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WHITE PAPER

FACILITY FOCUS: Next Generation Aseptic Manufacturing: An Eye-Opening Peek into the Future

By: Hite Baker

August 2017

DME White Paper Facility Focus: Next Generation Aseptic Manufacturing

Copyright© DME Alliance Inc. – All rights reserved – Do not reproduce without written permission Page 2

Introduction This Facility Focus Survey Report explores how to design sterile manufacturing facilities to make the best use of available modern technologies that will ensure products of the highest quality are consistently manufactured, over an extended life cycle, with robust regulatory compliance.

Advancements in technology and better aseptic manufacturing practices have dominated the facility-design landscape in recent years. These include:

Reliable Supply/ FDA metrics

Modernization/ Product Safety

• Aging Facilities • Barrier Technology & Automation • No Conventional Aseptic

Processing • Closed System Processing

Small Batch/ “Combi” Lines

RTU Components, Trays & Tubs

6 - Sigma

Single Use Disposable Revolution

Robotics

Operational Excellence

Risk Based Design

Challenges at FDA, EU, ROW

QbD/ QRM

PAT

Harmonization

These advancing trends can be complicated, but the key to making sense of the future of sterile manufacturing is to have a solid starting point, which is a commitment to Advanced Aseptic Processing to:

• Protect product for the sake of the patient, • Separate humans from critical zones using physical or dynamic air barriers, • Automate: reduce human error, reduce or eliminate interventions, • Isolators / RABS, • Closed systems, • Single-Use-Disposables.

If you own a legacy sterile manufacturing facility, then upgrade/modernize it using Advanced Aseptic Technology. If you are building a new sterile manufacturing facility, then incorporate Advanced Aseptic Processing.



In this Facility Focus survey report, you’ll learn about the trends, technologies, and tactics that leading sterile manufacturers are using to enhance manufacturing reliability, efficiency, and flexibility—as well as the benefits, challenges, and risks involved in embracing Advanced Aseptic Technology.

About the Facility Focus Survey DME invited engineers, manufacturers, and other life sciences professionals to participate in their second annual Facility Focus Aseptic Manufacturing survey to share their views on the latest trends and technologies affecting sterile manufacturing.

The survey consisted of various questions covering areas of cGMP manufacturing, modernization, biggest challenges, new technologies and which new technologies are most valuable, new equipment trends, future facilities, new filling machines and which features on the new fillers are most important and barriers to single use technology. Two niche topics were explored, including the use of mass spectrometry to detect lyo silicone oil leaks and the use of ebeam decontamination for ready-to-use tubs/ trays of primary containers.



Survey Participants Q1: What is your primary affiliation?

• Pharmaceutical 25% • Biologics/Biopharm 24% • Medical Device 12% • Both Pharma/Bio 9% • Consultant 7% • Other 7% • CMO/CDMO/CPO/CRO 6% • Vendor 3% • Generics 3% • Nutraceuticals/Vitamins 2% • Regulatory Authority 2% • Animal Health 1%

Figure 1 - Survey Participant Affiliation Overview



Q2: Which best describes your facility’s primary area of cGMP manufacturing?

• Biopharmaceuticals 22% • Sterile Drug Product 20% • No cGMP Manufacturing 11% • Packaging & Labeling 9% • Other Manufacturing 8% • Small Molecule Drugs 8% • Diagnostics 8% • Vaccines 6% • Non-Sterile Fill/Finish 4% • Blood Products 3% • HCT/Ps 2%

Figure 2 - Facility’s Primary Area of cGMP Manufacturing



cGMP Manufacturing

What are your plans to modernize your sterile facilities currently using legacy cleanrooms & equipment?

56% (23% + 21% + 12%) are not proactively planning to modernize their legacy facilities.

Note that 33% (21% + 12%) will modernize only if metrics indicate a problem or forced by FDA.

Figure 3 – Plans to Modernize Existing Sterile Facilities that Currently use Legacy Cleanrooms and Equipment



When do you anticipate that your company will upgrade your legacy sterile facility?

Nearly 2/3 (63%) say they plan to modernize. Only 16% have no plans to modernize.

Figure 4 – Timing of Plans to Modernize Existing Legacy Sterile Facilities



Manufacturing Technology

What is the biggest challenge associated with implementing “Advanced Aseptic Technology”?

Figure 5 – Biggest Challenges Associated with Implementing “Advanced Aseptic Technology”



Which advancements in aseptic technology would you find most valuable? (Rank 1-6, where 1 is first choice)

Figure 6 – Most Valuable Advancements in Aseptic Technology



New Equipment Trends

What new capabilities will you be implementing in your sterile facility within the next 5 years?

Figure 7 – New Capabilities You Plan to Implement in your Sterile Facility within the Next Five Years



Future Facilities

What is the most important aspect of facility design for future new sterile manufacturing facilities?

Figure 8 – Most Important Aspect of Facility Design for Future New Sterile Facilities



Mass Spectrometer of Silicone Oil Leaks The risks/ consequences of silicone-oil leaks from shelves or hoses inside a freeze dryer are sufficient to justify installing mass spectrometers to monitor and alarm each freeze dryer to preemptively detect silicone oil leaks?

Figure 9 – Are Mass Spectrometers Justified to Preemptively Detect Silicone Oil Leaks Inside Freeze Dryers – Agree or Disagree?



eBeam Decontamination of RTU Tubs and Trays

Is the high cost of eBeam decontamination of RTU tubs and trays justified?

Figure 10 – Is the High Cost of eBeam Decontamination of RTU Tubs and Trays Justified – Agree or Disagree?



Filling Machine Features How significant are these features for a new filling machine?

Figure 11 – What are the Significant Features for New Filling Machines?



Barriers to Single Use Technology How significant are these barriers to implementing SU Tech?

Figure 12 – What are the Barriers to Single Use Technology? Which are Significant Barriers?



Are Industry’s Legacy Sterile Manufacturing Facilities Evolving Out of Gap #1 Fast Enough?

This is a rhetorical question. There are an estimated 1000 to 2000 legacy Sterile facilities in the world that, without upgrading and modernization (or replacement), have an expanding gap between baseline GMPs (minimum legal requirements) and cGMPs (current good practices). Is industry upgrading and modernizing fast enough to evolve out of Gap #1?

Figure 13 – Are Legacy Sterile Facilities being Upgraded Fast Enough?



Is There More-or-Less Regulatory Guidance for Industry Needed for these Selected Topics?



Is There More-or-Less Regulatory Guidance for Industry Needed for these Selected Topics, continued



New Challenges Require a Different Mindset Modernizing your plant is not only a smart investment, it may very well be a mandatory one. A facility that may have been top-of-the-line just a couple decades ago might not even be compliant by today’s regulatory standards.

This requires a cGMP-savvy project team—both owner stakeholders and suppliers (e.g. architects, engineers, builders) —that understand the issues they face, and can generate solutions that are efficient and compliant.

Important Considerations for the Project Team The project team needs to:

• Understand the manufacturing process and how it integrates with the facility

• Have project managers with capital project experience renovating legacy processes and facilities

• Have engineers with subject matter expertise in designing GMP-classified space and critical utilities (particularly clean utilities such as CIP, clean steam, compendial water systems, etc.)

In many ways, legacy renovation projects are more difficult than “greenfield” designs of new facilities. They typically involve:

• Poorly-documented facilities and manufacturing processes

• Construction adjacent to ongoing GMP operations

• Limited construction and commissioning schedule windows

This requires a team that can anticipate problems and “turn over stones” where issues may arise that could derail the project at a later phase. It’s important to plan, but also to be flexible in case the design criteria shifts in response to new requirements or information discovered during the initial site survey and conceptual design process. Team members need to be agile to respond quickly to unanticipated issues that may crop up during the project.



About the Author

Hite Baker Principal Process Engineer, DME

An industry innovator in cGMP manufacturing, Hite’s focus is equipment and facility design for parenteral fill-finish operations. He has extensive experience in the regulated life sciences industry, including biopharmaceuticals, vaccine products, cleanroom facility design, and technology transfers. An expert in sterile manufacturing technology, Hite has led engineering design efforts for every stage of the process—from formulation to sterile filling to lyophilization —as well as for the isolation technology and cGMP facilities where drug products are manufactured.

Hite holds dual degrees in Mechanical and Electrical Engineering from Virginia Polytechnic Institute and State University,

He is an active member of ISPE and is a member of the SPP COP Steering Committee where he co-leads their barrier education track. He is a regular speaker on sterile manufacturing technology.

Contact Hite at [email protected], or 610.366.1744 x110.

mailto:[email protected]



About DME Facility Focus DME Facility Focus was designed to create a dialog within the industry regarding how we are going to meet the challenges presented by aging facilities, evolving regulatory requirements, new technology solutions and market changes in the pharmaceutical industry. It creates an

opportunity to take good concepts and turn them into practical facility designs. DME’s surveys were designed to touch on areas of both pain and opportunity—areas being transformed by technologies into the future facilities for cGMP manufacturing. They were also developed to help DME and other facility design professionals understand what manufacturers value most in the design of their facilities.

About DME Celebrating its 16th year in business, DME provides a wide array of engineering solutions for regulated life sciences industries. Our services include advanced technology facility design, MEP engineering, process engineering, operations improvement, and related consulting services. We are an excellent fit for projects requiring GMP manufacturing, cleanroom environments, or hygienic process technology. Our company leverages strong relationships with process architecture and construction management partners to deliver ‘engineering solutions for life’. Clients select DME because of our deep industry knowledge, professionalism, and team approach. For more information, visit www.DMEforLife.com or call 610-366-1744.

Advantages of Working with DME

The DME team has extensive experience in planning and executing renovations, upgrades, and expansions of legacy facilities. They reduce project risks by knowing how to ask the right questions early on, so unpleasant design compromises or change orders don’t come to light later on. When you’re looking at a manufacturing facility renovation or expansion, DME has the expertise to develop the optimum design approach.

DME’s experienced engineers will carefully analyze your operation, identifying the most effective means of refitting and repurposing your existing infrastructure.

DME will work with you to analyze your user requirements, equipment needs, and operational changes, and will collaborate with you to create a facility that not only meets today’s regulatory and safety parameters, but is also well positioned to accommodate future growth and changes.


www.DMEforLife.com

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Next Generation Aseptic Manufacturing: An Eye … · Next Generation Aseptic Manufacturing: An Eye-Opening Peek into the Future. ... Next Generation Aseptic Manufacturing : ... Mass