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Quotient Sciences has responded to the challenges associated with the manufacturing of today’s high-potency drug products by ensuring our facilities are capable of handling compounds with a maximum performance-based level of exposure classification.
Globela Pharma Pvt Ltd has uplifted our existing R & D facility, and installed fully functioning in house R & D center- with state of the art infrastructure, and experienced, skilled manpower.
Highly potent small-molecule and 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. Unlike better-known typical reactive chemicals, these Pharmaceutical Ingredients are designed to be biologically active in low concentrations. HPAPI’s can therefore harm researchers with adverse symptoms at very small exposure levels! Warfarin, for example, shares its chemical roots with rat poison! Advanced technologies that allow the delivery of drug substances directly to the site of action – tumour cells, infected cells, damaged organs – rather than acting systemically are leading to develop highly potent solid oral drugs with increased safety and efficacy. Using the most advanced methods of High Potency Product Manufacturing enables the use of highly potent active pharmaceutical ingredients (HPAPIs) that previously were not reasonable candidates due to higher toxicity to the patient when delivered using conventional approaches. Therefore, the companies that have Highly Potent Product Manufacturing facilities have seen a rise in their demand and significantly higher number of therapeutic drugs using Highly Potent Oral Solid Dosage formulations. The number of drug candidates classified as HPAPIs is increasing. Pharmaceutical manufacturers focused on developing Highly Potent Drug Products are in need of capacity suitable for the safe production, storage and transport of a growing range of high-potency compounds. Contract service providers – both contract development and manufacturing organisations (CDMOs) and CMOs – can help, but drug sourcing companies should only consider partnering with HPAPI CMO / CDMO firms that have a history of successfully producing and handling HPAPIs and continually investing in the most advanced safety equipment, HPAPI Containment and HPAPI Chemistry handling systems and Structured CGMP compliant manufacturing facilities. Recording data during manufacturing of high potency oral solid dosage forms is a must. Commercial Development and Manufacture of Highly Potent API Drug Products Good quality and high throughput manufacturing of HPAPIs as biologic drugs and HPAPIs as tablets requires an understanding of the potential risks associated with the production and handling of HPAPI tablet productions with specialized liquid and solid encapsulation systems are required to minimize risks. Proper facility design and engineering controls are the first requirement, which includes the heating, ventilation and air conditioning system, approaches to barrier isolation, the incorporation of gowning/de-gowning areas, and much more. Appropriate containment safeguards, and comprehensive quality management systems are also a must. Of course, expertise in synthetic organic chemistry and process development, scale-up, purification capabilities, and highly sensitive analytical instrumentation and techniques are also required. In addition, continuous education and training of chemists, engineers and operators is crucial to ensure that they are aware of the risks using personal protective equipment (PPE) and standard operating procedures (SOPs). Without highly skilled personnel and trained personnel, the safe and effective production of HPAPIs at HPAPI CMOs at specific dosage forms such as HPAPI tablets will be a challenge, even in the most advanced facilities. Because highly potent therapies are administered at very low doses, and increasingly they are developed for highly targeted populations, often they are low-volume products. As a result, in addition to CMOs with demonstrated expertise with HPAPI production as HPAPI tablets, pharmaceutical companies are looking for HPAPI CMOs that have the capability to support both the development and commercial manufacture of HPAPIs as biologics, HPAPI tablets and HPAPI injectables to reduce supply chain transfers. CMOs that can support a safe, reliable, and regulatory compliant supply chain of HPAPIs are most likely to succeed as preferred single-source supplier. Liquid Encapsulation for HPAPI Tablets Liquid formulations in hard-shell capsules or soft-gels are becoming a popular option for HPAPIs because of advantages such as improved safety and lower risk of potential exposure and product cross contamination. HPAPIs as tablets require specialized facilities and equipment to ensure that both personnel and the environment are protected from exposure. In terms of formulation and processing, there are several considerations in the development of a dosage form containing low concentrations of a highly potent drug substance. 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 HPAPIs and tablets, HPAPIs in encapsulated forms (HPAPI tablets) and HPAPIs as biologic drugs are the rise in the oncology therapeutics market. This has led to advances in the field of Development and Manufacture of Highly Potent API Drug Products in the need for better medicines for treating Cardiovascular, Central Nervous System, Hormonal, Eye, Infectious, and Metabolic and Inflammatory diseases. Besides processes of manufacture of all oral drug product dosage forms including HPAPI tablets, liquid formulations of high-potency compounds in hard-shell capsules or softgels are becoming a popular option because of the following advantages: 1. These formulations have long been recognized as one of the most successful drug-delivery technologies for challenging compounds. In addition, softgel technologies have a proven commercial record of bringing various types of highly potent solid oral drugs to market, such as hormones, vitamin D analogues, and other cytotoxic compounds. 2. Unlike tablets and capsules that involve powder production, liquid formulations do not present issues such as dust generation, and the hazards of product cross-contamination are minimized. Moreover, the processing of liquid formulations is more convenient and does not require complex and expensive engineering controls. 3. The highest risk with regard to manufacture of all oral drug product dosage forms is during the initial powder-handling stages (i.e., during dispensing of the drug and when it is being added to an aliquot of the vehicle). These steps are typically performed in an isolator or containment hood. 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. 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. Strong growth of both areas is a significant driver of increased demand for small molecule API 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 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. Advances in micro particle, capsule and syringe technologies, analytical methods, and containment systems are widening the safe formulating options for HPAPIs. To obtain capsules and tablets of HPAPIs, fluidized-bed coating technology (Wurster coating), which involves spraying of an HPAPI solution onto nonpareil beads that can then be filled into capsules or pressed into tablets, is an attractive alternative, according to Knox. Mini-tabs can also be used for multi-particulate HPAPI systems where single- or multi-layered coatings contain a functional coat with the active ingredient and a seal coat. 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 linked to the growth in biologics, oncology and generics. Nonetheless, the regulatory hurdles are more challenging and the investment required provides barriers to entry. Unique Delivery Systems for Developing Highly Potent Drug Products As Tablets 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 that provide some advantages because they are more suitable for the lower drug loads associated with HPAPIs. 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. 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 HPAPIs. Companies working on developing manufacturing technologies for high-potent API manufacturing, are giving due weightage to understanding the requirements for HPAPI manufacturing and related costs while undertaking expansions. Some HPAPI CMOs have opened specialized HPAPI manufacturing facilities that fully focus on developing encapsulated forms of HPAPI drug products, including small molecule drugs. Many contract API 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) production facilities. This investment may include specialized facilities for HPAPI–antibody conjugations that incorporate both handling of high potent APIs and biologics processing capabilities. Drug manufacturers are developing more high-potency compounds, 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 containment equipment and 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 therapy is the largest therapeutic products segment for the small molecule sector, followed by oncology. Strong growth of both areas is a significant driver of increased demand for small molecule API and HPAPI drug product contract manufacturing services. Highly Potent Formulation Oncology Manufacturing of non-cytotoxic oncological HPAPI products up to level OEB4 and cytotoxic oncological products up to level OEB5 is a very common requirement in the area of Highly Potent Formulation Oncology. HPAPI production plants should be checked for all the operating conditions that should be ensured correctly for handling such highly potent substances, both as solid and Injectable forms of highly potent solid drugs. A well-known HPAPI CDMO / CMO should have in-depth expertise in oncological manufacturing delivers with a long-standing reputation of quality and reliability in all regulated markets. Strong growth in anticancer therapies in recent years together with a shift in drug development towards more complex and potent compounds are driving the demand for Cytotoxics and High Potency Manufacturing capacities. For developing all other highly potent compounds for solid oral dosage forms Including Tablet HPAPIs, choose an expert in manufacturing oral Drug Products that delivers highly potent compounds (e.g. hormones, hormone blockers, oncologic compounds) up to level OEB4. A CMO with fully functional High Potent Oral Solid Dose product development facilities should have fully-contained sites which provide high volume equipment for granulation, drying, compression and tablet coating, as well as state-of-the-art PPE designed for flexible use in smaller batch sizes. Besides the standard technologies we also work with organic solvents, both in high shear granulation and fluid bed granulation processes. High Potency Product Manufacturing and Development in Solid Dosage Forms With advances in oral solid dose highly potent manufacturing and handling highly potent drugs, the level of risk management required is even higher. For oral solid dosage forms based on liquid encapsulation of highly potent APIs or compacting them into High Potent Oral Solid Dose tablets, rigorous care must be taken throughout the production process (granulation, mixing, tableting, etc.) to ensure the highest level of quality. In large scale Highly Potent Solid Dosage Manufacturing, 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. Automation process for oral solid dose highly potent manufacturing 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. Automation makes it possible to achieve a 100% remotely controlled manufacturing facility even for Highly Potent Solid Dosage Manufacturing with no human interaction during the manufacturing process and the fully automated solid-dosage form manufacturing suites used for large-volume products such as smoking cessation drugs as prime examples. These benefits can be harder to realize with smaller-volume products, which are often oncology drugs. Automated equipment is often not designed for smaller-scale operation. Thus, it may only be a solution if platform technologies are applied to a variety of compounds, such as dry granulation followed by capsule-filling for more than just one product in the portfolio. Here, of course, the issue of cross-contamination must then be addressed. Although single-use and disposable systems have not yet penetrated the solid dosage manufacturing sector to the degree of their usage in liquid and aseptic manufacturing, the idea of using disposable parts is promising. The use of such systems could allow for a tremendous reduction in cleaning verification and validation efforts as well as related analytical method development work. In addition, it could minimize the potential for contamination of operators and/or the environment. Isolated HPAPI containment facilities for both drug substances and drug product development and manufacturing 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 from grams to 100’s of kg • Handling of Merck Category 4 compounds • Potent solid dose formulation of batch sizes up to 10kg • Facilities FDA and MHRA inspected Using Isolators for highly potent solid oral drugs Some aspects to consider when using isolators while processing injectable, high-potency drugs are: • Containment of contamination, particularly airborne contamination • Individual protection of personnel • Management of cross-contamination • Aseptic processing and sterility of handled material and product • 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).
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