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,

When referring to this article, please cite it as Leon, A. Considerations for Analytical Testing for E&L. 

Articles

Considering the differences between small- and large-molecule drug products can help determine analytical testing methods for E&L. 

Considerations for Analytical Testing for E&L

In 2021, approximately 1.7 million children aged 0–14 years were living with HIV globally (1). In total, an estimated 110,000 children died from preventable AIDS-related causes in 2021, attributed mostly to inadequate access to HIV prevention, treatment, and care, with 75% occurring in children under 10 years of age (2). Among these 1.7 million children worldwide aged 0­–14 years living with HIV, only slightly more than half are on treatment. This is significantly lower than adults, with approximately 76% receiving antiretroviral treatment (ART). Without timely treatment, evidence shows that one third of children infected with HIV at birth will die by age one, and half by age two (3).

Age-appropriate treatment options are becoming increasingly important, as evidence shows that progress towards viral suppression among children receiving ART is much slower than that of adults receiving ART (4). In Europe, a step is being taken towards increasing the amount of treatment options for children with the European Union marketing authorization of Triumeq, a dispersable, single tablet formulation of the fixed-dose combination of abacavir, dolutegravir, and lamivudine (5). The treatment is from ViiV Healthcare, a company that specializes in HIV treatments.

“Triumeq … is now approved for the treatment of children living with HIV, weighing 14 kg to <25 kg,” explains Ana Puga, global paediatrics lead, ViiV Healthcare. “Dolutegravir prevents HIV viral DNA from integrating into the genetic material of human host cells by inhibiting the activity of the enzyme integrase, while abacavir and lamivudine interfere with reverse transcriptase, an enzyme needed for the virus to replicate” (6–8).

Targeting children within this weight range could be paramount, as very young children face a large number of obstacles regarding treatment options. “We know that children and young people living with HIV have specific treatment needs, and options that work for them can be limited. This treatment provides an age-appropriate formulation of the single-tablet regimen to a younger population, making it easier to administer to young children who may find it difficult to swallow a tablet,” says Puga. “Furthermore, by successfully initiating young children onto age-appropriate treatments, it may help them foster a positive relationship with their lifelong treatment regimen early on.” HIV treatment is a lifelong commitment, and can help people living with HIV lead longer, healthier lives. HIV treatments also reduce the risk of the transmission of HIV (9).

Early testing and treatment for HIV is also essential in decreasing the mortality and morbidity of children with the disease. The World Health Organization (WHO) recommends that infants who are born to mothers living with HIV should be tested for HIV by two months of age, during the duration of breastfeeding, and when breastfeeding ends, due to the continued risk of transmission during this period. Infants or children who test positive for HIV should be started on ARV immediately in order to suppress the HIV virus. This continues to be a serious obstacle due to how the newest and most effective ARVs are designed for adults, lacking child-friendly formulations (10). 

The accessibility of child-friendly HIV treatments has come a long way in recent years. “Since the approval of Triumeq in 2014, ViiV Healthcare has worked to accelerate the development, registration, and ultimately access to optimized pediatric antiretrovirals,” says Puga. “The EU’s Marketing Authorization marks a step forward in paediatric HIV care and means further treatment options should soon be available for young children living with HIV in Europe.”

The future looks hopeful for the improvement of treatment accessibility for children, with organizations like WHO, UNAIDS, and UNICEF partnering to bring together a new alliance aiming to eliminate AIDS in children by 2030. The new Global Alliance for Ending AIDS in Children by 2030 was announced at the International AIDS Conference in Montreal, Canada, in 2022. The aim of the alliance is to ensure that no child living with HIV is denied treatment by 2030, as well as to prevent new infant HIV infections. The alliance has put forth four major points of action, which are, “closing the treatment gap for pregnant and breastfeeding adolescent girls and women living with HIV and optimizing continuity of treatment; preventing and detecting new HIV infections among pregnant and breastfeeding adolescent girls and women; accessible testing, optimized treatment, and comprehensive care for infants, children, and adolescents exposed to and living with HIV; and addressing rights, gender equality, and the social and structural barriers that hinder access to services” (11). With new child-friendly treatment options becoming available, and global organizations taking a stand to ensure children are able to access these treatments, there is hope for further improving the mortality rate and morbidity of children living with HIV in the future.

1. UNAIDS. Global HIV & AIDS Statistics–2022 Fact Sheet. 

https://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf

2. Unicef. Global and Regional Trends. July 

https://data.unicef.org/topic/hivaids/global-regional-trends/

3. Children & AIDS. Treatment in Children Living with HIV. 

https://www.childrenandaids.org/paediatric_treatment

. Global Estimates of Viral Suppression in Children and Adolescents and Adults on Antiretroviral Therapy Adjusted for Missing Viral Load Measurements: A Multiregional, Retrospective Cohort Study in 31 Countries. 

5. Viiv Healthcare. ViiV Healthcare Receives EU Marketing Authorisation for Triumeq PD, the First Dispersible Single Tablet Regimen Containing Dolutegravir, a Once-daily Treatment for Children Living with HIV in Europe. Press release. 22 Feb. 2023.

6. National Institute for Health and Care Excellence. British National Formulary–Dolutegravir. 

https://bnf.nice.org.uk/drugs/dolutegravir/

7. National Institute for Health and Care Excellence. British National Formulary–Abacavir.

8. National Institute for Health and Care Excellence. British National Formulary – Lamivudine. 

https://bnf.nice.org.uk/drugs/lamivudine/

9. National Institutes of Health. HIV Treatment Adherence. US Department of Health and Human Services 

https://hivinfo.nih.gov/understanding-hiv/fact-sheets/hiv-treatment-adherence 

10. WHO. Treatment and Care in Children and Adolescents 

https://www.who.int/teams/global-hiv-hepatitis-and-stis-programmes/hiv/treatment/treatment-and-care-in-

11. WHO. New Global Alliance Launched to End AIDS in Children by 2030. News release. 2 Aug. 2022. 

When referring to this article, please cite it as A. Leon. A New Hope for Children Living with HIV. 

New child-friendly treatment options and initiatives are improving the outlook of children living with HIV in Europe. 

A New Hope for  Children Living with HIV

Regeneron Pharmaceuticals announced on March 22, 2023 that FDA has extended the approval of Evkeeza (evinacumab-dgnb) as an adjunct to other lipid-lowering therapies to treat children aged five to 11 with homozygous familial hypercholesterolemia (HoFH), an inherited condition characterized by extremely high low-density lipoprotein cholesterol (LDL-C). The treatment was initially approved in February 2021 as an adjunct to other lipid-lowering therapies in those aged 12 years and older with HoFH.

HoFH is an ultra-rare inherited condition that affects approximately 1300 people in the United States and is the most severe form of familial hypercholesterolemia, according to a company press release. Those living with HoFH are at risk for premature atherosclerotic disease and cardiac events even in their teenage years.

“At the Family Heart Foundation, we know that children with homozygous familial hypercholesterolemia, and those caring for them, often live in fear of what the future holds as they contend with the dangerously high levels of bad cholesterol, or LDL-C, caused by this genetic disorder,” said Mary McGowan, chief medical officer of the Family Heart Foundation, in the release. “Only 5% of rare diseases actually have an FDA-approved treatment. With this FDA approval, the HoFH community now has a much-needed treatment for young children, potentially making it possible for many to achieve recommended LDL-C levels much earlier in the course of this rare disease. This is a hopeful development for those living with HoFH.”
Source: 

FDA has approved Evkeeza for young children with homozygous familial hypercholesterolemia. 

FDA Approves Evkeeza for Young Children with Ultra-Rare Form of High Cholesterol

Roche announced on March 22, 2023 that it has entered into a collaboration with Eli Lilly to support the development of Roche’s Elecsys Amyloid Plasma Panel (EAPP), a blood test that aims to facilitate the earlier diagnosis of Alzheimer’s disease.

The EAPP is currently undergoing additional investigation to ensure clinical validation. The collaboration aims to support patients by improving the journey to a timely and accurate diagnosis and treatment of Alzheimer’s. If approved, the EAPP test would be an additional tool to identify low likelihood of amyloid pathology in symptomatic patients and determining whether further evaluation and testing may confirm a diagnosis.

According to a company press release, up to 75% of people living with the symptoms of Alzheimer’s do not have a diagnosis. Those who have received a diagnosis waited, on average, 2.8 years after symptom onset (1). The EAPP would be used as a tool to enable access to appropriate new therapies as they become available.

“We are excited to be collaborating with Lilly on such an important area of unmet medical need,” said Matt Sause, CEO of Roche Diagnostics, in the release. “Today, over 55 million people are living with dementia, and this is projected to increase to nearly 140 million by 20502. Collaboration is essential to ensure these people receive a timely and accurate diagnosis. The Elecsys Amyloid Plasma Panel has the potential to streamline a person's journey to diagnosis and, therefore, access to future treatment options.”

1. Johns Hopkins. Life Expectancy Following Diagnosis of Alzheimer’s Disease Depends on Age at Diagnosis. Johns Hopkins Bloomberg School of Public Health. Nov. 18, 2002. 

Roche and Lilly will collaborate on the development of Roche Diagnostics’ Elecsys Amyloid Plasma Panel.

Roche Collaborates with Lilly to Enhance Early Diagnosis of Alzheimer’s Disease 

PharmaBlock, a contract development and manufacturing organization focused on innovative chemistry and low-carbon manufacturing, announced on March 27, 2023 the opening of its new R&D facility in West Chester, Pa. The facility will expand the company’s footprint in the United States and increase its capacity to delivery good manufacturing practice (GMP) projects to global partners.

The new site includes 30,000 ft2 of lab space and includes process R&D labs, GMP suites, clean rooms, and GMP analytical labs. The site also enables flow chemistry, micro-packed bed hydrogenation, and solid-state chemistry capabilities. The site joins the company’s existing facility in Hatfield, Pa., and is a crucial addition to enhancing the delivery of clinical-stage API projects, according to a company press release.

"We are excited to celebrate the grand opening of our new research facility, which represents a significant milestone for our company," said Jing Li, president of PharmaBlock, in the release. "This state-of-the-art facility will enable us to provide our clients with the highest quality research and development solutions, and we look forward to continuing to innovate and advance."
Source: 

PharmaBlock has opened a new R&D facility in Pennsylvania, expanding its capacity to deliver GMP projects. 

PharmaBlock Opens New R&D Facility in Pennsylvania

Ingredion announced on March 24, 2023 that it has completed two strategic investments in India to expand into high-value pharmaceutical applications. The company acquired Amishi Drugs & Chemicals (AD&C), a manufacturer of superdisintegrants, lubricants, and viscosifiers, and secured a majority position in Mannitab Pharma Specialties, a supplier of specialty sugars to the pharmaceutical industry.

The investments complement Ingredion’s portfolio of starch, mannitol, and dextrose product offerings, as well as expand Mannitab’s manufacturing capacity for spray-dried mannitol for direct compression. Ingredion’s portfolio also now includes binders, fillers, superdisintegrants, lubricants, gelatin replacers for softgels, viscosofiers, encapsulation materials, and parenteral-grade dextrose.

“These investments are part of our strategy to expand our specialty pharmaceutical product portfolio to better serve our customers and diversify into high-value nonfood adjacencies,” said Jim Zallie, Ingredion’s president and CEO, in a company press release.

“Ingredion looks forward to partnering with pharma and nutraceutical formulators and helping them meet regulatory challenges, progress drug development, and identify emerging trends,” added Rana Kayal, global director for pharma and nutraceuticals, in the release.

Ingredion has completed two strategic investments in India with Amishi Drugs & Chemicals and Mannitab Pharma Specialties.