Continuous OSD Manufacturing – A Blog from the Perspective of the Patient Impact

Introduction:

Anyone doing a literature search will find that much has been written about and presented on regarding the significant technical processing and business case benefits of Continuous Manufacturing (CM) in the production of Oral Solid Dose Forms, namely Prescription Pharmaceutical Tablets. We’ve heard about the various direct compression, dry granulation and wet granulation CM platforms, the range of equipment design and configurations offered and the many facility size and construction cost reduction opportunities owners have seen. We’ve confirmed business case advantages, worked with QbD to achieve process robustness and have proved the platform capabilities to the FDA and other international regulatory agencies, who have, in turn, awarded the innovative owner firms with several recent drug approvals. 

The CM ball is clearly rolling and our industry is well positioned for even further advancement in this arena. Many new drug therapies are being developed on CM Platforms and it is anticipated that several more drug approvals will be given in the years ahead. 

“Continuous Manufacturing for OSD Pharma Drug Products  is a transformational processing platform that is here today - and is here to stay”

One area that has not been as widely publicized are the significant patient impacts and benefits CM has brought, via the life improving, life changing and life enhancing quality drug products being produced and supplied to market via the CM platform. In this blog, I would like to focus on the perspective of the patient and highlight three specific pharma firms who have recently won FDA approval and who’s CM produced products are truly making a life difference to many who are afflicted with horrible diseases.

CASE I: Vertex Pharmaceuticals (www.vrtx.com)

Vertex was the first pharmaceutical firm to secure a Continuous Manufacturing FDA product approval in July of 2015, with Orkambi. A 2nd product (Symdeko) was approved in early 2018. Both of their approved products are for the indication of Cystic Fibrosis (CF). CF is a rare genetic, life threating disorder that damages the lungs and digestive system. It affects the cells that produce mucus, causing the mucus to be excessively thick and sticky, reducing lung function. According to the Cystic Fibrosis Foundation Patient Registry, in the United States:

• More than 30,000 people in the US are living with cystic fibrosis (more than 70,000 worldwide).
• Approximately 1,000 new cases of CF are diagnosed each year.
• More than 75 percent of people with CF are diagnosed by age 2.
• More than half of the CF population is age 18 or older. 

Living with CF is difficult and often dictates a very restrictive lifestyle. Typical symptoms of CF include a chronic cough, weezing, difficulty breathing and germ growth in the lungs that people with healthy lung function tend not to have, increasing the opportunity for infection. Beyond the lungs CF also effects the digestive system and sweat glands.

Vertex’s Orkambi and Symdeko OSD Tablets work by getting more proteins to the cell surface and keeping them open to get a balance of salt and water in the lungs to improve function. These products are making a significant difference to those suffering with this in-curable disease.    

The tablets are produced via a fully integrated GEA Consigma 25 Continuous Processing Platform, producing approximately 25kg/hr of tablets. Powders are fed to the system via Intermediate Bulk Containers (IBC), process includes both dry roller compaction and wet granulation through to final coating, all in a continuous Process. The system includes additional componentry from K-Tron, Omega, Gerteis, Courtoy, Kramer and Sentronic.

Moving forward Vertex will focus on maximizing process and material characteristics data usage, automate the cleaning process, optimize COL quality and time and continue to refine the system for efficient operations.  

CASE II: Janssen Pharmaceuticals (www.janssen.com)

Janssen Pharmaceuticals was the second firm to secure a Continuous Manufacturing FDA product approval in April of 2016, with their product Prezista. This OSD product is a protease inhibitor antiviral that prevents human immunodeficiency virus (HIV) from multiplying in the body. Prezista is used to treat HIV, the virus that can cause acquired immunodeficiency syndrome (AIDS). HIV, is one of the world’s most serious health and development challenges. According to The Joint United Nations Programme HIV and AIDS (UNAIDS):

• There were approximately 36.7 million people worldwide living with HIV/AIDS at the end of 2016. Of these, 2.1 million were children (<15 years old).
• An estimated 1.8 million individuals worldwide became newly infected with HIV in 2016 – about 5,000 new infections per day. 
• Currently only 60% of people with HIV know their status.
• 1 million people died from AIDS-related illnesses in 2016, bringing the total number of people who have died from AIDS-related illnesses since the start of the epidemic to 35.0 million.
• Janssen’s Prezista OSD Tablets work to reduce the amount of HIV-1 in the patients blood. This is called viral load. Additionally the drugs works to increase the number of CD4+ (T) cells in the blood that help fight off other infections. This is a combination treatment this is making a difference in the lives of those who are suffering with this disease.    

Janssen has three global sites operating CM platforms and is making use of an integrated Direct Compression, at rates ranging from 25kg/hr to excess of 100kg/hr. Powders are fed to the system via vacuum conveyance to the feeders, on to blending, compression and coating, all in an uninterrupted, fully automated and PAT controlled continuous Process. . The system includes additional componentry from K-Tron, Glatt, Korsch, Gerteis, Courtoy, and others.

Moving forward, Janssen’s future perspective will focus on interchangeable unit operations, shared models, quicker change over, improved yields and RTR with easy retreiveable knowledge. 

CASE III: Eli Lilly Pharmaceuticals (www.lilly.com)

Eli Lilly is the most recent firm to secure a Continuous Manufacturing FDA product approval. In September of 2017, Verzenio received regulatory approval. This OSD product is for the treatment of Metastatic Breast Cancer, a cancer that has spread to other parts of the body. Breast cancer is the most common form of cancer in the United States and The National Cancer Institute at the National Institutes of Health estimates that over 250,000 women will be diagnosed with breast cancer in 2017 and over 40,000 will die of the disease.   

According to Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research "Verzenio provides a new targeted treatment option for certain patients with breast cancer who are not responding to treatment, and unlike other drugs in the class, it can be given as a stand-alone treatment to patients who were previously treated with endocrine therapy and chemotherapy,"

Lilly’s Verzenio is in a class of drugs known as CDK4 & 6 inhibitors. CDK4 & 6 are proteins that control how fast cells grow and divide. These proteins are found on both normal and cancer cells. They become overactive in MBC, causing cells to grow and divide uncontrollably. This leads to the spread of cancer. Verzenio interrupts these proteins and cells just as they are deciding to grow and divide. It slows down cancer cell growth and division, causing cancer cells to become inactive or even die. 

The Lilly System is a semi-integrated Direct Compression Continuous Processing Platform that includes highly accurate contained powder feed, blending and tablet compression. Powders are fed to the system via ILC Dover Chargebags (gravity transfer) to the feeders, on to blending and compression, all in an uninterrupted, fully automated and PAT controlled continuous Process. The system includes additional componentry from K-Tron, Korsch, Gericke, Bruker, Prozess and others.

A unique an innovative lift system supports the main process train allowing for ease of access, cleaning and change over. Eli Lilly won the 2017 ISPE Facility of the Year Award (FOYA) for applying this system in both their Indianapolis IN and Carolina Puerto Rico facilities.

Eli Lilly’s future perspective will focus on changeover improvements, automatic refill capability, containment improvements, encapsulation, RTF, Semi-Continuous coating and speeding treatments to patients. 

Summary:

In summary, OSD Continuous Manufacturing is not only having an impact on the way we design and configure our processing platforms and manufacturing facilities, but more importantly is having an impact on the lives of our patients.  As a Pharmaceutical Industry, we are making a difference and I hope this blog is one small example of just some of the human element progress being made. Thanks to all the dedicated professionals that are making this a reality.

Acknowledgements:

The author would like to acknowledge and thank the following firms for reference and other materials:

Vertex Pharmaceuticals

Janssen Pharmaceuticals

Eli Lilly

Food and Drug Administration (FDA)

Cystic Fibrosis Foundation

The Joint United Nations Programme HIV and AIDS (UNAIDS)

The National Cancer Institute

ISPE

An additional thanks to all of the other pharma owner firms, service providers, equipment and technology vendors, academia and others who are dedicated to improving the lives of our patients through there contributions to the pharmaceutical industry and continuous manufacturing.

About the author:

Dave DiProspero has 25+ years of pharmaceutical engineering experience in internationally regulated Oral Solid Dose Form manufacturing operations. He has worked as an owner's representative and as a direct employee for well-known equipment/technology suppliers and engineering firms. As an Associate/Director of Pharmaceutical Process Technology for CRB-Philadelphia, Dave is involved in front-end/back-end project consultation and planning, strategizing, design and engineering implementation/execution and is an experienced team communicator. He has a strong facility/process, design/engineering, containment, equipment, material handling and facility systems integration background. He is the current co-chair of the ISPE OSD Continuous Manufacturing Sub-Committee, a program committee member/session leader for the 2018 ISPE Continuous Manufacturing Conference and an industry advocate for Continuous Manufacturing.

Email: [email protected]