Prolytic – El nostre laboratori a Frankfurt / Alemanya

Three sites in Europe – One strong group

Prolytic GmbH va ser fundada l’any 2002 per un grup veterà de científics de Viatris GmbH, la unitat de negoci més gran de Degussa/ASTA Medica AG. El recentment constituït CRO, amb seu a Frankfurt, es va centrar en la prestació de serveis bioanalítics i de farmacocinètica als clients del sector farmacèutic. El 2020 Prolytic va passar a formar part del grup Kymos.

Coneix més sobre els nostres serveis

Instal·lacions prolítiques

La filial alemanya de Kymos, Prolytic, té la seu a Frankfurt del Main, a uns 20 minuts amb cotxe del centre de la ciutat i de l’aeroport internacional dins d’un vibrant districte de negocis que conté nombroses empreses farmacèutiques i biotecnològiques. Prolytic és un emplaçament certificat per GLP, que consta d’uns 1.000 m2 que inclou oficines principals, cafeteria, sales de reunions, sala d’emmagatzematge de mostres, arxiu GLP, garantia i gestió de qualitat, instal·lacions BSL2, així com tres laboratoris bioanalítics principals:

• Bioanàlisi de molècules petites (també conegut com Cromatografia)
• Bioanàlisi de grans molècules (també conegut com Biologia)
• Bioanàlisi d’àcids nucleics

Els nostres experts alemanys estan aquí per ajudar-te

Ron Wacker
Ron WackerDirector General del Lloc
Joan Puig de Dou
Joan Puig de DouConseller Delegat
Lisa Hentschel
Lisa HentschelResponsable del Departament de Biologia
Maria Fauth
Maria FauthResponsable del Departament de Cromatografia i Oligonucleòtids

Posar-se en contacte

Liraglutide and Semaglutide have become key players in the pharmaceutical and healthcare industry as they are both being used and have been approved not only as an anti-diabetic medication but also as an obesity and weight loss treatment.

In combination with the huge growth of the biosimilar market in recent years and their patent expiry dates, they are one of the prime targets for the development and release of new biosimilar drugs based on them. In this article, we will expand on both these GLP-1 receptor agonists and how can Kymos assist in the characterization and comparability studies of their biosimilars and the bioanalytical services we offer for them.

 

Introduction to Liraglutide and Semaglutide

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has important effects on glycemic control as it stimulates insulin secretion and inhibits glucagon release, making it the perfect candidate for a therapeutically effective anti-diabetic agent. However, due to the pharmacokinetic profile of GLP-1, its half-life is very short as it is rapidly degraded (less than 2 minutes intravenous and 1-2h subcutaneous) limiting its therapeutic potential in its native form.

Due to the necessity of extending this half-life, both Liraglutide and Semaglutide were developed. These glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have both extended half-lives while maintaining potency which has resulted in an effective treatment of Type-2 Diabetes. They were developed using structural modifications such as acylation with a fatty acid chain to facilitate albumin binding increasing its half-life to 13h after a single injection with Liraglutide, and then further refined to an increased human plasma half-life of 160h for Semaglutide which is also protected from dipeptidyl peptidase-4 cleavage. These modifications have made possible a daily dosage for Liraglutide, and a weekly dosage for Semaglutide in its injectable forms.

While the original goal of these peptides was to be therapeutically effective in people with Type-2 Diabetes, the effects on body weight were evident and due to these, versions of both Liraglutide and Semaglutide were developed for the treatment of obesity (the main difference being the quantity of dose; lower for diabetes and higher for weight loss).

 

Shortage of GLP-1 receptor agonists

While these therapeutic effects are beneficial for both diabetic and overweight patients, the weight loss effect has affected greatly the supply of these drugs. It has especially hit the type-2 diabetes population. We are currently experiencing a global shortage in supply due to an increase in off-label prescriptions of the diabetes versions being issued for weight loss instead of their original intended use.

Analyzing the current situation regarding GLP-1 receptor agonists, the formulations that are approved are as follows:

  • For Liraglutide:
    • Injectable form for Type-2 Diabetes treatment
    • Injectable form for weight loss and obesity
  • For Semaglutide:
    • Injectable form for Type-2 Diabetes treatment
    • Injectable form for weight loss and obesity
    • Oral tablets for Type-2 Diabetes treatment

In both Liraglutide and Semaglutide, there is a need for more supplies, as with all medications containing these active ingredients, a global supply shortage exists. This issue could potentially be addressed with the emergence of new biosimilars, expected to be released in the coming months and years as patent expiry dates approach, and in the case of Liraglutide, have already occurred.

 

Development of biosimilars

Biosimilars market is firmly established and constantly growing due to the emergence of new drugs and active ingredients like Liraglutide and Semaglutide. However, its development presents huge complexity and challenges. Regulatory approval of new biosimilars requires an extensive comparability exercise against established and marketed reference products as it must include quality and clinical studies to demonstrate a high percentage of similarity in both terms of structure and function.

Comparative quality studies include protein structure, biological function, and in vitro pharmacodynamic studies. They should include comprehensive analyses of the proposed biosimilar and reference medicinal product using sensitive and orthogonal methods to determine:

  • Similarities
  • Differences
  • Quantitative ranges of variability in the reference medicinal product

Comparative clinical studies are designed to confirm biosimilarity and to address any questions that may remain from previous analytical or functional studies. They include comparisons in terms of pharmacokinetics and studies of safety and efficacy in clinical studies.

 

Kymos’ experience with Liraglutide and Semaglutide

Kymos Group can assist biosimilar developers of GLP-1 receptor agonists with both quality and clinical comparability studies.

For quality comparability studies, we offer a comprehensive catalog of state-of-the-art analytical techniques coupled with extensive experience in their application to biosimilars. Specifically, for Liraglutide and Semaglutide, our biopharmaceutical and immunology departments have experience with:

  • FT-IR Analysis
  • Amino Acid Analysis
  • Peptide Mapping (MS/MS Analysis)
  • Bioactivity Studies
  • Gel Electrophoresis
  • Thioflavin T Assay Analysis
  • Cell-based assays (CBA) for potency

For clinical comparability studies, Kymos provides bioanalytical support for comparability studies, covering activities like/plasma serum level measurement of both reference and biosimilar proteins, PK calculations and statistics, and immunogenicity studies. Additionally, we also offer a full one-stop-shop solution including the clinical part available through our trusted clinical trials partners.

Regarding bioanalysis, we have developed bioanalytical methods for several GLP 1 analogs in plasma of different species with limits of quantification in the low ng/mL range, the required sensibility for current preclinical and clinical studies. For clinical bioequivalence studies, method validation is free of cost.

If you require assistance with your biosimilars or any of your CMC or bioanalytical studies, please do contact us at: https://kymos.com/contact or send us an email to commercial@kymos.com

Characterization of unknown impurities found in pharmaceutical substances and pharmaceutical products is a vital part of the regulatory approval process. According to ICH guidelines, if the estimation indicates an impurity content higher than 0.1%, it must be identified and characterized ensuring compliance with all regulatory requirements. This process is also known as impurity profiling.

The present article focuses on this process, giving more context about impurities and detailing what techniques and equipment are employed by Kymos when dealing with them.

 

Understanding impurities and their classification

Going by the WHO definition, an impurity is “any component present in the drug substance or drug product that is not the desired product, a product-related substance, or excipient including buffer components. It may be either process- or product-related”.

The source of these impurities then can be attributed to various phases of the synthetic process of the drug substance. They can be found on the starting materials, produced in the manufacturing process, created in the degradation process formed during storage and shipment, or even found on the solvents used during the manufacturing.

Combining the source, the composition, and the biological safety, the ICH has come with a major classification for impurities in drug substances:

  • Organic impurities:

    Found during the manufacturing process or created during the storage. They can be identified or unidentified. They include starting materials, by-products, intermediates, degradation products, reagents, ligands, and catalysts.

  • Inorganic impurities:

    Resulting from the manufacturing process and they are normally known and identified. Included are reagents, ligands, catalysts, heavy metals or other residual metals, inorganic salts, and other materials like filter aids or charcoal.

  • Residual solvents:

    Derived from the manufacturing process and classified based on the potential risk to human or animal health. You can read more about them in our recent article.

     

Guidelines on the control of impurities and their characterization

As mentioned before, ICH guidelines require that any unknown impurity present in the new drug substance with a level higher than 0.1% must be characterized. If they are above this threshold they need to be identified and individually specified in the specifications. Conversely, if an impurity falls below this limit, identification is generally unnecessary, except in situations where the potential harm is anticipated to be unusually high.

It’s worth noting that ICH guidelines require that degradation products detected in the stability studies of the drug product must also be identified if they have a level higher than the identification thresholds. These limits are found in the ICH Q3A (R2).

 

Techniques used for impurity profiling

When identifying impurities and degradation products, various methods can be employed. The conventional approach involves verifying the retention times of unknown analytes against their standards using a developed method, typically through spiking. When a peak is above the identification threshold it is marked for identification and structural elucidation. At Kymos, this process is commonly executed using UPLC or HPLC.

Although this has been the conventional method for many years, we predominantly use hyphenated techniques instead because they are faster and easier to use when several impurities must be characterized in a single sample. They are also preferred because we avoid potential problems when unstable impurities are formed or if there is a possibility of a secondary reaction during processing.

For these specific reasons, we have settled on using LC-MS as it has the potential to give nearly clear structural information about the unknown analyte, and also specifically the Orbitrap Mass Spectrometer.  

 

Kymos capacity and new facilities

In response to the sustained growth of our operations throughout 2023, and specifically to meet the needs of our clients regarding impurities analysis and testing, we have recently expanded our site in Italy with brand new facilities. This new building has three times the area of the previous plant and features three new laboratories designed with the “lean lab approach”.

This strategic investment not only will result in a substantial increase in our impurities analysis capacity but also broaden our range of services in research, development, and quality control of biopharmaceutical products.

The new laboratories have already received approval from the AIFA (Agenzia Italiana del Farmaco) following a thorough physical audit of the facilities, and we are ready to assist with any projects that come our way.

If you require assistance with your impurities characterization or any of your CMC or bioanalytical studies, please do contact us at: https://kymos.com/contact or send us an email to commercial@kymos.com

    Laboratories

    logotip de Kymos

    Barcelona
    Spain

    logotip de Prolytic

    Frankfurt
    Germany

    logotip de Pharmaprogress

    Ancona
    Italy

    Oficines de la UE

    París
    França

    Basilea
    Suïssa

    Milà
    Itàlia