Q&A: Bottom Spray (Wurster) Coating: Understanding the Challenges, Processing & Scale-Up Considerations

Tim Smith, Vector Corporation

Q: Process Airflow measurement indicated by the machine, are those shown as standard cfm, std m3/hr etc?
A: Each manufacturer of equipment would specify the units. F-V provides units based on the customer’s requirements. And do we need to correct for inlet temperature in order to get the actual volume? Yes, if the temperature is different than the reference standard temperature selected for the air flow station. If yes, how to convert? The first step is to know the volumetric air flow at the flow meter under flow conditions (temperature, pressure, and density of the air). An on-line calculator can assist with this, such as can be found at www.dwyer-inst.com/flowcalc/. Note that the initial calculation can be done with dry or moist air. In all processes the air has some moisture. In addition, air flow stations manufacturers may use a correction factor for their flow meters. Once the air flow is known at the flow conditions, the actual volumetric flow at the inlet to the fluid bed can be found utilizing the ideal gas law (reference slide 29 of the presentation).

Q: How does different type of filter affect scale-up? Can you give a more descriptive or specific example? 
A: A switch from bag to cartridge filters, or vice versa, can change the height of the fluid bed above the Wurster partition and therefore change the rate of drying before the product returns in the down bed. In addition, the differences in media may allow for differences in the size of particles being retained. 

Q: What in-process controls are available to monitor coating in real time? 
A: There are particle size analyzers that can be placed on systems to measure average film thickness (provided the beginning spherical core size is known); R&D studies have used NIR to measure coatings as well; however, models must be built for each product to apply it for controlling a given process. Some of the coating manufacturers have “computer tools” to calculate how much coating is required to provide a given thickness, but these tools are proprietary; one needs to contact the coating manufacturer for assistance.

Q: Can you clarify what is the particle/air velocity ratio? e.g. particle number /velocity? particle size/velocity? 
A: If I said “ratio” that was a mistake on my part. Ideally, you want the particle velocity through the spray zone to be the same in both the small and large systems. The particle velocity can be assumed to the same as the air velocity exiting the top of the Wurster partition.

Q: Can tablets be coated in a Wurster process? 
A: Yes; however, the tablets must be robust enough to withstand the vigorous movement that occurs. My personal recommendation would be to use a pan coater for coating tablets since it generally has a more gentle tablet movement as compared to a Wurster process.

Q: How aqueous coating be used for moisture sensitive actives? 
A: Since drying is occurring as fast as the coating is being applied to the product, the small amount of moisture and time it is in contact with the active may not be detrimental; however, that will be product dependent. 

Q: What is lowest RH% that can be achieved inside coater without causing spray-drying? 
A: While RH% of the incoming air has a bearing on how fast drying can occur, other factors are equally or more important with regards to spray drying of droplets; such as air temperature, air flow, percent moisture of solution being sprayed, and droplet size.

Q: Does Spray gun Nozzle size matter? 
A: Yes, as it will have a governing factor on droplet size. In lab scale equipment mostly 1.0 mm size is used whereas large scale equipment has 1.5 mm. A good rule to use as a starting point is to use 1000 times the atomization air flow as the solution flow. Increase this ratio if smaller droplets are desired.

Q: Please explain advantages of bottom spray and why not go for top spray standard fbd for spraying particles and tablets. 
A: Bottom spray is co-current with the product flow and therefore leads to more uniform coating application.

Q: Is it necessary to start spraying at a lower spray rate and then ramp up to target to avoid overwetting? 
A: While not required to commence spraying at a slower rate, it is a good place to start developing a process. Once you know how the process/product responds with no agglomeration, solution application can be started at faster rates.

Q: Can you please again elaborate the required evaporation rate for spray rate? 
A: In order to prevent over-wetting, the evaporation rate must equal the moisture addition rate. The moisture addition rate can be determined by multiplying the spray rate by the percent solvent in the solution/suspension. 

Q: How is the relationship between coating weight gain at small scale and larger scale provide similar drug release? 
A: Provided the same size cores are used at both scales, final moisture content is the same at both scales, and the coating has the same characteristics, the release should be similar.

Q: Is there a similar system to coat particles smaller than 1 micron? 
A: Not that I am aware of.

Q: Can you comment on how to evaluate substrate strength and its possible impact on coating film quality and consistency, especially for ER products? 
A: Friability testing is one way; another way is to put uncoated product in the machine and operate it under expected processing conditions to see how it withstands the vigorous product movement encountered during Wurster processing. If the product attrits, and the small particles are not allowed to leave the processing chamber, these particles can become entrapped in the coating layer and/or on the surface of the coating. This, in turn, will cause a faster release of the active.

Q: You mention the maximum relative size of the sprayed droplets of 1:10 to the size of the coated particle, while this is the maximum, where would you estimate the optimum? 
A: As small as possible without resulting in spray drying of the droplet.

Q: Is there any relationship between particle size and spray gun pressure or solution volume? 
A: If particle size is what is meant, I am not aware of any correlation. However, if droplet size is what is of concern, then yes, there is a relationship between atomization air velocity (volume or velocity is the result of pressure), solution velocity (related to flow), spray gun orifice, and solution viscosity, etc. The best way to determine the correlation is to conduct spray droplet tests for a given solution using a laser diffraction device to measure the droplet size. 

Q: Should the relative humidity of inlet air be under control?
A: Yes, for consistent control of a process; however, if the humidity can not be controlled, one must be able to adjust inlet air temperatures or spray rates to control the process. Note, I did not include process air volume as it really is fixed for a given Wurster process to provide proper product flow. 

Q: Can particles 10 to 100 microns be coated using Wurster coating? 
A: Yes, provided the particles have a narrow particle size distribution. If the distribution is too wide, the particles can agglomerate at a higher percentage. 

Q: How to avoid the doublets/ triplets cause due to static charge during process?
A: One way is to increase the “moisture” in the system. This can be done in a couple of ways:
1) by spraying as soon as the product begins moving or spraying faster (but this may not be sustainable for the duration of the process) and
2) by increasing the humidity level of the incoming process air (this usually means that a slower spray rate will be required to sustain the process).

Q: How can we get the mass flow rate of process air and atomization air? 
A: If you know the volumetric flow and the density of the air (function of humidity and temperature) you can calculate the mass flow rate … where mass flow = volumetric flow (volume/time) x density (mass/volume). 

David Preston
David Preston

Chairman

David Preston has had 38 years of healthcare experience with publicly – Traded and Private companies in the fields of Pharmaceutical’s, Animal Health and Biotechnology as a Board Member. The last 30 years of his experience has been in China, Taiwan and Hong Kong building successful high growth businesses. David Has been Chairman and CEO for Greater China for Sanofi and Boehringer – Ingelheim as well as the Janssen Corporation since 1991 in China. During this time he build high Growth businesses in China through diversified strategies in Innovative Pharmaceuticals, branded Generics, Biotechnology, and Animal Healthcare.


Key highlights in this period included building of the first Western Multinational Biotechnology C.M.O. facility as well as obtaining the first Test C.M.O.[ MAH] license. Establishment of a number of High tech Vaccine Plants, and R and D facilities in in the field of Animal Health. Signing and development of numerous JV’s as well as Wholly owned  Subsidiaries, Mergers and Acquisitions across Pharmaceutical’s, Animal Health, and Biotechnology industries.

 

David’s achievement’s in the Healthcare industry and it Growth and development in China is widely recognized By the Chinese Government and the City of Shanghai. In 2013 he was awarded the Silver Magnolia followed in 2015 the Gold Magnolia award. This was then followed by being awarded in 2017 the Honorary Citizen of Shanghai by 40th People’s Municipal Congress of Shanghai. David Holds a Business Science Degree .

This will close in 0 seconds

Filippo
Filippo de Vecchi

Director, Advent Partner

Filippo de Vecchi joined Advent in February 2000. He started in the Advent São Paulo office, then moved to Milan in 2002, in 2012 set up the Advent office in Shanghai and in 2016 set up the Hong Kong office. Before joining Advent, he was a senior consultant with Value Partners, in São Paulo and Milan, focusing on strategy and organization in the automotive, energy, cable and media sectors. He began his career at Wasserstein Perella & Co., working as an analyst in the Mergers and Acquisitions department in London and New York. Filippo holds an undergraduate degree cum laude in Economics, with a major in Business Administration, from the LUISS University and an MBA from Columbia Business School, where he currently serves as a member of the Board of Overseers.

This will close in 0 seconds

Andrew Li
Andrew Li

Director, Advent Partner

Andrew Li joined Advent in 2012. He previously worked at Warburg Pincus, HSBC PE, Solera Capital and Credit Suisse where he focused on the retail and consumer, healthcare, industrial, and energy sectors. Andrew has worked in finance and private equity throughout the U.S. and China since 1999. Andrew holds a BA from Middlebury College and an MBA from Harvard Business School.

This will close in 0 seconds

Michael Miltenberger
Michael Miltenberger

Director, Advent Partner

Michael Miltenberger joined Advent in 2011 as an associate on the healthcare team. Following business school, he rejoined Advent’s Boston office, focusing on healthcare investments. Prior to Advent, Michael was a consultant at McKinsey & Company in their Washington DC office, serving a range of healthcare and private equity clients. Michael earned a BA, cum laude, from Harvard College and an MBA from Harvard Business School, graduating with High Distinction as a Baker Scholar and a Harvey Fellow.

This will close in 0 seconds

Masood
Masood Tayebi, PhD

Director, Operating Partner

Dr. Masood Tayebi is the Founder of BioDuro. He currently serves as CEO of a nationwide real estate portfolio and is a Partner and Chief Executive Officer of the Bridgewest Group. Prior to BioDuro, Dr. Tayebi was Co-Founder and Chairman of Wireless Facilities, Inc. (NASDAQ: WFI), a global leader in telecommunications outsourcing.

Achievements
  • Co-Founder of Wireless Facilities, Inc.
  • Co-Founder of BioAtla, LLC
  • Recipient of the Ernst and Young 2000 Entrepreneur of the Year award in San Diego

This will close in 0 seconds

Kewen Jin
Kewen Jin, PhD

Director, Operating Partner

This will close in 0 seconds

Amit patel
Amit Patel

Director, Operating Partner

Amit Patel has twenty years of healthcare industry experience with publicly-traded, private equity-backed, and start-up companies in the capacity of executive, board member, advisor, and investor.  He is currently Executive Chairman of Azurity Pharmaceuticals (a NovaQuest Capital Management portfolio company) and a board member at BioDuro (Advent International portfolio company), Tergus Pharma (Great Point Partners portfolio company) and Calyptus Pharma.  Recently, Amit was SVP & President of Dosage Form Solutions at Capsugel, a KKR portfolio company (purchased from Pfizer in 2011 and sold to Lonza in 2017).


Prior to Capsugel, he worked at Dr. Reddy’s Laboratories, Inc. as EVP & Head of North America, and SVP & Head of Global Corporate Development & Strategic Planning. Earlier, Amit was VP of Corporate Development at CTIS, Inc., and Co-founder & CEO of MedOnTime, Inc. (acquired by CTIS).  He started his career as a strategy consultant with Marakon Associates. Amit holds an M.B.A. degree from Harvard Business School, a B.S. degree in Economics from the Wharton School of Business, University of Pennsylvania, and a B.A.S. degree in Systems Engineering from the Moore School of Engineering, University of Pennsylvania

This will close in 0 seconds

Haijun photo - 2.4.21 black and white
Haijun Dong

Chief Executive Officer

Dr. Haijun Dong currently serves as global CEO of BioDuro-Sundia. He previously was CEO for over 5 years at PharmaBlock Sciences Inc., a public company listed in the Shenzhen Stock Exchange (300725.SZ). The positions he held prior to PharmaBlock includes, among others, Senior Scientist at Boehringer Ingelheim Pharmaceuticals in Ridgefield, Connecticut; Senior Principal Scientist at Roche in Nutley, New Jersey; Head of DMPK and Drug Safety at Roche China R&D Company in Shanghai; Chief Operating Officer of Eli Lilly China R&D Center in Shanghai.

Dr. Dong received his PhD in organic chemistry from the University of Washington in Seattle, Washington, and MBA from China Europe International Business School in Shanghai. 

This will close in 0 seconds

Jeffery
Jeffery Blazevich

Chief Financial Officer

Jeff brings over 30 years of professional experience working for publicly traded, venture-backed, and private equity companies in the technology, health care and medical device industries. Prior to joining BioDuro, Jeff was the CFO for Zest Dental Solutions, a private-equity-owned manufacturer of a diverse portfolio of dental products.  From 2008 to 2013, he served as Senior Vice President and Corporate Controller for DJO Global, formerly a Blackstone-owned manufacturer of orthopedic products.

Jeff is a Certified Public Accountant and started his career at Ernst & Young LLP after receiving his bachelor’s degree in Accounting from the University of San Diego.

Achievements

 

  • Jeff held CFO positions at Vativ Technologies Inc. Staccato Communications, and Applied Micro Circuits Corporation, a publicly listed semiconductor company.

This will close in 0 seconds

TJ
TJ Deng, PhD

President, Discovery

Dr TJ Deng joined BioDuro in the initial stages of the company and helped BioDuro grow to an industry leading discovery services organization. He established and managed several scientific departments, including DMPK, before transitioning to a leader of the business and operations functions. Prior to joining BioDuro, Dr. Deng spent six years at PPD, in positions with increasing responsibilities from scientist to scientific manager.

Achievements

 

 

  • Developed the extractable/leachable capabilities at PPD
  • 18 years industry experience

This will close in 0 seconds

Kent
Kent M. Payne, PhD

President, Global CMC Solutions

Kent is distinguished as a business operator and leader in areas of sales, commercial manufacturing and product development. He has extensive executive experience in M&A as well as successfully running, start up, growth and turn around businesses. This includes both Fortune 500 and Private Equity environments. He combines strong business leadership, successful P&L track record, and technical background to strategically lead and grow enterprise value across Biotechnology and Pharmaceutical market segments. He has successfully led the geographic expansion of businesses into Europe, Asia, South America in addition to the United States.

He also currently serves as a board member for Goodwin Biotechnologies (a biological contract manufacturer), and board advisor for Vitruvias Therapeutics (a specialty generic pharmaceutical business)

Achievements

  • CEO Socorro Pharmaceuticals, a generic pharmaceutical company
  • President Americas, Qualicaps Inc.
  • Principal Consultant and Partner at CoreFactor LLC, providing executive strategic, licensing and operational advisory services to clients.
  • Vice President/General Manager Catalent Pharma Solutions, Inc. (a Blackstone Group company formed in 2007, formerly part of Cardinal Health)
  • Progressive leadership responsibility at: Novartis, Monsanto and G.D. Searle.
    Prior Board Positions:
  • Board Advisor, Corporate Strategy Office, Life Science Institute Inc. (a wholly-owned subsidiary of Mitsubishi Chemical Holdings.
  • Board member for Technophar, Inc.; Qualicaps, Inc.
  • Non-executive Chair and Board Member PDS Biotechnology (PDS

This will close in 0 seconds

Tommy
Tommy Broudy, PhD

Executive Vice President, Marketing

Tommy Broudy joined BioDuro as Executive Vice President, Translational Sciences in 2018 following the acquisition of Molecular Response, a patient-derived tumor modeling company he cofounded in 2010. Tommy is now leading BioDuro’s translational oncology group, with focus on in vivo and in vitro oncology testing services that help more efficiently translate novel anti-cancer medicines into the clinic. Tommy previously served as General Manager of Crown Bioscience San Diego, where he led the US preclinical operation. Prior to that, Tommy served as Director at AltheaDx, working closely with the Business Development and R&D teams to establish gene expression-based companion diagnostics for oncology therapeutics. He also spent six years at Affymetrix, where he managed the company’s pharmacogenomic and toxicogenomic solutions in support of pharmaceutical R&D.

Achievements

 

  • Earned his PhD at Rockefeller University in the Laboratory of Bacterial Pathogenesis and Immunology
  • Held postdoctoral appointments at Rockefeller and Stanford University studying host/microbial genomics

This will close in 0 seconds

Roy
Roy Xu

Chief Strategy Officer

Roy has over 25 years of healthcare industry experience.  He started his career as an orthopedic surgeon.  Roy joined Eli Lilly as a sales rep in 1997.  Since then he has had various roles in market research, business intelligence, BU head, strategy, regional general management, business development etc., both at Eli Lilly and Boehringer Ingelheim (BI).  Roy also spent more than two years in Germany where he was BI’s Director of Corporate Business and Enabling Strategy.

Roy obtained a bachelor’s degree in Clinical Medicine at Zhejiang Traditional Chinese Medicine University, and an MBA from Zhejiang University.

Achievements

 

  • 25 years of healthcare industry experience including Eli Lily and Boehringer Ingelheim. 
  • Former Director of Corporate Business & Enabling Strategy at oehringer Ingelheim in Germany.

This will close in 0 seconds

San Diego/圣地亚哥

BioDuro- San Diego Facility

Our San Diego site is our corporate headquarters. The facility is home to BioDuro’s drug product development technologies and has 9 GMP clean rooms. Development and manufacturing operations are conducted for projects up to Phase III clinical trials.

Size: 44,000 sq. ft.
Featured capabilites: Tableting, Coating, Hot Melt Extrusion, Spray Dried Dispersion

11011 Torreyana Rd.
San Diego
CA 92121
United States

This will close in 0 seconds

Beijing/北京

BioDuro Beijing
Operating since 2006, our Beijing site is home to BioDuro’s first wet chemistry operations. With 300 regular fume hoods and 18 scale-up chemistry hoods the Beijing facility houses most of BioDuro’s chemistry operations, while also hosting labs for biology and monoclonal antibody discovery.

Size: 100,000 sq. ft. 
Featured capabilities: Radioactivity Lab, Monoclonal Antibody Discovery, Medicinal Chemistry

No. 29 Life Science Park Road
Changping District Beijing,
102206
P.R. China

This will close in 0 seconds

Shanghai-Waigaoqiao/上海-外高桥

BioDuro- Shanghai Facility

Established in 2012, BioDuro’s Shanghai facility has been growing with its departments. The cutting edge facility contains labs for ADME, bioanalysis, in vitro assays and translational research. The site includes a 18,000 sq. ft vivarium and 20,000 sq. ft of office space.

Size: 92,000 sq. ft.
Featured capabilities: Scale-up Chemistry, Discovery Biology, DMPK, In Vivo Pharmacology

No. 233 North Fu Te Road
Waigaoqiao Free Trade Zone
Shanghai, 200131
P.R. China

This will close in 0 seconds

Cathy
Cathy Yen

Director, Operating Partner

Cathy joined the Board of Directors of BioDuro-Sundia in 2020, with the Advent-led acquisition of Sundia and creation of BioDuro-Sundia. Prior to that, she was Chairman of the Board at Sundia Meditech Group, where she was the key architect of Sundia’s strategic vision and growth. Under her leadership, Sundia solidified its position as one of the leading pre-clinical CROs in China.

Prior to Sundia, Cathy had a distinguished career as a seasoned venture capitalist, having led numerous investments in high-growth companies in Asia. Cathy served as a Partner of AsiaVest Partners, TCW/YFY Ltd., a global venture capital firm, for over a decade, Vice President at Global Financial Services, Vice President at Crimson Ventures/Chinatrust Bank and Senior Manager at Fortune Capital. She brings over 20 years of experience in corporate finance, accounting, strategic planning and private equity investments.

This will close in 0 seconds

Wuxi/无锡

Wuxi - BioDuro

Established in 2019, BioDuro-Sundia’s fully integrated discovery facility located at the heart of Jiangsu Wuxi Life Science & Technology Industrial Park with plans of growing staff to 1000+ scientists

Size: 300,000 sq. ft.
Featured capabilities:
Discovery Chemistry & Biologics, Biology, DMPK, Pharmacology, CMC Services

no.1699,Huishan avenue

Huishan Economic 

Development Zone,Wuxi

P.R. China

This will close in 0 seconds

Hebei/河北

Hebei - Sundia
Established in 2011, this pilot plant this handles mg to kg scale up

Size: 45,208 sq. ft.

Featured capabilities: SFFS Chemistry: mg to kg scale up
(150 hood)

238 Changjiang Road

Shijiazhuang,

Hebei province
P.R. China

This will close in 0 seconds

Taiwan/台湾

Taiwan - Sundia (1)
Our site in Taiwan supports Discovery Biology and Chemistry

Size: 3,352sq.ft.
Featured capabilities: Chemistry;Biology

7F, No. 107, Sec. 4

Ren Ai Road,

Da-an District,

Taipei, Taiwan

This will close in 0 seconds

Bengbu/蚌埠

Bengbu - Sundia
Scheduled to open in fall of 2020, this site is designed to handle API manufacturing and additional expertise in intermediates, GMP starting material upto IND enabling sttudies

Size: 43,056 sq. ft.
Featured capabilities: Intermediates, GMP starting materials, API manufacturing

Mohekou Industrial Park,

Huaishang District, Bengbu, 

Anhui province
P.R. China

This will close in 0 seconds

Shanghai-Changli/上海-长利园区

Shanghai-changli - Sundia-min (1)
Our Shanghai-Changli site supports FTE cheimistry and advanced Discovery Chemistry processes.

Size: 71,844 sq. ft.
Featured capabilities: Chiral Analytical Lab, Analytical and Purification Lab, NMR Lab, Synthetic Lab, Parallel Synthesis Lab, Flash Chromatography Lab..(380 hoods)

法拉第路251号8号楼;

Building 8, 251 Faladi Road,

Zhangjiang Hi-Tech Park,

Shanghai,China
P.R. China

This will close in 0 seconds

Shanghai-Halei/上海哈雷园区

Shanghai-halei - Sundia
Opened recently in 2018, BioDuro-Sundia’s Shanghai-Halei contains facilities that supports both Discovery and CMC parts of the drug development & manufacturing process. Facilities include amorphous dispersion techniques like SDD & Discovery Biology.

Size: 31,043 sq. ft.

Featured capabilities: Formulation : Preformulation, Wet Granulation, Compression, Tablet Coating, Fluid Bed Room, Spray Dryer, Hot Melt Extrusion, Dry Granulation Biology: Kinase selectivity, Cellular Assay, Compound Screen, Immune oncology service

哈雷路917弄1号;

Building 1, 917 Halei Road,

Zhangjiang Hi-Tech Park,

Shanghai,China

This will close in 0 seconds

Shanghai-Kelun/上海-克伦

Shanghai-kelun - Sundia-min (1)
Established in 2008, our Shangahi-Kelun site is desgined to handle advanced process and analytical chemistry including process GMP and non-GMP kilo lab

Size: 98,503 sq. ft.

Featured capabilities: general chemistry; Process: GMP & non-GMP kilo lab, Process analytical, Column Purification , Flow Chemistry. Analytical: 22 HPLC/UPLC. 8 Stability Chambers . DMPK: animal PK, Bioanlysis Metabolite ID, In Vitro Studies, In- Life studies

Building 8, 388 Jialilue Road,
Zhangjiang Hi-Tech Park,

Shanghai China, 201203

This will close in 0 seconds

Jim-Li
Jim Li PhD

President, Global CMC Solutions (China)

Dr. Li has led a distinguished career in the pharmaceutical industry, having spent over 18 years at various companies including Henkel, Wyeth, Pfizer and Wuxi Apptec in the area of process research and medicinal chemistry. During his career, he was involved in numerous drug discovery programs such as COPD, asthma, Rheumatoid/osteoarthritis, and diabetes. Dr. Li has co-authored more than 60 research articles and patents.

Dr. Li received his Ph.D in Organic Chemistry from University of Central Lancashire UK followed by a Postdoctoral fellow at the University of Chicago with Dr. Philip Eaton.

Achievements

  • Earned his PhD at University of Central Lancashire UK 
  • Held postdoctoral appointments at University of Chicago with Dr Philip Eaton
  • Dr. Jim Li was chief executive officer of Sundia. In this role, Dr. Li was responsible for the oversight of all business divisions across the organization as well as formulating and driving key strategies for diversifying and growing the company. Dr. Li also leads the company’s executive committee, helping to drive Sundia’s overall global strategy.

This will close in 0 seconds