Everything You Should Know About Cytotoxic Compound API Manufacturing for Selecting a Top CDMO / CMO What are Cytotoxic Compounds? Often we get questions coming up like what is cytotoxicity and how is it different from anticancer drugs and antioxidants. Some people even get asked whether there is any relation among these molecules and their pharmacological activities. This can be a pertinent question for situations when a scientist has just synthesized a specialized molecule like an indole-based heterocyclic compound. The protocol followed is that he must have screened its cytotoxicity through cytotoxicity tests and from that report, the scientist or formulation expert must have concluded that the synthesized molecules are less toxic. But the compounds have to go through additional analyses and characterizations in order that their cellular bio-activity and their therapeutic action against the diseased cells can be clearly understood, along with the dosage volumes and routes of administration. This requires a good knowledge of Cytotoxicity and the activity of toxic agents, foreign molecules and disease causing particles (e.g. viruses) so that drug molecules are accurately characterized. While determining the cytotoxicity of molecules and characterizing drug substances, an important aspect to consider is Antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC is described as the cell-killing ability of certain lymphocytes (White Blood Cells), where the target cell is marked by an antibody. Other types of cellular cytotoxicity are: • Lymphocyte-mediated cytotoxicity, which is mediated by antibodies, and • Complement-dependent cytotoxicity (CDC), which is mediated by the complement system. In the development processes of pharmaceutical APIs, Cytotoxicity is defined as the quality of being toxic to cells. Chemical substances which are used to disrupt the activity of certain diseased cells are considered as cytotoxic compounds (e.g. phenolic compounds are considered highly cytotoxic). Treating cells with a cytotoxic compound can result in a variety of cell fates. The cells may undergo necrosis, in which they lose membrane integrity and die rapidly as a result of cell lysis. The other fate is that the cells can stop actively growing and dividing (a decrease in cell viability), or the cells may activate a genetic program of controlled cell death (apoptosis). Cytotoxic compounds definition: Cytotoxic compounds often become confusing with biologically active molecules like antioxidants; however, it has to be made clear that antioxidants are substances that prevent damage to cells caused by free radicals (better known as Reactive oxygen species). Free radicals are molecules that have lost an electron, which makes them unstable. These free radicals basically take electrons from other molecules in effort to achieve stability, ultimately creating new free radicals in the process. If this process keeps continuing, it can cause damage to DNA, leading to the possible development of cancer. Quality control measures such as Cytotoxicity assays are widely used by the pharmaceutical industry to screen for cytotoxicity in compound libraries. Researchers can either look for cytotoxic compounds, if they are interested in developing a therapeutic that targets rapidly dividing cancer cells, for instance; or they can screen "Cytotoxics" from initial high-throughput drug screens for unwanted cytotoxic effects before investing in their development as a pharmaceutical. Process Development and Manufacture of the Cytotoxic Drug-Linker Payload The development of Antibody-drug conjugates (ADCs) requires the capability to develop and manufacture highly potent Cytotoxic ADCs (Cytotoxic API manufacturing) from proof of concept through to non-clinical and clinical use, late stage as well as commercial manufacturing. If a API manufacturing company or HPAPI CMO has expanded its Bioconjugation capabilities by adding a dedicated suite for developing and manufacturing cytotoxic ADCs up to Safebridge level 4/5, it can be considered as the right CMO for commercial scale production of Antibody-drug conjugates with cytotoxicity of drug substances are controlled on the basis of potency, volume and micro-particle activity. A fully equipped Biotechnology manufacturing company has a robust production design for Highly Potent and Cytotoxic Compounds which will be executed according to the required process development & manufacturing strategy, especially for high containment cytotoxic capabilities. Containment by Design for Cytotoxic Manufacturing There is a growing client interest in application of development-scale equipment (containment equipment) such as tablet presses. Traditionally, manufacturers opted to retrofit existing equipment for enclosure in an isolator, but this strategy comes with fundamental problems as previously, the tablet presses were not designed to be contained and retrofitting them requires modifications that could compromise the presses’ precision and integrity. To overcome these difficulties during high containment cytotoxic capabilities, equipment providers have begun to produce isolator-ready devices that can easily be retrofitted for containment and provide better “high containment cytotoxic capabilities.” Managing Risk in the Manufacture of Oncology Drugs The market for oncology-related clinical trials has also grown. Oncology represented 17.8%, or the largest share of clinical trial starts in 2005 (Ibid p. 47). With regard to oncology products in development, anticancer compounds rank first worldwide with 2,467 compounds in development as of March 2006 (Parexel’s Pharmaceutical R&D Statistical Sourcebook 2006/2007, p. 49, IMS Life Cycle R&D Focus). The understanding of the molecular basis of cancer pathology is much better now and this clarity has opened up the chances of cancer treatments becoming more specialized in terms of targeting molecular pathways. However, because these agents are essentially cytostatic in nature (i.e., they limit cell proliferation but do not result in a decrease in tumor mass), they will continue to be used in combination with traditional cytotoxic agents which will decrease tumor mass, ultimately leaving the patient tumor-free and able to live longer and with a better quality of life. Currently, according to global sales figures data, cytotoxic products represent about $10 billion of the $37 billion oncology market. About $8 billion of this comes from three parenterally administered drugs — Eloxatin (oxaliplatin), Taxotare (docetaxel) and Gemzar (gemcitabine) — all of which are generics since 2014. The global market for cytotoxic products is estimated to peak over $13 billion, but shrink to about $11 billion due to generic price according to recent statistics. Key Considerations for Manufacturing Cytotoxic Products As was previously discussed, cytotoxic agents represent compounds whose exposure limits are as low as 0.03 µg/m3 over eight hours. In order to protect production operators and the surrounding environment from exposure, manufacturing operations typically are performed in barrier isolator systems or closed restricted access barrier systems (cRABS). The use of these systems allows for complete containment of the environment where the product is manipulated. Within any cRABS or barrier isolator system, the air is HEPA-filtered before being exhausted out of the isolator via a dedicated duct that is directed out of the room. Many advanced isolator systems can both clean and sterilize in place to eliminate the need for disassembly and potential exposure between batches. In a multi-product facility, disposable tubing/parts are typically used to facilitate quicker batch change-over. However, physical cleaning of the product-contact or product-exposed surfaces is necessary to show absence of the last product before the isolator is opened to the general room environment. Lyophilization Lyophilization of cytotoxic agents requires additional containment and specialized handling. In the case of manually loaded/unloaded lyophilizers, it is crucial to consider personnel protection from product spill as this could result in the personnel carrying residue into adjacent areas. Application of Cytotoxic and Potent Compounds in ADC Development Cytotoxic APIs are used in the production of Antibody drug conjugates (ADCs) for which it is necessary to have a conjugation process and technology transfer or need development of a new conjugation process for the production, quality control and supply of cytotoxic compounds in a separate cGMP manufacturing facility. Selection of an appropriate linker is important and you should be able to choose a reputed HPAPI CMO or HPAPI development partner that demonstrates tremendous flexibility in this regard who can: • Utilize your proprietary linker, or • Employ our proprietary and license-free Linker Technologies, including • Non-cleavable, thioether-based SteadFastTM Linker Technology, or • Cleavable, disulfide- or hydrazone-based FlexReleaseTM Linker Technology Industry Standards for Manufacturing of Cytotoxic Pharmaceuticals and Cytotoxic Payloads An appropriate cytotoxic payload and cytotoxic compounds assay, even for cytotoxic pharmaceuticals, has to be selected to which the target cancer cell demonstrates susceptibility is critical to evaluate a payload of the appropriate potency and specificity under the Safebridge or Merck classification systems (e.g., protein toxin, cytotoxic peptide or small molecule cancer drug). A CMO that partners for the production and scale up of Highly Potent and Cytotoxic Compounds should be able to work with cytotoxic payloads up to Safebridge Level 3 within its own facilities (e.g., doxorubicin or methotrexate); however, for ADCs utilizing highly potent cytotoxic payloads (cytotoxic drugs examples: maytansine, auristatin, DM4, or tubulysin) requiring a Safebridge level 4 / Merck level 5 facility, some CMOs choose to collaborate with other renowned inspected facilities where they can seamlessly execute all conjugation processes for delivering high Highly Potent and Cytotoxic Compounds within an internal high-containment facility from proof-of-concept through late-stage clinical trials and large-scale cGMP manufacturing or commercial products. There are specialized API development companies that have a dedicated laboratory and infrastructure addressing the needs of clients that provide specifications for manufacturing of Cytotoxic Pharmaceuticals with highly potent synthetic molecules including containment solutions for beta-lactams (antibiotics). While selecting the CMO for delivery of Highly Potent and Cytotoxic Compounds, be sure that whether your CMO works onsite or offsite at a partner’s facility, your cytotoxic APIs will be developed at the earliest stages in a scalable, GMP-compliant, economical and efficient process that is designed to manufacture Cytotoxic ADC products in an expedient manner and meet all appropriate quality requirements relative to safety, purity, identity, potency and immunogenicity. Manufacturing Solid dosage, cytotoxic and high potent sterile injectable drugs Collaborate with the list of CMO partners listed on PharmaCompass to design and synthesize novel, cleavable linkers based on peptide or other appropriate linkages for the large scale production of Cytotoxic API Products and high potency drug compounds. It is important to check the capabilities of CMOs for their quality assurance measures and inspections, and check how they are conducting various processes for constructing homogeneous antibody drug conjugates. Antibody drug conjugates (ADCs) are synthesized by conjugating a cytotoxic drug or Cytotoxic Products referred to as “payload” to a monoclonal antibody. The payloads are conjugated using amino or sulfhydryl specific linkers that react with lysine or cysteine residues on the antibody surface. A typical antibody contains over 60 lysine residues and up to 12 cysteine residues as potential conjugation sites. The desired DAR (drugs/antibody ratio) depends on a number of different factors and ranges from two to eight drugs/antibody. The discrepancy between the number of potential conjugation sites and the desired DAR, combined with use of conventional conjugation methods that are not site-specific, results in heterogeneous ADCs that vary in both DAR and conjugation sites. Heterogeneous ADCs contain significant fractions with suboptimal DARs that are known to possess undesired pharmacological properties. At PharmaCompass, you can find API manufacturing partners that dedicate cGMP facilities to manufacturing injection products with HPAPI, Hormone, and Cytotoxic Handling. Choosing the right CMO from this list means that you can be rest assured that for Manufacturing Cytotoxic & High Potency Compounds, you have the top rated API manufacturing expert for cytotoxic APIs. Take the best contract manufacturing services / CMOs for generic cytotoxic injectable drugs from this fresh list of Manufacturers of Cytotoxic Drugs. Rise in the Production and development services for HPAPIs and Cytotoxic Products Currently, the HPAPIs and Cytotoxic Drugs Manufacturing Market has a rising demand due to the push for targeted therapies. Cytotoxic drug compounds and High potency compounds such as high potency active pharmaceutical ingredients (HPAPIs) & cytotoxic drugs manufacturers have become the key focus of researchers and manufacturers worldwide. Capable pharmaceutical manufacturing companies focused on HPAPI, Hormone, and Cytotoxic Handling are increasing their resources for development and manufacture of HPAPIs. HPAPIs, which include cytotoxic APIs, are drug substances that are formulated to manufacture high potency drug products. Cytotoxic drugs are a category of highly potent drug products and, due to their increased utility in the treatment of cancer indications, have gained wide attention in recent years. Manufacturing highly potent compounds is an emerging area of investments and partnerships which is evident from the surge in the expansion of existing production facilities of pioneering pharmaceutical manufacturing organizations across the globe. Now more number of HPAPI and cytotoxic compound development companies are aiming to achieve success in highly potent API manufacturing. The latest entrants in the cytotoxic drugs list are Orphan cytotoxic compounds. While this is an advancement that has come recently, it is important to remember that Manufacturers of Cytotoxic Drugs have quite a large number of challenges to tackle. A well-equipped HPAPI CMO should have the capability to handle challenges facing oncology pharmacies and cytotoxic compounding. This means that the highest priority has to be given to aseptic preparation of cytotoxic compounds while selecting the CMO for HPAPI and cytotoxic product development for different dosage forms and therapeutic subclasses such as Solid dosage, cytotoxic and high potent sterile injectable drugs. Cytotoxic Drug Dispersal, Cytotoxic Safety, and Cytotoxic Waste Management Through the process of potent API manufacturing, handling cytotoxic drugs such as antibody-drug conjugates (ADCs) in a Cytotoxic & High Potency Compounds Manufacturing Facility represents a challenge based on the potency of the compounds. Manufacturers of Cytotoxic Drugs have to understand that they are dealing with toxic derivatives of compounds which are dangerous to humans if they accidentally get in contact with the skin, are inhaled, or are ingested, either as pure compounds in their solid state or as a solution dissolved in a co-solvent. Any contamination of people involved in the manufacturing process without safe Handling of cytotoxic drugs has to be avoided. Manufacturers of Cytotoxic Drugs are required to furnish all infrastructural and equipment handling details to inspection officers, including reports of adverse events that occur at HPAPIs and Cytotoxic Drugs Manufacturing units. On the other hand, biopharmaceuticals such as cytotoxic APIs need to be protected simultaneously against any contamination from the manufacturing personnel. Safe handling of cytotoxic compounds in a biopharmaceutical development company requires effective training on HPAPIs & cytotoxic drugs handling protocols. Therefore, a tailor-made work environment in a HPAPIs and Cytotoxic Drugs Manufacturing Facility is mandatory in order to manufacture ADCs including cytotoxic API conjugated with antibodies. Importance of Safety Manuals for Manufacturers of Cytotoxic Drugs Appropriate technical equipment and safety protocols are supposed to be kept in place to prevent potential hazardous substances from being contaminated or exposed. Hence, the Cytotoxic and Potent Compounds are contained at Cytotoxic Contract Manufacturing Facility units to ensure safe handling of cytotoxic compounds. In addition, clearly defined working procedures based on risk assessments as well as proper training for all personnel involved in the manufacturing process are essential requisites at Cytotoxic Commercial Manufacturing Units to safely handle these highly potent pharmaceuticals. Certain precautions have to be followed by skilled personnel during cytotoxic drugs handling. Cytotoxic drugs handling is a serious task as cytotoxic drugs are intended primarily for the treatment of cancer. Cytotoxic drugs are used widely in healthcare settings as well as in the community in the treatment of cancers as well as other diseases. Handling cytotoxic drugs in isolators and Safety Considerations for cytotoxic APIs Operators can be exposed to cytotoxic drugs through factors such as: • Breathing air contaminated with cytotoxic drug as a powder, or aerosol or vapour; • Skin contact with the drug itself or contaminated surfaces, some of these drugs can pass through intact skin; • Accidental ingestion. Cytotoxic drugs are used in the therapy of various neoplastic conditions, organ transplantation, and collagen vascular disorders and are used in oncology, radiotherapy, transplant, and immunology units. Their use in other hospital departments and outside the hospital in clinics and elsewhere is also increasing owing to increase in the incidence of carcinomas, transplants, and immunological diseases. It is important to know about cytotoxic precautions PPE (personal precaution equipment) used during Cytotoxic & High Potency Compounds Manufacturing. The toxicity of cytotoxic drugs means that they can present significant risks to those who handle them. Occupational exposure can occur when control measures are inadequate. Exposure may be through skin contact, skin absorption, inhalation of aerosols and drug particles, ingestion and needle stick injuries resulting from the following activities: • Drug preparation • Drug administration • Handling patient waste • Transport and waste disposal, or • Cleaning spills. The disposal of genotoxic waste raises serious safety issues, both inside hospitals and after disposal, and should be given utmost attention. It includes cytotoxic drugs, vomit, urine, or feces from patients treated with cytotoxic drugs. Technically, genotoxic means toxic to the deoxyribonucleic acid (DNA). • Advanced Chemical Synthesis • Antibody Drug Conjugates (ADC) • Fermentation • Peptides • Continuous Flow Technology Inadequate control measures could lead to: • Abdominal pain, hair loss, nasal sores, vomiting, and liver damage • Contact dermatitis and local allergic reactions. • Fetal loss in pregnant women and malformations in the children of pregnant women • Alterations to normal blood cell count • Abnormal formation of cells and mutagenic activity or mutations forming Trends in High Tox Manufacturing The overall trends in high Tox manufacturing indicate that certain cytotoxic drugs come with the special containment requirements for manufacturing highly potent active pharmaceutical ingredients and cytotoxic drugs. Many Contract Manufacturing Organizations (CMO’s) invest in building additional capacity. While there are tremendous benefits and a strong promise with HPAPIs and cytotoxics, there are also considerable challenges facing oncology pharmacies and cytotoxic compounding, as well as additional risks associated with production of potent & cytotoxic compounds, especially in a multiproduct CMO environment. HPAPIs and Cytotoxic Drugs Manufacturing Landscape for the future shows that the HPAPI market is currently cited as one of the most important segments of pharmaceutical industry. The market is currently dominated by contract manufacturers. Though some pharmaceutical companies have invested in building in-house capabilities, the capital intensive nature and specialized containment requirements make the role of contract manufacturers more crucial. SAFC, Lonza and Evonik are amongst the pioneers in the field of manufacturing highly potent compounds. In addition, new entrants such as Medichem and Wuxi Pharma have also recently sprung up. The growing number of investments and partnerships in this field are evident of the current market intensity. Majority of the investments in recent years have been expansion programs which reflect that manufacturers are keen to expand their existing production facilities to meet the growing demand. Looking at the ongoing focus, we certainly believe that stakeholders will continue to invest in this area. The current market landscape will gradually evolve as manufacturers look to gain competitive advantage in the near future.