Owing to the advancement in clinical pharmacology and oncology domain, and the rising demand for targeted therapeutics and precision medicines, high potency active pharmaceutical ingredients (HPAPIs) and cytotoxic drugs have become one of the key areas of interest to researchers and drug manufacturers across the globe. HPAPIs, due to their selective mode of action, are effective in much smaller quantities than other therapeutic products. They offer a significant set of advantages over traditional APIs. This has led to their widespread production and extensive use in the treatment of various indications including hormonal imbalances, oncological disorders and respiratory disorders. Further, they are stable compounds and are retained (in their active form) within the body for longer durations, thereby decreasing the frequency of their administration. It is worth mentioning that more than 40% of the total number of drugs available worldwide are classified as highly potent.
Further, the characteristics of HPAPIs include:
API or intermediate with biological activity less than or equal to 150 µg per kilogram of body weight
API or intermediate with an Occupational exposure limit (OEL) less than or equal to 10μg / m
Highly selective API or intermediate with a potential to cause cancer, mutations, developmental effects or reproductive toxicity at small doses
Classification of HPAPIs
Presently, there is no officially established system for categorizing the HPAPIs. However, the safebridge banding system operating standards and four tier classification system (based on the potency and toxicity of the compounds) are the most widely recognized and followed.
Different Types of HPAPIs
The new generation of APIs being developed are highly complex in nature, including peptides, HPAPIs, oligonucleotides and sterile APIs. As the global market for pharmaceutical solutions is increasing, pressure to bring biological APIs in different biological forms is rising and with the rising demand of targeted therapies, antibody-drug conjugates (ADCs) and cytotoxic drugs have gained wide attention in the field of HPAPIs.
Antibody-Drug Conjugates: ADCs are monoclonal antibodies (mAbs) attached to surface antigens by chemical or a liable linker. The ADCs bind to specific proteins or peptides in cancer cells with very high specificity and efficacy influencing the biological functions. The linked drug enters the diseased cell and kills them without harming other cells. ADCs are responsible for combining mAbs with the cancer killing cytotoxic drugs, allowing differentiation between healthy and diseased tissue.
Cytotoxic Drugs: Cytotoxic drugs are therapeutic agents that are known to have a toxic effect on cells, mainly affecting cell reproduction. They have the ability to prevent rapid growth and division of cells. Hence, they are commonly used in the treatment of cancer, as part of the chemotherapy regime. They can also inhibit or prevent the function of cells. Besides cancer, they are also increasingly being used for other medical conditions such as rheumatoid arthritis, multiple sclerosis and other auto immune disorders.
Hormones: Biologic HPAPIs which are not classified as oncology drugs include hormones, narcotics and retinoids. Hormones are chemicals produced by endocrine glands. They are termed as chemical messengers of the body as they travel via blood from tissues to organs and are responsible for growth and development, metabolism, sexual function, reproduction and mood of a person.
Peptides: Peptides have developed as highly potent signal transduction molecule exhibiting strong physiological effects and are natural biological molecules having group of amino acids linked by peptide bonds. They consist of two or more amino acids and are synthesized naturally from transcription of a sequence of genetic code. A molecule having 2-50 amino acids is considered as peptide whereas, group of peptides are responsible for forming a protein. Peptides often play the role of hormones and act as biologic messengers transferring information from one tissue to another. The peptide binds to the extracellular domain of cell membrane and exerts its effect.
Steroids: Steroids are man-made chemicals which act like hormones to reduce inflammations. There are two types of steroids, corticosteroids and anabolic steroids. Corticosteroids are produced by adrenal gland and play a role in controlling stress to decrease inflammation whereas, anabolic steroids regulate the manufacturing of testosterone in the testicles and the ovaries. They are used for treating various problems such as arthritis, asthma, autoimmune diseases (such as lupus and multiple sclerosis), skin conditions (such as eczema and rashes) and some kinds of cancer.
Considerations of Handling High Potency Active Pharmaceutical Ingredients
HPAPIs have difficult handling requirements which require various measures to be taken into consideration such as primary containment measures and secondary containment solutions. These measures are taken to quantify exposure limits and ensure safety of employees. Some of the features that are required in the plant or manufacturing site to produce HPAPIs are outlined below:
The main HPAPI manufacturing unit should be at negative pressure relative to its surrounding areas. This precaution is taken to prevent any potentially harmful contaminant from escaping the production area. This is in contrast to the containment requirements at manufacturing facilities of traditional APIs. In API production plants, the main concern is to protect the product from being contaminated by humans and / or the surrounding environment. Hence, a positive pressure is maintained within the API production area.
The plant should be equipped with proper containment strategy and facilities such as glove box isolators, exhaust ventilation, rapid transfer ports, laminar air flow hoods and Clean-in-Place (CIP) systems.
The facility should be designed to include airlocks and changing vestibules (for employees to change their clothes) with adequate pressure differentials, restricted access to ensure that only authorized employees enter the HPAPI production area, misting showers to remove dust particles and / or other contaminants from garments, and Heating Ventilation and Air Conditioning (HVAC) environmental control systems to maintain unidirectional air flow.
Secondary containment strategy include personnel training and awareness programs.
Personal protective equipment (PPE) should be provided to all the working staff employed in the production and storage units.
Contract Manufacturing in HPAPIs and Cytotoxic Drugs
The HPAPI manufacturing process is complex and is associated with several challenges. The production of such drug products requires specialized working environments, stringent manufacturing protocols, skilled labor and high costs. Further, the biggest challenge in cytotoxic drugs manufacturing domain is the prevention of cross contamination across formulations and protection of operators across the supply chain of the drug product. Various large scale drug manufacturing companies have installed in-house high potency manufacturing capabilities. However, most of the small and mid-sized players lack the necessary resources to meet the aforementioned requirements and set up dedicated HPAPI and cytotoxic drugs manufacturing operations. This has led to an increased demand for contract manufacturing service providers in this field.
The fast-growing oncology drugs market is a major driver of the HPAPIs and cytotoxic drugs manufacturing domain; in fact, more than 60% of the HPAPIs are being developed for the treatment of cancers. However, owing to the several challenges associated with HPAPI manufacturing, majority of the pharmaceutical companies prefer to outsource their manufacturing operations. In addition, the contract HPAPI manufacturers have been involved in making significant investments in order to expand their respective capabilities and working capacities. Some of the companies have even established new facilities dedicated to manufacturing of highly potent / cytotoxic compounds.