Alivia Leon

Analyzing extractables and leachables (E&L) is paramount to ensuring the safety of a drug product and determining any toxicological risks. Examining extractables can help identify potential risks of leachables contaminating or affecting the quality of a drug product. Extractables can be extracted through the use of solvents under certain extraction conditions or can be forced out with high heat without solvents. Extractables may be potential leachables, but not all extractables leach into drug products. Leachables migrate from the container into the drug product or directly to the patients under normal storage or use (1).

Potential sources of leachables include primary packaging components, secondary packaging components, intermediate manufacturing components, or APIs. There are also E&L that can be introduced from the component molding process and can end up becoming a leachable, such as mold release agents or lubricants (1).

Various regulatory guidelines have been published due to the potential safety risks that leachables pose. FDA published a guidance included in the 

 Title 21 that highlights guidelines on drug product containers and closures, such as:

“Drug product containers and closures must not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.

“Container closure systems must provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product.

“Drug product containers and closures must be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use. Such depyrogenation processes must be validated,” (2).

 General Chapter <665> Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products in 2022, which will come into effect in 2026 (3). The document highlights analytical methods of risk assessment of E&L, including biologic drugs.

The Product Quality Research Institute (PQRI) published two industry guidance documents, titled 

Safety Threshold and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products

Safety Thresholds and Best Demonstrated Practices for Extractables and Leachables in Parenteral Drug Products (Intravenous, Subcutaneous, and Intramuscular)

 (5) that highlight industrial details on how E&L assessments should be performed. The combination of both regulatory and industrial guidance documents provides a fleshed-out guideline for E&L analysis.

Differences between small- and large-molecule drugs

Leachables can interact with small-molecule and large-molecule drugs in different ways, which is a key consideration when testing for E&L in biologics versus small molecules. Biologics can be immunogenic, and a leachable may interact with a protein and trigger an immune response (6). The efficacy of a biologic drug may also potentially be reduced through interactions of leachables with drug molecules through post-translational modification biochemical reactions, such as oxidation, aggregation, or unfolding, explained Lester Taylor, pharma marketing manager at Agilent (7).

Biologic drugs are sensitive and complex. Extractables or potential leachables that may migrate into a drug product have the potential to interact, and therefore, affect the product quality, safety, or stability, explained Fran DeGrazio, vice-president, global scientific affairs and technical services, West Pharma. Additionally, large molecules have greater surface areas, and interactivity can lead to conformational modifications and other interactions that may impact product quality (7).

A main concern for leachables in small-molecule drugs is the specific toxicity/genotoxicity profiles, said Dr. Wayland Rushing, senior scientific advisor at ABC Laboratories. However, with biologics, there is also the concern of the ability of the leachable to interact with the biologic product itself. Many biologics are very sensitive to metal content. As a result, additional monitoring of the metal content may be required (8).

Key components such as semi-volatile organic compounds, non-volatile organic compounds, volatile organic compounds, and metals can be identified during an E&L study. For extractable studies, exaggerated conditions are often used to emulate a “worst-case scenario,” and the data are used to help determine what further studies are needed to mitigate future risks. Examples of analytical techniques used to detect E&L include gas chromatography mass spectrometry, liquid chromatography mass spectrometry, and inductively coupled plasma-mass spectrometry (9). Taking these differences into consideration can help identify the right tests to use for detecting E&L.

1. Yu, X., and Wood, D. Analytical Testing—Extractables and Leachables
Testing for Pharmaceutical Products. 

2. CFR Title 21, 211.94 (Government Printing Office, Washington, DC).

3. USP. General Chapter <665>, Plastic Components and Systems Used to Manufacture Pharmacueitcal Drug Products and Biopharmaceutical Drug Substances and Products.

 Safety Threshold and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products.

 Safety Thresholds and Best Demonstrated Practices for Extractables and Leachables in Parenteral Drug Products (Intravenous, Subcutaneous, and Intramuscular).

6. Moffatt, F. Extractables and Leachables in Pharma-A Serious Issue. (Solvias, accessed March 9, 2023).

7. Siew, A. E&L Risk Assessment for Biologic Drug Products. 

8. Hernandez, R. Special Considerations for Extractables and Leachables Testing in Biological Products. 

9. Thermo Fisher Scientific. Extractables and Leachables: Regulatory Requirements for Vaccine and Biologic Products. (Thermo Fisher Scientific,

Articles

E&L analytical testing methods can be determined through pointed consideration of the differences small- and large-molecule drug products.

E&L Analytical Testing Considerations

GSK and BELLUS Health announced on April 18, 2023 that they have entered into an agreement under which GSK will acquire BELLUS, a Canada-based late-stage biopharmaceutical company focused on therapeutics for refractory chronic cough (RCC), for approximately $2 billion.

The acquisition will provide GSK access to camlipixant, a highly selective P2X3 antagonist currently in Phase III development for the first-line treatment of adult patients with RCC. The treatment has an anticipated regulatory approval and launch in 2026. There are currently no approved medicines for RCC in the United States and European Union (EU), according to a company press release.

An estimated 28 million patients suffer from chronic cough, with 10 million patients globally and 6 million in the US and EU suffering from RCC for more than one year, according to the release. RCC is defined as a persistent cough that lasts for more than eight weeks that does not respond to treatment for an underlying condition or is otherwise unexplained.

“Patients suffering from severe forms of refractory chronic cough can experience [more than] 900 coughs daily, resulting in quality-of-life issues,” said Luke Miels, chief commercial officer, GSK, in the release. “Camlipixant, a novel, highly selective P2X3 antagonist, has the potential to be a best-in-class treatment with significant sales potential. This proposed acquisition complements our portfolio of specialty medicines and builds on our expertise in respiratory therapies.”
Source: 

GSK has reached an agreement to acquire late-stage biopharmaceutical company BELLUS Health.

GSK and BELLUS Health Enter Acquisition Agreement

SAB Biotherapeutics, a US-based clinical-stage biopharmaceutical company, announced on April 18, 2023 that FDA has granted breakthrough therapy designation to SAB-176, an investigational therapeutic, for post-exposure prophylaxis for Type A and Type B influenza illness in high-risk patients. FDA also granted the treatment fast track designation on April 13, 2023.

SAB-176 is a fully human, multi-epitope-binding, broadly neutralizing immunoglobulin antibody therapeutic being developed for several influenza indications, including treatment of high-risk patient populations as well as pre- and post-exposure prophylaxis.

FDA’s breakthrough therapy designation expedites the development and review of a medicine that is intended to treat a serious or life-threatening condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over therapies currently available.

“Influenza continues to pose considerable health concerns both in the [United States] and on a global scale. This [b]reakthrough [t]herapy designation signifies an important step forward in our fight against this disease," said Eddie Sullivan, co-founder, president, and CEO of SAB Biotherapeutics, in a company press release. "Even though both designations can be requested early in development, the requirements for [b]reakthrough [t]herapy designation are higher than those for the [f]ast [t]rack program. For [b]reakthrough [t]herapy designation, the improvement demonstrated must be substantial. We are proud that, based on generated preclinical and clinical evidence, SAB-176 has received both [b]reakthrough and [f]ast [t]rack designations, a combination rarely seen. These designations further assure us that SAB-176 has a clear regulatory and clinical development path to progress this important therapeutic.”

SAB Biotherapeutics has received both breakthrough and fast track designations from FDA for its lead antibody drug candidate for treating influenza.

FDA Grants Breakthrough Therapy Designation to SAB Biotherapeutics for Influenza Immunotherapy

AbbVie announced on April 17, 2023 that the European Commission (EC) has approved RINVOQ (upadacitinib), an oral Janus kinase (JAK) inhibitor, for the treatment of adult patients with moderately to severely active Crohn’s disease who have had an inadequate response, lose response, or were intolerant to either conventional therapy or a biologic agent.

Crohn’s disease is a chronic, systemic disease that manifests as inflammation within the gastrointestinal tract. It is progressive, potentially producing complications that require urgent medical care. According to a company press release, a significantly higher proportion of patients treated with RINVOQ achieved the co-primary endpoints of endoscopic response and clinical remission and the key secondary endpoint of corticosteroid-free clinical remission at weeks 12 and 52 compared to placebo.

"Crohn's disease is a burden that can present patients with daily, often uncomfortable challenges," said Laurent Peyrin-Biroulet, professor of gastroenterology and head of the inflammatory bowel disease group at the gastroenterology department, University Hospital of Nancy, France, in the press release. "These studies demonstrated RINVOQ's ability to achieve key treatment targets, including endoscopic outcomes and symptomatic relief, that are critical for patients and beneficial for long-term care."

AbbVie’s RINVOQ has received European Commission approval for the treatment of moderately to severely active Crohn’s disease.

AbbVie Receives European Commission Approval for Crohn’s Disease Therapeutic 

FDA announced on April 17, 2023 the approval of Israel-based cell therapy company Gamida Cell’s Omisirge (omidubicel-onlv), a substantially modified allogeneic cord blood-based cell therapy to quicken the recovery of neutrophils, a subset of white blood cells, in the body and reduce the risk of infection.

The therapy is intended for use in adults and pediatric patients aged 12 years and older with blood cancers planned for umbilical cord blood transplantation following a myeloablative conditioning regimen, such as radiation or chemotherapy. Gamida Cell will manufacture Omisirge at its good manufacturing practice facility in Kiryat Gat, Israel. The company expects to deliver the cell therapy to transplant centers within 30 days after the start of manufacturing.

Stem cell transplantation is a common treatment for blood cancers. The procedure involves insertion of healthy stem cells in the body to help restore normal production and function of blood cells. Generally, a patient will undergo therapies such as radiation or chemotherapy before this kind of transplant, which may weaken an individual’s immune system. As a result, a frequent and serious risk of this treatment is the occurrence of severe and sometimes deadly infections.“

Today’s approval is an important advance in cell therapy treatment in patients with blood cancers,” said Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, in an FDA press release. “Hastening the return of the body’s white blood cells can reduce the possibility of serious or overwhelming infection associated with stem cell transplantation. This approval reflects [FDA]’s continued commitment to supporting development of innovative therapies for life-threatening cancers.” 

Gamida Cell’s therapy is meant to reduce the risk of infection following stem cell transplantation. 

FDA Approves Gamida Cell’s Cell Therapy for Treating Blood Cancers

Novo Nordisk announced on April 12, 2023 a collaboration with Aspect Biosystems to develop bioprinted tissue therapeutics designed to replace, repair, or supplement biological functions inside the body with the aim of delivering a new class of disease-modifying treatments for diabetes and obesity.

The partnership will leverage Aspect’s proprietary bioprinting technology and Novo Nordisk’s technology in stem cell differentiation and cell therapy development and manufacturing. Aspect is to receive $75 million in initial payments and up to $650 million in future milestone payments per product arising from the collaboration, plus tiered royalties. Novo Nordisk will receive an exclusive, worldwide license to use Aspect’s bioprinting technology to develop up to four products for the treatment of diabetes and/or obesity.

“We are thrilled to partner with Novo Nordisk to create breakthrough therapeutics that could transform the lives of millions of people around the world,” said Tamer Mohamed, CEO, Aspect Biosystems, in a company press release. “This partnership leverages Aspect’s full-stack tissue therapeutic platform, talented team and bold vision, and reinforces our strategy to create bioprinted tissue therapeutics through partnerships with global industry leaders while also advancing our internal therapeutic pipeline.”

Under this partnership, the two companies will develop bioprinted tissue therapeutics for diabetes and obesity. 