drug. It’s given once, maybe twice. We had to argue that the benefit far outweighed any theoretical risk. And the regulators accepted that.”
As pharmaceutical formulations become more complex, with the rise of biologics, mRNA therapies and combination products, the margin for error in drug stability is shrinking. These advanced therapies are often highly sensitive to environmental changes and chemical interactions, meaning even trace levels of leachables from packaging materials can compromise their effectiveness, safety or shelf life. In this evolving landscape, advanced E&L testing could help ensure that increasingly sophisticated drugs, such as antibody- drug conjugates (ADCs) – a class of targeted cancer therapies that combine the precision of antibodies with the cell-killing power of cytotoxic therapeutics – remain safe, effective and stable. “Some ADCs don’t even reach the tumour because their linkers aren’t stable enough,” Erexson explains. A leachable could hypothetically accelerate that degradation or interact with the payload, he explains. “These are powerful drugs, and they’re sensitive to even minor changes in their environment.” Cell and gene therapies present toxicologists with additional challenges, due to the use of ancillary materials. Such compounds are used during manufacturing but aren’t intended to be present in the therapeutic. They are often complex biological materials, such as recombinant insulin and human serum albumin, which could potentially interact with the final product. Regulatory agencies have responded to pharma’s more complex medicines with increasingly detailed guidance. In the US, the United States Pharmacopeia (USP) chapters 1663 and 1664 address
www.worldpharmaceuticals.net
best practices for designing E&L studies, including storage conditions and analytical thresholds.
New guidance Globally, ICH Q3E is being developed to provide harmonised guidance for assessing and controlling E&L in drug products. For medical devices and combination products, ISO 10993-17 is the primary reference for toxicological risk assessment, and was updated in 2023. Not everyone is pleased with how these standards are evolving, though. “The new version of ISO 10993-17 is 73 pages of verbose garbage,” Erexson says. “It adds complexity without actually improving patient safety.”
“By the numbers, everything failed. But this [was] a life-saving drug. It’s given once, maybe twice. We had to argue that the benefit far outweighed any theoretical risk. And the regulators accepted that.”
One major concern is regulatory divergence. “The
FDA’s Center for Devices and Radiological Health (CDRH) is now relying almost exclusively on ISO 10993-17,” Erexson claims, “while ignoring ICH Q3E, which is not smart.”
While it is true that CDRH relies heavily on ISO 10993-17 for medical devices, the ICH Q3E is a guideline specifically for extractables and leachables in drug products, while ISO 10993-17 is for the biological evaluation of medical devices, which includes assessing leachable substances. These are distinct regulatory frameworks for different product types. So, there is an argument that it is more a matter of different guidelines applying to different regulatory domains. However, this disconnect could lead to duplicated studies, delayed approvals and unnecessary cost burdens, particularly for multinational drug developers juggling submissions in multiple regions. One of the most important lessons Erexson has learned over his career is the value of early collaboration. Too often, toxicologists are brought in after the materials have already been selected, he says: “Then we’re expected to make the toxicology problem go away. More often than not, this is not possible.” He argues that toxicologists should be involved at the very start of product development, alongside formulation scientists, packaging engineers and quality assurance teams. This proactive approach can help avoid packaging material choices that are later flagged for E&L issues, saving time and money, and ensuring patient safety isn’t compromised under regulatory pressure. As the pharmaceutical landscape continues to evolve, so too must the discipline of E&L. New therapeutic modalities bring fresh challenges. But the core principle remains unchanged: packaging must protect the drug, not alter it. ●
39
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85
