What are Highly potent active pharmaceutical ingredients (HPAPIs and HPAPI)? Highly potent active pharmaceutical ingredients (HPAPIs) are usually compounds used 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 Highly Active Pharmaceutical Ingredients (HAPI) using state of the art development methods 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 spare 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. Important Points to consider regarding HPAPI Chemistry that affect HPAPI Manufacturing facilities: The current growth trend of HPAPI development requires that HPAPI Manufacturing facilities are capable of processing Small molecule chemistry from gram to 10kg batch size, Glass and Hastelloy® C-22 PLC-controlled reactors up to 100L, Distillation, cryogenic, and hydrogenation capabilities, Aurora® filter isolation, drying, and packaging, and Versatile enclosed processing space for expanded portable capabilities. HPAPI containment and equipment handling is an important aspect of HPAPI chemistry during HPAPI manufacturing in specialized HPAPI CMOs, wherein Multiple Levels of HPAPI Containment has become a basic prerequisite using Versatile Howorth Air Technology downflow booths, ensuring fully enclosed process equipment, Isolator and ChargePoint® technologies, Isolated double-HEPA filtration airflow and keeping Interlocked personnel and materials flow airlocks with misting shower decontamination. A Well Equipped Approach to HPAPI Suite Design at a Multi-Use High Potency API Manufacturing Facility: As the HPAPI CMOs cope up with an upsurge in the number of types of HPAPIs, it is of essence that we look at the basic attributes of HPAPIs. The APIs deemed to be highly potent fall into one of the 4 important categories: 1. A pharmacologically active ingredient or intermediate with biological activity at approximately 150 ?g/kg of body weight or below in humans (therapeutic daily dose at or below 10 mg) is known as a highly potent API (HPAPI). 2. A pharmacologically active ingredient or intermediate with high selectivity (i.e., ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental effects, or reproductive toxicity at low doses is also known as an HPAPI denoted generally as High Potency API (HPAPI). 3. An active pharmaceutical ingredient or intermediate with an occupational exposure limit (OEL) at or below 10 ?g/m3 of air as an 8-h time-weighted average are also known as HPAPIs. 4. The potency of pharmaceutical chemicals is often characterized by OELs in ?g/m3; the lower the value, the more potent the chemical and the greater the level of containment that is required, hence, by default, a novel compound of unknown potency and toxicity is often considered as an HPAPI and the contract manufacturing organizations which work dedicatedly on HPAPIs are called as HPAPI CMOs. The development and manufacture of Highly Potent Active Pharmaceutical Ingredients (HPAPI) in a multi-use facility faces challenges of technical, procedural, and a perception-based nature. Fundamentally, it all starts with the use of the right tool for the job. So an efficient HPAPI CMO needs to focus on utilizing a risk-based approach to facility and equipment design when faced with the unique challenges of being a Contract Development and Manufacturing Organization (CDMO) which are: 1. User requirement specification development 2. Containment strategy risk assessment 3. Process hazard analysis 4. Flexible and expandable design 5. Validation strategy 6. Product changeover A HPAPI CMO works on developing all types of HPAPIs including small molecules, biopharmaceutical compounds as well as small antibody molecules that are highly potent and most usually used as oncologic drugs. Currently, there is a significant increase in the number of highly potent APIs going through development and clinical trials, and into the production environment with OELs much below 10 ?g/m3. These processes require specialized HPAPI containment facilities and more infrastructural investments to ensure that employees and their environment are protected from exposure. Considering a basic facility design of a typical kilo-laboratory (using glassware for HPAPI handling in HPAPI CMOs), the main features of handling of High Potent APIs are as follows: 1. Room pressure differentials designed for containment (with monitoring and verification), with the main HPAPI-handling area at negative pressure to surrounding rooms 2. Airlocks and vestibules around HPAPI manufacturing and laboratory spaces to provide gowning and de-gowning areas and proper pressure differentials 3. Restricted access to ensure that only the necessary trained employees enter the HPAPI-handling areas 4. HVAC (heating, ventilation, and air conditioning) systems designed for single-pass air—no return, with temperature, humidity, and particulate controls 5. Misting showers as part of de-gown and exit vestibules to rinse personal protective equipment (PPE) and gowning prior to removal 6. Filtration and capture of contaminants, with safe-change filters, both point source (within the isolator, ventilated enclosure) and the general HVAC exhaust system 7. Preventive maintenance and change-control procedures should be present at High Potency API (HPAPI) manufacturing facilities to ensure that equipment and systems continue to operate properly and according to design specifications. The global HPAPI CMOs are broadly classified as Innovative HPAPI CMOs and Generic HPAPI CMOs based on customer base. Based on business type, the HPAPI CMOs can be Captive HPAPI manufacturers or Merchant HPAPI CMOs. HPAPI CMOs are segmented on the basis of molecule type as Synthetic HPAPI developing CMOs and Biotech HPAPI CMOs. The HPAPI CMOs can be classified into Oncology, Cardiovascular, Central Nervous System, Hormonal, and Glaucoma & Eye Diseases, Infectious, metabolic, inflammatory diseases as well as other therapeutic areas. Increasing incidence of chronic and age-related diseases, rapid growth in oncology market, growing demand for Antibody Drug Conjugates (ADC), technological advancements in high-potency compounds market, growing number of HPAPI CMOs are some of the factors which are driving the high-potency drug substances market. Requirement of large investments, stringent safety and handling specifications associated with production of HPAPI, stringent regulations are the factors hindering the market. As a long established supplier of high potency active pharmaceutical ingredients (high potency APIs), a capable HDAPI CDMO should have a wide range of experience and expertise in developing, manufacturing and handling highly potent and cytotoxic compounds or highly potent and cytotoxic APIs. North America accounts for the highest market share of High Potency APIs (HPAPI) in 2016 followed by European markets. However, Asian countries especially China and India are on the road to become the emerging HPAPI manufacturing hub since the largest number of highly potent APIs for pre-clinical trials & commercial use are being developed here. In the Asia-Pacific region, HPAPI demand is projected to grow further. High potency active pharmaceutical ingredients or High Potency API (HPAPI) market is a growing concept and is considered to be a boost to the pharmaceutical industry. Patented high potency drug development majorly dominates the HPAPI CMOs market. The branded High Potency APIs (HPAPI) sector constitutes the major share of this market but the patents of this branded sector are expected to expire in the coming few years that will help HPAPI manufacturers to cater to multiple clients by producing the generic version of the High Potency API (HPAPI) based products in bulk. Here we also present a partial list of HPAPI CMOs and scale up operations, globally as follows: • Abbott Laboratories • AbbVie Contract Manufacturing • ADC Biotechnology • ADC Therapeutics • Aenova Group Gmbh • Agno Pharma • Ajinomoto (Althea Inc.) • Alcami Corporation • AlkermesPlc • Almac Group • Ampac Fine Chemicals • Amri Global • Anvi Pharma • Astrazeneca(Spirogen) • Asymchem Laboratories • Avanthera S.A. • Avara Pharmaceutical Services • Axcellerate Pharma Services • Bachem • Baxter International • Bayer • Biocon Limited Understanding the requirements for HPAPI manufacturing and related costs is critical for a CMO or pharmaceutical company interested in expanding or adding HPAPI capacity. The manufacturing facilities developed for HPAPI synthesis often cost upwards of $50 million and several HPAPI CMOs have expanded their CGMP pilot plants, kilo-laboratories, bacterial and fungal fermentation-derived HPAPI manufacturing units and scaling up new commercial-scale HPAPI facilities. Small-molecule HPAPI manufacturing: Often, CDMOs may have to choose to build a new commercial-scale HPAPI plants following than making several expansions and configuration-related changes at the current plant with HPAPI Manufacturing Capabilities. At the time to make decisions to expand CDMO services, one has to consider whether they want to expand the HPAPI manufacturing services by building from scratch rather than acquiring another building or CMO which would have inevitably require a great deal of retrofitting arrangements. When it comes to HPAPI facility design, it is seen that the better option is to build a facility according to the type of products to be manufactured in that facility rather than to try and build into existing facilities, which may not have the containment principles in place already. Since HPAPIs are most often developed into small molecule drugs, a separate facility for their production is desirable. Not only does that bring in place accurate allocation of resources, but it also allows no room for contamination between different High Potency API (HPAPI)s or equipment handling issues at the time of delivery, keeping the workflow seamless and producing highest quality outputs. Commercial scale High Potency APIs (HPAPI) production should be capable of manufacturing, handling, and transferring large volumes of product up to 4000 L or more. This capacity will allow for batches of potent compounds to be manufactured in the range of hundreds of kilograms. The material-handling systems being designed should have capacities for full containment on a large scale. Additionally, an HPAPI CMO has to add a milling and micronization area in the facility for potent compounds, which together has to adhere to Category IV standards, as defined by SafeBridge Consultants. Antibody–drug conjugates: To receive SafeBridge certification for high-potency antibody–drug conjugation suites, high degrees of calibration are necessary, as well as quality checks at regular intervals at all high-potency API manufacturing (High Potency APIs) facilities. For a high-potency conjugation suite it is necessary to take the best practices in facility design, operator training, operator safety, and conjugation and biologics capabilities. A high-potent conjugation facility has to be designed from its inception as a containment facility. Some key factors in designing such a facility are room-pressure differentials, with appropriate monitoring and verification, to ensure that the pressure of the major handling area is negative to its surrounding airlocks and vestibules. Single-pass air is used with temperature, humidity, and particulate controls. Misting showers are part of the de-gowning and exit process for operators and equipment. The suite also has filtration and capture equipment, both with the isolators and with the exhaust system of the heating, ventilation, and air-conditioning system. Isolators and fume hoods are used for certain operations as are biologic safety cabinets. Other facility designs such as unidirectional flow and restricted access are consistent with most recently built biologics facilities. Traditional biologics facilities that produce proteins and antibodies in mammalian-cell-culture or bacterial fermentation are designed to have the suites where purification occurs be positive to their surroundings. However, when working with potent products, such as viruses or biologics that are conjugated to highly potent APIs, processes are performed in a suite negative to the surrounding rooms to ensure the potent compounds are contained within the working environment," as explained by SAFC Pharma’s Business Development Head, David Backer. "Protection of the operators is also an absolute requirement. The operators are well trained in operating with protective garments and wear respirators," he adds. "Training in the handling of high-potent products is ongoing and essential. Changeover processes are validated and in place." It is useful to employ a negative-room-pressure concept at HPAPI manufacturing and handling facilities for viral-vaccine manufacturing, small-molecule HPAPI manufacturing and potent antibody–drug conjugation suites. An HPAPI CMO /CDMO can include this approach at its fermentation facility as well, which will target potent and cytotoxic molecules, and for large-scale, small-molecule HPAPI commercial manufacturing capabilities. As with all HPAPI facilities, operator safety is a key consideration. Demonstrating that controls are in place to ensure the highest levels of safety to workers and the environment is an important consideration. The operators have to be well trained in operating with protective garments and wear respirators. Training in the handling of high-potent products is ongoing and essential. Changeover processes have to be validated and in place. Additionally, Safe Bridge certification adds assurance that there will not be interruptions in High Potency APIs manufacturing due to safety concerns.