AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

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
 

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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.

link http://pubs.acs.org/doi/abs/10.1021/op5000336

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
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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: jan.recho@phosphonics.com.

Experience

Systems Developer

Clearsy

– Present (1 year 6 months)

Scientist

PhosphonicS

(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.

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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: amrendrakr@drreddys.com (A.K.R.)., *E-mail:sripabba85@yahoo.co.in (P.S.).

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////// QbD, DoE, FMEA, ANOVA, Design space.
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FDA published generic user fee for 2017: for ANDA, DMF, and for Facility (API, FDF)

 regulatory  Comments Off on FDA published generic user fee for 2017: for ANDA, DMF, and for Facility (API, FDF)
Aug 032016
 

 

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http://www.raps.org/Regulatory-Focus/News/2016/07/26/25394/FDA-Lowers-ANDA-Fee-Rates-for-2017/

Generic drugmakers submitting abbreviated new drug applications (ANDAs) and prior approval supplements (PAS) will see their US Food and Drug Administration (FDA) fee rates drop in 2017, though all other rates, including those for drug master files (DMF) and facility fees will increase when compared to 2016.

For FY 2017, the generic drug fee rates are: ANDA ($70,480, down from $76,030 in 2016), PAS ($35,240, down from $38,020 in 2016), DMF ($51,140, up from $42,170 in 2016), domestic active pharmaceutical ingredient (API) facility ($44,234, up from $40,867 in 2016), foreign API facility ($59,234, up from $55,867 in 2016), domestic finished dose formulation (FDF) facility ($258,646, up from $243,905), and foreign FDF facility ($273,646, up from $258,905 in 2016).

The new fees are effective 1 October 2016 and will remain in effect through 30 September 2017.

FDA explained the increases and decreases in fees, noting that for ANDA and PAS fees, the agency is expecting an increase in the number of submissions estimated to be submitted in FY 2017 when compared to 2016. For 2017, the agency estimates that approximately 891 new original ANDAs and 439 PASs will be submitted and incur filing fees.

Fees for DMFs will increase, meanwhile, because of an expected decrease in the number of submissions estimated to be submitted in 2017 (FDA is estimating 379 fee-paying DMFs for 2017), when compared to the estimated submissions from 2016.

And all facility fees will increase in 2017 when compared to the previous year because of a decrease in the number of facilities that self-identified (the total number of FDF facilities identified through self-identification was 675, of which 255 were domestic facilities and 420 foreign facilities; while the total number of API facilities self-identified was 789, of which 101 were domestic facilities and 688 were foreign facilities), FDA said.

How FDA Calculates the Fees

In order to calculate the ANDA fee, FDA estimated the number of full application equivalents (FAEs) that will be submitted in FY 2017, which is done by assuming ANDAs count as one FAE and PASs (supplements) count as one-half of an FAE, since the fee for a PAS is one half of the fee for an ANDA.

The Generic Drug User Fee Act (GDUFA) also requires that 75% of the fee paid for an ANDA or PAS filing be refunded if either application is refused due to issues other than a failure to pay the fees.

And since this is the last year of this iteration of GDUFA (the next version is still in the works), the agency is allowed to further increase the fee revenues and fees established if such an adjustment is necessary to provide for not more than three months of operating reserves for the first three months of FY 2018, though FDA estimates that the GDUFA program will have carryover balances for such activities in excess of three months of such operating reserves, so FDA will not be performing a final year adjustment.

To pay the fees, companies must complete a Generic Drug User Fee Cover Sheet, available at http://www.fda.gov/gdufa and generate a user fee identification (ID) number. Payment must be made in US currency drawn on a US bank by electronic check, check, bank draft, US postal money order or wire transfer.

Federal Register Notice

See more at: http://www.raps.org/Regulatory-Focus/News/2016/07/26/25394/FDA-Lowers-ANDA-Fee-Rates-for-2017/#sthash.FNo99XHR.dpuf

 

 

/////////////FDA,  generic user fee,  2017, ANDA, DMF,  Facility, API, FDF

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Written Confirmation expired: Can an API still be imported when produced earlier?

 regulatory  Comments Off on Written Confirmation expired: Can an API still be imported when produced earlier?
Jul 282016
 

 

What needs to be considered if an API is produced in the time period of a valid written confirmation but imported after this confirmation has expired? This is answered in a revised Q&A Document of the EU Commission.

see………http://www.gmp-compliance.org/enews_05432_Written-Confirmation-expired-Can-an-API-still-be-imported-when-produced-earlier_15432,15354,15367,Z-QAMAP_n.html

The EU Commission has updated its Question and Answers Document “Importation of active substances for medicinal products for human use” (now version 7). In this updated version, the question “Can an API batch manufactured during the period of validity of a written confirmation be imported into the EU once the written confirmation is expired?”

In the answer it is referred to Article 46(b)(2)(b) of Directive 2001/83/EC, where it is defined that APIs can only be imported if they are manufactured in accordance with EU GMP or equivalent, and accompanied by a written confirmation from the competent authority of the exporting third country certifying this.

But what if an API is produced in the time period of a valid written confirmation but imported after this confirmation has expired?

In the respective answer the EU Commission states that “it is legitimate to consider that the guarantees of equivalence provided by the written confirmation apply to any API batch in the scope of the written confirmation which was released for sale within the period of validity of the written confirmation, even if not exported in that time period.”

So the answer is ‘yes’, it still can be imported. But it needs to be accompanied by the expired written confirmation together with appropriate documentation which proves “that the whole consignment has been manufactured and released for sale by the quality unit before the expiry date of the written confirmation” and “provides a solid justification of why a valid written confirmation is not available.”

An import without any written confirmation is not possible.

 

///////////API, produced, time period of a valid written confirmation, imported, confirmation has expired, revised Q&A Document of the EU Commission.

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Sreeni Labs Private Limited, Hyderabad, India ready to deliver New, Economical, Scalable Routes to your advanced intermediates & API’s in early Clinical Drug Development Stages

 companies, INDIA, MANUFACTURING, new drugs, PRECLINICAL, PROCESS, regulatory  Comments Off on Sreeni Labs Private Limited, Hyderabad, India ready to deliver New, Economical, Scalable Routes to your advanced intermediates & API’s in early Clinical Drug Development Stages
Jul 162016
 

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Sreeni Labs Private Limited, Hyderabad, India is ready to take up challenging synthesis projects from your preclinical and clinical development and supply from few grams to multi-kilo quantities. Sreeni Labs has proven route scouting ability  to  design and develop innovative, cost effective, scalable routes by using readily available and inexpensive starting materials. The selected route will be further developed into a robust process and demonstrate on kilo gram scale and produce 100’s of kilos of in a relatively short time.

Accelerate your early development at competitive price by taking your route selection, process development and material supply challenges (gram scale to kilogram scale) to Sreeni Labs…………

INTRODUCTION

Sreeni Labs based in Hyderabad, India is working with various global customers and solving variety of challenging synthesis problems. Their customer base ranges from USA, Canada, India and Europe. Sreeni labs Managing Director, Dr. Sreenivasa Reddy Mundla has worked at Procter & Gamble Pharmaceuticals and Eli Lilly based in USA.

The main strength of Sreeni Labs is in the design, development of innovative and highly economical synthetic routes and development of a selected route into a robust process followed by production of quality product from 100 grams to 100s of kg scale. Sreeni Labs main motto is adding value in everything they do.

They have helped number of customers from virtual biotech, big pharma, specialty chemicals, catalog companies, and academic researchers and drug developers, solar energy researchers at universities and institutions by successfully developing highly economical and simple chemistry routes to number of products that were made either by very lengthy synthetic routes or  by using highly dangerous reagents and Suzuki coupling steps. They are able to supply materials from gram scale to multi kilo scale in a relatively short time by developing very short and efficient synthetic routes to a number of advanced intermediates, specialty chemicals, APIs and reference compounds. They also helped customers by drastically reducing number of steps, telescoping few steps into a single pot. For some projects, Sreeni Labs was able to develop simple chemistry and avoided use of palladium & expensive ligands. They always begin the project with end in the mind and design simple chemistry and also use readily available or easy to prepare starting materials in their design of synthetic routes

Over the years, Sreeni labs has successfully made a variety of products ranging from few mg to several kilogram scale. Sreeni labs has plenty of experience in making small select libraries of compounds, carbocyclic compounds like complex terpenoids, retinal derivatives, alkaloids, and heterocyclic compounds like multi substituted beta carbolines, pyridines, quinolines, quinolones, imidazoles, aminoimidazoles, quinoxalines, indoles, benzimidazoles, thiazoles, oxazoles, isoxazoles, carbazoles, benzothiazoles, azapines, benzazpines, natural and unnatural aminoacids, tetrapeptides, substituted oligomers of thiophenes and fused thiophenes, RAFT reagents, isocyanates, variety of ligands,  heteroaryl, biaryl, triaryl compounds, process impurities and metabolites.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They can also take up custom synthesis and scale up of medchem analogues and building blocks.  They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving couple of PO based (fee for service) projects.

Some of the compounds prepared by Sreeni labs;

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See presentation below

LINK ON SLIDESHARE

Managing Director at Sreeni Labs Private Limited

 

Few Case Studies : Source SEEENI LABS

QUOTE………….

One virtual biotech company customer from USA, through a common friend approached Sreeni Labs and told that they are buying a tetrapeptide from Bachem on mg scale at a very high price and requested us to see if we can make 5g. We accepted the challenge and developed solution phase chemistry and delivered 6g and also the process procedures in 10 weeks time. The customer told that they are using same procedures with very minor modifications and produced the tetrapeptide ip to 100kg scale as the molecule is in Phase III.

 

One East coast customer in our first meeting told that they are working with 4 CROs of which two are in India and two are in China and politely asked why they should work with Sreeni Labs. We told that give us a project where your CROs failed to deliver and we will give a quote and work on it. You pay us only if we deliver and you satisfy with the data. They immediately gave us a project to make 1.5g and we delivered 2g product in 9 weeks. After receiving product and the data, the customer was extremely happy as their previous CRO couldn’t deliver even a milligram in four months with 3 FTEs.

 

One Midwest biotech company was struggling to remove palladium from final API as they were doing a Suzuki coupling with a very expensive aryl pinacol borane and bromo pyridine derivative with an expensive ligand and relatively large amount of palldium acetate. The cost of final step catalyst, ligand and the palladium scavenging resin were making the project not viable even though the product is generating excellent data in the clinic. At this point we signed an FTE agreement with them and in four months time, we were able to design and develop a non suzuki route based on acid base chemistry and made 15g of API and compared the analytical data and purity with the Suzuki route API. This solved all three problems and the customer was very pleased with the outcome.

 

One big pharma customer from east coast, wrote a structure of chemical intermediate on a paper napkin in our first meeting and asked us to see if we can make it. We told that we can make it and in less than 3 weeks time we made a gram sample and shared the analytical data. The customer was very pleased and asked us to make 500g. We delivered in 4 weeks and in the next three months we supplied 25kg of the same product.

 

Through a common friend reference, a European customer from a an academic institute, sent us an email requesting us to quote for 20mg of a compound with compound number mentioned in J. med. chem. paper. It is a polycyclic compound with four contiguous stereogenic centers.  We gave a quote and delivered 35 mg of product with full analytical data which was more pure than the published in literature. Later on we made 8g and 6g of the same product.

 

One West coast customer approached us through a common friend’s reference and told that they need to improve the chemistry of an advanced intermediate for their next campaign. At that time they are planning to make 15kg of that intermediate and purchased 50kg of starting raw material for $250,000. They also put five FTEs at a CRO  for 5 months to optimize the remaining 5 steps wherein they are using LAH, Sodium azide,  palladium catalyst and a column chromatography. We requested the customer not to purchase the 50kg raw material, and offered that we will make the 15kg for the price of raw material through a new route  in less than three months time. You pay us only after we deliver 15 kg material. The customer didn’t want to take a chance with their timeline as they didn’t work with us before but requested us to develop the chemistry. In 7 weeks time, we developed a very simple four step route for their advanced intermediate and made 50g. We used very inexpensive and readily available starting material. Our route gave three solid intermediates and completely eliminated chromatographic purifications.

 

One of my former colleague introduced an academic group in midwest and brought us a medchem project requiring synthesis of 65 challenging polyene compounds on 100mg scale. We designed synthetic routes and successfully prepared 60 compounds in a 15 month time.  

UNQUOTE…………

 

The man behind Seeni labs is Dr.Sreenivasa  Reddy Mundla

Sreenivasa Reddy

Dr. Sreenivasa Reddy Mundla

Managing Director at Sreeni Labs Private Limited

Sreeni Labs Private Limited

Road No:12, Plot No:24,25,26

  • IDA, Nacharam
    Hyderabad, 500076
    Telangana State, India

Links

LINKEDIN https://in.linkedin.com/in/sreenivasa-reddy-10b5876

FACEBOOK https://www.facebook.com/sreenivasa.mundla

RESEARCHGATE https://www.researchgate.net/profile/Sreenivasa_Mundla/info

EMAIL mundlasr@hotmail.com,  Info@sreenilabs.com, Sreeni@sreenilabs.com

Dr. Sreenivasa Mundla Reddy

Dr. M. Sreenivasa Reddy obtained Ph.D from University of Hyderabad under the direction Prof Professor Goverdhan Mehta in 1992. From 1992-1994, he was a post doctoral fellow at University of Wisconsin in Professor Jame Cook’s lab. From 1994 to 2000,  worked at Chemical process R&D at Procter & Gamble Pharmaceuticals (P&G). From 2001 to 2007 worked at Global Chemical Process R&D at Eli Lilly and Company in Indianapolis. 

In 2007  resigned to his  job and founded Sreeni Labs based in Hyderabad, Telangana, India  and started working with various global customers and solving various challenging synthesis problems. 
The main strength of Sreeni Labs is in the design, development of a novel chemical route and its development into a robust process followed by production of quality product from 100 grams to 100’s of kg scale.
 

They have helped number of customers by successfully developing highly economical simple chemistry routes to number of products that were made by Suzuki coupling. they are able to shorten the route by drastically reducing number of steps, avoiding use of palladium & expensive ligands. they always use readily available or easy to prepare starting materials in their design of synthetic routes.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving PO based projects

Experience

Founder & Managing Director

Sreeni Labs Private Limited

August 2007 – Present (8 years 11 months)

Sreeni Labs Profile

Sreeni Labs Profile

View On SlideShare

Principal Research Scientist

Eli Lilly and Company

March 2001 – August 2007 (6 years 6 months)

Senior Research Scientist

Procter & Gamble

July 1994 – February 2001 (6 years 8 months)

Education

University of Hyderabad

Doctor of Philosophy (Ph.D.), 
1986 – 1992

 

PUBLICATIONS

Article: Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

Jianye Zhang · Zhiqian Dong · Sreenivasa Reddy Mundla · X Eric Hu · William Seibel ·Ruben Papoian · Krzysztof Palczewski · Marcin Golczak

Article: ChemInform Abstract: Regioselective Synthesis of 4Halo ortho-Dinitrobenzene Derivative

Sreenivasa Mundla

Aug 2010 · ChemInform

Article: Optimization of a Dihydropyrrolopyrazole Series of Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: Discovery of an Orally Bioavailable Transforming Growth Factor-β Receptor Type I Inhibitor as Antitumor Agent

Hong-yu Li · William T. McMillen · Charles R. Heap · Denis J. McCann · Lei Yan · Robert M. Campbell · Sreenivasa R. Mundla · Chi-Hsin R. King · Elizabeth A. Dierks · Bryan D. Anderson · Karen S. Britt · Karen L. Huss

Apr 2008 · Journal of Medicinal Chemistry

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Feb 2008 · ChemInform

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Nov 2007 · Tetrahedron

Article: Dihydropyrrolopyrazole Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: A Novel Benzimidazole Series with Selectivity versus Transforming Growth Factor-β Type II Receptor Kinase and Mixed Lineage Kinase-7

Hong-yu Li · Yan Wang · Charles R Heap · Chi-Hsin R King · Sreenivasa R Mundla · Matthew Voss · David K Clawson · Lei Yan · Robert M Campbell · Bryan D Anderson · Jill R Wagner ·Karen Britt · Ku X Lu · William T McMillen · Jonathan M Yingling

Apr 2006 · Journal of Medicinal Chemistry

Read full-textSource

Article: Studies on the Rh and Ir mediated tandem Pauson–Khand reaction. A new entry into the dicyclopenta[ a, d]cyclooctene ring system

Hui Cao · Sreenivasa R. Mundla · James M. Cook

Aug 2003 · Tetrahedron Letters

Article: ChemInform Abstract: A New Method for the Synthesis of 2,6-Dinitro and 2Halo6-nitrostyrenes

Sreenivasa R. Mundla

Nov 2000 · ChemInform

Article: ChemInform Abstract: A Novel Method for the Efficient Synthesis of 2-Arylamino-2-imidazolines

Read at

[LINK]

Patents by Inventor Dr. Sreenivasa Reddy Mundla

  • Patent number: 7872020

    Abstract: The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole monohydrate.

    Type: Grant

    Filed: June 29, 2006

    Date of Patent: January 18, 2011

    Assignee: Eli Lilly and Company

    Inventor: Sreenivasa Reddy Mundla

  • Publication number: 20100120854

    Abstract: The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate.

    Type: Application

    Filed: June 29, 2006

    Publication date: May 13, 2010

    Applicant: ELI LILLY AND COMPANY

    Inventor: Sreenivasa Reddy Mundla

  • Patent number: 6066740

    Abstract: The present invention provides a process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydroyrimidine derivatives by preparing the corresponding activated 2-thio-subsituted-2-derivative in a two-step, one-pot procedure and by further reacting yields this isolated derivative with the appropriate amine or its salts in the presence of a proton source. The present process allows for the preparation of 2-amino-2-imidazolines, quanidines, and 2-amino-3,4,5,6-tetrahydropyrimidines under reaction conditions that eliminate the need for lengthy, costly, or multiple low yielding steps, and highly toxic reactants. This process allows for improved yields and product purity and provides additional synthetic flexibility.

    Type: Grant

    Filed: November 25, 1997

    Date of Patent: May 23, 2000

    Assignee: The Procter & Gamble Company

    Inventors: Michael Selden Godlewski, Sean Rees Klopfenstein, Sreenivasa Reddy Mundla, William Lee Seibel, Randy Stuart Muth

TGF-β inhibitors

US 7872020 B2

Sreenivasa Reddy Mundla

The present invention provides 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl) -5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate, i.e., Formula I.

Figure US07872020-20110118-C00002

EXAMPLE 1 Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole monohydrate

Figure US07872020-20110118-C00008

Galunisertib

1H NMR (CDCl3): δ=9.0 ppm (d, 4.4 Hz, 1H); 8.23-8.19 ppm (m, 2H); 8.315 ppm (dd, 1.9 Hz, 8.9 Hz, 1H); 7.455 ppm (d, 4.4 Hz, 1H); 7.364 ppm (t, 7.7 Hz, 1H); 7.086 ppm (d, 8.0 Hz, 1H); 6.969 ppm (d, 7.7 Hz, 1H); 6.022 ppm (m, 1H); 5.497 ppm (m, 1H); 4.419 ppm (t, 7.3 Hz, 2H); 2.999 ppm (m, 2H); 2.770 ppm (p, 7.2 Hz, 7.4 Hz, 2H); 2.306 ppm (s, 3H); 1.817 ppm (m, 2H). MS ES+: 370.2; Exact: 369.16

ABOVE MOLECULE IS

https://newdrugapprovals.org/2016/05/04/galunisertib/

Galunisertib

Phase III

LY-2157299

CAS No.700874-72-2

 

 

READ MY PRESENTATION ON

Accelerating Generic Approvals, see how you can accelerate your drug development programme

Accelerating Generic Approvals by Dr Anthony Crasto

KEYWORDS   Sreenivasa Mundla Reddy, Managing Director, Sreeni Labs Private Limited, Hyderabad, Telangana, India,  new, economical, scalable routes, early clinical drug development stages, Custom synthesis, custom manufacturing, drug discovery, PHASE 1, PHASE 2, PHASE 3,  API, drugs, medicines

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Indian Generics 2016

 PROCESS, regulatory  Comments Off on Indian Generics 2016
Aug 032015
 

 

The generic APIs market is expected to continue to rise faster than the branded/innovative APIs, by 7.7%/year to reach $30.3 billion in 2016. Asia-Pacific is expected to show the fastest growth rates (10.8%/year). The 24 fastest growing markets will include 11 in Asia-Pacific, seven in Eastern Europe and CIS, four in Africa-Middle East and two in Latin America (Figure ).

Figure  – Top growth markets for generic APIs to 2016

By 2016, China will account for 27.7% of the global generic API merchant market, while the US will have fallen to 23.8%; the mature markets as a whole will see their share fall from 41.8% in 2012 to 36.9%. India will be the third largest, with a 7.2% share.

 

 

 

 

 

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GMP IN AN API PILOT PLANT

 regulatory  Comments Off on GMP IN AN API PILOT PLANT
Jul 102015
 

 

GMP……API PILOT PLANT

PRESENTATION

 

Pilot plant and scale-up techniques are both integral and critical to drug discovery and development process for new medicinal products. A major decision focuses on that point where the idea or process is advanced from a research oriented program targeted towards commercialization.

The speed of drug discovery has been accelerating at an exponential rate. The past two decades particular have witnessed amazing inventions and innovations in pharmaceutical research, resulting in the ability to produce new drugs faster than even before.

The new drug applications (NDAs) and abbreviated new drug applications (ANDA) are all-time high. The preparation of several clinical batches in the pilot plant provides its personnel with the opportunity to perfect and validate the process. Also different types of laboratories have been motivated to adopt new processes and technologies in an effort to stay at the forefront scientific innovation.

 MY PRESENTATION

 

 

Pharmaceutical pilot plants that can quickly numerous short-run production lines of multiple batches are essential for ensuring success in the clinical testing and bougainvilleas study phases. Drug formulation research time targets are met by having a well-designed facility with the appropriate equipment mix, to quickly move from the laboratory to the pilot plant scale 1. In pilot plant, a formula is transformed into a viable, robust product by the development of a reliable and practical method of manufacture that effects the orderly transition from laboratory to routine processing in a full scale production facility where as the scale up involves the designing of prototype using the data obtained from the pilot plant model.

Pilot plant studies must includes a close examination of formula to determine its ability to withstand batch-scale and process modifications; it must includes a review of range of relevant processing equipment also availability of raw materials meeting the specification of product and during the scale up efforts in the pilot plant production and process control are evaluated, validated and finalized.

pilot pic 12

In addition, appropriate records and reports issued to support Good Manufacturing Practices and to provide historical development of the production formulation, process, equipment train, and specifications

A manufacturer’s decision to scale up / scale down a process is ultimately rooted in the economics of the production process, i.e., in the cost of material, personnel, and equipment associated with the process and its control.

 When developing technologies, there are a number of steps required between the initial concept and completion of the final production plant. These steps include the development of the commercial process, optimization of the process, scale-up from the bench to a pilot plant, and from the pilot plant to the full scale process. While the ultimate goal is to go directly from process optimization to full scale plant, the pilot plant is generally a necessary step.

Reasons for this critical step include: understanding the potential waste streams, examination of macro-processes, process interactions, process variations, process controls, development of standard operating procedures, etc. The information developed at the pilot plant scale allows for a better understanding of the overall process including side processes. Therefore, this step helps to build the information base so that the technology can be permitted and safely implemented.

Should be versatile pilot plant that is entirely GMP and facilitates the development of API’s in scalable, safe and environmentally friendly ways.

pilot pic 6

The combination of  facilities,  experience and flexibility enable  an integral Contract Manufacturing service ranging from laboratory to industrial scale; it should manufacture under regulation small amounts of high added value active substances or key intermediate products.

pilot pic 4

 

pilot pic 5

Product quality: Operations that depend on people for executing manual recipes are subject to human variability. How precisely are the operators following the recipe? Processes that are sensitive to variations in processing will result in quality variation. Full recipe automation that controls most of the critical processing operations provides very accurate, repeatable material processing. This leads to very highly consistent product quality.

pilot pic 11

 Improved production: Many biotech processes have extremely long cycle times (some up to 6 months), and are very sensitive to processing conditions. It is not uncommon for batches to be lost for unexplained reasons after completing a large portion of the batch cycle time. The longer the batch cycle time and the more sensitive production is to processing conditions, the more batch automation is justified. Imagine losing a batch of very valuable product because the recipe was not precisely followed!

 Process optimization: Increasing the product yield can be done by making small changes in processing conditions to improve the chemical conversions or biological growth conditions. Manual control offers a limited ability to finely implement small changes to processing conditions due to the inherent lack of precision in human control. Conversely, computers are very good at controlling conditions precisely. In addition, advanced control capabilities such as model predictive control can greatly improve process optimization. This results in higher product yield and lower production cost. This consideration is highly relevant to pilot plant facilities where part of the goal is to learn how to make the product.

 Recordkeeping: A multi-unit recipe control system is capable of collecting detailed records as to how a batch was made and relates all data to a single batch ID. Data of this nature can be very valuable for QA reporting, QA deviation investigations, and process analysis.

 Safety: Operators spend less time exposed to chemicals when the process is fully automated as compared to manual control. Less exposure to the process generally results in a safer process.

A good batch historian should be able to collect records for a production run to include the following information:  Product and recipe identification

 User defined report parameters

 Formulation data and relevant changes

 Procedural element state changes (Operations, unit procedures, procedures)

 Phase state changes

 Operator changes

 Operator prompts and responses

 Operator comments

 Equipment acquisitions and releases

 Equipment relationships

 Campaign creation data (recipe, formula values, equipment, etc.)

 Campaign modifications

 Campaign execution activity

 Controller I/O subsystem events from the Continuous Historian

 Process alarms

 Process events

 Device state changes.

 

Raw materials

Buildings and facilities. GMPs under the 21 Code of Federal Regulations (CFR) Part 211.42 state that buildings or areas used in the receiving, storage, and handling of raw materials should be of suitable size, construction and location to allow for the proper cleaning, maintenance, and operation (7). The common theme for this section of CFR Parts 210 and 211 is the prevention of errors and contamination. In principle, the requirements for buildings and facilities used in early phase manufacturing are not significantly different than those for later phases or even commercial production. However, there are some areas that are unique to early clinical trial manufacturing.

Control of materials. The CFR regulations under Part 211.80 provide good direction with respect to lot identification, inventory, receipt, storage, and destruction of materials (7). The clear intent is to ensure patient safety by establishing controls that prevent errors or cross-contamination and ensure traceability of components from receipt through clinical use. In general, the requirements for the control of materials are identical across all phases of development, so it is important to consider these requirements when designing a GMP facility within a laboratory setting.

Combination Glass/Glass-lined reactors

For example, all materials must be assigned a unique lot number and have proper labeling. An inventory system must provide for tracking each lot of each component with a record for each use. Upon receipt, each lot should be visually examined for appropriate labeling and for evidence of tampering or contamination. Materials should be placed into quarantine or in the approved area or reject area with proper labeling to identify the material and prevent mix-ups with other materials in the storage area. Provision should be made for materials with special storage requirements (e.g., refrigeration, high security). The storage labeling should match the actual conditions that the material is being stored and should include expiry/retest dates for approved materials. Although such labeling is inconvenient for new materials where the expiration or retest date may change as more information is known, this enables personnel to be able to determine quickly whether a particular lot of a material is nearing or exceeding the expiration or retest date. General expiry/retest dates for common materials should be based on manufacturer’s recommendation or the literature.

Finally, there are clear regulatory and environmental requirements for the destruction of expired or rejected materials. It is important to observe regional and international requirements regarding the use of animal sourced materials (12). It is recommended to use materials that are not animal sourced and that there be available certification by the raw material manufacturers that they contain no animal sourced materials. If animal sourced raw materials must be used, then certifications by the raw material manufacturers that they either originate from certified and approved (by regulatory bodies) sources for use in human pharmaceuticals, or that the material has been tested to the level required for acceptance by regulatory agencies (following US, EU, or Japanese guidelines, as applicable) is required.

Direct advantages for customers 

  • Shorter implementation time for product by determination of the product suitability as well as the necessary process cycle
  • Optimized adjustment of the processing times in the production lines (trains) by relatively precise estimation of the drying times
  • Definition of effective cleaning processes (CIP/WIP and SIP)
  • Definition of the selection criteria based on the weighting of the customer, e.g.: drying time, quality (form of crystal, activity, etc.), cleanout, ability of CIP, price

 

An overview of further trials and test functions, that can be realized in the new pilot plant facility:

  • Product tests for determination of suitability
  • Scale-up tests as basis for the extrapolation on production batches regarding drying time, filling degree, crystalline transformation and grain spectrum
  • Optimization of the process cycle
  • Optimization of the machine
  • Data acquisition and analysis

SEE THIS SECTION IN ACTION…………..KEEP WATCHING

Case study 1

Designed and equipped for the manufacturing of solid oral dosage form
Hammann

PlantaFabri

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:

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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

 

pilot pic

 

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pilot pic 3

 

 

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 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

pilot pic 8

 

 

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.02.004

Equipment – C.02.005

Personnel – C.02.006

Sanitation – C.02.007 & C.02.008

Raw Material Testing – C.02.009 & C.02.010

Manufacturing Control – C.02.011 & C.02.012

Quality Control Department – C.02.013, C.02.014 & C.02.015

Packaging Material Testing – C.02.016 & C.02.017

Finished Product Testing – C.02.018 & C.02.019

Records – C.02.020, C.02.021, C.02.022, C.02.023 & C.02.024

Samples – C.02.025 & C.02.026

Stability – C.02.027 & C.02.028

Sterile 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 imidazole 14 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.

Kilogram-scale synthesis of an imidazole API precursor.
Scheme 20 Kilogram-scale synthesis of an imidazole API precursor.

 

 

 

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Definitions

Plant:  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.

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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.

Mixing Figure 1
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-ups
As 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

http://apic.cefic.org/pub/5gmpdev9911.pdf

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

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