DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR earlier GLENMARK LS Research centre as consultant,Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, [email protected]

Rush , few seats, ACS INDUSTRY SYMPOSIUM RECENT ADVANCES IN DRUG DEVELOPMENT IN PARTNERSHIP WITH DR. REDDY’S LABORATORIES HYDERABAD, INDIA 11-12 NOVEMBER 2016

CONFERENCE Comments Off

Nov 032016

ACS INDUSTRY SYMPOSIUM

RECENT ADVANCES IN DRUG DEVELOPMENT IN PARTNERSHIP WITH DR. REDDY’S LABORATORIES HYDERABAD, INDIA

11-12 NOVEMBER 2016

click http://acssymposium.org.in/

for registrations

QbD Sitagliptin

QbD Comments Off

Oct 302016

Application of On-Line NIR for Process Control during the Manufacture of Sitagliptin

George Zhou^*, Shane Grosser, Lei Sun, Gabriel Graffius, Ganeshwar Prasad, Aaron Moment, Angela Spartalis,Paul Fernandez, John Higgins, Busolo Wabuyele, and Cindy Starbuck

Global Science, Technology and Commercialization, Merck Sharp & Dohme Corporation P.O. Box 2000, Rahway, New Jersey 07065, United States

Org. Process Res. Dev., 2016, 20 (3), pp 653–660

DOI: 10.1021/acs.oprd.5b00409

Publication Date (Web): February 12, 2016

*E-mail: [email protected].

Abstract

The transamination-chemistry-based process for sitagliptin is a through-process, which challenges the crystallization of the active pharmaceutical ingredient (API) in a batch stream composed of multiple components. Risk-assessment-based design of experiment (DoE) studies of particle size distribution (PSD) and crystallization showed that the final API PSD strongly depends on the seeding-point temperature, which in turn relies on the solution composition. To determine the solution composition, near-infrared (NIR) methods had been developed with partial least squares (PLS) regression on spectra of simulated process samples whose compositions were made by spiking each pure component, either sitagliptin free base (FB), water, isopropyl alcohol (IPA), dimethyl sulfoxide (DMSO), or isopropyl acetate (IPAc), into the process stream according to a DoE. An additional update to the PLS models was made by incorporating the matrix difference between simulated samples in lab and factory batches. Overall, at temperatures of 20–35 °C, the NIR models provided a standard error of prediction (SEP) of less than 0.23 wt % for FB in 10.56–32.91 wt %, 0.22 wt % for DMSO in 3.77–19.18 wt %, 0.32 wt % for IPAc in 0.00–5.70 wt %, and 0.23 wt % for water in 11.20–28.58 wt %. After passing the performance qualification, these on-line NIR methods were successfully established and applied for the on-line analysis of production batches for compositions prior to the seeding point of sitagliptin crystallization.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00409?journalCode=oprdfk

Next…………..

A biocatalytic manufaturing route for januvia – Society of Chemical …

www.soci.org/~/media/Files/…/2011/…/Jake_Janey_Presentation.ashx

Nov 2, 2011 – 9 Steps, 52% overall yield, >100Kg of sitagliptin prepared ….. FDA filings requires “Quality by Design”: A way to allow process changes within.

A PRESENTATION

Example of QbD Application in Japan

https://www.pmda.go.jp/files/000213677.pdf

Aug 11, 2016 – QbD assessment experience in Japan … Number of Approved Products with QbD … Active Ingredient : Sitagliptin Phosphate Hydrate.

WILL BE UPDATED WITH MORE, WATCH OUt

/////////

Name	Explanation
Active Pharmaceutical Ingredient (API)	An active pharmaceutical ingredient (API) is a substance used in a finished pharmaceutical product, intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.
Annual Product Reviews (APR)	The Annual Product Reviews (APR) include all data necessary for evaluation of the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. The APR is required by the U.S. Code of Federal Regulations.
ANVISA	The Brazilian Health Surveillance Agency (in Portuguese, Agência Nacional de Vigilância Sanitária) is a governmental regulatory body in Brazil. Similar to the FDA in the United States, it oversees the approval of drugs and other health products and regulates cosmetics, food products, and other health-related industries.
Biologic License Application (BLA)	The Biologics License Application (BLA) is a request for permission to introduce, or deliver for introduction, a biologic product into commerce in the U.S.
CFDA	The China Food and Drug Administration is similar to the FDA in the United States and is responsible for regulating food and drug safety.
cGMP	Current Good Manufacturing Practices govern the design, monitoring, and control of manufacturing facilities and processes and are enforced by the US FDA. Compliance with these regulations helps safeguard a drug’s identity, strength, quality, and purity.
COFEPRIS	The Federal Commission for Protection against Sanitary Risks (in Spanish, Comisión Federal para la Protección contra Riesgos Sanitarios) is a government agency in Mexico. It regulates food safety, drugs, medical devices, organ transplants, and environmental protection.
Common Technical Document (CTD)	The Common Technical Document (CTD) is the mandatory common format for new drug applications in the EU and Japan, and the U.S. The CTD assembles all the Quality, Safety and Efficacy information necessary for a drug application.
European Medicines Agency (EMA)	The European Medicines Agency (EMA) is a decentralised agency of the European Union (EU), located in London. It began operating in 1995. The Agency is responsible for the scientific evaluation, supervision and safety monitoring of medicines developed by pharmaceutical companies for use in the EU.
Food and Drug Administration (FDA)	The Food and Drug Administration (FDA) is an agency within the U.S. Department of Health and Human Services. The FDA is responsible for the approval of new pharmaceutical products for sale in the U.S. and performs audits at the companies participating in the manufacture of pharmaceuticals to ensure that they comply with regulations.
Human growth hormone	A growth hormone (GH or HGH) is a peptide hormone produced by the pituitary gland that stimulates growth in children and adolescents. It is involved in several body processes, including cell reproduction and regeneration, regulation of body fluids, and metabolism. It can be produced by the body (ie, somatotropin) or genetically engineered (ie, somatropin).
In-Process Control (IPC)	In-Process Controls (IPC) are checks performed during production in order to monitor and if necessary to adjust the process to ensure that the product conforms its specification.
Interferons (INFs)	Interferons are proteins produced by the body as part of the immune response. They are classified as cytokines, proteins that signal other cells to trigger action. For example, a cell infected by a virus will release interferons to stimulate the defenses of nearby cells.
Interleukins	Interleukins are proteins produced by cells as an inflammatory response. Most interleukins help leukocytes communicate with and direct the division and differentiation of other cells.
Investigational Medicinal Product Dossier (IMPD)	The Investigational Medicinal Product Dossier (IMPD) is the basis for approval of clinical trials by the competent authorities in the EU. The IMPD includes summaries of information related to the quality, manufacture and control of the Investigational Medicinal Product, data from non-clinical studies and from its clinical use.
Investigational New Drug (IND)	An Investigational New Drug application is provided to the FDA to obtain permission to test a new drug in humans in Phase I – III clinical studies. The IND is reviewed by the FDA to ensure that study participants will not be placed at unreasonable risk.
Marketing Authorization Application (MAA)	The Marketing Authorization Application (MAA) is a common document used as the basis for a marketing application across all European markets, plus Australia, New Zealand, South Africa, and Israel. This application is based on a full review of all quality, safety, and efficacy data, including clinical study reports.
Master batch records	These general manufacturing instructions, which are required by cGMP, are the bases for a precise, detailed description of a pharmaceutical manufacturing process. They ensure that all proper ingredients are included, each process step is completed, and the process is controlled.
Medicines and Healthcare Products Regulatory Agency (MHRA)	The Medicines and Healthcare products Regulatory Agency (MHRA) regulates medicines, medical devices and blood components for transfusion in the UK. MHRA is an executive agency, sponsored by the Department of Health.
MFDS	The Ministry of Food and Drug Safety (formerly the Korean Food & Drug Administration) is a government agency that oversees the safety and efficacy of drugs and medical devices in South Korea.
Monoclonal antibodies	Monoclonal antibodies are antibodies made in a laboratory from identical immune cells that are clones of a single cell. They are distinct from polyclonal antibodies, which are made from different immune cells.
NDA	A New Drug Application (NDA) is the vehicle submitted to the FDA by drug companies in order to gain approval to market a new product. Safety and efficacy data, proposed package labeling, and the drug’s manufacturing methods are typically included in an NDA.
New Drug Application (NDA)	The New Drug Application (NDA) is the vehicle through which drug sponsors formally propose that the FDA approve a new chemical pharmaceutical for sale and marketing in the U.S.
Oligonucleotides	These short nucleic acid chains (made up of DNA or RNA molecules) are used in genetic testing, research, and forensics.
Parenteral	Parenteral medicine is taken or administered in a manner other than through the digestive tract. Intravenous and intramuscular injections are two examples.
Peptide hormones	Peptide hormones are proteins secreted by organs such as the pituitary gland, thyroid, and adrenal glands. Examples include follicle-stimulating hormone (FSH) and luteinizing hormone. Similar to other proteins, peptide hormones are synthesized in cells from amino acids.
PMDA	The Pharmaceuticals Medical Devices Agency is an independent administrative agency that works with the Ministry of Health, Labour and Welfare to oversee the safety and quality of drugs and medical devices in Japan.
Process Analytical Technology (PAT)	These analytical tools help monitor and control the manufacturing process, including accommodating for variability in material and equipment, in order to ensure consistent quality.
Product Quality Reviews (PQR)	The Product Quality Reviews (PQR) of all authorized medicinal products, is conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product, to highlight any trends and to identify product and process improvements. The PQR is required by the EU GMP Guideline.
Quality by Design (QbD)	This concept involves a holistic, proactive, science- and risk-based approach to the development and manufacturing of drugs. At the heart of QbD is the idea that quality is achieved through in-depth understanding of the product and the process by which it is developed and manufactured.
Restricted Access Barrier System (RABS)	This advanced aseptic processing system provides an enclosed environment that reduces the risk of contamination to the product, containers, closures, and product contact surfaces. As a result, it can be used in many applications in a fill-finish area.
Scale-up	Scale-up involves taking a small-scale manufacturing system developed in the laboratory to a commercially viable, robust production process.
Six Sigma	Six Sigma is a set of quality management methods, techniques, and tools used to improve manufacturing, transactional, and other business processes. The goal is to enhance quality (as well as employee morale and profits) by identifying and eliminating the cause of errors and process variations.
Target Product Profile (TPP)	This key strategic document summarizes the features of an intended drug product. Characteristics may include the dosage form, route of administration, dosage strength, pharmacokinetics, and drug product quality criteria.
TFDA	The Taiwan Food & Drug Administration is a governmental body devoted to enhancing food safety and drug quality in that country.

Critical Impurities in Pharmaceutical Water

regulatory Comments Off

Oct 272016

Image result for Pharmaceutical Water

The quality of the source water used to produce pharmaceutical water plays an important role for both the design of the treatment and the validation of the water system. FDA Warning Letters over the past few years have shown that compliance with the specification of pharmaceutical water is not enough. A validation of the treatment process is expected. This includes documentation of the process capacity to produce pharmaceutical water according to specification. If we do not know the quality of the source water, however, the purification capacity is not known either. As a consequence, fluctuations of the quality of the source (feed) water quality may lead to water that does not comply with the specification after purification. Or it is not known up to which quality level of the source water pharmaceutical water that complies with the specification can be produced. Therefore, it is important to know the impurities respectively their concentration in the source (feed) water.
The production of pharmaceutical water is always based on drinking water. The specifications for drinking water however (for Germany, stipulated in the Trinkwasserverordnung; for the U.S., in the National Primary Drinking Water Regulation) are defined very broadly compared to Pharmacopoeial specifications.

The quality of the drinking water varies widely as well, as drinking water may come from different sources (ground water or surface water). Even the ground water quality varies locally, e. g., depending on the season. This is why water purification plants for the pharmaceutical industry are not ready-made goods, but individual solutions that have to be developed by the future user and the plant supplier together. The plant supplier will always ask about the quality of the drinking water so that he can offer the appropriate processing technologies.

In particular, he will need the following information. For this purpose, it is useful to provide the plant engineer with various drinking water analyses over a minimum period of twelve months.

For the design of a pharmaceutical water plant, the indicator parameters according to the Trinkwasserverordnung (conductivity, iron, manganese, sulphate and pH value) are important, as the amount of the ionic load determines the treatment process. For instance, a single-stage or double-stage reverse osmosis may be sufficient to obtain adequate quality at low conductivity levels. Iron and manganese are limited by the drinking water ordinance, but will lead to irreversible membrane damage at the reverse osmosis plant when their limits (according to the Trinkwasserverordnung) are exceeded.

Image result for Pharmaceutical Water

Furthermore, information on the total hardness is indispensable, as it has a major influence on the design of the softening plant – as well as on carbonate hardness or base capacity which are used to calculate the amount of dissolved carbon dioxide. This parameter restricts the use of EDI or may require further treatment, such as membrane degassing.

Depending on the origin of the drinking water, a responsible plant engineer should measure the colloid index (SDI 15) before designing the plant. Especially with surface water, higher amounts are to be expected. A colloid index of more than 5%/min can already have a negative impact on the operation of a reverse osmosis plant (membrane blocking and/or fouling) and may require additional treatment techniques, such as ultrafiltration before the main plant. While the colloid index is never determined via the water supplier, the silicate content is often indicated in the drinking water analysis. A silicate content of more than 25 ppm can become critical for a combination of reverse osmosis and EDI and should also be determined in case it is not indicated in the analysis.

All microbiological parameters have been regulated in the Trinkwasserverordnung. However, you should always remember that the supplier guarantees the quality only up to the point of transfer. With regards to the total bacteria count in particular, regular tests are necessary in order to identify seasonal fluctuations.

http://www.gmp-compliance.org/enews_5532_Critical-Impurities-in-Pharmaceutical-Water_n.html

Image result for Pharmaceutical Water

////////////Critical Impurities, Pharmaceutical Water

FDA presentation at the ECA Conference Particles in Parenterals

regulatory Comments Off

Oct 272016

Image result for visual inspection of medicinal products for parenteral use.

At the Particles in Parenterals Conference Dr Stephen Langille from the US FDA gave a talk on the FDA’s current thinking with regard to the visual inspection of medicinal products for parenteral use.

http://www.gmp-compliance.org/enews_05610_FDA-presentation-at-the-ECA-Conference-Particles-in-Parenterals_S-PTK_n.html

Dr Stephen Langille from the US FDA gave a talk on the FDA’s current thinking with regard to the visual inspection of medicinal products for parenteral use. In his presentation he showed the number of recalls caused by visible particulate matter over the last 11 years. For him, most of the recalls were justified when the types of particles found were taken into consideration. He also emphasized that something is possibly wrong in the visual inspection process if particles found in the market are bigger than 1000 µm.

The prevention of particles is very important to him. From his perspective the best particle is one which is not in the product. Also important to him are threshold studies, meaning to show the minimum particle size which can still be detected (dependent of product and type of container). These threshold studies are crucial for the setup of the test sets and the qualification of the inspectors of the manual inspection. He also mentioned the semi-automated inspection process. For him semi-automated inspection is good for detecting container-closure issues, like missing stoppers. But he also questioned whether an inspection time of about one second is suitable to detect particles with a size of 200µm for example. In the discussion he was asked about FDA’s opinion on the USP chapter <790>. In his opinion, USP chapter <790> can be an effective tool for ensuring that the manufacturing process and 100% inspection process are adequate to limit visible particle contamination. However, cGMPs must be followed during the manufacturing and visual inspection process. Meeting the requirements of USP <790> should not be used to excuse not meeting cGMPs.

You will find the complete presentation in the members area of the ECA webpage.

.///////////FDA presentation, ECA Conference , Particles in Parenterals

The impact of the FDA Combination Products Guidance on Nasal and Oral Inhalation Drug Products

regulatory Comments Off

Oct 272016

Image result for Oral Inhalation and Nasal Drug Products

The FDA draft guidance for combination products has a substantial impact on the development of Oral Inhalation and Nasal Drug Products (OINDPs) as it requires that the manufacturers have to be compliant not only with CGMPs for the drugs (21 CFR Parts 210 and 211) but also with the quality system (QS) regulations for devices (21 CFR Part 820). Find out more about the FDA Draft Guidance for Combination Products.

http://www.gmp-compliance.org/enews_05639_The-impact-of-the-FDA-Combination-Products-Guidance-on-Nasal-and-Oral-Inhalation-Drug-Products_15462,Z-QCM_n.html

Based on the CGMP requirements for single-entity and co-packaged combination products (21 CFR Part 4) the manufacturers of Oral Inhalation and Nasal Drug Products (OINDPs) have to be compliant with CGMPs for the drug constituent part(s) (21 CFR Parts 210 and 211) and the quality system (QS) regulations for device constituent part(s) (21 CFR Part 820).

This can be achieved either by a drug CGMP-based streamlined approach (21 CFR 4.4(a)) or a QS regulation-based streamlined approach (21 CFR 4.4(b)). Following the first approach the combination product manufacturers have to be compliant with the drug CGMP and device QS regulation requirements:

– 21 CFR 820.20 – Management responsibility
– 21 CFR 820.30 – Design controls
– 21 CFR 820.50 – Purchasing controls
– 21 CFR 820.100 – Corrective and preventive actions
– 21 CFR 820.170 – Installation
– 21 CFR 820.200 – Servicing

The OINDP manufacturers have to be clearly stated in their submission and at the initiation of a pre-approval inspection (PAI) whether they are operating under the drug CGMP or QS regulation-based approach.

Here you can see the complete FDA Draft Guidance on Combination Products including the requirements for Oral Inhalation and Nasal Drug Products.
////// FDA Combination Products Guidance, Nasal and Oral Inhalation, Drug Products

Counterfeit of medicines causes 37,000 job losses in EU Pharma Industry

regulatory Comments Off

Oct 272016

Image result for Counterfeit medicine

Counterfeit medicine is an increasing problem for public health and economy. This is no longer a problem of certain regions such as Asia and Africa. It has now also become an issue in the EU and US. The European Union Intellectual Property Office (EUIPO) published a press release on 29 September 2016 in which they state that fake medicines cost the EU pharmaceutical sector 10.2 billion Euro every year. Read more about the latest figures on counterfeit medicines

http://www.gmp-compliance.org/enews_05605_Counterfeit-of-medicines-causes-37-000-job-losses-in-EU-Pharma-Industry_15356,S-QSB_n.html

Counterfeit medicine is an increasing problem for public health and economy. This is no longer a problem of certain regions such as Asia and Africa. It has now also become an issue in the EU and the US. In the past, counterfeit medicines could not enter the legal supply chain in the EU and US. But the problem has now also been arising in western countries. A number ofcases of counterfeit medicines were detected recently. In order to cope with this increasing problem, the EU has introduced a regulation which requires that as of 9th February 2019 certain medicinal products can only enter the EU market if a 2D barcode is used as a safety feature. This code must be applied on the packaging in readable form.

The European Union Intellectual Property Office (EUIPO) published a press release on 29 September 2016 in which they state that fake medicines cost the EU pharmaceutical sector 10.2 billion Euro every year. The counterfeit products cause a loss of 4.4% of the legitimate sales of pharmaceuticals. This means “37,700 jobs directly lost across the pharmaceutical sector in the EU” according to the report. Only for Germany, an annual loss of 1 billion Euro has been calculated which caused a direct job loss of 6,951. Regarding other countries, the figures are: Italy 1.59 billion, France 1 billion, Spain 1,17 billion and UK 605 million loss annually.

Source: Press Release EUIPO, September 29, 2016

//////////Counterfeit of medicines, 37,000 job losses, EU Pharma Industry

Reformatsky and Blaise Reactions in Flow as a Tool for Drug Discovery. One Pot Diversity Oriented Synthesis of Valuable Intermediates and Heterocycles

FLOW CHEMISTRY, flow synthesis Comments Off

Oct 232016

Compound 3aa was obtained as pale yellow oil (163 mg, 92% yield).MS (ESI): mass calcd. for C12H16O3, 208.1099; m/z found, 209.1102 [M+H] + .

1H NMR (CHLOROFORM-d, 400MHz): δ = 7.45 (d, J=7.7 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H), 7.21-7.27 (m, 1H), 4.37 (s, 1H), 4.00-4.18 (m, 2H), 2.97 (d, J=15.9 Hz, 1H), 2.79 (d, J=15.9 Hz, 1H), 1.55 (s, 3H), 1.08-1.18 ppm (m, 3H).

13C NMR (CHLOROFORM-d, 101MHz): δ = 173.1, 147.3, 128.6, 127.3, 124.9, 73.2, 61.4, 46.9, 31.1, 14.4 ppm

The application of Reformatsky and Blaise reactions for the preparation of a diverse set of valuable intermediates and heterocycles in a one-pot protocol is described. To achieve this goal, a novel green activation protocol for zinc in flow conditions has been developed to introduce this metal efficiently into -bromoacetates. The organozinc compounds were added to a diverse set of ketones and nitriles to obtain a wide range of functional groups and heterocyclic systems in a one pot procedure.

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC02619B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Reformatsky and Blaise Reactions in Flow as a Tool for Drug Discovery. One Pot Diversity Oriented Synthesis of Valuable Intermediates and Heterocycles.

Jesus Alcazar, Antonio de la Hoz, Angel Diaz, Lena Huck and Mateo Berton

Green Chem., 2016, Accepted Manuscript

DOI: 10.1039/C6GC02619B

////////////Reformatsky, Blaise Reactions , Flow chemistry, Drug Discovery. One Pot, Diversity Oriented Synthesis, Valuable Intermediates, Heterocycles.

QbD in Pharma Development World Congress 2017, SelectBio, 20-21 April, 2017, Radisson Hyderabad HITEC City, India

CONFERENCE, QbD Comments Off

Oct 212016

http://selectbiosciences.com/images/DEL_QBD_20Oct.html

QbD in Pharma Development World Congress 2017 Registration

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SELECTBIO are offering 3 for the price of 2 on all delegate passes. To take advantage of this offer contact us by email, phone or click the Contact Us button below. Looking for more than 3 passes? Contact us for more information on our special rates for large groups.

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The refined Radisson Hyderabad Hitec City features the prompt services, such as a concierge, and comfortable, air-conditioned rooms you need for a satisfying visit. You can stay fit with laps in the swimming pool and fitness centre, or relax in your suite with 24-hour room service and free Wi-Fi access. The aminities include Satellite TV, Work desk, Wi-Fi access, Tea and coffeemaker, Bottles of mineral water, Large bathrooms with separate rain showers, Large wardrobe, Mini barWrap up a day of meetings with authentic Indian cuisine at Cascade or exotic Asian specialties at The Oriental Blossom. Treat your colleagues to drinks at Zyng lounge bar, or if the weather is nice, gather outside at Poolside Grill for a barbecued meal.
A business centre is also available to help you complete work while staying at this Hitec City hotel in the heart of Gachibowli, a new-age IT suburb of Hyderabad, near the Hyderabad International Convention Centre.
SELECTBIO has negotiated special rates (see below) to include buffet breakfast, and Wi-Fi. Standard Room Single/Double – INR 4500/5000+Tax
To make your reservation at these discounted rates please contact Sakshi Modgil at [email protected]. We recommend early booking to avoid disappointment.

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International visitors will require an invitation letter to obtain their Business visa. We will only provide invitation letters to customers that are fully registered for the event. In the event of an unsuccessful visa application we will refund the full delegate fee paid.
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Visa Invitation Requirement
Please ensure that the above form is duly complete, as it will expedite the preparation of an invitation letter. Also mention clearly, to whom the invitation letter should be addressed as per the requirement of the country of origin.
For more information on Indian visa’s applications for International visitors, please contact your local Indian embassy.
Please plan sufficiently in advance because processing of Indian Visa Application may take 4-6 weeks.

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//////////QbD, Pharma Development, World Congress, 2017, SelectBio, Radisson Hyderabad HITEC City, India

Development and Manufacturing GMP Scale-Up of a Continuous Ir-Catalyzed Homogeneous Reductive Amination Reaction

PROCESS, SYNTHESIS, Uncategorized Comments Off

Oct 202016

Evacetrapib

The design, development, and scale up of a continuous iridium-catalyzed homogeneous high pressure reductive amination reaction to produce 6, the penultimate intermediate in Lilly’s CETP inhibitor evacetrapib, is described. The scope of this report involves initial batch chemistry screening at milligram scale through the development process leading to full-scale production in manufacturing under GMP conditions. Key aspects in this process include a description of drivers for developing a continuous process over existing well-defined batch approaches, manufacturing setup, and approaches toward key quality and regulatory questions such as batch definition, the use of process analytics, start up and shutdown waste, “in control” versus “at steady state”, lot genealogy and deviation boundaries, fluctuations, and diverting. The fully developed continuous reaction operated for 24 days during a primary stability campaign and produced over 2 MT of the penultimate intermediate in 95% yield after batch workup, crystallization, and isolation.

Development and Manufacturing GMP Scale-Up of a Continuous Ir-Catalyzed Homogeneous Reductive Amination Reaction

Scott A. May^*, Martin D. Johnson^*, Jonas Y. Buser, Alison N. Campbell, Scott A. Frank, Brian D. Haeberle‡, Philip C. Hoffman, Gordon R. Lambertus, Adam D. McFarland, Eric D. Moher, and Timothy D. White ,

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States

D. Declan Hurley^*, Aoife P. Corrigan, Olivia Gowran, Niall G. Kerrigan, Marie G. Kissane, Regina R. Lynch, Paul Sheehan, and Richard D. Spencer ,

Eli Lilly SA, Dunderrow, Kinsale, Cork, Ireland

Shon R. Pulley§ and James R. Stout

D&M Continuous Solutions, LLC, Greenwood, Indiana 46113, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00148

Publication Date (Web): October 19, 2016

*E-mail (Scott A. May): [email protected]., *E-mail: (Martin D. Johnson): [email protected]., *E-mail: (Declan D. Hurley):[email protected].

link http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00148

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

/////////continuous manufacturing, deviation boundaries, Evacetrapib, flow chemistry, GMP, homogeneous catalysis, hydrogen, hydrogenation, iridium, lot genealogy, LY2484595, online HPLC, process analytical technologies, reductive amination, start up and shutdown transitions, state of control, steady state, [Ir(COD)Cl]₂

Experimental and Chemoinformatics Study of Tautomerism in a Database of Commercially Available Screening Samples

Uncategorized Comments Off

Oct 182016

We investigated how many cases of the same chemical sold as different products (at possibly different prices) occurred in a prototypical large aggregated database and simultaneously tested the tautomerism definitions in the chemoinformatics toolkit CACTVS. We applied the standard CACTVS tautomeric transforms plus a set of recently developed ring–chain transforms to the Aldrich Market Select (AMS) database of 6 million screening samples and building blocks. In 30 000 cases, two or more AMS products were found to be just different tautomeric forms of the same compound. We purchased and analyzed 166 such tautomer pairs and triplets by ¹H and ¹³C NMR to determine whether the CACTVS transforms accurately predicted what is the same “stuff in the bottle”. Essentially all prototropic transforms with examples in the AMS were confirmed. Some of the ring–chain transforms were found to be too “aggressive”, i.e. to equate structures with one another that were different compounds.

Experimental and Chemoinformatics Study of Tautomerism in a Database of Commercially Available Screening Samples

Laura Guasch^†, Waruna Yapamudiyansel^†, Megan L. Peach^§, James A. Kelley^†, Joseph J. BarchiJr.^†, and Marc C. Nicklaus^*^†

^† Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States

^§ Basic Science Program, Chemical Biology Laboratory, Leidos Biomedical Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States

J. Chem. Inf. Model., Article ASAP

DOI: 10.1021/acs.jcim.6b00338, http://pubs.acs.org/doi/full/10.1021/acs.jcim.6b00338

Publication Date (Web): September 26, 2016

*E-mail: [email protected].

Laura Guasch
Chemoinformatics Data Scientist
National Institutes of Health
National Cancer Institute (NCI): National Institute of Health
Bethesda, MD, United States
https://www.researchgate.net/profile/Laura_Guasch, https://uk.linkedin.com/in/lguasch
a highly motivated computational chemist and cheminformatician that employ, analyze, and develop computer-based methods to aid in the drug discovery. I enjoy working with experimentalists from the fields of biology, pharmacy, medicine and chemistry on answering relevant questions in drug discovery.
Specialties: CADD; Virtual screening; Pharmacophores; Docking; Homology modeling; Quantum chemistry; SAR/QSAR; ADME/Tox modeling; Drug metabolism; Chemoinformatics; Data mining; Molecular informatics.

Research experience
Feb 2012–present PostDoc Position
National Institutes of Health · National Cancer Institute (NCI): National Institute of Health · Chemical Biology Laboratory
United States · Frederick
Development of novel approaches for tautomerism analysis. Structure-based and ligand-based identification and design of anti-cancer and anti-viral agents.
Jan 2009–Jun 2009 Research Intern
University of Innsbruck · Institute of General, Inorganic and Theoretical Chemistry · Theoretical Chemistry
Austria · Innsbruck
Discovery of Natural Product PPAR-gamma Partial Agonists by a Pharmacophore-Based Virtual Screening Workflow.
Sep 2007–Dec 2011 PhD Student
Universitat Rovira i Virgili · Department of Biochemistry and Biotechnology · Nutrigenomics Research Group
Spain · Tarragona
Identification of natural products as antidiabetic agents using computer-aided drug design methods.
Jan 2007–Jun 2007 Research Fellow
Universitat Rovira i Virgili · Department of Physical and Inorganic Chemistry · Quantum Chemistry Group
Spain · Tarragona
Prediction of enantiomeric excesses in asymmetric catalysis using a new QSSR approach based on three-dimensional DFT molecular descriptors
Jul 2006–Aug 2006 Summer Intership
Barcelona Science Park · Quantum Simulation of Biological Processes
Spain · Barcelona
Structure and electronic configuration of compound I intermediates Penicillium vitale catalases using techniques of molecular dynamics simulation


Education
Sep 2007–Jun 2008 Universitat Rovira i Virgili
Nutrition and Metabolism · Master of Science
Spain · Tarragona
Sep 2004–Jun 2007 Universitat Rovira i Virgili
Biochemistry · BSc
Spain · Tarragona
Sep 2002–Jun 2007 Universitat Rovira i Virgili
Chemistry · Bachelor of Science
Spain · Tarragona


Awards & achievements
Dec 2011 Award: European Doctorate Mention
Dec 2011 Award: PhD Extraordinary Award

Marc C. Nicklaus, Ph.D.
Senior Scientist
Chemical Biology Laboratory
Head, Computer-Aided Drug Design (CADD) Group
Dr. Nicklaus received his Ph.D. in applied physics from the Eberhards-Karls-Universitat, Tubingen, Germany, and then served as a postdoctoral fellow in the Molecular Modeling Section of the then called Laboratory of Medicinal Chemistry, NCI. He became a staff fellow in 1998, and a Senior Scientist in 2002. In 2000, he founded, and has been heading since then, the Computer-Aided Drug Design (CADD) Group.
Dr. Nicklaus pioneered work on making large small-molecule databases and related chemoinformatics tools available to the scientific public on the CADD Group’s web server. He also pioneered the analysis of conformational energies of small molecule ligands bound to proteins. As Head of the CADD Group, he oversees the group’s research program in chemoinformatics, fundamentals of protein-ligand interactions, and in silico screening for targets of high interest to NCI. He makes the latter resources available in collaborative projects to improve NCI’s efforts in hit identification and drug design.
Link to additional information about Dr. Nicklaus’ research.
Areas of Expertise
1) chemoinformatics, 2) small-molecule databases, 3) protein-ligand interactions, 4) (quantitative) structure-activity relationships, 5) computer-aided drug design, 6) computational chemistry
CONTACT INFO
Marc C. Nicklaus, Ph.D.

Center for Cancer Research

National Cancer Institute

Building 376, Room 207

Frederick, MD 21702-1201

Ph: 301-846-5903
[email protected](link sends e-mail)
PERMALINK


Research
Publications
Biography
Team

Computer-Aided Drug Design. The Computer-Aided Drug Design (CADD) Group is a research unit within the Chemical Biology Laboratory (CBL) that employs, analyzes, and develops computer-based methods to aid in the drug discovery, design, and development projects of the CBL and other researchers at the NIH. We split our efforts about evenly between support-type projects and research projects initiated and conducted by CADD staff members. We are implementing many projects, and making available resources developed by the CADD Group, in a Web-based manner. This offers three advantages: (1) it frees all users, including the group members themselves, from platform restraints and the concomitant expenses for specific software/hardware, (2) it makes resources and results immediately available for sharing among all collaborators regardless of their location, and (3) helps, without additional effort, further the mission of the NCI as a publicly funded institution by providing data and services directly to the (scientific) public.
Chemical Identifier Resolver (CIR). CIR works as a resolver for many different chemical structure identifiers (e.g. chemical names, InChI, SMILES etc.) and allows one to convert the given structure identifier into a full structure representation or another structure identifier including references to particular databases in which the corresponding structure or structure identifier occurs. CIR offers a simple to use, programmatic application programming interface (API) based on URLs requested by HTTP. This allows easy linking of CIR and its content to other scientific web services and program packages. CIR currently provides access to 120 million structure records.
Enhanced NCI Database Browser. The Enhanced NCI Database Browser can be used to search the 250,000-compound Open NCI Database. This dataset is the publicly available part of the half-million structure collection assembled by the NCI’s Developmental Therapeutics Program during the program’s 50+ years of screening compounds against cancer and, more recently, AIDS. Visit the CADD Group’s home page or the Enhanced NCI Database Browser service for more information.
Fundamentals of Protein-Ligand Interactions. The non-covalent binding of a drug to the binding site of an enzyme (or other biomacromolecule) is the fundamental process of most drug actions. In spite of a vast body of experimental data available on protein-ligand complexes, mostly obtained by X-ray crystallography, there are still open questions of how this binding process occurs at the atomic and quantitative energetic level. One of the issues is the range of conformational energies one can expect to find for the small-molecule ligand bound to proteins, which we found to be higher than generally assumed. This has led us to broader questions regarding x-ray crystallographic methodologies, such as whether quantum-mechanical refinement (or re-refinement) of protein ligand structures may improve structural quality in various ways.
HIV Integrase. A long-standing interest of our group has been HIV integrase (IN) as a drug development target. This enzyme catalyzes the integration of the viral DNA into the human DNA, which is an essential step in the viral replication cycle. Only a handful of approved drugs so far are based on IN inhibition. We have been utilizing all available experimental results, be they structural, mechanistic, or biochemical, to model and better understand inhibition of IN by small molecules. A recent expansion of these efforts is our work aimed at developing HIV microbicides for the prevention of infection with HIV by topical application such as vaginal gels.
Among our main collaborators are Stephen Hughes and Yves Pommier, NCI; Wolf-Dietrich Ihlenfeldt, Xemistry, Germany; Vladimir Poroikov, Russian Academy of Medical Sciences, Moscow; and Raul Cachau, Leidos, FNLCR.
Scientific Focus Areas:
Biomedical Engineering and Biophysics, Chemical Biology, Computational Biology, Structural Biology