What’s on the minds of groups involved in drug-product manufacturing in 2015? They’re applying quality by design (QbD) principles and process analytical technology (PAT) to formulation and fill–finish. High- throughput and single-use technologies are helping them improve process economics as well as sterility and flexibility. Formulators are redrawing the lines between drug substance and drug product manufacturing, especially when it comes to preformulation analysis. Fill–finish groups are working out the details of new types of container– closures and delivery devices. They all share case studies to help one another solve similar problems. And they’re applying lessons learned so far to develop biosimilars and new product modalities.

Biologics manufacturing can be thought of as a continuum, but divided into discrete wavelengths (areas of expertise) along that spectrum: from production of the active molecule upstream to purification of it downstream to formulation and packaging of that drug substance into a drug product at the end. Analytical laboratory work supports all those efforts along the way through product characterization, process validation, and so on. Many people also think in terms of “drug- substance” and “drug-product” manufacturing, with the latter often performed at different facilities from the former.

This is the first year the BPI Conference offers a specific drug- product and fill–finish track. But it’s not the first time the magazine has considered these topics. From the beginning, we have sought out contributions from formulators and other drug-product specialists. See the “Archives” box at the end of this chapter for a few examples just going back to 2011. We have documented the adoption of QbD, the emergence of new products and technologies, and the conversion of a “black-box” craft into a more transparent, scientific, and technological process.

BPI’s marketing and digital content strategist, Leah Rosin, conducted the following interviews as the conference program came together this summer. Participants addressed combination products and cell therapies, lyophilization, and single-use technologies. Here, in Q&A format, is what they had to say.

Sujit BaSu (Shire)
Sujit Basu is vice president and head of drug and combination product development at Shire in Lexington, MA. He will be joining us for the “Drug Product Case Studies: Visual Inspections, Combination Products, and Viscosity Challenges” session on Thursday morning, 29 October 2015. Basu’s talk is titled “Combination Product Development: Drug Product Development and Fill–Finish Challenges and Strategies.”

Abstract: Combination products hold the promise of innovative solutions to deliver complex therapies. Many rare diseases include significant central nervous system (CNS) manifestations with marked negative effects on patient and caregiver quality of life, as well as high economic costs to families and payers. Over 50% of patients with lysosomal storage disorders (LSDs) also suffer from CNS disease. Most biological drugs are macromolecules that do not cross the blood–brain barrier (BBB). Direct intrathecal administration may be a novel way to deliver deficient enzymes to the CNS, bypassing the BBB. Shire is developing combination products for treating the three most prevalent LSDs that cause devastating CNS disease in children. They include specific and selective sulfatase enzymes delivered through an innovative intrathecal drug-delivery device (IDDD).

This presentation focuses on practical product-development strategies implemented to address Drug-Product Development challenges specific to drug–device combination- product development for rare diseases. This includes case studies on the design and use of preformulation, formulation, and device development approaches. The complexity of these products and accelerated development time lines demand that we understand early on the relationships among drug structure, function, manufacturing process, device design requirements, human factor engineering, and drug– device compatibility and that we continue learning after the products are licensed.

Can you describe the combination product(s) you’ll be talking about? At Shire, we are developing several combination products for diseases and specialty conditions. I would specifically like to mention our three pipeline programs for LSDs with enzyme replacement therapy and a novel DDD to overcome the BBB and achieve delivery to the CNS. With this approach, we are addressing diseases that are difficult to treat.

Can you elaborate on the biggest challenges in developing a formulation and delivery device in tandem? For a combination product to meet the target product profile (TPP), both the drug product and device must meet and contribute to the TPP and the overall benefit of the final product for patients. We want to emphasize that device development is not a small bolt-on to the overall drug-product development; they are of equal importance. In our experience, this comes together best when the QbD approach for drug- product development is integrated with the design control of the device. Both device and drug are appropriately developed, and we get the best value of the combination product for patients.

What about human-factor considerations? Human-factor engineering is an important aspect of combination-product development. We need to understand and define the users (and, in turn, their requirements). Broadly, with human- factor engineering and related formative and summative studies, our goal is to ensure that risk is reduced to an acceptable minimum. This area of combination-product development is still evolving, and we need to get the right balance of human-factor engineering and the development speed and cost of development. There’s a lot of good dialogue going on between the industry and the regulators on this topic.

What else do you think formulation scientists may find of interest about your talk? I think they would appreciate the tremendous interplay between drug product and medical device. We are characterizing those with many studies on materials compatibility, and extractables and leachables studies, for example. Formulation scientists also should appreciate that developing a product for intrathecal administration and CNS delivery is not the same as typical intravenous or subcutaneous administration.

Aside from speaking, why are you attending the BPI Conference? This is a great forum to get a pulse of all the innovative solutions toward some of the most pressing technological challenges that the industry is facing. Personally, I will be trying to identify some strategic partners and collaborators to work together on solving some of these technological challenges in front of us and developing safe and efficacious combination products.

>> Listen to the full interview

John Duguid (Vericel Corporation)
John Duguid is a principal scientist at Vericel Corporation in Cambridge, MA. He will be joining us for the “Real-Time Release” session on Thursday afternoon, 29 October 2015. Duguid’s talk is titled “Rapid Microbiological Methods for Real-Time Release of Autologous Cell Therapy Products.”

Abstract: Rapid detection of contaminants is essential for autologous cell therapy products with short shelf lives. Developing, validating, and implementing rapid microbiological methods can facilitate real-time release of these products. Application of a risk-based approach during development mitigates most issues before validation and facilitates successful implementation.

How does a risk-based approach during development mitigate issues of contamination for autologous cell therapy products? We’ve applied a risk-based approach in two areas: first to contamination control; second, to developing, validating, and implementing rapid microbiological methods.

Autologous cell therapy products have very short shelf lives, so we don’t have time to complete a conventional growth-based test before product release. For contamination control, we strategically choose in-process sampling points for sterility and mycoplasma testing to minimize the number of upstream aseptic manipulations needed between testing and product release. But for developing, validating, and implementing rapid methods, we used a failure mode and effects analysis (FMEA) to identify the most likely design and process failures before validation and implementation.

Can you elaborate on how and when rapid microbiological methods should be developed? Because these are patient-specific products with short shelf lives (measured in days or hours), we typically release product on the same day it is manufactured. That requires microbiological methods that take less than a day. We started method development early in product development to allow adequate time for validation. So we can include the rapid methods in regulatory marketing applications as alternatives to the official methods of lot release.

For autologous cell therapy products, how can contamination risk be minimized? There are four main sources of contamination risk: donor tissue, raw materials, cross- contamination, and personnel. Contamination from donor tissue depends on a surgeon’s skill and is minimized by a training program we have in place as well as antibiotics added to the transport medium. We control contamination from raw materials through rigorous incoming materials inspection and testing. Patient and lot segregation, environmental controls, and process validation minimize cross contamination. Training, qualification, and detailed standard operating procedures (SOPs) minimize contamination from personnel.

What tools or technologies are especially helpful? We can easily detect growth contamination from bacteria and fungi during cell culture because the media used to grow mammalian cells also readily support the growth of microorganisms. Nucleic-acid–based techniques with single-copy detection limits (e.g., polymerase chain reaction, PCR) are more helpful for readily detecting low- level contaminants or mycoplasma, for example, which often elude visual detection from turbidity or pH changes.

Aside from speaking, why are you attending the BPI Conference? I’m looking forward to the chance to interact with my peers and learn from key industry opinion leaders.

>> Listen to the full interview

Lisa Hardwick (Baxter Healthcare)
Lisa Hardwick is a research scientist at Baxter Healthcare in Bloomington, IN. She will be joining us for the “Lyophilization Strategies for Biologics” session on Wednesday afternoon, 28 October 2015. Her talk is titled “Biopharmaceutical Lyo Products: Scale-Up from Lab to Manufacturing.”

Abstract: The unique challenges of freeze-drying biologics will be discussed, with a focus on the following considerations in transferring a laboratory-developed product to manufacturing scale: formulations, cycle optimization using design-space principles, and equipment capabilities.

What challenges are unique to lyophilized product scale-up? You have all the challenges of scaling up a liquid fill, you still have to do that. But it’s just a prelude to the lyophilization process, which takes a lot of time and uses expensive equipment. Although freeze-dryers all operate on the same basic properties of heat and mass transfer, the functionality of each piece of equipment depends on its scale and design. There are many other variables between laboratory scale and large-scale production batches. Some things you have to consider include cleanliness of the container– closure system, vials and stoppers, and the air-quality classification of the room where the freeze dryer is located. You have to think about the design of the freeze-drying equipment and the amount of thermoradiation contributed by the number of vials in each lyophilization run. All those things and many more can make the same lyo cycle run differently in the laboratory than it runs on production equipment.

How can design-space principles can be used in lyophilization scale- up? We use design-space principles to determine acceptable conditions for a product during primary drying. We have a knowledge space — this is everything we know about our product (what temperature we want it to be during primary drying, for instance). We have process monitoring and control in our freeze-dryer. We know equations of heat and mass transfer that govern freeze-drying. Knowing all this, we test a product within the control space, the limits within which we know our equipment can control itself. No matter how much the equipment varies, the product will remain the correct temperature. Sometimes we can even widen that control space and make the temperature of the shelf go a little warmer or a little colder. But, we have to test and prove every one of those different variables in process conditions.

Generally, the control space is smaller than it needs to be. Really, if you use everything you know (your knowledge space) you can come up with a design space that is quite a bit wider. So when you have process deviations, it’s okay as long as you’ve established this design space. You can allow for some of those deviations.

Any freeze dryer (including small ones in development labs) can be used to measure two key things in setting up design space. First, you measure the heat-transfer coefficient of the vial you’ll be using, then you measure the lyo cake’s resistance to mass-transfer (water vapor that occurs during sublimation in primary drying). You can use these two measured variables in basic equations of heat and mass transfer to determine what combinations of shelf temperature and chamber pressure will keep the product sufficiently cold during primary drying. Instead of testing each specific combination to determine how it affects the product, any combination that falls within the calculated design space is considered acceptable. These conditions affect the product in essentially the same way in any freeze-dryer.

There is one caveat: You can’t use an infinite combination of variables. It depends on the equipment. Every freeze-dryer has a maximum sublimation rate that it can achieve and maintain. You have to take that into account when creating your design space. Equipment capability forms one boundary of it. Even if certain parameters might be acceptable for a product, they might not be acceptable for the equipment. Luckily, the maximum sublimation rate for a dryer doesn’t change. It’s not product-specific, so you can determine what that is with water. Once you establish that, it can be a part of the design space for every product.

Differences that will occur in scale-up do not necessarily lie in product temperature during primary drying. If you’re using design space, then you’ve calculated what that’s going to be. But you do need to know that during scale-up, the amount of time primary drying takes will vary. Design space will tell you what conditions to use, but it won’t necessarily tell you how much time it will take.

How is equipment a challenge in scale-up? There are some basic design differences: e.g., where the condenser is located. Is it at the bottom of the biochamber or in a separate box connected to that? If it is in a separate box (that passageway between chamber and condenser), then you need to think about the ratio of the shelf surface area to the size of the opening. If the condenser is inside the biochamber, then you need to take into account the baffles between it and the shelf because they will affect the flow of water vapor from products in the chamber to the condenser coils.

Another thing to think about is the rate at which the shelf temperature and chamber pressure can change. You have a little sports car in your lab and this big Land Cruiser in production. Sometimes you can’t get that big production dryer to “turn on a dime” like you can in the lab.

Different gauges can be used to measure and even control chamber pressure. It’s important to consider what each dryer uses and make a fair and equal comparison between the two. The type of temperature- measurement device used and the placement of that device can affect the knowledge of what is happening.

Is there anything else that you think a formulation scientist might be interested in from your talk? Formulation of a lyo product is important. Biologics formulations can be challenging. Sometimes the very ingredients you have to add to protect proteins from the damaging effects of freezing or drying can affect the lyo cycle itself. These ingredients tend to be amorphous compounds. They have low temperature requirements during primary drying, so you may have to use a combination of shelf temperature and chamber pressure that will make sublimation rates even slower because you’re trying to keep your product cold enough to make those amorphous compounds happy. And the colder you run primary drying, the longer it takes.

Sometimes proteins are sensitive to pH shifts, freeze concentrates, and ice-interface interactions. You have to think about all these things during the first steps of lyophilization (freezing). So sometimes you have to work a little harder to finesse that freezing step.

Aside from speaking, why are you attending the BPI Conference? A lot of my job focuses on the point at which development links to manufacturing. So I’m really looking forward to the new things they’re adding this year, the tracks that deal with drug product (fill–finish and formulation).

>> Listen to the full interview

Chris Smalley (Merck and Company)
Chris Smalley is director of engineering and global technical operations at Merck and Company near Philadelphia, PA. He will be joining us for the “Drug Product Case Studies: Filling Technologies” session on Thursday morning, 29 October 2015. Smalley’s talk is titled “Single-Use: Adding Flexibility to Fill–Finish.”

Abstract: Whether you have a product early in its life cycle and you’re trying to build a facility that will meet forecasted sales, or you have a mature product that is declining in sales but still crowding your facility schedule, single-use technology could offer a solution to make your facility more flexible in terms of batch size, speed of change- over, optimum runs, and so on. Do you have an aging facility that is beginning to raise concerns about patient risk? Perhaps the containment properties of single-use systems would be the right technological injection to give new life to that facility.

Can you elaborate on refreshing a facility with single-use systems? Several green-field facilities were designed to incorporate single-use systems. The Shire facility in Massachusetts is a good example. But for an existing facility, perhaps an aging facility with some HVAC issues or a water-for-injection (WFI) system that isn’t large enough to meet increasing demands, single-use systems can provide a solution that could be implemented quickly. The best experience I can point to, though, involves new products that have come out of phase 2 clinical studies with great prospects and also a great sense of urgency. Single-use systems provided the flexibility to scale up and meet those launch needs immediately.

What are the advantages to using single-use technology in fill–finish operations? Many facilities have been using single-use systems far upstream for things like media and buffer preparation. But in fill–finish, they can offer a great advantage by shortening change-over times, increasing capacity by shortening that period you spend down between operations. Well-designed systems, especially those using molded connectors, can significantly reduce the number of aseptic connections that need to be made. That increases confidence in your operations, and it also can reduce the incidence of leaks or connection failures, which again increases confidence in your fill– finish operations.

Are there any concerns? The leading concerns that most people share regarding single-use systems in fill and finish are extractables/ leachables and particulates. I believe that as an industry we are getting a better handle on the former, especially with publication of the Biophorum Operation Group’s (BPOG’s) standardized extractables protocol. But more work needs to be done to address particulates, especially for biological processes for which using final filters (sterilizing filters) might be impossible. Particulates can be reduced during manufacture of single-use systems, but during shipment, handling, set- up, and use, the flexing of a single- use system can generate new particulates. Those that could show up in our final dosage form do remain a concern.

How do you ensure that you’ll have the equipment you’ll need when you need it? The supply chain relies on partnership and a great deal of trust between suppliers and users. A record of deliveries and response to orders (including a history of customized assemblies, which subsequently may need to be gamma- irradiated) dictates the safety stock that users need to maintain. But standardized single-use systems would add the confidence that what’s needed would be there on time.

Aside from speaking, why are you attending the BPI Conference? There are a lot of conferences to choose from, and it’s important to value the time. This is the largest bioprocessing event, and there is always a topic of interest being presented. Uniquely, there are problem-solving moderated discussions. On Thursday morning, “Single-Use and Disposable Technologies in Bioprocess Development” and “Container– Closure Integrity Testing and Technology” are of great interest to me.

>> Listen to the full interview

These interviews have been edited from transcripts for space and style.

Formulation and Drug-Product Sessions

Tuesday, 27 October 2015 8:00–9:45 am New Paradigms in Drug Product Manufacturing 10:15–11:45 am Process Analytical Technologies and QbD Applied to Drug Product Manufacturing High-Throughput Analytical Methods for Quality Control 1:25–3:00 pm Integrating Drug Substance and Drug Product Manufacturing Biosimilar Product Quality, Characterization, and Comparability

Wednesday, 28 October 2015 10:30 am–12:00 pm Lyophilization Strategies for Biologics 1:40–3:15 pm New Strategies and Technologies in Aseptic Filling Processes 4:00–5:30 pm Particulates, Container Closure and Packaging Components

Thursday, 29 October 2015 8:00 am–12:00 pm Drug Product Case Studies: Visual Inspection, Combination Products and Viscosity Challenges Drug Product Case Studies: Filling Technologies 11:00 am–12:00 pm Beyond Antibodies: Production of New Modalities 2:00–5:00 pm Real-Time Release Formulation Strategies for Biotherapeutics

Drug-Product Articles from the BPI Online Archives

Patel J, et al. Stability Considerations for Biopharmaceuticals, Part 1: Overview of Protein and Peptide Degradation Pathways. January 2011.

Rios M. Combination Products for Biotherapeutics. February 2011.

Saggers J. Minimizing Variation of Volume Withdrawn from a Vial Drug Package. March 2011.

Jenness E, Gupta V. Implementing a Single-Use Solution for Fill– Finish Manufacturing Operations. May 2011.

Riedman D, Martin J. A Case Study in Qualification of Single-Use Filling Manifolds for Particles and Endotoxins. May 2011.

McLeod LD, Montgomery SA, Scott C. Fill and Finish for Biologics. June 2011.

Reynolds G, Paskiet D. Glass Delamination and Breakage. December 2011.

The Kavli Foundation, Scott C. Fight Cancer with Nanotechnology. May 2012.

Maggio E. Polysorbates, Immunogenicity, and the Totality of the Evidence. November 2012.

Evans C, Geiselhart E. Understanding the Patient Journey. December 2012.

Stauss B. Safety, Flexibility, and Efficiency. December 2012.

Cossins A, Hooker A. Preformulation Development of a Recombinant Targeted Secretion Inhibitor. February 2013.

Perkins M. Tunable Half-Life Technology. March 2013. Kling J. PEGylation of Biologics. March 2013.

Mire-Sluis A, et al. Drug Products for Biological Medicines, Parts 1 and 2. April and June 2013.

Hulse J, Cox C. In Vitro Functional Testing Methods for Monoclonal Antibody Biosimilars. June 2013.

Maggio E. Biosimilars, Oxidative Damage, and Unwanted Immunogenicity. June 2013.

Breit J, DuBose D. Spray-Dry Manufacture of Vaccine Formulations. October 2013.

Steele A, Arias J. Accounting for the Donnan Effect in Diafiltration Optimization for High-Concentration UFDF Applications. January 2014.

Kling J. Highly Concentrated Protein Formulations: Finding Solutions for the Next Generation of Parenteral Biologics. May 2014.

Zambaux J-P, Barry J. Development of a Single-Use Filling Needle. May 2014.

Mattuschka J, Santa-Maria V. A Critical Mission: Clinical Trial Material Storage and Distribution. September 2014.

Straka A. Sterilization Effects on Elastomer Characteristics and Functionality in Parenteral Delivery Systems. November 2014.

Puri M, et al. Evaluating Freeze–Thaw Processes in Biopharmaceutical Development: Small-Scale Study Designs. January 2015.

Castleman L. Simulating Seal Life with Finite-Element Analysis. February 2015.

Bird P, Hutchinson N. Automation of a Single-Use Final Bulk Filtration Step: Enhancing Operational Flexibility and Facilitating Compliant, Right–First-Time Manufacturing. March 2015.

Palm T, et al. The Importance of the Concentration-Temperature- Viscosity Relationship for the Development of Biologics. March 2015.

Rios M. Special Report on Product Stability Testing: Developing Methods for New Biologics and Emerging Markets. May 2015.

Shah D, Bleck G, Collins IJ. Compatibility Assessment of a Model Monoclonal Antibody Formulation in Glass and Blow–Fill–Seal Plastic Vials. October 2015.