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What Are the Salient Features of HPAPIs CMOs / CDMOs for Development of HPAPIs as Capsules? Highly potent active pharmaceutical ingredients (HPAPIs) are the compounds used extensively today for the treatment of respiratory disorders, cancer and hormonal imbalances. The key factors driving the demand for highly potent active pharmaceutical ingredients (HPAPIs) are the rise in the oncology therapeutics market as well as the surge in the need for better medicines for treating Cardiovascular, Central Nervous System, Hormonal, Eye, Infectious, Metabolic and Inflammatory diseases. 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 Highly Active Pharmaceutical Ingredients (HAPI) 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 conjugate technology, which uses 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. Although this emerging market is attractive, it presents a significant challenge for pharmaceutical manufacturers to upgrade existing facilities that are set up to handle only non-potent APIs—the challenge being the major cost associated with the specialized containment needed to ensure that employees and their environment are protected from exposure. Many contract manufacturers 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) High Potency Product Manufacturing facilities. This investment may include specialized facilities for HPAPI–antibody conjugations that incorporate handling of all forms high potent APIs biologics (HPAPI capsules, HPAPI ADCs, HPAPI biologics etc.) processing capabilities. Highly active or potent pharmaceutical ingredients (HPAPIs) comprise different compounds, 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. While there is an upsurge in the number of types of HPAPIs, it is important to keep in mind the essential attributes of HPAPI biologics. Highly potent drug product manufacturers 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 (HPAPI CMOs and CDMOs), which have been actively building up capacity over the past few years. However, a systematic and scientific approach is needed. Simply having containment equipment and basic procedures will not be enough to ensure safety. Highly Potent Drug Products: Manufacturing, Challenges and Scope of Future Growth Typically, large pharmaceutical companies have the industrial hygienists and occupational toxicologists on staff to evaluate the potential risks of any new HPAPI, and to conduct the necessary safety assessments. Potent API Contract Manufacturing at smaller companies and CDMOs/CMOs may not have all types of staff experts. Teams that visit potential oral solid dose highly potent manufacturing partners may be so focused on cGMP guidelines and product specifications that may overlook worker safety and environmental risk from exposure to HPAPIs. In addition, HPAPI CDMOs / HPAPI CMOs may not have done a sufficiently thorough assessment to determine whether they can handle a potent new drug safely. Failure to vet potential partners thoroughly can lead to regulatory problems with the Occupational Health and Safety Administration (OSHA), United States and potential legal liability. HPAPI Encapsulation Capacity Plays a Big Role in Developing HPAPI Capsules A high quality encapsulation capacity for highly potent active pharmaceutical ingredient (HPAPI) manufacturing services is vital for development of HPAPIs as capsules or tablets. High Potent Oral Solid Dose Formulation processes involve processing an adequately maintained set of containment valves offers a proven method for the transfer of powder, granular and semi-solid ingredients within GMP manufacturing of cytotoxic, antibiotics and hormonal therapies ensuring the safe handling of a wide range of ingredients: • Highly Potent Active Ingredients (HPAPI) • Seed • Intermediates • Tablets • Capsules The processes involved in HPAPI manufacturing and HPAPI handling for production of HPAPIs as Capsules are: 1. Dispensing 2. Vessel Charging 3. Filtration / Drying 4. Sieving 5. Milling 6. Sampling Critical containment performance targets and other key process requirements are realized with specialized oral solid dose highly potent manufacturing valves using a range of options and accessories. Additionally, high containment of highly potent solid oral drugs to Nanogram levels is an important step for HPAPIs manufacturing especially in oral solid dose highly potent manufacturing. Critical containment and high volume containment performance involves the following processes: 1. Manual or fully automated operation 2. Washing and Cleaning in Place (WIP, CIP) 3. Nitrogen purging 4. In-line sampling Manufacture of all oral drug product dosage forms used as targeted therapies has to be customized so that they can be administered in much lower doses because they are distributed within the body to a specific site of action, rather than systemically. Side effects are also significantly reduced. Highly Potent Oral Solid Dosage drugs – those with occupational exposure limits (OELs) of < 1 ?g/m3 – also require much lower doses. Antibody-drug conjugates (ADCs) are both highly targeted and highly potent and consequently have received significant attention from bio/pharmaceutical manufacturers. Contract development and manufacturing organizations (CDMOs) specialized in developing highly potent solid oral drugs with established track records in the successful development, scale-up and commercialization of highly potent small-molecule APIs, biologic drug substances and formulated products are benefitting from the growing number of ADCs in development. All steps can be performed for development of highly potent solid oral drugs, starting from dispensing to film coating, in an engineering controlled environment. The Application of Highly Potent APIs in Different Types of Therapies is Expanding Fast The overall scope for highly potent active pharmaceutical ingredients as biologics (HPAPI biologics) is expanding at a healthy pace, in large part due to the production of Antibody-drug conjugates (HPAPI ADCs). Some estimates suggest that approximately 25% of drugs on the market today are formulated with Cytotoxic and High Potency drug substances. Although these products require huge manufacturing investments, the scope of demand for oral solid dose highly potent manufacturing at HPAPI CMOs / HPAPI CDMOs has been rising at about 10% per year. While small-molecule high-potency compounds currently account for the largest percentage of sales as far as HPAPI CMOs are concerned, the biologic HPAPIs segment, including highly potent solid oral drugs (HPAPI capsules), and ADCs, is the most lucrative and can grow up to a high compound annual growth rate (CAGR) of 14.7% from 2015 to 2022. Increasing numbers of generic HPAPIs will drive growth in this segment as well. Regionally, North America currently accounts for the greatest percentage of sales ($4.5 billion in 2014) for Highly Potent Oral Solid Dosage drugs, but the highest growth rate (14.0%) will be seen in Asia Pacific. Most HPAPIs are intended as anti-cancer therapies (including ADCs), but there are many highly potent compounds developed for other therapeutic applications, such as diabetes, cardiovascular disease and central nervous system and musculoskeletal disorders. Nearly 290 small molecule targeted therapies in development for the treatment of cancer will be delivered as biologic HPAPIs. There are also large numbers of highly potent biologic drugs (HPAPI biologics) – including antibodies and ADCs, among others, that are in the pharmaceutical industry pipeline. Examples of biologic HPAPIs that are not classified as oncology drugs include hormones, narcotics, and retinoids. HPAPI CMOs and HPAPI CDMOs Are the Trailblazers of the HPAPI drug development revolution The manufacture of highly potent compounds requires specialized facilities, equipment, operating procedures and operator skills and training. In addition, because of the limited doses required for HPAPIs, generally only relatively small volumes of HPAPI biologic drug substances and formulated HPAPIs are needed. As a result, investment by branded HPAPI biologics drug manufacturers, and particularly small oral solid dose highly potent manufacturing partners has been in the high level of specialized equipment and expertise often is not economically viable. While some large pharmaceutical companies have invested in in-house capabilities, most have elected to outsource the development and manufacture of HPAPIs and formulated potent drugs to contract service providers. For oral solid dosage forms based on highly potent APIs, rigorous care must be taken throughout the production process (granulation, mixing, tableting, etc.) to ensure the highest level of quality. Shielding operators from exposure to these highly potent drugs is paramount. Initially, for operator protection, the emphasis was placed on the use of extensive personal protective equipment (PPE), but more recently, it has shifted to the use of contained equipment and automation. Various pharma majors already utilize or plan to acquire specialized, HPAPI research, development and/or manufacturing capabilities from CDMOs. In addition, nearly 40% use or plan to use CDMOs for potent packaging activities. HPAPI Drug manufacturers also rely heavily on CDMOs that offer specialized technologies for enhancement of the delivery of potent compounds (BCS Class II – IV compounds including peptides). The most popular services in this area are the development of controlled release formulations and excipients that enhance bioavailability. Specific production capabilities of interest include solvent-capable rotor and rotor-fluidized bed processing, as well as Wurster column bead drying, layering and coating. Globally, CMOs / CDMOs with High Potency Product Manufacturing capacity are focused on Highly Potent Oral Solid Dosage / HPAPI manufacturing; approximately 40% of their 130-plus production facilities are dedicated to manufacturing of both HPAPI capsules and cytotoxic drugs. Many have recently expanded their capabilities, including Capsugel, Idifarma, Labochim, Medichem, OPKO Health, ScinoPharm, WuXi PharmaTech and Fermion, among others. Since, 2006, more than 100 investments involving the addition of new facilities and / or expansion of existing capacities have happened to scale up operations in dedicated HPAPI CMOs. In addition, the market research firm notes that over 15% of CMOs/CDMOs have established comprehensive services in order to support both HPAPI and formulated cytotoxic drug manufacturing. Examples include AbbVie, AMRI, Baxter, Corden Pharma and Fareva. Challenges are numerous in the Manufacture of all oral drug product dosage forms: Not only the potency and cytotoxicity of HPAPIs pose challenges to HPAPI manufacturing, the low dosages often require specialized formulating technologies such as liquid fill hard HPAPI capsules (LFHC) and soft gelatin HPAPI capsules, to ensure that drug delivery occurs appropriately. Facilities must have controlled airflow (single-pass) and pressure systems with filtration capabilities, airlocks and vestibules around both laboratory and manufacturing suites. The use of isolators and automated handling equipment is increasingly common as a means for effectively minimizing the potential for exposure of operators and the environment to Potent API Contract Manufacturing. Industrial hygiene and extensive operators training programs are also essential. Appropriate facilities, engineering controls and safety protocols during Cytotoxics and High Potency Manufacturing are increasingly imperative as newer HPAPIs as capsules under development have ever declining OELs. These very low exposure levels create further challenges with respect to analysis and the need for ever higher levels of containment. Highly Potent Oral Solid Dosage products are processed to produce ADCs pose additional manufacturing challenges. Not only are both biopharmaceutical and chemical manufacturing capabilities needed, the ability to conjugate highly potent small-molecule APIs to biologic components is required along with Highly Potent Formulation Oncology expertise. As importantly, the conditions used to ensure safety and sterility conflict while potent api contract manufacturing is underway. Sterility of biopharmaceuticals including Highly Potent Oral Solid Dosage capsules is typically achieved by using positive pressure to prevent any contaminants from entering the production area. When working highly potent solid dosage manufacturing, however, negative pressure is utilized to reduce exposure to operators. One approach to this problem is to dissolve the HPAPI in a separate isolator in a different room that is under negative pressure. Once in solution the risk of exposure via airborne contamination is reduced, and thus the remaining production steps – conjugation of the payload to the antibody, purification and final formulation / filling can be performed in other areas under positive pressure. It is also essential to ensure that no free small-molecule HPAPI remains in the final ADC product following conjugation of the payload to the antibody. Any residual high-potency drug substance left in the product following the final purification step could pose a significant safety risk for patients. Risk management guides decisions in facility design and operation for highly potent drugs. Risk management is always a priority in highly potent solid dosage manufacturing. With highly potent drugs, the level of risk management required is even higher. For oral solid dosage forms based on highly potent APIs, rigorous care must be taken throughout the production process (granulation, mixing, tableting, etc.) to ensure the highest level of quality. Shielding operators from exposure to these highly potent drugs is paramount. Initially, for operator protection, the emphasis was placed on the use of extensive personal protective equipment (PPE), but more recently, it has shifted to the use of contained equipment and automation. With exposure of operators a real concern, separating them from the drug product is critical. “The real equipment breakthrough for the manufacture of highly potent solid dosage drugs in terms of both safety and efficiency has come in the form of automation.

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