Highly potent small-molecules and HPAPI biologic drugs are typically considered to be those APIs that have an occupational exposure limit (OEL) of ? 10g/m3 of air as an 8-hour time-weighted average. Many candidates under development today have significantly lower OELs. Because highly potent therapies are administered at very low doses, they are developed for highly targeted populations and are low-volume products. As a result, in addition to CMOs with demonstrated expertise with HPAPI production, pharmaceutical companies are looking for partners that have the capability to support both the development and commercial manufacture of highly potent compounds to avoid any need for process transfers. CMOs that can support a safe, reliable, and regulatory compliant supply chain of HPAPI injectables are most likely to succeed as preferred single-source HPAPI suppliers. Manufacturing HPAPIs as Sterile Injectables require advanced encapsulation and drug delivery technologies that allow the delivery of drug substances based on High Potency APIs directly to the site of action – tumour cells, infected cells, damaged organs – rather than acting systemically are leading to High Potency APIs (HPAPI) based drugs with increased safety and efficacy. This approach also enables the use of highly potent active pharmaceutical ingredients (HPAPIs) that previously were not reasonable candidates due to their toxicity to the patient when delivered using conventional approaches. With the use of rapidly progressing encapsulation and drug delivery technologies, Parenteral Drugs & Highly-Potent Compounds have come into the mainstream API development area. High-potency active pharmaceutical ingredients (HPAPIs) comprise different types of molecules and different types of dosage forms, but share one deadly characteristic: the potential to inhibit production of specific enzymes and cause cancer, mutations, development effects, or sickness, at very low doses, in those exposed to them. Whether they are HPAPI tablets, HPAPI biologic drugs or HPAPI injectables, the essential attributes of HPAPIs should not change. Drug manufacturers / HPAPI CMOs or CDMOs are developing more potent drugs, and despite the lack of specific environmental and safety regulations, HPAPIs have become fertile ground for contract manufacturing and contract development and manufacturing organizations (CMOs and CDMOs), which have been actively building up capacity over the past few years. Experts warn, however, that a systematic and scientific approach is needed. Simply having HPAPI containment equipment and training personnel on basic procedures will not be enough to ensure safety. The strong growth in this sector drives downstream trends in the HPAPIs CMO market such as an increased demand for HPAPIs as injectables in a secondary manufacturing capacity. Anti-viral therapies are the largest therapeutic products segment for the small molecule sector, followed by oncology. Using High Potency APIs, strong growth of both areas is a significant driver of increased demand for small molecule API / High Potency APIs and HPAPI drug product contract manufacturing services – HPAPI CMOs. The main factor to consider is the high quality encapsulation capacity required for highly potent active pharmaceutical ingredient (HPAPI) manufacturing services that determines the development of HPAPIs as capsules or tablets. Formulating low dose HPAPIs as high potent sterile injectable drugs Though highly potent, HPAPIs may not require specific dosage forms. Any formulation strategy for HPAPIs should address potential issues with proper handling to ensure personnel safety and consider the homogeneity of the formulation and the drug content analysis. Formulators working with highly potent APIs (HPAPIs) are increasingly challenged to ensure the safety of both personnel during development and manufacturing and healthcare workers and patients when using the final drug products. That means addressing potential issues with the homogeneity of the formulation, drug content analysis, and proper handling of the high potent sterile injectable drugs. Advances in micro particle, capsule and syringe technologies, analytical methods, and containment systems are widening the safe formulating options for HPAPIs. The HPAPI injectables sector can be expected to owing to the demand of the oncology sector. HPAPI Manufacturing capacity shortages for sterile and aseptic fill have been driving investment into additional capacity. This is one of the fastest growing areas of application of Highly Potent APIs linked to the growth in biologics, oncology and generics. Nonetheless, the regulatory hurdles are more challenging and the investment on Highly Potent APIs development required provides barriers to entry. Unique delivery systems While HPAPIs do not have special drug delivery requirements; the dosage form chosen must ultimately address patient safety, compliance, clinical performance, and manufacturability, according to Knox. There are, however, certain dosage forms of Highly Potent APIs that provide some advantages because they are more suitable for the lower drug loads associated with HPAPIs. Extended-release parenteral formulations are also well suited for HPAPIs. He specifically notes that extended-release, bioabsorbable poly(lactide-co-clycolide) (PLG) microparticles reduce side effects, improve therapeutic efficacy, and increase patient compliance. Like other parenteral formulations using High Potency APIs (HPAPI), the administration of suspensions of injectable micro particles (HPAPI injectables) is limited by the injection volume. HPAPIs / High Potency APIs (HPAPI) are ideal for encapsulation with PLG micro particles because they are dosed at microgram and milligram quantities like some High Potency APIs, which mean less API (less mass) is needed to meet the injection volume requirements. In turn, HPAPIs / High Potency APIs can be delivered from PLG microparticles for weeks and months following a single administration from a single HPAPI injectable product. These formulation advantages also apply to extended-release and rod-shaped HPAPI injectable PLG implants which makes High Potent API (HPAPI) development a suitable business development opportunity for HPAPI CMOs. Given the safety issues and growing number of options for low-dosage drugs using High Potency APIs, choosing the right dosage form for an HPAPI injectable product can be challenging. The goal of a HPAPI CMO that produces HPAPI injectables / sterile High Potency APIs (HPAPI) is to look at the least complex dosage-form options first, because conventional approaches save on development time and costs. Success in developing low dosage forms of Highly Potent APIs for sterile Highly Potent API products can be obtained by dry blending a formulation for filling capsules or making tablets at drug loads in the 0.01% w/w range, depending on the API / Highly Potent API properties. Dosage strengths at 10 µg or lower for Highly Potent APIs, especially for sterile High Potency APIs (HPAPI) products often require special considerations, such as oral solutions, liquid-filled capsules, or granulation and coating techniques with the active ingredient dissolved in a spray solution. New encapsulation technologies Some renowned CDMOs have developed novel Form EZE technology, an improved microencapsulation process for the manufacture of PLG micro particles. This is a continuous, closed-equipment process for encapsulating High Potency APIs (HPAPIs) which involves an emulsion-based extraction and affords 20% higher yields with less post-process handling of HPAPI Chemistry and HPAPI Containment technologies. This process shortens unit operations time, reduces waste, and can be scaled down from commercial-size manufacturing, all advantages when working with HPAPIs. The emulsion is generated by a packed-bed column that produces a defined, narrow size distribution of micro particles that allows the use of smaller-diameter needles and affords the administration of more micro particles for drug delivery over longer durations. Another benefit is that the PLG micro particles made for High Potency APIs using the Form EZE technology are much easier to administer by injection and safer to use, according to Tice. Because of the size distribution of the micro-particles with High Potency APIs and the assurance of no large particles or agglomerates, they do not clog needles during injection. “When injection procedures are less prone to complications, particularly when HPAPIs are involved, improved safety to the patient and the healthcare worker is achieved,” he comments. The availability of both gelatin and hydroxypropyl methyl cellulose (HPMC / Hypromellose) capsules designed specifically for liquid formulations of HPAPIs and micro-spray sealing and banding technologies have enabled greater application of this delivery technology for highly potent compounds. Opportunities for liquid delivery outside of softgels, which can be an expensive technology to invest in during the early stages of development, represent a real advantage,” he states. In addition, liquid-filled hard shell encapsulation machines now have faster filling and sealing speeds and provide more in-line process checking (temperature, speed, fill weight), as well as automatic in-line feedback with process analytical technology. Consequently, the scope of application of HPAPIs in specific dosage forms is growing faster than the overall API high potent sterile injectable drugs market, and the percentage of drug candidates classified as HPAPIs is increasing. HPAPI manufacturers are in need of capacity suitable for the safe production, storage and transport of a growing range of potent compounds. Contract service providers – both contract development and manufacturing organisations (CDMOs) and CMOs – can help, but drug companies should only consider partnering with firms that have a history of successfully producing and handling HPAPIs and continually investing in the most advanced safety equipment, systems and processes. The manufacture of HPAPIs presents many challenges; however, given the high toxicity, complications of HPAPI chemistry of these compounds and safety is the first and foremost consideration. The injectables sector is expected to grow at a strong CAGR of 10.5% until 2021, meaning this sector has the largest share of absolute growth. In terms of Contract manufacturing injectables, manufacturing capacity shortages for sterile and aseptic fill have been driving investment into additional capacity. This is one of the fastest growing areas linked to the growth in biologics, oncology and generics. Nonetheless, the regulatory hurdles are more challenging and the investment required provides barriers to entry. Sterile Contract Manufacturing? CMO s that have robust engineering controls, risk assessment and risk management processes in place to ensure a safe work environment and prevent cross-contamination. An Industry-leading CMO specializes in the GMP manufacture and sterile fill/finish of vials and contract manufacturing injectables. Pharmaceutical companies that outsource HPAPI development and manufacturing look for a CMO that has a proven track record for both safely and effectively managing projects involving highly potent compounds. Such a record includes not only successful commercial production of HPAPIs, but also an excellent audit history, comprehensive documentation and regulatory records. These present significant barriers to entry both for new competing HPAPI products and CMO suppliers providing these highly-specialized drugs i. e. small molecules or HPAPIs and delivery device combinations. In terms of future growth of HPAPI, China is expected to be the main driver; however, the USA will remain the largest single market ahead of the EU. A growing number of approved pharmaceutical drugs contain high-potency active pharmaceutical ingredients (HPAPIs), which has led to an explosive growth in demand for the production of HPAPIs using state of the art development methods of high-potency active pharmaceutical ingredients (HPAPIs) whilst adhering to cGMP guidelines. Another reason why the demand for HPAPIs is thriving is because of advances in clinical pharmacology. There is particular interest in HPAPI–antibody drug conjugate technology (HPAPI ADCs), which use monoclonal antibodies to selectively deliver HPAPIs to specific cancer tumors. When conjugated to the antibody, the HPAPI targets cancer cells specifically and thereby spares non-target cells many of the toxic effects. One of the earliest examples is Mylotarg (gemtuzumab ozogamicin), which is commercialized for treating acute myeloid leukemia. Many HPAPI CMOs are also building new facilities that are designed specifically for the manufacture of HPAPIs, which require an investment of millions of dollars beyond typical GMP (good manufacturing practices) production facilities. This investment may include specialized facilities for HPAPI–antibody conjugations that incorporate both handling of high potent APIs, including aseptic filling of high potency drugs and HPAPI biologics processing capabilities to establish it as a specialty sterile-solutions brand. Important Considerations for Manufacturing High-Potency Drugs Using Isolators Isolated HPAPI containment facilities for both drug substances with complex fill-finish treatments should be made available with the following High Containment considerations: • Isolated Class 100,000 suites designed with the most advanced barrier technology, including sophisticated clean-in-place systems • Engineering controls for product containment in segregated suites with dedicated HEPA filtration systems (inbound and exhaust) and individual egress points • Preclinical and clinical trials supply – from 10g to 10’s of kg • Commercial scale manufacturing (Scalable Sterile Manufacturing) from grams to 100’s of kg • Handling of Merck Category 4 compounds during sterile manufacturing of high potency compounds • Potent solid dose formulation of batch sizes up to 10kg • Facilities FDA and MHRA inspected Significance of Using Isolators for Sterile Manufacturing of highly potent injectable drugs Some aspects to consider for HPAPI Containment when using isolators while processing injectable, high-potency drugs are: • Containment of contamination, particularly airborne contamination • Individual protection of personnel skilled in sterile fill-finish of vials • Management of cross-contamination • Aseptic processing and sterility of handled material and product • Aseptic filling and lyophilization of conventional, biologic and cytotoxic drugs into vials. • Efficiency of biodecontamination cycles • Efficiency of barriers and their integrity • Management of the environmental impact as a result of the process (i.e., refluent, industrial waste, liquids, gas, and air). Choose a CDMO / CMO with HPAPI manufacturing capabilities that bring longevity of experience in handling complex sterile manufacturing challenges. The CMO with expertise in Aseptic Technologies Crystal® - Aseptic Filling of Injectable Drugs is the right one for you. The processes involved in aseptic filling of injectable drugs have always been very challenging for the pharmaceutical industry. It should be specially checked that no contamination accidents should happen while Contract manufacturing injectables processes are underway. Even if they are rare, they will still be significantly recorded low according to the 20 billion injections and infusions made every year. The best HPAPI CDMO is the one that can navigate complexity in HPAPI Chemistry, HPAPI Containment and check potency levels for all types of HPAPI Manufacturing needs. Complex Sterile Manufacturing of HPAPIs can be a complicated process. Sterile Manufacturing of Cytotoxics, Antibody-Drug Conjugates (ADCs), highly potent compounds, biologics, and lyophilized products present many challenges and require specialized understanding of Sterile Manufacturing (eg Cytotoxics High Potent ADCs) with expertise in the following specialized processes: - Scalable Sterile Manufacturing, - Sterile Oncology Formulation, - Sterile Fill/Finish, and - Aseptic Manufacturing. The sterile oncology manufacturing facility should undergo proper inspection and have an inspection report for cGMP. The sterile oncology manufacturing facility is designed for Band-5 compounds with PPEs and consists of a sterile liquid filling line equipped with a washing machine, depyrogenating tunnel, filling / capping, sealing, an external washing machine and a glovebox in the dissolution area. The liquid filling machine is also connected to a freeze dryer. At cGMP manufacturing facilities that specialize in Contract manufacturing projects for HPAPI injectables have classified areas for aseptic processing to minimize biological contamination. All personnel involved in sterile operations are fully qualified on aseptic techniques and Japanese quality standards. Sterile Manufacturing of High Potency compounds requires dedicated and trained personnel focused on o Customized product in ready-to-fill or bulk syringes o Proprietary technologies that ensure patient’s safety and accurate dosing o Opportunity for single-dose administration of your products o Reliable supply with products that meet the highest-quality standards o Also equipped with Containment and Handling technologies for highly potent and cytotoxic APIs Developing HPAPIs as Parenteral / Sterile drug products requires a Bio-decontaminated Environment The automatic cycle of bio-decontamination during Complex Sterile Manufacturing of HPAPIs guarantees the reproducibility of the process. Manual disinfection with oral solid dose highly potent manufacturing is a time-consuming activity that may not be consistently performed and is dangerous because of the continuous exposure of operators to sanitizing agents. Bio-decontaminating agents such as vaporized hydrogen peroxide achieve sterilization by the dispersion of gas. The gas can reach all surfaces exposed to its contact, even the hidden ones. Its products are oxygen and water, which are harmless. Isotechniques also exceed the onerous barrier created by the modality of clothing and microbiological control. The CMO Manufacturing HPAPIs as Sterile Injectables Should Exhibit the Following Areas of Expertise: • Sterile Solutions & Suspensions (Aqueous/Non-aqueous suspensions) • In-situ Salt Formations • Nanoparticles & Liposomes • Stable emulsions • Lyophilized Products • Oncological compounds, including different formulations such as sterile lyophilized vials • Injectable liquids