BEZ235 (NVP-BEZ235)Dactolisib

4-​[2,​3-​dihydro-​3-​methyl-​2-​oxo-​8-​(3-​quinolinyl)-​1H-​ imidazo[4, ​5-​c]quinolin-​1-​yl]-​α,​α-​dimethyl-​benzeneacetonitrile
2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-1H,2H,3H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile
2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)- phenyl]-propionitrile
Chemical Formula:  C₃₀H₂₃N₅O
CAS Number: 915019-65-7
Molecular Weight: 469.54
PHASE 2, NOVARTIS
CANCER, BLADDER

NVP-BEZ235 is a dual inhibitor of phosphatidylinositol 3-kinase (P13K)and the downstream mammalian target of rapamycin (mTOR) by binding to the ATP-binding cleft of these enzymes. It specifically blocks the dysfunctional activation of the P13K pathway and induce G(1) arrest. NPV-BEZ235 has been shown to inhibit VEGF induced cell proliferation and survival in vitro and VEGF induced angiogenesis in vivo. It has also been shown to inhibit the growth of human cancer in animal models.
BEZ-235 is an orally active phosphatidylinositol 3-kinase (PI3K) inhibitor in early clinical trials at Novartis for the treatment of advanced breast cancer, renal cell carcinoma, solid tumors and castration-resistant prostate cancer. Phase I clinical trials were also under way at the company for the treatment of glioma, however, no developments in this indication has been reported. Phase II clinical trials are ongoing at Johann Wolfgang Goethe Universität for the treatment of relapsed or refractory acute leukemia.
PI3Ks perform various functions, promoting cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. Mutations leading to increased activity of PI3Ks, including faulty production or action of PI3K antagonists, have been found in many cancers.

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WO 2006122806
http://www.google.com/patents/WO2006122806A2?cl=en

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WO 2008064093
2-methyl-2-[4-(3-methyl- 2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile of formula I (compound I),

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Pilot plant scaleup techniques used in pharmaceutical manufacturing from Sunil Boreddy Rx

Anthony crasto scaleup techniques & pilot plant from Anthony Melvin Crasto Ph.D

Designed and equipped for the manufacturing of solid oral dosage forms, specialized in high-activity substances (cytostatic, cytotoxic, hormonal, hormone inhibitors). It has ancillary areas for the proper management of materials intended for clinical trials of new drugs. Equipment:

• • Oystar Hüttlin Pilotmix 75T single-pot high shear mixer.
• • Container mixer, 60 and 200 liters containers.
• • Fette 1200iC rotary tablet press, fully equipped for formulation development and manufacturing.
• • Oystar Manesty XL Lab 01 tablet coater, with interchangeable drums.
• • IMA Clinipack blister machine.
• • Quadro Comill sieve
• • Capsunorm 2000 manual capsul filler
• • Sepha press-out deblister
• • Fette Gratex deduster
• • Process control laboratory: Dr. Schleuniger tablet hardness tester, Erweka tablet disintegration tester, Erweka friability tester, Mettler Toledo moisture content determination equipment.

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CASE STUDY 2

OPERATION OF PILOT PLANT FOR CLINICAL LOTS OF BIOPHARMACEUTICALS http://www.peq.coppe.ufrj.br/biotec/presentations/Papamichael_RioDeJaneiro2009_secure.pdf         

CASE STUDY 3

Good Manufacturing Practices in Active Pharmaceutical Ingredients Development http://apic.cefic.org/pub/5gmpdev9911.pdf Example below 3. Introduction Principles basic to the formulation of this guideline are: · Development should ensure that all products meet the requirements for quality and purity which they purport or are represented to possess and that the safety of any subject in clinical trials will be guaranteed. · During Development all information directly leading to statements on quality of critical intermediates and APIs must be retrievable and/or reconstructable. · The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. All quality related activities should be defined and documented. Any GMP decision during Development must be based on the principles above. During the development of an API the required level of GMP control increases. Using these guidelines, the appropriate standard may be implemented according to the intended use of the API. Firms should apply proper judgement, to discern which aspects need to be addressed during different development stages (non-clinical, clinical, scale-up from laboratory to pilot plant to manufacturing site). Suppliers of APIs and/or critical intermediates to pharmaceutical firms should be notified on the intended use of the materials, in order to apply appropriate GMPs. The matrix (section 8) should be used in conjunction with text in section 7, as is only intended as an initial guide. READ MORE AT.... http://apic.cefic.org/pub/5gmpdev9911.pdf 

CASE STUDY 4

http://www.steroglass.it/doc_area_download/ita/process/20LT_PILOT_PLANT.pdf   

CASE STUDY 5

  Health Canada http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/question/gmp-bpf-eng.php The Good Manufacturing Practices questions and answers (GMP Q&A) presented below have been updated following the issuance of the "Good Manufacturing Practices Guidelines, 2009 Edition Version 2 (GUI-0001)". This Q&A list will be updated on a regular basis. Premises - C.02.004Equipment - C.02.005Personnel - C.02.006Sanitation - C.02.007 & C.02.008Raw Material Testing - C.02.009 & C.02.010Manufacturing Control - C.02.011 & C.02.012Quality Control Department - C.02.013, C.02.014 & C.02.015Packaging Material Testing - C.02.016 & C.02.017Finished Product Testing - C.02.018 & C.02.019Records - C.02.020, C.02.021, C.02.022, C.02.023 & C.02.024Samples - C.02.025 & C.02.026Stability - C.02.027 & C.02.028Sterile Products - C.02.029     

CASE STUDY 6

CASE STUDY 7

  http://www.niper.gov.in/tdc_2013.pdf     

CASE STUDY 8

Multi-kilo scale-up under GMP conditions

Examples of flow processes being used to produce exceptionally large amounts of material are becoming increasingly common as industrial researchers become more knowledgeable about the benefits of continuous reactions. The above examples from academic groups serve to illustrate that reactions optimized in small reactors processing tens to hundreds of mg hour⁻¹ of material can be scaled up to several grams per hour. Projects in process chemistry are often time-sensitive, however, and production of multiple kg of material may be needed in a short amount of time. An example of how the efficient scaling of a flow reaction can save time and reduce waste is provided by a group of researchers at Eli Lilly in their kg synthesis of a key drug intermediate under GMP conditions . In batch, ketoamide 13 was condensed with NH₄OAc and cyclized to form imidazole14 at 100 °C in butanol on a 1 gram scale. However, side product formation became a significant problem on multiple runs at a 250 g scale. It was proposed that this was due to slow heat up times of the reactor with increasing scale, as lower temperatures seemed to favour increased degradation over productivecyclization. Upon switching to a 4.51 mL flow reactor, another optimization was carried out which identified methanol as a superior solvent that had been neglected in batch screening due to its low boiling point at atmospheric pressure. Scale-up to a 7.14 L reactor proceeded smoothly without the need for reoptimization, and running on this scale with a residence time of 90 minutes for a six-day continuous run provided 29.2 kg of product after recrystallization (approximately 207 g hour⁻¹). The adoption of a flow protocol by a group of industrial researchers in a scale-up with time constraints demonstrates both the effectiveness and maturity of flow chemistry. While the given reaction was used to produce kilograms of material for a deadline, continuous operation without further optimization could produce over 1 metric tonne of product per year in a reactor that fits into a GC oven.       .................................. DefinitionsPlant: A plant is a place where an industrial or manufacturing process takes place. It may also be expressed as a place where the 5 M’s that are; man, materials, money, method and materials are brought together for the manufacture of products. Pilot Plant: A part of a manufacturing industry where a laboratory scale formula is transformed into a viable product by development of reliable practical procedures of manufacturing. Scale-Up: This is the art of designing a prototype based on the information or data obtained from a pilot plant model. cGMP: current Good Manufacturing Processes refer to an established system of ensuring that products are consistently produced and controlled according to quality standards. It is designed to minimize risk involved in any industrial design. GMP covers all aspects of production from the starting materials, premises and equipment to the training and personal hygiene of staff within industries. Detailed, written procedures are essential for each process that could affect the quality of the finished product. There must be a system to provide documented proof that correct procedures are consistently followed at each step in the manufacturing process every time a product is made.

SCALING UP FROM PILOT PLANTS

When scaling up, it is of utmost importance to consider all aspects of risk and futuristic expansion. The pilot plant is usually a costly apparatus and therefore the decision of building it is always a hard one. The function of a pilot plant is not just to prove that the laboratory experiments work, but;

1. To test technologies that are about to be implemented on industrial plants before establishment
2. To evaluate performance specifications before the actual installation of industrial plant.
3. Evaluation of reliability of mathematical models within real environment.
4. Economic considerations for production involving process optimization and automated control systems.

GMP GENERAL PRACTISES

Facilities and Equipment Systems

• Ø Cleaning and maintenance
• Ø Facility layout and air handling systems for prevention of cross-contamination (e.g. Penicillin, beta-lactams, steroids, hormones, cytotoxic, etc.)
• Ø Specifically designed areas for the manufacturing operations performed by the firm to prevent contamination or mix-ups.

Facilities

• Ø General air handling systems
• Ø Control system for implementing changes in the building
• Ø Lighting, potable water, washing and toilet facilities, sewage and refuse disposal
• Ø Sanitation of the building, use of rodenticides, fungicides, insecticides, cleaning and sanitizing agents.

GMP FOR PLANT DESIGN

The application of GMP to plant design is primary to the establishment of such plants. Regulatory boards have precedence over these operations helping to establish a proper and functional system in plant design. Design Review l Conceptual drawings; From plant design drawings which are inspected and approved by cGMP regulatory bodies (such as Department of Petroleum Resources in Nigeria), approvals are issued depending on adherence to specifications such as muster points, proper spacing of fuel sources from combustion units and other more elaborate considerations. l Proposed plant layouts; A choice of location for plant and layout play an important role on environmental impact. Hence, environmental impact assessment is a major part of GMP. Industries must be located at least 100M from closest residential quarter (depending of materials processed in plant). l Flow diagrams for facility For optimization and efficiency purposes, flow diagrams for complete refinery process are important for review with intent to ensure they conform to GMP l Critical systems and areas Some areas in a plant may require extra safety precautions in operations. The cGMP makes provision for such special considerations with the creation of customized set of operational guidelines that ensure safety and wellness of staff and environment alike. cGMP EXAMPLE: FOOD PROCESSING PLANT Outlined below are the cGMP considerations in the establishment and handling of a food processing plant. Safety of Water 1. Process water is safe, if private supply should be tested at least annually. 2. Backflow prevention by an air gap or back flow prevention device. Sinks that are used to prepare food must have an air-gap.Food Contact Surface 1. Designed, maintained, and installed so that it is easy to clean and to withstand the use, environment, and cleaning compounds. 2. If cleaning is necessary to protect against microorganisms, food-contact surfaces shall be cleaned in this sequence: wash with detergent, rinse with clear water, and then use an approved sanitizer. The sanitizer used shall be approved for use on food-contact surfaces. UA three-compartment ware washing sink or other equivalent methods shall be used for this purpose. 3. Gloves shall be clean/sanitary. Outer garments suitable. Prevention of Cross-Contamination 1. Food handlers use good hygienic practices; hands shall be washed before starting work, after absence from work station, or when they become contamination (such as with eating or smoking). 2. Signs shall be posted in processing rooms and other appropriate areas directing employees that handle unprotected food, food-contact surfaces, food packaging materials to wash their hands prior to starting to work, after each absence from the work station, and whenever hands may become contaminated. 3. Plant design so that the potential for contamination of food, food-contact surfaces, or packaging materials is reduced to the extent possible. 4. Physical separation of raw and finished products.Hand Washing Sinks and Toilet Facilities 1. Hand washing sinks, properly equipped, shall be conveniently located to exposed food processing areas. Ware washing sinks shall not be used for this purpose. 2. Adequate supply of hot and cold water under pressure. 3. Toilet facilities; adequate and accessible, self-closing doors. 4. Sewage disposal system shall be installed and maintained according to State law. Protection from Adulteration (Food, Food Contact Surfaces, and Packaging Materials) 1. Food processing equipment designed to preclude contamination with lubricants, fuel, metal fragments, contaminated water, or other sources of contamination. 2. Food processed so that production methods to not contaminate the product. 3. Raw materials, works-in-process, filling, assembly, packaging, and storage and transportation conducted so that food is not contaminated. 4. Protection from drip and condensate overhead. 5. Ventilation adequate and air not blown on food or food-contact surfaces. 6. Lights adequately shielded. 7. Compressed air or gas mechanically introduced adequately filtered.

Scope of services

• Engineering support
• Representation of the construction owner (equipment, construction: supervision of general contractors, GMP concept draft)
• Basic and detailed design
• Support during the implementation phase
• Clean room planning (incl. lab areas)
• Construction management
• Qualification
• Validation support

Toxic Items: Labelling, Use, and Storage 1. Products used approved and used according to product’s label. 2. Sanitizer used on food-contact surfaces must be approved for that use. 3. Shall be securely stored, so unauthorized use is prevented. Personnel Disease Control 1. Food handler, who has illness or open lesion, or other source of microbiological contamination that presents a reasonable possibility of contamination of food, food-contact surfaces, or packaging materials shall be excluded from such operations. 2. Adequate training in food protection, dangers of poor personal hygiene, and unsanitary practices shall be provided. 3. Management shall provide adequate supervision and competent training to ensure compliance with these provisions. Pest Control 1. Management shall provide an adequate pest control program so that pests are excluded from the plant. 2. Program shall ensure that only approved pesticides are used and applied per the product’s label.Plant Construction and Design 1. Walls, floors, and ceilings constructed so that they can be adequately cleaned and kept in good repair. 2. Adequate lighting provided. 3. Adequate ventilation or controls to minimize odours and vapours. 4. Adequate screening or protection of outer openings. 5. Grounds maintained free of litre, weeds, and pooling water. 6. Roads, yards, and parking lots maintained so that food is not contaminated. Equipment 1. Equipment, utensils, and seams on equipment – adequately cleanable, properly maintained, designed, and made of safe materials. 2. Refrigerators and freezers equipped with adequate thermometer. 3. Instruments and control devices – accurate and maintained. 4. Compressed air or gas designed/treated so that food is not contaminated. Equipment. Most equipment used to manufacture early GMP drug product is be managed under a qualification, preventive maintenance, and calibration program for the GMP facility. However, in early development, there may occasionally be a need to use equipment that is not part of such a program. Rather than performing a comprehensive qualification for a piece of equipment not expected to be frequently used, an organization may choose to qualify it for a single step or campaign. Documentation from an installation qualification/operational qualification (IQ/OQ) and or performance verification at the proposed operating condition is sufficient. For example, if solution preparation needs a mixer with a rotation speed of 75 rpm, then documentation in the batch record using a calibrated tachometer to verify that the mixer was operating at 75 rpm will suffice. The use of dedicated or disposable equipment or product contact parts may be preferable to following standard cleaning procedures to ensure equipment is clean and acceptable for use. However, not all equipment or equipment parts are disposable or may have a substantial cost that makes disposal prohibitive. In that case, the product contact parts could be dedicated to a specific drug substance for use in drug product manufacture. Dedicating product contact parts to a compound may be costly and may be avoided in some cases by carefully considering product changeover and effective cleaning methods when purchasing equipment. Another item to consider with respect to equipment, is that the more complicated the equipment is to run or maintain, the less desirable it might be for early GMP batches. In most cases, simple equipment is adequate and will uses less material and consume less total time for preparation, operation, and cleaning activities. Weights and Measures 1. Scales used to measure net weight of contents shall be designed so they can be calibrated. 2. Products in interstate commerce – net weights/measurements also in metric.   CONCLUSION Plant establishment is an activity that has kept rising from the inception of the industrial revolution until date. Giving rise to increase in raw material demand, increased pollution levels, higher energy demand, and overall greater economic output. As history and record keeping has served for an even longer period, it becomes necessary for adaptation to be made to avoid incidents and accidents that have occurred previously and also those that can be anticipated without actual devastating effect. The development of the GMP is as a result of observed challenges in industry and environment over years of industrialization. It becomes necessary to upset these poor trends that have developed as a result of industrialization by so doing increasing the pros and reducing the cons. GMP protects consumer, produce, equipment, and conserves the processes as a whole, leading to a more efficient sustainable process defining a new standard for yields and profit and eliminating the tendency of compromise made by industrialists to increase overall profits at the risk of staff and environment.   Batch documentation and execution Batch record documentation preparation. Manufacturing documentation is a basic requirement for all phases of clinical development. 21 CFR Parts 211.186 and 211.188 describe master production and batch production records, respectively (7). The stated purpose of the master production record is to "assure uniformity from batch to batch." Although the record assurance is important for a commercial validated manufacturing process, it does not necessarily apply to clinical-development batches. Material properties, manufacturing scale, and quality target product profile frequently change from batch to batch. Therefore, batch production records are the appropriate documentation for clinical trial supplies. Batch production records for Phase 1 materials should minimally include:

• Name, strength, and description of the dosage form
• A complete list of active and inactive ingredients, including weight or measure per dosage unit and total weight or measure per unit
• Theoretical batch size (number of units)
• Manufacturing and control instructions.

These minimum requirements are consistent with the FDA Guidance for Industry: cGMP for Early Phase Investigational Drugs, which requires a record of manufacturing that details the materials, equipment, procedures used and any problems encountered during manufacturing (2). The records should allow for the replication of the process. On this basis, there is flexibility in the manner for which documentation of batch activities can occur, provided that the documentation allows for the post execution review by the quality unit and for the retention of these records.   Batch documentation approvals. Review and approval of executed batch records by the Quality unit is required per 21 CFR Part 211.192 (7). This review and approval is required for all stages of clinical manufacturing. Pre-approvals of batch records should be governed by internal procedures as there is no requirement in CFR 21 that the Quality unit pre-approves the batch record (though this is highly recommended in order to minimize the chance of errors). Indeed, Table I shows that pre-approval of batch records by the Quality Unit is practiced by all 10 companies that participated in the IQ Consortium's drug-product manufacturing survey related to early development. Batch records must be retained for at least 1 year after the expiration of the batch according to CFR Part 211.180, but many companies keep their GMP records archived for longer terms. Room clearance. 21 CFR Part 211.130 requires inspection of packaging and labeling facilities immediately before use to ensure that all drug products from previous operations have been removed. This inspection should be documented and can be performed by any qualified individual. Although line clearance for bulk manufacture is not specifically mentioned in the CFR, it is expected that a room clearance be performed. At a minimum, this clearance should be performed prior to the initiation of a new batch (i.e., prior to batch materials entering a processing room). Hold time. During the early stages of development, final dosage form release testing confirms product quality and support establishment of hold times later in the clinical development. There is no requirement to establish hold times for work in process in early development. Specific formulation and stability experience, which is usually limited at this stage of development, should be leveraged to assess any substantial variations from expected batch processing times. The data gathered from these batches and subsequent development can be used to help establish hold times for future batches. (Exceptions to this approach may include solution or suspension preparations used in solid dosage form manufacturing, where procedures typically govern allowable hold times to ensure the absence of microbial contamination in the final product.) Change control. Changes to raw materials, processes, and products during early development are inevitable. It is not required that these changes be controlled by a central system but rather may be appropriately documented in technical reports and manufacturing batch records. Any changes in manufacturing process from a previous batch should be captured as part of the batch record documentation and communicated to affected areas. The rationale for these changes should also be documented as this serves as a source for development history reports and for updating regulatory filings. The authors recommend that those changes that could affect a regulatory filing be captured in a formal system. Process changes. Process parameters should be recorded but do not need to be predetermined because processes may not be fixed or established in early development. Given the limited API availability in early development, a clinical batch is often the first time a product is manufactured at a particular scale or using a particular process train. Therefore, process changes should be expected. Process trains and operating parameters must be documented in the batch record but changes should not trigger an exception report or CAPA. Changes should be documented as an operational note or modification to the batch record in real time. Such changes driven by technical observations should not require prior approval by the Quality unit, but should have the appropriate scientific justification (via formulator/scientist) or the appropriate flexibility built into the batch record to allow for the changes. This documentation should be available for Quality review prior to product disposition. Calculation of yield. Actual yields should be calculated for major processing steps to further process understanding and enable optimization of processes. Expected yield tolerances are not always applicable to early development manufacture. At this stage of early development, when formulation and process knowledge is extremely limited, there may be no technical basis for setting yield tolerances and, therefore, this yield may not be an indicator of the quality of the final product. In-process controls and R&D sampling. In-process tests and controls should follow basic requirements of GMPS to document consistency of the batch. For capsule products, these requirements may include capsule weights and physical inspection. For tablet products, compression force or tablet hardness and weights should be monitored together with appearance. R&D sampling, defined as samples taken for purposes of furthering process understanding but not utilized for batch disposition decisions, is a normal part of all phases of clinical manufacturing. In early development manufacturing, a sampling plan is required for in-process control tests, but not for R&D samples. However, for the purpose of material accountability, R&D sampling should be documented as part of batch execution. For these samples, testing results may be managed separately, and are not required to be included in regulatory documentation. Facilities and equipment Regardless of the scale of manufacturing, the facility used for manufacturing clinical trial supplies must meet the basic GMP requirements as described in the regulations and guidance documents. Below are three scenarios for early development and the advantages of each as pertaining to early development. The first involves a pilot plant facility designed and equipped for routine GMP operations. The second scenario aims to establish a GMP area within a laboratory environment. The third example focuses on conducting GMP manufacturing or leveraging the practice of pharmacy in close proximity to the clinical site. GMP facility for drug-product manufacture. The traditional approach in GMP drug-product manufacture is to use a dedicated facility (often called a pilot plant) for early phase clinical trials. Advantages of this approach include that the quality systems for the facility (i.e., maintenance, calibration, cleaning, change management, CAPA, and documentation) are well defined, and that training and other activities required for maintaining GMP compliance are centralized. Other drivers to use a pilot plant in early development may be the need for specialized equipment, or larger batch sizes in special situations. GMP area within a laboratory setting. In some cases, it may be advantageous to establish a GMP area within a "laboratory setting" (i.e., a drug-development facility not dedicated to the production of clinical supplies) for the manufacture of drug product in early development. The rationale for this approach might be to avoid the significant investment in setting up a dedicated facility and to create simpler, more flexible systems that meet GMP requirements but are tailored for the specific activity envisioned. Examples where this approach might be considered include the need for special containment not available in the pilot-plant; the need to work with radioactive or hazardous materials, use of controlled substances and the production of "one-off manufactured" product used for proof of concept. The business rationale should be documented and approved by the manufacturing and Quality groups. As long as the appropriate GMP controls are maintained, especially as related to operator safety, cleaning, and prevention of cross-contamination, there is no compliance barrier to using "lab-type" facilities for the manufacturing of early phase clinical batches. Before GMP manufacturing is initiated, however, a risk assessment should be conducted and documented. Inclusion of representatives from Quality, analytical, clinical manufacturing, product development, and environmental health and safety would be prudent. When selecting/designing an early development clinical manufacturing facility, consideration should be made for the receipt, storage, dispensing, and movement of materials. The manufacturing processes in the nondedicated area must protect the product, patient, and the manufacturing operators. Additionally, companies should consider what items are appropriate for the manufacture. For example, the use of a certified laminar flow hood may be a better choice for manufacturing than a fume hood, because the former is designed to prevent contamination of the product, protect the operator, and the laboratory environment. In addition, with the appropriate cleaning, a laminar flow hood can more easily be used for multiple products. Small scale/manual equipment or procedures may be the best approach because the space is likely to be limited. With a small batch size, the use of small scale or manual equipment/procedures will minimize yield loss. Additional measures to be assessed include appropriate gowning and operator personal protection devices, area and operator monitoring for potent or radiolabeled drug exposure, and so forth. Documentation of the facility preparation, product manufacture, and the return of the facility to the previous state, if needed, is recommended. This documentation should describe the rationale for the manufacture in the nondedicated area, risk assessment, preparation of the area, cleaning procedures, and list of responsible persons. This documentation can reference existing procedures or standard operating procedures (SOPs) along with documents associated with the meetings and preparation for the manufacture of the batch. Batch records and cleaning records should be part of the documentation and should follow the company's data-retention policy. Receipt and approval Specifications. It is a GMP requirement that all raw materials for the manufacture of drug product have appropriate specifications to ensure quality. The compendial requirements should be used for setting specifications provided the material is listed in at least one pharmaceutical compendium (e.g., US, European, and Japanese Pharmacopeias). It is important that the use of materials meeting the requirements of a single compendium is acceptable for use in early phase clinical studies conducted in the US, Europe, and Japan. For example, a material that meets USP criteria and is used in the manufacture of a drug product should be acceptable for use in early clinical studies in the European Union. In the absence of a pharmaceutical compendium monograph, the vendor specification and/or alternative compendial specifications such as USP's Food Chemical Codex should guide specification setting. In any case, the sponsor is responsible for the establishment of appropriate specifications. Therefore, it is the authors' position that good practice is to have at least a basic understanding of the manufacture, chemistry, and toxicology of the materials to guide appropriate specification setting. Material testing and evaluation. The minimum testing required for incoming materials is visual inspection and identification. However, as mentioned above, the appropriate tests should be determined for the material based on the knowledge of the manufacture, chemistry, and toxicology. If the vendor is qualified, then the certificate of analysis may be acceptable in conjunction with the visual inspection and identification testing (see "Vendor Qualification" section below). Approval for use. Ideally, manufacture of a bulk drug product should begin with approved material specifications and with materials that are fully tested and released. However, there are circumstances where it may not be feasible to start manufacture with approved specifications and fully tested and released materials, including API. Manufacturing prior to final release (sometimes called manufacturing "at risk") may be acceptable, however, because the quality system ensures that all specifications are approved, test results are within specifications, and all relevant documents are in place before the product is released for administration to humans. The "risk" must lie fully with the manufacturer and not with the patient. Vendor qualification. Vendors supplying excipients, raw materials, or API must be qualified by the sponsor. Appropriate qualification should depend on the stage of development and an internal risk assessment. For, example if a vendor has a history of supplying the pharmaceutical industry and the material is to be used in early development, a paper assessment (e.g., a questionnaire) should be sufficient. If a supplier does not have a history of supplying the pharmaceutical industry, a risk assessment should be performed and depending on the outcome a site audit may be required prior to accepting material for use. Ideally, vendors should be qualified prior to using raw materials for manufacture. However, it is acceptable for qualification to proceed in parallel as long as documentation/risk assessments are available prior to product release and as in the previous section all risk lies with the manufacturer and not the patient.   A production mixing unit is usually not geometrically similar to the mixer used for process development. Such differences can make scale-up from the laboratory or pilot plant challenging. A solution to these problems is to systematically calculate and evaluate mixing characteristics for each geometry change. Geometric similarity is often used in mixing scale-up because it greatly simplifies design calculations. Geometric similarity means that a single ratio between small scale and large scale applies to every length dimension (see figure). With geometric similarity, all of the length dimensions in the large-scale equipment are set by the corresponding dimensions in the small-scale equipment. The only remaining variable for scale-up to large-scale mixing is the rotational speed — one or more mixing characteristics, such as tip speed, can be duplicated by the appropriate selection of a large-scale mixer speed. The two most popular and effective geometric scale-up methods are equal tip speed and equal power per volume. Equal tip speed results when the small-scale mixer speed is multiplied by the inverse geometric ratio of the impeller diameters to get the large-scale mixer speed: N2 = N1(D1/D2) Equal power per volume involves a similar calculation, except the geometry ratio is raised to the two-thirds power: N2 = N1(D1/D2)(2/3) This expression for power per volume only applies strictly for turbulent conditions, where the power number is constant, but is approximately correct for transition-flow mixing. Avoid mix-upsAs we have seen, taking successive steps allows the development of alternative solutions to scale-up. Similar methods can be used to scale-down process problems for investigation in a pilot-plant or laboratory simulation. Here, too, non-geometric similarity often is a problem. Such scale-down calculations should help pinpoint appropriate operating speeds to test in the small-scale mixer. In any scale-up or scale-down evaluation, some variables can be held constant while others must change. For example, even with geometric similarity, scale-up will result in less surface per volume because surface area increases as the length squared and volume increases as length cubed. Similarly, keeping blend time constant rarely is practical with any significant scale change. Larger tanks take longer to blend than smaller ones. Also, Reynolds number is expected to increase as size increases. In addition, standard operating speeds or available impeller sizes may necessitate a final adjustment to the scale-up calculations. Rules for scale-up always have exceptions but understanding the effects of scale-up, especially non-geometric scale-up, can provide valuable guidance. Indeed, appreciation of the tradeoffs involved in non-geometric scale-up may be crucial for success with large-scale mixing processes.

REFERENCES

1 https://docs.google.com/viewer?url=http%3A%2F%2Fwww.sunbio.com%2Fsub%2FSunbio%2520GMP%2520Capabilty.ppt 2 http://apic.cefic.org/pub/5gmpdev9911.pdf 3 http://www.pharmtech.com/early-development-gmps-drug-product-manufacturing-small-molecules-industry-perspective-part-iii?rel=canonical"ICH Q7a. Good Manufacturing Practice for Active Pharmaceutical Ingredients" (Draft 6, October 19th, 1999, section 19). "ICH Q6a. Specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances". "Good Manufacturing Practices for Active Pharmaceutical Ingredients" (EFPIA / CEFIC Guideline, August, 1996). "Quality Management System for Active Pharmaceutical Ingredients Manufacturers" (APIC/CEFIC May 1998). "Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients", The International Pharmaceutical Excipients Council (October 1995). "21 Code of Federal Regulations, parts 210 to 211", U.S. Food & Drug Administration. "Guide to inspection of Bulk Pharmaceutical Chemicals", U.S. Food & Drug Administration, (Revised Edition: May 1994). “Guidance for Industry. ANDAs: Impurities in Drug Substances”, U.S. Food and Drug Administration, CDER (June 1998). "Guideline on the Preparation of Investigational New Drug Products", U.S. Food & Drug Administration, CDER (March 1991). "EC Guides to GMP, Annex 13: Manufacture of Investigational Medicinal Products" (Revised Dec. 1996). "GMP Compliance during Development", David J. DeTora. Drug Information Journal, 33, 769-776, 1999. FDA Guidance documents on internet address: http://www.fda.gov/cder/guidance /index.htm EMEA Guidance documents on internet address: http://www.eudra.org. .................... DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

amcrasto@gmail.com

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Fresolimumab
GC 1008, GC1008
UNII-375142VBIA
cas 948564-73-6
Structure

• immunoglobulin G4, anti-(human transforming growth factors beta-1, beta-2 (G-TSF or cetermin) and beta-3), human monoclonal GC-1008 γ4 heavy chain (134-215′)-disulfide with human monoclonal GC-1008 κ light chain, dimer (226-226”:229-229”)-bisdisulfide
• immunoglobulin G4, anti-(transforming growth factor β) (human monoclonal GC-1008 heavy chain), disulfide with human monoclonal GC-1008 light chain, dimer

For Idiopathic Pulmonary Fibrosis, Focal Segmental Glomerulosclerosis,and Cancer
An anti-TGF-beta antibody in phase I clinical trials (2011) for treatment-resistant primary focal segmental glomerulosclerosis.
A pan-specific, recombinant, fully human monoclonal antibody directed against human transforming growth factor (TGF) -beta 1, 2 and 3 with potential antineoplastic activity. Fresolimumab binds to and inhibits the activity of all isoforms of TGF-beta, which may result in the inhibition of tumor cell growth, angiogenesis, and migration. TGF-beta, a cytokine often over-expressed in various malignancies, may play an important role in promoting the growth, progression, and migration of tumor cells.


Fresolimumab (GC1008) is a humanmonoclonal antibody^[1] and an immunomodulator. It is intended for the treatment of idiopathic pulmonary fibrosis (IPF), focal segmental glomerulosclerosis, and cancer^[2][3] (kidney cancer and melanoma).
It binds to and inhibits all isoforms of the protein transforming growth factor beta (TGF-β).^[2]

History

Fresolimumab was discovered by Cambridge Antibody Technology (CAT) scientists^[4] and was one of a pair of candidate drugs that were identified for the treatment of the fatal condition scleroderma. CAT chose to co-develop the two drugs metelimumab (CAT-192) and fresolimumab with Genzyme. During early development, around 2004, CAT decided to drop development of metelimumab in favour of fresolimumab.^[5]
In February 2011 Sanofi-Aventis agreed to buy Genzyme for US$ 20.1 billion.^[6]
As of June 2011 the drug was being tested in humans (clinical trials) against IPF, renal disease, and cancer.^[7][8] On 13 August 2012, Genzyme applied to begin a Phase 2 clinical trial in primary focal segmental glomerulosclerosis^[9] comparing fresolimumab versus placebo.
As of July 2014, Sanofi-Aventis continue to list fresolimumab in their research and development portfolio under Phase II development.^[10]

References

1 WHO Drug Information
2 National Cancer Institute: Fresolimumab

• 3 Statement On A Nonproprietary Name Adopted By The USAN Council – Fresolimumab
• 4 Grütter, Christian; Wilkinson, Trevor; Turner, Richard; Podichetty, Sadhana; Finch, Donna; McCourt, Matthew; Loning, Scott; Jermutus, Lutz; Grütter, Markus G. (2008-12-23). “A cytokine-neutralizing antibody as a structural mimetic of 2 receptor interactions”. Proceedings of the National Academy of Sciences105 (51): 20251–20256. doi:10.1073/pnas.0807200106. ISSN 0027-8424. PMC 2600578. PMID 19073914.
• 5 http://www.independent.co.uk/news/business/news/cat-may-abandon-skin-drug-after-trial-results-disappoint-569445.html
• 6 http://www.bbc.co.uk/news/business-12477750
• 7 http://www.genengnews.com/gen-news-highlights/scientists-trigger-white-fat-to-become-brown-fat-like-to-treat-obesty-and-type-2-diabetes/81245389/
• 8 Clinicaltrials.gov for Fresolimumab
• 9 http://clinicaltrials.gov/show/NCT01665391
• 10 http://en.sanofi.com/rd/rd_portfolio/rd_portfolio.aspx

Fresolimumab

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	TGF beta 1, 2 and 3
Clinical data
Legal status	Investigational
Identifiers
CAS Number	948564-73-6
ATC code	None
ChemSpider	none
KEGG	D09620
Chemical data
Formula	C6392H9926N1698O2026S44
Molar mass	144.4 kDa

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Monoclonal antibodies for the immune system
Immune system (“-l(i[m])-“)	Human (“-limu-“) immunosuppression: Abrilumab Adalimumab Anifrolumab Atorolimumab Belimumab Brodalumab Carlumab Dupilumab Durvalumab Eldelumab Fresolimumab Golimumab Lerdelimumab Lirilumab Mavrilimumab Metelimumab Morolimumab Namilumab Oxelumab§ Placulumab Sarilumab Sifalimumab Tabalumab Ulocuplumab Varlilumab immune activation: Ipilimumab Nivolumab Pembrolizumab Tremelimumab Urelumab other: Bertilimumab Zanolimumab Mouse (“-limo-“) Afelimomab Elsilimomab Faralimomab Gavilimomab Inolimomab Maslimomab Nerelimomab Odulimomab Telimomab aritox Vepalimomab Zolimomab aritox Chimeric (“-lixi-“) Basiliximab Clenoliximab Galiximab Gomiliximab Infliximab Keliximab Lumiliximab Priliximab Teneliximab Vapaliximab Humanized (“-lizu-“) immunosuppressive:Aselizumab Apolizumab Benralizumab† Cedelizumab Certolizumab pegol Daclizumab Eculizumab Efalizumab Epratuzumab Erlizumab Etrolizumab Fontolizumab Itolizumab Lampalizumab Ligelizumab Lulizumab pegol Mepolizumab Mogamulizumab Natalizumab Ocrelizumab Omalizumab Ozoralizumab Pascolizumab Pateclizumab Pembrolizumab Pexelizumab Pidilizumab PRO 140† Reslizumab Rontalizumab Rovelizumab Ruplizumab Quilizumab Samalizumab Siplizumab Talizumab Teplizumab Tocilizumab Toralizumab Tregalizumab Vatelizumab Vedolizumab Visilizumab TGN1412§ non-immunosuppressive:Ibalizumab† Chimeric + humanized (“-lixizu-“) Otelixizumab
Interleukin (“-k(i[n])-“)	Human (“-kinu-“) Briakinumab Canakinumab Fezakinumab Fletikumab Guselkumab Secukinumab Sirukumab Tralokinumab Ustekinumab Humanized (“-kizu-“, “-kinzu-“) Anrukinzumab Clazakizumab Enokizumab Gevokizumab Ixekizumab Lebrikizumab Olokizumab Perakizumab Tildrakizumab
Inflammatory lesions (“-les-“)	Mouse (“-leso-“) Besilesomab Fanolesomab‡ Lemalesomab Sulesomab
#WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III v t e Index of the immune system Description Physiology cells autoantigens autoantibodies complement surface antigens IG receptors Disease Allergies Immunodeficiency Immunoproliferative immunoglobulin disorders Hypersensitivity and autoimmune disorders Neoplasms and cancer Treatment Procedures Drugs antihistamines immunostimulants immunosuppressants monoclonal antibodies

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The Year In New Drugs

http://cen.acs.org/articles/94/i5/Year-New-Drugs.html
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Patiromer is a powder for suspension in water for oral administration, approved in the U.S. as Veltassa in October, 2015. Patiromer is supplied as patiromer sorbitex calcium which consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion. Each gram of patiromer is equivalent to a nominal amount of 2 grams of patiromer sorbitex calcium. The chemical name for patiromer sorbitex calcium is cross-linked polymer of calcium 2-fluoroprop-2-enoate with diethenylbenzene and octa-1,7-diene, combination with D-glucitol. Patiromer sorbitex calcium is an amorphous, free-flowing powder that is composed of individual spherical beads.
Veltassa is a powder for suspension in water for oral administration. The active ingredient is patiromer sorbitex calcium which consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion.

Each gram of patiromer is equivalent to a nominal amount of 2 grams of patiromer sorbitex calcium. The chemical name for patiromer sorbitex calcium is cross-linked polymer of calcium 2-fluoroprop-2-enoate with diethenylbenzene and octa-1,7-diene, combination with D-glucitol.

Mechanism of Action

Veltassa is a non-absorbed, cation exchange polymer that contains a calcium-sorbitol counterion. Veltassa increases fecal potassium excretion through binding of potassium in the lumen of the gastrointestinal tract. Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, resulting in a reduction of serum potassium levels.

Treatment of Hyperkalemia
Hyperkalemia is usually asymptomatic but occasionally can lead to life-threatening cardiac arrhythmias and increased all-cause and in-hospital mortality, particularly in patients with CKD and associated cardiovascular diseases (Jain et al., 2012; McMahon et al., 2012; Khanagavi et al., 2014). However, there is limited evidence from randomized clinical trials regarding the most effective therapy for acute management of hyperkalemia (Khanagavi et al., 2014) and a Cochrane analysis of emergency interventions for hyperkalemia found that none of the studies reported mortality or cardiac arrhythmias, but reports focused on P_K (Mahoney et al., 2005). Thus, recommendations are based on opinions and vary with institutional practice guidelines (Elliot et al., 2010; Khanagavi et al., 2014). Management of hyperkalemia includes reducing potassium intake, discontinuing potassium supplements, treatment of precipitating risk factors, and careful review of prescribed drugs affecting potassium homeostasis. Treatment of life-threatening hyperkalemia includes nebulized or inhaled beta-agonists (albuterol, salbutamol) or intravenous (IV) insulin-and-glucose, which stimulate intracellular potassium uptake, their combination being more effective than either alone. When arrhythmias are present, IV calcium might stabilize the cardiac resting membrane potential. Sodium bicarbonate may be indicated in patients with severe metabolic acidosis. Potassium can be effectively eliminated by hemodialysis or increasing its renal (loop diuretics) and gastrointestinal (GI) excretion with sodium polystyrene sulfonate, an ion-exchange resin that exchanges sodium for potassium in the colon. However, this resin produces serious GI adverse events (ischemic colitis, bleeding, perforation, or necrosis). Therefore, there is an unmet need of safer and more effective drugs producing a rapid and sustained P_K reduction in patients with hyperkalemia.
In this article we review two new polymer-based, non-systemic oral agents, patiromer calcium (RLY5016) and zirconium silicate (ZS-9), under clinical development designed to induce potassium loss via the GI tract, particularly the colon, and reduce P_K in patients with hyperkalemia.
1. Patiromer calcium
This metal-free cross-linked fluoroacrylate polymer (structure not available) exchanges cations through the gastrointestinal (GI) tract. It preferentially binds soluble potassium in the colon, increases its fecal excretion and reduces P_K under hyperkalemic conditions.
The development program of patiromer includes several clinical trials. An open-label, single-arm study evaluated a titration regimen for patiromer in 60 HF patients with CKD treated with ACEIs, ARBs, or beta blockers (clinicaltrials.gov identifier: NCT01130597). Another open-label, randomized, dose ranging trial determined the optimal starting dose and safety of patiromer in 300 hypertensive patients with diabetic nephropathy treated with ACEIs and/or ARBs, with or without spironolactone (NCT01371747). The primary outcomes were the change in P_K from baseline to the end of the study. Unfortunately, the results of these trials were not published.
In a double-blind, placebo-controlled trial (PEARL-HF, NCT00868439), 105 patients with a baseline P_K of 4.7 mmol/L and HF (NYHA class II-III) treated with spironolactone in addition to standard therapy were randomized to patiromer (15 g) or placebo BID for 4 weeks (Pitt et al., 2011). Spironolactone, initiated at 25 mg/day, was increased to 50 mg/day on day 15 if P_K was ≤5.1 mmol/L. Patients were eligible for the trial if they had either CKD (eGFR<60 ml/min) or a history of hyperkalemia leading to discontinuation of RAASIs or beta-blockers. Compared with placebo, patiromer decreased the P_K (-0.22 mmol/L, while P_K increased in the placebo group +0.23 mmol/L, P<0.001), and the incidence of hyperkalemia (7% vs. 25%, P=0.015) and increased the number of patients up-titrated to spironolactone 50 mg/day (91% vs. 74%, P=0.019). A similar reduction in P_K and hyperkalemia was observed in patients with an eGFR <60 ml/min. Patiromer produced more GI adverse events (flatulence, diarrhea, constipation, vomiting: 21% vs 6%), hypokalemia (<4.0 mmol/L: 47% vs 10%, P<0.001) and hypomagnesaemia (<1.8 mg/dL: 24% vs. 2.1%), but similar adverse events leading to study discontinuation compared to placebo. Unfortunately, recruited patients had normokalemia and basal eGFR in the treatment group was 84 ml/min. Thus, this study did not answer whether patiromer is effective in reducing P_K in patients with CKD and/or HF who develop hyperkalemia on RAASIs.
A two-part phase 3 study evaluated the efficacy and safety of patiromer in the treatment of hyperkalemia (NCT01810939). In a single-blind phase (part A) 243 patients with hyperkalemia and CKD (102 with HF) on RAASIs were treated with patiromer BID for 4 weeks: 4.2 g in patients with mild hyperkalemia (5.1-<5.5 mmol/L, n=92) and 8.4 g in patients with moderate-to-severe hyperkalemia (5.5-<6.5 mmol/L, n=151). Part B was a placebo-controlled, randomized, withdrawal phase designed to confirm the maintained efficacy of patiromer and the recurrent hyperkalemia following that drug’s withdrawal. Patients (n=107) who completed phase A with a normal P_K were randomized to continue on patiromer (27 with HF) or placebo (22 with HF) besides RAASIs for 8 weeks. The primary endpoint was the difference in mean P_K between the patiromer and placebo groups from baseline to the end of the study or when the patient first had a P_K <3.8 or ≥5.5 mmol/L. In part A patiromer produced a rapid reduction in P_K that persisted throughout the study in patients with and without HF (-1.06 and -0.98 mmol/L, respectively; both P<0.001 vs. placebo); three-fourths of patients in both groups had normal P_K (3.8-<5.1 mmol/L) at 4 weeks. In part B patiromer reduced P_K (-0.64 mmol/L) in patients with or without HF (P<0.001). As compared with placebo, fewer patients, with or without HF, presented recurrent hyperkalemia in the patiromer group or required RAASI discontinuation regardless of HF status (Pitt, 2014). Patiromer was well-tolerated, with a safety profile similar to placebo even in HF patients. The most common adverse events were nausea, diarrhea, and hypokalemia.

INDICATIONS AND USAGE

Veltassa is a potassium binder indicated for the treatment of hyperkalemia.
Veltassa should not be used as an emergency treatment for lifethreatening hyperkalemia because of its delayed onset of action.
Patiromer (USAN, trade name Veltassa) is a drug used for the treatment of hyperkalemia (elevated blood potassium levels), a condition that may lead to palpitations and arrhythmia (irregular heartbeat). It works by binding potassium in the gut.^[1][2]

Medical uses

Patiromer is used for the treatment of hyperkalemia, but not as an emergency treatment for life-threatening hyperkalemia, because it acts relatively slowly.^[2] Such a condition needs other kinds of treatment, for example calcium infusions, insulin plus glucose infusions, salbutamol inhalation, and hemodialysis.^[3]
Typical reasons for hyperkalemia are renal insufficiency and application of drugs that inhibit the renin–angiotensin–aldosterone system (RAAS) – e.g. ACE inhibitors, angiotensin II receptor antagonists, or potassium-sparing diuretics– or that interfere with renal function in general, such as nonsteroidal anti-inflammatory drugs (NSAIDs).^[4][5]

Adverse effects

Patiromer was generally well tolerated in studies. Side effects that occurred in more than 2% of patients included in clinical trials were mainly gastro-intestinal problems such as constipation, diarrhea, nausea, and flatulence, and also hypomagnesemia (low levels of magnesium in the blood) in 5% of patients, because patiromer binds magnesium in the gut as well.^[2][6]

Interactions

No interaction studies have been done in humans. Patiromer binds to many substances besides potassium, including numerous orally administered drugs (about half of those tested in vitro). This could reduce their availability and thus effectiveness,^[2] wherefore patiromer has received a boxed warning by the US Food and Drug Administration (FDA), telling patients to wait for at least six hours between taking patiromer and any other oral drugs.^[7]

Pharmacology

Mechanism of action

Patiromer works by binding free potassium ions in the gastrointestinal tract and releasing calcium ions for exchange, thus lowering the amount of potassium available for absorption into the bloodstream and increasing the amount that is excreted via the feces. The net effect is a reduction of potassium levels in the blood serum.^[2][4]
Lowering of potassium levels is detectable 7 hours after administration. Levels continue to decrease for at least 48 hours if treatment is continued, and remain stable for 24 hours after administration of the last dose. After this, potassium levels start to rise again over a period of at least four days.^[2]

Pharmacokinetics

Patiromer is not absorbed from the gut, is not metabolized, and is excreted in unchanged form with the feces.^[2]

Physical and chemical properties

The substance is a cross-linked polymer of 2-fluoroacrylic acid (91% in terms of amount of substance) with divinylbenzenes (8%) and 1,7-octadiene (1%). It is used in form of its calcium salt (ratio 2:1) and with sorbitol (one molecule per two calcium ions or four fluoroacrylic acid units), a combination called patiromer sorbitex calcium.^[8]

• 2-fluoroacrylic acid
• o-divinylbenzene
• p-divinylbenzene
• 1,7-octadiene

Patiromer sorbitex calcium is an off-white to light brown, amorphous, free-flowing powder. It is insoluble in water, 0.1 Mhydrochloric acid, heptane, and methanol.^[2][8]
Hyperkalemia Is a Clinical Challenge
Hyperkalemia may result from increased potassium intake, impaired distribution between the intracellular and extracellular spaces, and/or conditions that reduce potassium excretion, including CKD, hypertension, diabetes mellitus, or chronic heart failure (HF) (Jain et al., 2012). Additionally, drugs and nutritional/herbal supplements (Table 1) can produce hyperkalemia in up to 88% of hospitalized patients by impairing normal potassium regulation (Hollander-Rodríguez and Calvert, 2006; Khanagavi et al., 2014).
Although the prevalence of hyperkalemia in the general population is unknown, it is present in 1-10% of hospitalized patients depending on how hyperkalemia is defined (McMahon et al., 2012; Gennari, 2002). Hyperkalemia is a common problem in patients with conditions that reduce potassium excretion, especially when treated with beta-adrenergic blockers that inhibit Na⁺,K⁺-ATPase activity or RAAS inhibitors (RAASIs) [angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists or renin inhibitors] that decrease aldosterone excretion (Jain et al., 2012; Weir and Rolfe, 2010). The incidence of hyperkalemia with RAASIs in monotherapy is low (≤2%) in patients without predisposing factors, but increases with dual RAASIs (5%) and in patients with risk factors such as CKD, HF, and/or diabetes (5-10%) (Weir and Rolfe, 2010). Thus, hyperkalemia is a key limitation to fully titrate RAASIs in these patients who are most likely to benefit from treatment. Thus, we need new drugs to control hyperkalemia in these patients while maintaining the use of RAASIs.

History

Studies

In a Phase III multicenter clinical trial including 237 patients with hyperkalemia under RAAS inhibitor treatment, 76% of participants reached normal serum potassium levels within four weeks. After subsequent randomization of 107 responders into a group receiving continued patiromer treatment and a placebo group, re-occurrence of hyperkalemia was 15% versus 60%, respectively.^[9]

Approval

The US FDA approved patiromer in October 2015.^[7] The drug is not approved in Europe as of January 2016.

References

• 1 Henneman, A; Guirguis, E; Grace, Y; Patel, D; Shah, B (2016). "Emerging therapies for the management of chronic hyperkalemia in the ambulatory care setting". American Journal of Health-System Pharmacy73 (2): 33–44. doi:10.2146/ajhp150457. PMID 26721532.
• 2FDA Professional Drug Information for Veltassa.
• 3Vanden Hoek TL, Morrison LJ, Shuster M, Donnino M, Sinz E, Lavonas EJ, Jeejeebhoy FM, Gabrielli A; Morrison; Shuster; Donnino; Sinz; Lavonas; Jeejeebhoy; Gabrielli (2010-11-02). "Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care". Circulation122 (18 Suppl 3): S829–61. doi:10.1161/CIRCULATIONAHA.110.971069. PMID 20956228.
• 4Esteras, R.; Perez-Gomez, M. V.; Rodriguez-Osorio, L.; Ortiz, A.; Fernandez-Fernandez, B. (2015). "Combination use of medicines from two classes of renin-angiotensin system blocking agents: Risk of hyperkalemia, hypotension, and impaired renal function". Therapeutic Advances in Drug Safety6 (4): 166. doi:10.1177/2042098615589905. PMID 26301070.
• 5Rastegar, A; Soleimani, M (2001). "Hypokalaemia and hyperkalaemia". Postgraduate Medical Journal77 (914): 759–64. doi:10.1136/pmj.77.914.759. PMC 1742191. PMID 11723313.
• 6Tamargo, J; Caballero, R; Delpón, E (2014). "New drugs for the treatment of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors -- hype or hope?". Discovery medicine18 (100): 249–54. PMID 25425465.
• 7"FDA approves new drug to treat hyperkalemia". FDA. 21 October 2015.
• 8RxList: Veltassa.
• 9Weir, Matthew R.; Bakris, George L.; Bushinsky, David A.; Mayo, Martha R.; Garza, Dahlia; Stasiv, Yuri; Wittes, Janet; Christ-Schmidt, Heidi; Berman, Lance; Pitt, Bertram (2015). "Patiromer in Patients with Kidney Disease and Hyperkalemia Receiving RAAS Inhibitors". New England Journal of Medicine372 (3): 211. doi:10.1056/NEJMoa1410853. PMID 25415805.

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Fidaxomicin (C₅₂H₇₄Cl₂O₁₈, M_r = 1058.0 g/mol)
Launched - 2011 MERCK, Clostridium difficile-associated diarrhea
CUBIST ....INNOVATOR
OPT-80
PAR-101
Also tiacumicin B or lipiarmycin A3,
A bacterial RNA polymerase inhibitor as macrocyclic antibiotic used to treat clostridium difficile-associated diarrhea (CDAD).
SYNTHESIS


REFERENCES
US 4918174
WO 2006085838
J ANTIBIOTICS 1987, 40, PG 567-574 AND 575-588

Idaxomicin(trade names Dificid, Dificlir, and previously OPT-80 and PAR-101) is the first in a new class of narrow spectrum macrocyclicantibiotic drugs.^[2] It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis.^[3][4] Fidaxomicin is non-systemic, meaning it is minimally absorbed into the bloodstream, it is bactericidal, and it has demonstrated selective eradication of pathogenicClostridium difficile with minimal disruption to the multiple species of bacteria that make up the normal, healthy intestinal flora. The maintenance of normal physiological conditions in the colon can reduce the probability of Clostridium difficile infection recurrence.^[5][6]
Fidaxomicin is an antibiotic approved and launched in 2011 in the U.S. for the treatment of Clostridium difficile-associated diarrhea (CDAD) in adults 18 years of age and older. In September 2011, the product received a positive opinion in the E.U. and final approval was assigned in December 2011.
First E.U. launch took place in the U.K. in June 2012. Optimer Pharmaceuticals, now part of Cubist (now, Merck & Co.), is conducting phase III clinical trials for the prevention of Clostridium difficile-associated diarrhea in patients undergoing hematopoietic stem cell transplant
In 2014 Astellas initiated in Europe a phase III clinical study for the treatment of Clostridium difficile infection in pediatric patients. Preclinical studies are ongoing for potential use in the prevention of methicillin-resistant Staphylococcus (MRS) infection.


The compound is a novel macrocyclic antibiotic that is produced by fermentation. Its narrow-spectrum activity is highly selective for C. difficile, thus preserving gut microbial ecology, an important consideration for the treatment of CDAD.
It is marketed by Cubist Pharmaceuticals after acquisition of its originating company Optimer Pharmaceuticals. The target use is for treatment of Clostridium difficile infection.
In May 2005, Par Pharmaceutical and Optimer entered into a joint development and collaboration agreement for fidaxomicin. However, rights to the compound were returned to Optimer in 2007. The compound was granted fast track status by the FDA in 2003. In 2010, orphan drug designation was assigned to fidaxomicin in the U.S. by Optimer Pharmaceuticals for the treatment of pediatric Clostridium difficile infection (CDI). In 2011, the compound was licensed by Optimer Pharmaceuticals to Astellas Pharma in Europe and certain countries in the Middle East, Africa, the Commonwealth of Independent States (CIS) and Japan for the treatment of CDAD. In 2011, fidaxomicin was licensed to Cubist by Optimer Pharmaceuticals for comarketing in the U.S. for the treatment of CDAD. In July 2012, the product was licensed by Optimer Pharmaceuticals to Specialised Therapeutics Australia in AU and NZ for the treatment of Clostridium difficile-associated infection. OBI Pharma holds exclusive commercial rights in Taiwan, where the compound was approved for the treatment of CDAD in September 2012, and in December 2012, the product was licensed to AstraZeneca in South America with commercialization rights also for the treatment of CDAD. In October 2013, Optimer Pharmaceuticals was acquired by Cubist.
Fidaxomicin is available in a 200 mg tablet that is administered every 12 hours for a recommended duration of 10 days. Total duration of therapy should be determined by the patient's clinical status. It is currently one of the most expensive antibiotics approved for use. A standard course costs upwards of £1350.^[7]
Fidaxomicin (also known as OPT-80 and PAR-101 ) is a novel antibiotic agent and the first representative of a new class of antibacterials called macrocycles. Fidaxomicin is a member of the tiacumicin family, which are complexes of 18-membered macrocyclic antibiotics naturally produced by a strain of Dactylosporangium aurantiacum isolated from a soil sample collected in Connecticut, USA.
The major component of the tiacumicin complex is tiacumicin B. Optically pure R-tiacumicin B is the most active component of Fidaxomicin. The chiral center at C(19) of tiacumicinB affects biological activity, and R-tiacumicin B has an R-hydroxyl group attached at this position. The isomer displayed significantly higher activity than other tiacumicin B-related compounds and longer post-antibiotic activity.
Tiacumicins are a family of structurally related compounds that contain the 18-membered macrolide ring shown below.
At present, several distinct Tiacumicins have been identified and six of these
(Tiacumicin A-F) are defined by their particular pattern of substituents R¹, R², and R³ (US Patent No. 4,918,174; J. Antibiotics, 1987, 575-588).
The Lipiarmycins are a family of natural products closely related to the Tiacumicins. Two members of the Lipiarmycin family (A3 and B3) are identical to Tiacumicins B and C respectively (J. Antibiotics, 1988, 308-315; J. Chem. Soc. Perkin Trans 1, 1987, 1353-1359).
The Tiacumicins and the Lipiarmycins have been characterized by numerous physical methods. The reported chemical structures of these compounds are based on spectroscopy (UV-vis, IR and ^!H and ¹³C NMR), mass spectrometry and elemental analysis (See for example: J. Antibiotics, 1987, 575-588; J. Antibiotics, 1983, 1312-
1322).
Tiacumicins are produced by bacteria, including Dactylosporangium aurantiacum subspecies hamdenensis, which may be obtained from the ARS Patent Collection of the Northern Regional Research Center, United States Department ofAgriculture, 1815 North University Street, Peoria, IL 61604, accession number NRRL
18085. The characteristics of strain AB 718C-41 are given in J. Antibiotics, 1987,567-574 and US Patent No. 4,918,174.
Lipiarmycins are produced by bacteria including Actinoplanes deccanensis (US Patent No. 3,978,211). Taxonomical studies of type strain A/10655, which has been deposited in the ATCC under the number 21983, are discussed in J. Antibiotics,1975, 247-25.
Tiacumicins, specifically Tiacumicin B, show activity against a variety of bacterial pathogens and in particular against Clostridium difficile, a Gram-positive bacterium (Antimicrob. Agents Chemother. 1991, 1108-1111). Clostridium difficile is an anaerobic spore-forming bacterium that causes an infection of the bowel.
As per WIPO publication number 2006085838, Fidaxomicin is an isomeric mixture of the configurationally distinct stereoisomers of tiacumicin B, composed of 70 to 100% of R-tiacumicin B and small quantities of related compounds, such as S-tiacumicin B and lipiarmycin A4. Fidaxomicin was produced by fermentation of the D aurantiacum subspecies hamdenensis (strain 718C-41 ). It has a narrow spectrum antibacterial profile mainly directed against Clostridium difficile and exerts a moderate activity against some other gram-positive species.
Fidaxomicin is bactericidal and acts via inhibition of RNA synthesis by bacterial RNA polymerase at a distinct site from that of rifamycins. The drug product is poorly absorbed and exerts its activity in the gastrointestinal (Gl) tract, which is an advantage when used in the applied indication, treatment of C. difficile infection (CDI) (also known as C. difficile-associated disease or diarrhoea [CDAD]). Fidaxomicin is available as DIFICID oral tablet in US market.
Its CAS chemical name is Oxacyclooctadeca-3,5,9, 13, 15-pentaen-2-one, 3-[[[6-deoxy-4-0-(3,5dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-0-methyl-P-D-manno pyranosyl]oxy]methyl]-12[[6-deoxy-5-C-methyl-4-0-(2-methyl-1 -oxopropyl)- -D-lyxo-hexo pyranosyl]oxy]-1 1 -ethyl-8-hydroxy-18-[(1 R)-1 -hydroxyethyl] -9,13,15-trimethyl-, (3E.5E, 8S.9E.1 1 S.12R.13E, 15E.18S)-.
Structural formula (I) describes the absolute stereochemistry of fidaxomicin as determined by x-ray.

(I)
WIPO publication number 2004014295 discloses a process for preparation of Tiacumicins that comprises fermentation of Dactylosporangium aurantiacum NRRL18085 in suitable culture medium. It also provides process for isolation of tiacumicin from fermentation broth using techniques selected from the group consisting of: sieving and removing undesired material by eluting with at least one solvent or a solvent mixture; extraction with at least one solvent or a solvent mixture; Crystallization; chromatographic separation; High-Performance Liquid Chromatography (HPLC); MPLC; trituration; and extraction with saturated brine with at least one solvent or a solvent mixture. The product was isolated from /so-propyl alcohol (IPA) having a melting point of 166-169 °C.
U.S. Patent No. 7378508 B2 discloses polymorphic forms A and B of fidaxomicin, solid dosage forms of the two forms and composition thereof. As per the ‘508 patent form A is obtained from methanol water mixture and Form B is obtained from ethyl acetate.
J. Antibiotics, vol. 40(5), 575-588 (1987) discloses purification of Tiacumicins using suitable solvents wherein tiacumicin B exhibited a melting point of 143-145 °C.
PCT application WO2013170142A1 describes three crystalline forms of Fidaxomicn namely, Form-Z, Form-Z1 and Form-C. IN2650/CHE/2013 describes 6 crystalline polymorphic forms of Fidaxomicin namely, Forms I, Form la, Form II, Form Ha, Form III and Form Ilia).

Mechanism

Fidaxomicin binds to and prevents movement of the "switch regions" of bacterial RNAP polymerase. Switch motion is important for opening and closing of the DNA:RNA clamp, a process that occurs throughout RNA transcription but especially during opening of double standed DNA during transcription initiation.^[8] It has minimal systemic absorption and a narrow spectrum of activity; it is active against Gram positive bacteria especially clostridia. The minimal inhibitory concentration (MIC) range for C. difficile (ATCC 700057) is 0.03–0.25 μg/mL.^[3]

Clinical trials

Good results were reported by the company in 2009 from a North American phase III trial comparing it with oral vancomycin for the treatment of Clostridium difficile infection (CDI)^[9][10] The study met its primary endpoint of clinical cure, showing that fidaxomicin was non-inferior to oral vancomycin (92.1% vs. 89.8%). In addition, the study met its secondary endpoint of recurrence: 13.3% of the subjects had a recurrence with fidaxomicin vs. 24.0% with oral vancomycin. The study also met its exploratory endpoint of global cure (77.7% for fidaxomicin vs. 67.1% for vancomycin).^[11]Clinical cure was defined as patients requiring no further CDI therapy two days after completion of study medication. Global cure was defined as patients who were cured at the end of therapy and did not have a recurrence in the next four weeks.^[12]
Fidaxomicin was shown to be as good as the current standard-of-care, vancomycin, for treating CDI in a Phase III trial published in February 2011.^[13] The authors also reported significantly fewer recurrences of infection, a frequent problem with C. difficile, and similar drug side effects.

Approvals and indications

For the treatment of Clostridium difficile-associated diarrhea (CDAD), the drug won an FDA advisory panel's unanimous approval on April 5, 2011^[14] and full FDA approval on May 27, 2011.^[15]

PAPER
Enantioselective synthesis of putative lipiarmycin aglycon related to fidaxomicin/tiacumicin B
Angew Chem Int Ed 2015, 54(6): 1929
Enantioselective Synthesis of Putative Lipiarmycin Aglycon Related to Fidaxomicin/Tiacumicin B (pages 1929–1932)
Dr. William Erb, Dr. Jean-Marie Grassot, Dr. David Linder, Dr. Luc Neuville and Prof. Dr. Jieping Zhu
Article first published online: 24 NOV 2014 | DOI: 10.1002/anie.201409475

PAPER
Total synthesis of the glycosylated macrolide antibiotic fidaxomicin
Org Lett 2015, 17(14): 3514
http://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b01602
http://pubs.acs.org/doi/suppl/10.1021/acs.orglett.5b01602/suppl_file/ol5b01602_si_001.pdf
The term "Tiacumicin B" refers to molecule having the structure shown below:
Example 1
Dactylosporangium aurantiacum subsp. hamdenensis AB 718C-41 NRRL 18085 (-20 °C stock), was maintained on 1 mL of Medium No. 104 (Table 1). After standard sterilization conditions (30 min., 121 °C, 1.05 kg/cm²) the seed flask (250 mL) containing Medium No. 104 (50 mL) was inoculated with AB 718C-41 NRRL 18085 on a shaker (set @ 250 rpm) at 30 °C for 72 hr. Five percent vegetative inoculum from the first passage seed flask was then transferred aseptically to a fermentation flask containing the same ingredients as in Table 1.
Table 1: Ingredients of Medium No. 104
Fermentation flasks were incubated on a rotary shaker at 30 °C for 3 to 12 days. Samples of the whole culture fermentation broth were filtered. The filter cake was washed with MeOH and solvents were removed under reduced pressure. The residue was re-constituted in methanol to the same volume of the original fermentation broth. Analysis was performed using a Waters BREEZE HPLC system coupling with Waters 2487 2-channel UV/Vis detector. Tiacumincins were assayed on a 50 x 4.6 μm I.D., 5 μm YMC ODS-A column (YMC catalog # CCA AS05- 0546WT) with a mobile phase consisting of 45% acetonitrile in water containing 0.1% phosphoric acid at a flow rate of 1.5 mL/minute. Tiacumicins were detected at 266 nm. An HPLC chromatogram of a crude product (Tiacumicin B retention time @ 12.6 minutes) is shown in Fig. 1. In this example the crude yield of Tiacumicin B was about 250 mg/L after 7 days. After purification by HPLC, the yield of Tiacumicin B was about 100 mg/L.
Example 2
After standard sterilization conditions (30 min, 121 °C, 1.05 kg/cm²) the seed flask (250 mL) containing Medium No. 104 (50 mL) was inoculated with AB 718C- 41 NRRL 18085 and incubated on a shaker (set @ 250 rpm) at 30° C for 72 hr. Five percent vegetative inoculum from the first passage seed flask was transferred aseptically to a seed flask containing the same ingredients as in Table 1 and was incubated on a rotary shaker at 30 °C for 72 hr. Five percent inoculum from the second passage seed flasks was then used to inoculate with AB 718C-41 NRRL 18085 in a 5-liter fermenter containing Medium No. 104 (2.5 L). Excessive foam formation was controlled by the addition of an antifoaming agent (Sigma A-6426). This product is a mixture of non-silicone organic defoamers in a polyol dispersion.
Glucose consumption was monitored as a growth parameter and its level was controlled by the addition of the feeding medium. Feeding medium and conditions in Example 2 were as follows:
Feeding medium:
Fermenter Medium: No. 104
Fermenter Volume: 5 liters
Sterilization: 40 minutes, 121° C, 1.05 kg/cm²
Incubation Temperature: 30 °C.
Aeration rate: 0.5-1.5 volumes of air per culture volume and minute
Fermenter Agitation: 300-500 rpm
The fermentation was carried out for 8 days and the XAD-16 resin was separated from the culture broth by sieving. After washing with water the XAD-16 resin was eluted with methanol (5-10 x volume of XAD-16). Methanol was evaporated and the oily residue was extracted three times with ethyl acetate. The extracts were combined and concentrated under reduced pressure to an oily residue. The oily residue was dried and washed with hexane to give the crude product as a pale brown powder and its HPLC chromatogram (Tiacumincin B rete tion time @ 11.8 minutes) is shown in Figure 2. This was purified by silica gel column (mixture of ethyl acetate and hexane as eluent) and the resultant material was further purified by RP-HPLC (reverse phase HPLC) to give Tiacumicin B as a white solid. The purity was determined to be >95% by HPLC chromatography and the chromatogram (Tiacumincin B retention time @ 12.0 minutes) is shown in Figure 3. Analysis of the isolated Tiacumincin B gave identical ^!H and ¹³C NMR data to those reported in J. Antibiotics, 1987, 575-588, and these are summarized below. Tiacumicin B: mp 129-140 °C (white powder from RP-HPLC); mp 166-169 °C (white needles from isopropanol); [α]_D²⁰-6.9 (c 2.0, MeOH); MS m/z (ESI) 1079.7(M + Na)⁺; H NMR (400 MHz, CD₃OD) δ 7.21 (d, IH), 6.59 (dd, IH), 5.95 (ddd, IH), 5.83 (br s, IH), 5.57 (t, IH), 5.13 (br d, IH), 5.09 (t, IH), 5.02 (d, IH), 4.71 (m, IH), 4.71 (br s, IH), 4.64 (br s, IH), 4.61 (d, IH), 4.42 (d, IH), 4.23 (m, IH), 4.02 (pentet, IH), 3.92 (dd, IH), 3.73 (m, 2H), 3.70 (d, IH), 3.56 (s, 3H), 3.52-3.56 (m, 2H), 2.92 (m, 2H), 2.64-2.76 (m, 3H), 2.59 (heptet, IH), 2.49 (ddd, IH), 2.42 (ddd, IH), 2.01 (dq, IH), 1.81 (s, 3H), 1.76 (s, 3H), 1.65 (s, 3H), 1.35 (d, 3H), 1.29 (m, IH), 1.20 (t, 3H), 1.19 (d, 3 H), 1.17 (d, 3H), 1.16 (d, 3H), 1.14 (s, 3H), 1.12 (s, 3H), 0.87 (t, 3H); ¹³C NMR (100 MHz, CD₃OD) δ 178.4, 169.7, 169.1, 154.6, 153.9, 146.2, 143.7, 141.9, 137.1, 137.0, 136.4, 134.6, 128.5, 126.9, 125.6, 124.6, 114.8, 112.8, 108.8, 102.3, 97.2, 94.3, 82.5, 78.6, 76.9, 75.9, 74.5, 73.5, 73.2, 72.8, 71.6, 70.5, 68.3, 63.9, 62.2, 42.5, 37.3, 35.4, 28.7, 28.3, 26.9, 26.4, 20.3, 19.6, 19.2, 18.7, 18.2, 17.6, 15.5, 14.6, 14.0, 11.4.
PATENT
http://www.google.com/patents/US7378508
macrolide of Formula I:
DIFICID (fidaxomicin) is a macrolide antibacterial drug for oral administration. Its CAS chemical name is Oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-Omethyl- β-D- mannopyranosyl]oxy]methyl]-12-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxohexopyranosyl] oxy]-11-ethyl-8 -hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-,(3E,5E,8S,9E,11S,12R,13E,15E,18S)-. The structural formula of fidaxomicin is shown in Figure 1.





Patent
WO 2016024243, New patent, Dr Reddy’s Laboratories Ltd, Fidaxomicin
WO2016024243,  FIDAXOMICIN POLYMORPHS AND PROCESSES FOR THEIR PREPARATION
DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara Hills, Telangana State, India Hyderabad 500034 (IN)
CHENNURU, Ramanaiah; (IN).
PEDDY, Vishweshwar; (IN).
RAMAKRISHNAN, Srividya; (IN)
Aspects of the present application relate to crystalline forms of Fidaxomicin IV, V & VI and processes for their preparation. Further aspects relate to pharmaceutical compositions comprising these polymorphic forms of fidaxomicin


The occurrence of different crystal forms, i.e., polymorphism, is a property of some compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physico-chemical properties.
Polymorphs are different solid materials having the same molecular structure but different molecular arrangement in the crystal lattice, yet having distinct physico-chemical properties when compared to other polymorphs of the same molecular structure. The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, “Tricky Business,” Science News, August 21 , 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.
There remains a need for additional polymorphic forms of fidaxomicin and for processes to prepare polymorphic forms in an environmentally-friendly, cost-effective, and industrially applicable manner.

G.V. Prasad, chairman, Dr Reddy’s Laboratories
EXAMPLES
Example 1 : Preparation of fidaxomicin Form IV:
Fidaxomicin (0.5 g) and a mixture of 1 ,4-Dioxane (10 mL), THF (10 ml) and water (20mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:
Starting temperature: 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 6 hours.
After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40^°C to a constant weight to produce crystalline fidaxomicin form-IV.
Example 2: Preparation of fidaxomicin Form V:
Fidaxomicin (1 g) and a mixture of propylene glycol (10 mL) and water (20mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:
Starting temperature is 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 6 hours.
After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40°C to a constant weight to produce crystalline fidaxomicin form-V.
Example 3: Preparation of fidaxomicin Form VI:
Fidaxomicin (0.5 mg) and MIBK (10 mL) were charged in Easy max reactor (Mettler Toledo) and the mixture was heated to 80°C. n-heptane (20 mL) was added to the solution at the same temperature. The mixture was stirred for 1 hour. The reaction mass was then cooled to 25°C. Solid formed was filtered at 25°C and dried at 40°C in air tray dryer (ATD) to a constant weight to produce crystalline fidaxomicin form VI.
Example 4: Preparation of fidaxomicin Form V:
Fidaxomicin (500 mg) and a mixture of R-propylene glycol (5 mL) and water (15 mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:
Starting temperature is 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 2 hours.
After completion of temperature cycling process, the slurry was filtered and dried at 25°C to produce crystalline fidaxomicin form-V.
Example 5: Preparation of fidaxomicin Form V:
Fidaxomicin (1 g) and a mixture of S-propylene glycol (3 ml_) and water (30 mL) were charged in Easy max reactor (Mettler Toledo). The reactor was set to temperature cycle with following parameters:
Starting temperature is 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 2 hours.
After completion of temperature cycling process, the slurry was filtered and dried at 25°C to produce crystalline fidaxomicin form-V.
Example 6: Preparation of fidaxomicin Form V:
Fidaxomicin (40 g) and a mixture of propylene glycol (400 mL) and water (1600 mL) were charged in Chem glass reactor. The reactor was set to temperature cycle with following parameters:
Starting temperature is 25 °C;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 60 °C over a period of 2 hours;
Cooled to 0 °C over a period of 2 hours;
Temperature raised to 25 °C over a period of 2 hours;
Temperature maintained at 25 °C for 6 hours.
After completion of temperature cycling process, the slurry was filtered under suction, followed by drying in air tray dryer (ATD) at 40°C to a constant weight to produce crystalline fidaxomicin form-V.


The 10-member board at pharmaceutical major Dr Reddy’s thrives on diversity. Liberally sprinkled with gray hairs, who are never quite impressed with powerpoint presentations, “they want information to be pre-loaded so that the following discussions (at the board level) are fruitful,” says Satish Reddy, Chairman, Dr Reddy’s. That said, the company has now equipped its board members with a customized application (that runs on their tablets) to manage board agenda and related processes.
see at
http://articles.economictimes.indiatimes.com/2014-10-31/news/55631761_1_board-members-board-agenda-dr-reddy-s

Dr. Reddy’s Laboratories Managing Director and Chief Operating Officer Satish Reddy addressing

References

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ARNONE A ET AL: "STRUCTURE ELUCIDATION OF THE MACROCYCLIC ANTIBIOTIC LIPIARMYCIN", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, CHEMICAL SOCIETY, LETCHWORTH; GB, 1 January 1987 (1987-01-01), pages 1353-1359, XP000578201, ISSN: 0300-922X, DOI: 10.1039/P19870001353

Fidaxomicin

Systematic (IUPAC) name
3-(((6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl)oxy)-methyl)-12(R)-[(6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl)oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one
Clinical data
Trade names	Dificid, Dificlir
Licence data	US FDA:link
Pregnancy category	AU:B1 US:B (No risk in non-human studies)
Legal status	AU:S4 (Prescription only) CA: ℞-only UK:POM (Prescription only) US:℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	Minimal systemic absorption[1]
Biological half-life	11.7 ± 4.80 hours[1]
Excretion	Urine (<1%), faeces (92%)[1]
Identifiers
CAS Number	873857-62-6
ATC code	A07AA12
PubChem	CID 11528171
ChemSpider	8209640
UNII	Z5N076G8YQ
KEGG	D09394
ChEBI	CHEBI:68590
ChEMBL	CHEMBL1255800
Synonyms	Clostomicin B1, lipiarmicin, lipiarmycin, lipiarmycin A3, OPT 80, PAR 01, PAR 101, tiacumicin B
Chemical data
Formula	C52H74Cl2O18
Molar mass	1058.04 g/mol

US4918174

26 Sep 1986

17 Apr 1990

Abbott Laboratories

Tiacumicin compounds

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