Statistical DoE Approach to the Removal of Palladium from Active Pharmaceutical Ingredients (APIs) by Functionalized Silica Adsorbents

 QbD, regulatory  Comments Off on Statistical DoE Approach to the Removal of Palladium from Active Pharmaceutical Ingredients (APIs) by Functionalized Silica Adsorbents
Nov 032016

Abstract Image

The influence of four parameters (temperature, scavenging time, amount of scavenger, and concentration of palladium in the solution) on the efficiency of Pd removal from a cross-coupling reaction, using a commercially available Pd scavenger, SPM32, was studied. The DoE-based method employed yielded more information than is readily attainable from standard adsorption isotherms and kinetics experiments. The optimal regime of scavenging was identified; intuitive and nonintuitive effects of temperature, scavenging time, and scavenger amounts were highlighted; and a mathematical model quantifying predicted Pd removal from the synthetic intermediate was built.


Statistical DoE Approach to the Removal of Palladium from Active Pharmaceutical Ingredients (APIs) by Functionalized Silica Adsorbents

PhosphonicS Ltd., 44c Western Avenue, Milton Park, Abingdon, OX14 4RU, United Kingdom
Org. Process Res. Dev., 2014, 18 (5), pp 626–635
DOI: 10.1021/op5000336
Publication Date (Web): April 14, 2014
Copyright © 2014 American Chemical Society

Preparation of tert-butyl 2-[(4-cyanophenyl)amino]propanoate (3).

4-Bromobenzonitrile (18.20 g, 100 mmol), L-alanine tert-butyl ester hydrochloride (21.73 g, 120 mmol), ±BINAP (1.25 g, 2 mmol) and cesium carbonate (48.87 g, 150 mmol) were added to a 3-neck round bottom flask containing a magnetic stirrer. Toluene (167 mL) was added and a reflux condenser, thermometer and a rubber septum were attached. Argon gas was bubbled through as the heterogeneous mixture was warmed to reflux temperature with slow agitation from the magnetic stirrer. Palladium acetate (0.45 g, 2 mmol) was added quickly through one of the side-arm joints and de-gassing was continued for 5 min. The reaction mixture was kept under argon at reflux and the disappearance of 4-bromobenzonitrile was monitored by GC-MS. After 16-24 h, the reaction mixture was filtered through a sinter funnel, washed with toluene and then filtered through a nylon membrane (Sigma Aldrich catalogue no. Z290793, 0.45 µm pore size) and washed with toluene. This crude reaction mixture was used in the DoE matrix without further purification.

Experimental results

NMR δC (62.9 MHz, CDCl3): 172.7, 150.0, 133.7, 120.4, 112.7, 99.3, 82.3, 51.7, 28.0, 18.5 ppm.

NMR δH (250 MHz, CDCl3): 7.39 (2H, d, J = 8.8 Hz, Ph), 6.52 (2H, d, J = 8.8 Hz, Ph), 4.85 (1H, d, J = 7.4 Hz, NH), 4.01 (1H, quintet, J = 7.4 Hz, CH(Me), 1.43 (9H, s, tBu), 1.42 (3H, d, J = 7.4 Hz, Me).

GC/MS: GC method used: hold at 50 °C for 4 min; increase temperature from 50 to 280 °C at 30 °C / min; hold at 280 °C for 5 min. Peaks were recorded and identified as follows: 4-Bromobenzonitrile: 10.05 min. Molecular peak observed at m/z = 181 for the 79Br isotope, m/z = 183 for the 81Br isotope L-alanine tert-butyl ester hydrochloride: not observed. Retention time less than 5 min, peak lost within the solvent front. Product: 13.64 min. Molecular peak observed at m/z = 246, main fragment at m/z = 146 (M – CO2 t Bu) Side product (not identified or quantified, minor peak): 14.56 min.

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Jan Recho

Jan Recho

Jan Recho

Systems developer at Clearsy

Corresponding Author *E-mail:


Systems Developer


– Present (1 year 6 months)



(3 years 6 months)

• Design and synthesis of silica supported transition metals scavengers and catalysts (Pd, Rh, Ru) for the pharmaceutical industry.
• Management of fine chemistry customer projects
• Process optimisation (Quality by Design – QbD, Design of Experiments – DoE).
• Business development activities for the French market

Junior researcher

Institut des Matériaux de Nantes

(4 years 8 months)Nantes Area, France

Synthesis and characterisation of a cellulose derived, organosilane-based, bio-material for cartilage growth.
Work in imidazolium and pyridinium ionic liquids.


QbD Sitagliptin

 QbD  Comments Off on QbD Sitagliptin
Oct 302016



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

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
Copyright © 2016 American Chemical Society


Abstract Image

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.



A biocatalytic manufaturing route for januvia – Society of Chemical ……/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.





Example of QbD Application in Japan

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



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.

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

 CONFERENCE, QbD  Comments Off on QbD in Pharma Development World Congress 2017, SelectBio, 20-21 April, 2017, Radisson Hyderabad HITEC City, India
Oct 212016


QbD in Pharma Development World Congress 2017 Registration

3 for 2 Offer

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.

Radisson Hyderabad HITEC City

Radisson Hyderabad HITEC City


To find low cost flights, try the following websites:


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 We recommend early booking to avoid disappointment.

Sakshi Modgil's Profile PhotoSAKSHI MODGIL

Visa Requirements
International visitors travelling from outside India will require a Business visa.
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.

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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SELECTBIO Ltd, Woodview, Bull Lane, Sudbury, CO10 0FD, United Kingdom.

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


QbD: Controlling CQA of an API

 QbD  Comments Off on QbD: Controlling CQA of an API
Sep 132016

The importance of Quality by Design (QbD) is being realized gradually, as it is gaining popularity among the generic companies. However, the major hurdle faced by these industries is the lack of common guidelines or format for performing a risk-based assessment of the manufacturing process. This article tries to highlight a possible sequential pathway for performing QbD with the help of a case study. The main focus of this article is on the usage of failure mode and effect analysis (FMEA) as a tool for risk assessment, which helps in the identification of critical process parameters (CPPs) and critical material attributes (CMAs) and later on becomes the unbiased input for the design of experiments (DoE). In this case study, the DoE was helpful in establishing a risk-based relationship between critical quality attributes (CQAs) and CMAs/CPPs. Finally, a control strategy was established for all of the CPPs and CMAs, which in turn gave rise to a robust process during commercialization. It is noteworthy that FMEA was used twice during theQbD: initially to identify the CPPs and CMAs and subsequently after DoE completion to ascertain whether the risk due to CPPs and CMAs had decreased.




Image result for Quality by Design in Action 1: Controlling Critical Quality Attributes of an Active Pharmaceutical Ingredient

Image result for Quality by Design in Action 1: Controlling Critical Quality Attributes of an Active Pharmaceutical Ingredient

Quality by Design in Action 1: Controlling Critical Quality Attributes of an Active Pharmaceutical Ingredient

CTO-III, Dr. Reddy’s Laboratories Ltd, Plot 116, 126C and Survey number 157, S.V. Co-operative Industrial Estate, IDA Bollaram, Jinnaram Mandal, Medak District, Telangana 502325, India
Department of Chemistry, Osmania University, Hyderabad, Telangana 500007, India
Org. Process Res. Dev., 2015, 19 (11), pp 1634–1644
*Telephone: +919701346355. Fax: + 91 08458 279619. E-mail: (A.K.R.)., * (P.S.).





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////// QbD, DoE, FMEA, ANOVA, Design space.

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