Testing the Limits of Extractables and Leachables

There are two main threats posed by extractables and leachables (E&L), contamination from unwanted impurities such as nitrosamine or chromium causing toxicity issues and diminution of drug efficacy or potency by destabilizing or perturbing the API. From a system-wide perspective, the E&L threat posed by manufacturing equipment is small, versus lifetime container closure and material packaging of drug products. The effects of the former are comparatively sudden and obvious (and hence easier to spot), versus the slow chemical transformation that might occur in the latter. In this sense, leachables are a subset of their parent extractables.

Recalls of nitrosamine-contaminated drugs “underscore the need for robust analytical methods and risk-based approaches for E&L and nitrosamines testing. Additionally, drug product manufacturers must ensure that toxic elemental impurities are under a state of control in their products” (1). There are many courses of instruction one can take to learn how to implement good monitoring of E&L. In line with wider industry trends, risk-based approaches to E&L testing for small molecules, especially, are becoming more commonly implemented, and the salient issue of nitrosamine contamination has certainly accelerated that trend.

Plasticizers, stabilizers, lubricants, or colorants are well-known components of medication packaging systems. The effects they have on product and patient safety partly depend on which patients, when, and through what delivery system. Aerosols, sprays, and transdermal packaging are high risk compared to tablets, capsules, or topical powders. Andrew Feilden, European E&L strategic director, Element Materials Technology, when looking back on how some regulations were formed, said, “Inhalation aerosols and sprays are deemed to have the highest likelihood of packaging component-dosage form interaction and the highest degree of concern based on the route of administration. As such, it is not too surprising that most of the early work on regulatory requirements focused on orally inhaled and nasal drug products. It was groups such as the International Pharmaceutical Aerosol Consortium on Regulation & Science that initiated and built on supply chain interaction and understanding” (2).

There is an interplay between the permitted concentration limit (PCL), the maximum daily dosage (MDD), and product material design. It is interesting to consider predictive modeling versus exposure for E&L and how far the industry has come with artificial intelligence (AI) in advancing predictive modeling and where the limits lie.

Medical devices and combination products

Over the past few years, there has been an increased prevalence for products to be classified as drug-device combination products. This classification leads to several additional considerations and challenges, not least with E&L study design and regulatory review of these studies. According to Nicholas Morley, principal scientist at Element Materials Technology, “Regional differences can exacerbate this and make it even more challenging for products seeking registration in multiple markets. Extractable and leachable studies performed on medicinal products typically follow standards and guidelines set out by the Product Quality Research Institute (PQRI) and the US Pharmacopeia (USP), whereas studies performed on medical devices follow standards set out by the International Organization for Standardization (ISO). Depending on the device type, there may be requirements to meet multiple different standards and guidelines which have similar aims (i.e., determining patient risk due to the product) but use different approaches to achieve them.”

No pun intended, this compounds an already complex process when trying to set minimums and maximums for E&L testing, particularly for high-potency drugs. Morley continues, saying, “When designing and performing studies on drug-device combination products, it is crucially important to have a deep understanding of the similarities and differences between the various extractable and leachable standards and guidelines, as well as the different regional expectations, and review authorities when designing E&L studies to minimize potential deficiencies and delays in approval.”

Single-use systems

Where possible, the industry is accelerating migration toward continuous manufacturing and single-use systems (SUS). With regard to E&L, setting baselines and comparing differences can be helped by standardized protocols, which can facilitate “like-for-like assessments between each supplier’s SUS products and components” for end-users of SUS, according to Dan Rosen, vice-president and general manager of bioproduction at Thermo Fisher Scientific (3).

As said earlier, leachables being a subset of extractables, extractables testing can show which leachables might emanate from the material under standard conditions, or extreme conditions, and through simulation or modeling. However, one wrinkle to pay attention to is that new or different leachables might form during sterilization, storage, or use (3).

There is talk about a migration away from the well-characterized and established response of materials to gamma irradiation versus (due to lack of gamma testing capacity) employing less understood X-ray sterilization methods. “Current theories suggest that the E&L profile should be similar after X-ray or gamma sterilization, but it is important to perform extractables testing, says the Bio-Process Systems Alliance (BPSA)” (3).

According to Lalit Saxena, senior director of MSAT at Samsung Biologics, “Regulatory requirements are becoming increasingly stringent with respect to patient safety, and thus more in-depth risk assessment to implement single-use technologies for late-stage downstream unit operations is required” (4). Saxena pointed to the European Union’s Annex 1 as an example of regulatory expectations. Challenges are also being created by compliance with United States Pharmacopeia (USP) <788> (for particulate matter) and USP <85> (for endotoxin certification) for single-use materials. Customized single-use assemblies increase the complexity, especially with components from multiple vendors, according to Saxena (4).

Regulations

The impact on E&L study design can be easily overlooked. To understand this, it is important to determine who is responsible for the review of the extractable and leachable studies.

“Different E&L guidelines apply to pharmaceutical container closure systems (e.g., USP or PQRI) compared to medical devices (ISO). In additional, the different regional organizations can have their own specific requirements or interpretations. Extractables studies on container closure systems and single-use manufacturing process components often employ binary solvent systems,” states Morley. “Whereas CDRH [the Center for Devices and Radiological Health] prefers extractable studies to be performed using pure solvents. When a product is classified as a drug-device combination product (e.g., a pre-filled syringe containing an active drug-product), extractable studies may need to meet the requirements of the pharmaceutical container closure guidelines as well as the medical device standards simultaneously. Within the EU, if a drug-device product is classified as integral as is the case for pre-filled syringes, a notified body opinion is required prior to receiving a MAA [marketing authorization applications] approval. When designing and performing studies on drug-device combination products, it is crucially important to have a deep understanding of the similarities and differences between the various extractable and leachable standards and guidelines,” he concludes.

Predictive modeling and new analytics

One of the great new tools for pharmaceuticals is the rise and integration of AI models and programing. Opinions vary in degree of enthusiasm, with many highly supporting greater inclusion, implementation, and reliance on such systems. But there are minority reports circulating among the E&L expert community. When asked how far the industry has come with AI in advancing predictive modeling for E&L, Rick Reiley, technical director, Extractus, replies, “We have not come far at all.” He points out that, “this is about the data sets available to train AI. The first problem is the data itself: data needs to be marked up with mass assignments, and modern software suites (Masshunter, UniFi/masslynx, and xcalibur) can do this. [However,] it is important to have correct identification of compounds as chromograph systems can vary the elution profile (ideally, compound assignments should be confirmed with a standard or reference material which are not always commercially available).”

Reiley continues to draw attention to a lack of extractable data sets that directly link to leachable data sets.“The vast majority of extractable data sets,” emphasizes Reiley, “do not have a corresponding leachable data set to train the AI, and those that do exist are not available for AI teams as these are company secrets. If you make a product and you disclose data to a regulatory body, the data [are] flat (no data files, just summary data and chromatograms/spectra) as giving more information invites greater scrutiny. If an AI algorithm were to find additional peaks from raw data, it would trigger review of a product license and potentially pull a product from the market.”

While on this subject, Reiley goes on to discuss a third hurdle regarding extractable data sets. “Very few have good data (meaning that peaks are not identified confidently, performed with rigor [usually single extraction with single injection] or separated chromatographically). There are problems with sensitivity limit of quantification (LOQ) that is not low enough), poor chromatography, poor identification (either none or letting the library decide) as well as inappropriate separation technique so the peaks are lost in noise or solvent peaks,” he states.

This last hurdle could be overcome by original equipment manufacturers (both instrument and packaging/material vendors) “as they don’t directly market drugs/medical devices, but they have incentives to avoid the research. You will have to source the materials for an extractable and leachable study, but it would need to be a large data set. Ideally, you would want to pick something with multiple suppliers (you don’t want to alienate a potential or current client), and it would require a lot of guesswork as E&L studies start with a risk assessment (calculating analytical evaluation threshold [AET] will vary depending on a number of factors). The alternative would be an independent body or an academic research group, but it would require a lot of funding (industry would not fund this) as E&L studies are expensive due to instrumentation and time required,” concludes Reilly.

Traditional analytics for identifying extractables and leachables are liquid or gas chromatography combined with mass spectroscopy (LC–MS or GC–MS). But according to Fran Adar, principal Raman applications scientist, Horiba Scientific, “From my discussions with Mark Witkowski [at FDA], I understand that the standard LC–MS and GC–MS techniques have difficulty identifying inorganic materials. In contrast, Raman spectroscopy is equally active for inorganic and organic compounds” (5).

Adar went on to say, “What Raman can do that those standard techniques cannot is identify minute amounts of material—typically 1–2 μm2 × 1–5 μm deep. And there are no waste products from the analysis that need to be disposed of. Is the information the same? Maybe yes and maybe no. The measurement is done on intact material whereas MS tears the molecule apart. There may be cases where information is lost in tearing the molecule apart” (5).

It could be that new tools from other application areas may migrate over to help out the E&L field before too long. There is certainly interest there, and some room for improvement.

References

1. Panzade, P. Nitrosamines, Elemental Impurities, Extractables and Leachables: A New Normal for the Pharma Industry. Webinar. Catalent. PharmTech.com. Oct. 2, 2023.
2. Feilden, A. Material Management and the Impact on Extractables and Leachables,” BioPharm Intern. 2022 35 (7) 41–43.
3. Markarian, J. Analyzing Extractables and Leachables in Single-Use Systems. Pharm. Technol. 2022 46 (10) 48-51.
4. Challener, C. Benefiting from Single-Use Tech Downstream. BioPharm Intern. 2024 37 (4).
5. Adar, F. Exploration of the Use of Raman Microscopy to the Identification of Extractables and Leachables from Polymeric Containers. Spectroscopy 2022 37 (11) 8-13. DOI: 10.56530/spectroscopy.sc1575j6

About the author

Chris Spivey was previously the editorial director of Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®

Vol. 48, No. 4

April 2024

Pages: 28-30

Citation

When referring to this article, please cite it as Spivey, C. Testing the Limits of Extractables and Leachables. Pharmaceutical Technology® 2024 48 (4).