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On the Cusp of ChangeP.2

Meeting New Biopharma Filling Challenges

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Vaccine Temperature Monitoring

in Pharma FacilitiesP.7

Five Questions to Ask Biopharma CMOs

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LIQUID DOSE TRENDS

THE CHANGING pharmaceutical landscape is a popu-lar discussion point as of late. Armed with a fresh, non-blockbuster-reliant business model and treatment options that are expanding from small molecules to a range of new, more targeted therapies, the industry is at what PwC calls, “a critical juncture.”

Parenteral drug delivery is the second largest segment of this transformative pharmaceutical market — eclipsed only by the more mature oral solid dosage forms — accounting for nearly 30 percent of total pharma market share. According to Freedonia Group research, the market for parenteral drug delivery products is projected to rise over 10 percent annually to $86.5 billion in 2019.

Parenteral drugs — which enter the body via injection or infusion, rather than through the gastrointestinal tract — are taking a strong position alongside the more established oral solid dose forms and are quickly coming into their own.

As biologic drug approvals rise, the parenteral drug pipeline has followed suit by shifting from small molecules to complex biologics. A significant percentage of new drugs in the product pipeline are biologics. Of the Novel Drug Approvals for 2015, 32 were small molecules and 12 were biologics. All 12 approved biologics are delivered parenterally, as well as seven of the 32 new small molecules. Including Astella’s Cresemba (approved in both parenteral and capsule form), the 2015 parenteral drug approval total is 20.

CURRENT CHALLENGESNo matter what the dosage form, pharmaceutical manu-facturers are up against the same challenges: pressures to increase speed and reduce costs, expand product pipe-lines and meet more stringent regulatory requirements.

According to Hal Baseman, CEO, Valsource LLC and Immediate past Chair of the PDA (Parenteral Drug Association), several specific challenges are at the

Parenteral drug manufacturers are sharpening capabilities and coming into their own

By Karen Langhauser, Chief Content Director

ON THE CUSP OF CHANGE

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2O16 Liquid Dose Trends www.pharmamanufacturing.com

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forefront of parenteral drug discussions, so much so that task forces and initiatives by trade organizations, such as PDA, have been formed to address these topics and help identify areas in which manufacturers can improve. Examples include:

Aging facilities: Aging facilities with ineffective process control systems may be a signifcant contributor to the drug shortage problem. Owners of aging facilities are often choosing between continuing to use old, perhaps outdated technologies previously validated, or modernizing the facility with new, more effective technology closer to the industry standard.

Offshore manufacturing: The need to reduce costs has increased the number of pharmaceuticals and APIs manufactured and sourced from abroad, especially from India and China. While more mature markets have spent decades defining quality culture, companies in emerging markets may lack the experience level necessary for effective contamination control, especially when it comes to the complexity of sterile injectables.

Harmonization of global requirements/regulations: While the FDA used to be what Baseman calls the “gold standard” for regulatory guidance, advancements made in Europe and Asia have created multiple levels of regulatory expectations. Differing requirements often create redundant efforts and drug approval challenges.

“Oftentimes it does not appear that regulatory expectations from different countries are aligned. But this is often a misconception stemming from differing terminology and nuances,” explains Baseman. “But on a positive note, there is an increase in awareness and discussion between regulators, and they are working to better harmonize expectations.”

Quality management: The number of industry drug shortages that have impacted parenteral medications is significant. Many of these drug shortages, according to Martin VanTrieste, senior vice president, Quality at Amgen Inc., could be avoided by developing a robust

quality system, designing in product quality and establishing a culture of quality.

“I believe that there are three essential elements for product quality in parenteral medications. First, a modern quality system that is robust, simple and sustainable that provides knowledge to individuals and the organization. Second, strong support from R&D to develop and characterize robust raw materials, manufacturing processes and products using a Quality by Design approach. Third, a culture of quality that instills flawless execution and continuous improvement at all levels of the organization. By having developed these three elements, an organization can achieve quality beyond compliance,” says VanTrieste.

PICKING UP THE PACEWhile the injectable drug sector faces some of the same practical difficulties in adopting change that inhibit conventional pharma, change is on the horizon. Ac-cording to Baseman, “The industry has faced challenges bringing new technologies into practice. However, those in the industry are starting to realize how the use of new technology can truly reduce risk.” There are several areas in particular where parenterals are seeing improvement:

Isolators/barrier systems: The need for process improvement has led to the introduction of encouraging innovations and ideas, including the use of advanced aseptic filling/packaging systems such as barrier systems and isolators. These technologies are designed to reduce the impact of personnel and the environment on product quality.

“More and more the industry is adopting these technologies to reduce risk. We are seeing better designs that lead to better assurance of sterility and productivity,” says Baseman.

Real-time detection: For years there has been a gradual increase in the use of rapid microbiological methods within the injectable drug industry, but still

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there has not been the mass migration to rapid micro. As regulators continue to push for real-time quality assurance, the industry is slowly modernizing its means of environmental monitoring and in-process product testing.

“Most companies are still using traditional methods for monitoring the environment for microbial growth and these can take days to produce results,” notes Baseman.

But as the industry builds a business case, establishing a tangible ROI for rapid microbiology, forward-thinking companies are opting for faster results, with increased accuracy and consistency.

Advanced analytics: McKinsey & Co. explains advanced analytics as the application of elaborate statistics and mathematical tools to business data in order to assess and improve business practices. While success in pharma has historically depended heavily on research and product innovation, manufacturers are starting to realize that in order to achieve true operational excellence, they must further develop capabilities in advanced analytics.

“With the advancement in computing power, the use of advanced analytics has enabled continuous improvement to happen at a much faster rate and higher quality levels,” says VanTrieste.

Amgen has used advanced analytics to work with raw materials suppliers to identify, track and control variability, which has reduced the variability of Amgen’s manufacturing process. Amgen works with its suppliers to collect the supplier’s raw material manufacturing process and performance data. Then Amgen combines the supplier’s raw material data with Amgen’s manufacturing and performance data. Using multivariate statistical process control, it can turn years’ worth of data into knowledge for both Amgen and the supplier.

This knowledge can then be used to prevent batches from failing specifications and subsequently being rejected, to improve Amgen’s manufacturing process capabilities and even to improve yields.

PACKAGING CONSIDERATIONS Recent trends toward complex proteins — mainly offered in liquid form and administered parenterally — has increased the demand for flexible, safe and economical production possibilities.

Jeffrey Reid, Global Market Manager for WHEATON Industries, recently spoke at Interphex 2016 about key considerations for packaging parenteral products. In his presentation, Reid outlined the essential processes that a primary packaging component must undergo when utilized for parenterals.

To review, the process starts off with the pre-sterilization process known as particulate cleaning. The process consists of four major steps: 1. Sterile air blowing; 2. Three USP purified water rinses; 3. One final rinse with water for injection; and 4. Final sterile air blowing (test limits are outlined in USP 788).

This is followed by depyrogenation, meant to reduce the amount of bacterial endotoxins that can be found in a packaging component (test methods outlined in USP 85). Lastly is a sterilization process. There are three main methods for sterilization including high temperature and pressure sterilization, chemical sterilization or radiation sterilization (test methods outlined in USP 71) and, according the Reid, “the method of choice is strictly dependent on the chemical characteristics that make up the packaging component.”

Packaging components need to meet or exceed these three standards in order to be utilized for injectables. Smart suppliers such as WHEATON and Bosch (see: Meeting New Biopharma Filling Challenges in this issue) are stepping in and providing assistance to manufacturers in the form of pre-sterilized containers. Since the preparatory steps for pre-sterilized containers have already been carried out by the supplier, the drugmaker then does not have to purchase or operate machines for sterilization and depyrogenation.

PRIVILEGE & RESPONSIBILITIES“Producing medications is a complex and difficult endeavor, and it is critical to get it right for patients. Serv-ing patients is a privilege and this privilege comes with significant responsibilities,” emphasizes VanTrieste.

Delivering quality medications in a robust and reliable supply chain is a huge responsibility. The standards for drugs directly injected into patients must be nothing short of uncompromising.

As parenteral manufacturers gain proficiency, they are utilizing new technologies and practices to better assess quality. “Manufacturers are using risk and science to make better informed decisions, and this is quite encouraging for the future,” concludes Baseman.

“MOST COMPANIES ARE STILL USING TRADITIONAL METHODS FOR MONITORING THE ENVIRONMENT FOR MICROBIAL GROWTH AND THESE CAN TAKE DAYS TO PRODUCE RESULTS.”

— HAL BASEMAN, CEO, VALSOURCE LLC

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PHARMACEUTICAL COMPANIES and equipment manufacturers all over the world are facing new chal-lenges due to the continuing boom in biopharmaceuti-cals. These individualized and costly medications require development and production processes to be as flexible, safe and efficient as possible. Leading machine manufac-turers have been working full speed on new systems — and are now presenting the first groundbreaking results. By integrating several previously separate processing steps, the latest filling and closing machines can be used for multiple types of pre-sterilized primary packaging.

The worldwide market for biopharmaceuticals is experiencing a continuously strong demand and is predicted to grow to more than $167 billion in 2015.1 Some 80 percent of these worldwide sales are generated by leading markets such as the United States, Germany, Japan, France and Italy. However, the so-called “pharmerging markets” such as China and India are also expected to augment their share in biopharmaceuticals by more than 8 percent by 2015. Particularly in China, an increase in widespread diseases along with an aging population is driving the development of new biopharmaceutical compounds. According to the World Health Organization (WHO), around 8 percent of cancer patients (one million people) lived in India in 2012, leading to the production of increasingly complex formulations.2

CHANGING DEMANDS FOR MANUFACTURERSThis trend towards ever more complex proteins is present-ing pharmaceutical manufacturers with new challenges. On the one hand, the biotechnology market segment is characterized by highly individualized products that are adapted to patients’ personal needs and the genetic mark-ers of pathogens. On the other hand, such medication, which is mainly offered in liquid form and administered parenterally, is also expensive to manufacture. Unlike manufacturers of blockbuster medication, biopharmaceu-tical companies, laboratories and research facilities pro-duce smaller batches in larger time intervals. Nonetheless — or precisely because of this — they strongly depend on flexible, safe and economical production possibilities.

Here, manufacturers of pre-sterilized primary glass packaging make an important contribution. While pre-sterilized syringes have been in the market for many years, some of these manufacturers have now added other containers to their portfolio. With the support of leading equipment manufacturers, they started the production and development of pre-sterilized, ready-to-fill vials and cartridges. The pre-sterilized glass containers are generally delivered to the customer in a tub sealed with Tyvek, with each container individually inserted into a so-called plastic nest. The sealed tubs, in turn, are protected by a bag made of plastic and Tyvek. Since the preparatory steps for these pre-sterilized containers have

How equipment manufacturers are meeting the needs of biopharmaceutical companies with new concepts

By Klaus Ullherr, product manager, Bosch Packaging Technology

Meeting New Biopharma

Filling Challenges

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already been carried out by the supplier, the purchase and operation of upstream machines for loading and washing, or for sterilization and depyrogenation is no longer necessary.

PACKAGING AND FILLING FLEXIBILITYHowever, even the most advanced primary packaging is only profitable when it is processed on equally advanced equipment. Filling small volumes of biopharmaceutical drugs into pre-sterilized glass containers requires plat-forms that process the containers with the utmost flex-ibility. At the same time, these platforms must satisfy the need for high product yields and low space requirements, as well as for maximum product and operator safety.

The more types of packaging can be filled and closed with a single machine, the greater the space savings for the user. By integrating both filling and capping processes into one single machine, the need for a separate capping machine is omitted. Thus, pharmaceutical developers and manufacturers can conduct the entire processes in a small space. Another important requirement for the latest filling and closing machines is their compatibility with different filling systems. This not only allows pharmaceutical companies to adjust their filling operations according to particular packaging and medication types. The ability to use filling technologies with single-use components also offers a cost-effective alternative to expensive cleaning operations for product contact parts.

COMBINING MAXIMUM PRODUCT YIELD/SAFETYThe high development costs of biopharmaceutical drugs call for maximum efficiency of filling operations. Utiliz-ing quickly exchangeable format parts for the different packaging types is just as important as reducing prod-uct loss to a minimum. For instance, the latest filling technologies achieve almost 100 percent product yields, while a statistical in-process control (IPC) ensures that glass containers leave the filling machine with exactly the required amount of liquid.

The individual ingredients of biopharmaceuticals are just as characteristic as the stringent safety conditions that are required for their development and processing. The focus is on protecting medications from microbial contamination and ensuring the machine operator’s safety. To avoid human interference with the substances, filling and closing machines should feature a high degree of automation and be compatible with different barrier systems, such as Restricted Access Barrier Systems (RABS) and isolators. The pre-sterilized containers can be fed into the filling module either manually or semi-automatically. If automatic tub and bag openers are incorporated upstream, the result is a complete and

fully automated filling and closing line for pre-sterilized containers.

A GROUNDBREAKING ALTERNATIVENew, pre-sterilized containers offer biopharmaceutical manufacturers a greater choice of primary packaging options. This new diversity has also changed processing requirements. Technological advancement is far from be-ing completed. However, by combining proven machine platforms, different filling technologies and multiple packaging options, equipment manufacturers have paved the way for more flexible, efficient and safe processes. As a result, new filling and closing machines are already establishing themselves as groundbreaking alternatives for biopharmaceutical filling operations.

REFERENCES 1 IMARC Research Inc.: Global Biopharmaceutical Market Report (2012-2015). 2 Sandhu, Gupreet: Cancer Comes to the Developing World (Contract Pharma July/August 2014).

ABOUT THE AUTHORKlaus Ullherr has a degree in electrical engineering. After working in the electrical industry as project manager for several years, he joined Bosch Packaging Technology’s Pharma Liquid product division in 2000. Since 2002 he has been product manager for syringes and filling systems with global product responsibility. Ullherr is a member of the “PDA Interest Group pre-filled syringes” and works as an expert in the DIN/ISO group for primary packaging. He is also a well-known speaker at conferences, specializing in solutions for fill/finish equip-ment for pre-filled syringes, as well as single-use filling systems.

FXS Combi is a newly developed system for the efficient processing of

pre-sterilized packaging.

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VaccineTemperature Monitoring in

Pharma FacilitiesHow to choose the right continual monitoring

system for your vaccine monitoring application

By Stew Thompson, CAS DataLoggers

IMPROPER TEMPERATURE control is a leading cause of lost vaccine supplies. When vaccines aren’t main-tained at the proper temperature (typically 2-8 degrees Celsius/35-46 degrees Fahrenheit), they quickly lose potency. The CDC’s 2014 Vaccine Storage and Handling Toolkit, which provides vaccine storage and handling best practices, recommends using a temperature monitor-ing system for every medical storage unit to best avoid losing valuable vaccine supplies.

Continual monitoring systems provide an automated solution for temperature monitoring and alarming needs for pharmacy manufacturing facilities. These systems feature internal temperature sensors (or connect with external sensors) to record the ambient temperature of the manufacturing environment and can also log temperature data of storage unit interiors where vaccines are kept. These systems store data in a variety of ways with a view to satisfying regulatory requirements regarding vaccine safety.

A continual monitoring system can handle temperature monitoring, alarming and data storage — all with a view to protecting products and proving best practices. Data can be stored to internal memory, flash drive or even uploaded to a cloud storage web service. For example, a wireless system can remotely monitor any healthcare environment using medical storage units.

Many businesses and facilities are still new to this technology and are initially unsure of which of the many systems and manufacturers on the market to choose for their application. If you’re considering a monitoring system to help keep you in compliance, your search can be made easier by considering the following short list of questions:

WHAT SENSOR TYPE DO YOU WANT TO USE?Temperature data loggers are a cost-effective way to mon-itor temperature in vaccine storage units or the ambient temperature in storage areas. Environmental monitor-ing is also a useful way to ensure you get an alarm when HVAC systems fail.

Most temperature data loggers have inputs for specific sensor types. If you already know the temperature sensor type you plan to use, this will help narrow down your search. Many systems use the different types of sensors including RTDs, thermistors or thermocouples (by type). Specific systems such as these are typically lower cost than those which take data from several sensor types.

If you don’t know which sensor types you’d like to use, there are many universal systems flexible enough to log data from many different sensor types.

You can also use a glycol buffer vial to stabilize your temperature readings. Many temperature probes are small enough to fit inside medical fridges and freezers, so

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they’re easy to place for reliable readings. When selecting a sample rate, taking a reading every 15-30 minutes is fine. More than that will fill up the logger’s memory too fast.

HOW DO YOU WANT TO STORE/RETRIEVE DATA? CDC regulations mandate that those storing vaccines need to not only log, but also store the temperature his-tory electronically. Many kinds of data loggers can store vaccine temperature data, ranging from a single-channel USB temperature data logger to multi-channel tempera-ture monitoring systems with sophisticated alarming and offsite, secure cloud-based data storage.

Cloud storage is convenient as it enables users to download measurement data for offline analysis, and view it in reports, charts and graphs. Administrators can modify the system configuration online from any Internet-enabled location. Data online can easily be downloaded as a CSV file and loaded into most database applications.

Cloud storage services typically charge on a monthly or yearly basis, although a few manufacturers offer a limited amount of free space.

WIRED OR WIRELESS?Given your building’s particular network or lack thereof, you may want either a wired or a wireless system to give you access to your data. Ethernet and WiFi are two popu-lar choices, respectively. Your facility’s physical layout and resultant wireless range may be a factor. Consider where the datalogger and/or wireless gateway would need to be installed. Many models of datalogger can operate on either battery or AC power.

The systems come in both WiFi and LAN-wired versions allowing you to continually monitor temperature in a refrigerator or freezer and also providing customized alarming and data storage.

Wireless dataloggers can take the form of standalone pods or wireless repeaters transmitting data to a nearby wireless gateway which sends it out to the Web. When specifying your system, be sure that its indoor wireless range is wide enough to cover the area under

monitoring. Some pods can act as repeaters to boost the wireless signal.

WHAT LEVEL OF ALARM CAPABILITY IS NEEDED?When considering a system to monitor vaccine supplies, automated alarming is the most important feature to weigh. Nowadays there’s no excuse for missing an alarm when you can receive alarms and view data online from your mobile device.

First, decide what you need — local or remote alarm capability? If you need visual alarms, diagnostic LEDs show the room’s current environmental status. Some monitoring systems are audible/visual only, some can even go out to emails or even place phone calls to designated personnel.

A few alarm systems automatically send email, SMS text message, pager or phone sequentially dialed voice messages. Many can also send alarm notifications in case of power or Internet outages, which is a godsend when your medical storage units fail at 3 a.m.! In case of outages, make sure that the logger has a data buffer so it’ll keep recording if your power or Internet goes out, or at least an alarm to indicate this.

Continual monitoring systems are an ideal way to monitor medical storage units and help protect your vaccine supplies, meet regulatory requirements and ensure patient safety. Whether you want to go wireless or wired, a single system will record temperature readings, transmit alarms, and store and download data. By reviewing your wish list of features, you’ll arrive at the ideal system configuration for your specific vaccine monitoring application.

Temperature data loggers

record vaccine temperature

and also send alarms to email or

auto-transmit all data to a cloud server.

CDC REGULATIONS MANDATE THAT THOSE STORING VACCINES NEED TO NOT ONLY LOG, BUT ALSO STORE THE TEMPERATURE HISTORY ELECTRONICALLY.

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BIOPHARMACEUTICAL MANUFACTURING involves large-molecule drug substances that are biologi-cally produced using recombinant technologies such as microbial fermentation or mammalian cell culture. It is significantly more complex than the manufacturing processes for traditional small molecule drugs (SMD), which is often a matter of scaling-up a tightly controlled chemical recipe.

As a producer of biologics, a biopharmaceutical company is entrusted to make safe medicines for the public. Quite often this responsibility is delegated to an outside contracted organization. There are substantially more contract manufacturing organizations that service the SMD industry; with less choice and a higher complexity, identifying a biologic CMO can be difficult.

Large molecule CMOs expect questions that put the spotlight on an expertise that has been won through

deep experience, and which can be more difficult to identify. Any well established CMO expects the typical generic questions about the size of their staff, their project management style and quality record, but the complexity of biologics makes it imperative to consider some “tough” questions that need asking when seeking a more specialized large molecule CMO.

ASK THESE QUESTIONS

1 HOW WILL THE CMC SECTION OF THE IND BE

HANDLED?

Get right into the nitty-gritty details. When it comes to biologics, the Chemistry, Manufacturing and Controls (CMC) requirement is significantly more complex for bio-

1 2 3 4 5

FIVE QUESTIONS TO ASK Biopharma CMOs

Large molecule CMOs expect questions that put the spotlight on an expertise that has been won through deep experience, and which can be more difficult to identify

by Angelo P. Consalvo, Enteris Bio

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logics. All of the manufacturing activity is going to boil down to a comprehensive CMC section in the biopharma-ceutical company’s investigational new drug application (IND). That’s the ultimate goal, and for both commercial therapeutic products and clinical material, a CMC section grows, as drug development progresses, and will have to be filed as part of the regulatory requirement.

The CMC houses all the manufacturing results and much more — control and release of raw materials and cell banks, method of manufacture and process controls, container closure system, and quality system details — essentially all the information that has been collected on behalf of the client biopharmaceutical company, or in this case, by the CMO. Still, IND responsibility always lies with the client biopharmaceutical company.

As a biologics manufacturer, it is vitally important that the CMO you engage is going to understand what the CMC requirements are, and most importantly, be one step ahead in knowing what information is necessary to gather for that filing. The best CMO is one who can help you amass all the information and prepare and write those regulatory and compliance items for you. Look for a CMO with the personality of an experienced guide, not a follower.

2 SCALE-UP IS ALMOST COMPLETE.

WHAT HAPPENS NEXT?

More often than not, a client comes to a CMO with a process they have been scaling for months or years and, often, that may be too late. Decisions that could adversely impact licensing and regulatory approvals may have already been made. The best CMOs like to see the process scale-up early, so they can help clients avoid the errors that have caused others to stumble. Early on there is still time to advise and to suggest changes.

A willingness to ask tough questions about the process of a client’s scale-up is important. While such questions at an early stage of the relationship may seem intrusive, it suggests just the opposite — a biologics CMO who understands your process deeply enough to ask the right questions. Look for the CMO who has walked EMA and FDA through their facilities as a matter of course. Ask how many times those regulatory agencies have visited

and ask for the results. This is linked to choosing a CMO that has strong CMC and process development expertise, one that can provide technical and written support for regulatory filings.

3 WHAT PROCESS IS USED TO MONITOR

OUTSOURCED ACTIVITIES AND MAINTAIN

RELATIONSHIPS WITH EXTERNAL SUPPLIERS

AND LABS?

Great biologics CMOs like this question, because it separates the good from the great. How does a prospective CMO partner monitor outsourced activity and what kind of relationships do they have with external suppliers and labs? A one-way relationship will not work. Ask to see documents that reveal a strong two-way dialogue with outsourcing laboratories and other research organizations.

One example: Raw material release seems simple. The CMO buys the raw materials, but the testing for USP or EP compliance is outsourced. Some CMOs do this in-house, but these are few, since these services are expensive and time consuming. It involves more than simple procurement. All those materials have to be released, sent back out to an independent lab for ID testing, and (if USP or EP) must meet the specifications for that reagent, for example. All of this interaction requires the CMO to have forged strong relationships with these testing labs.

A great CMO will have a team or even a single individual who has more than a cameo relationship with these laboratories, and has become intimate with every step of the process. They can demonstrate their true “ownership” of these external relationships and show them as an integral part of the CMO quality system. As a follow-up question, ask a potential CMO, “How are outsourced activities integrated into the internal quality system?

4 QUESTION THE

“CULTURE OF DEVELOPMENT.”

Even if you are just interested in commercial manufacturing, ask about the “culture of development” when you interview a target CMO. Occasionally, as mentioned previously, a biotech company comes to a CMO with an unfinished or poorly designed process. It may be that since the client requires just a small amount of clinical material, they have developed their process quickly and, thus, it may not be completely reliable. In this common scenario, having an eye “back” toward development when evaluating the manufacturing process can be useful for identifying simple roadblocks

THE COMPLEXITY OF BIOLOGICS MAKES IT IMPERATIVE TO CONSIDER “TOUGH” QUESTIONS WHEN SEEKING A CMO.

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and solutions. The new term is CDMO (Contract Development Manufacturing Organization). A CMO partner does not need to show the bandwidth (and expense) of a full development laboratory. This subtle line of questioning is really asking about intellectual services — and process development experience. A “culture of development” mentality in a CMO manufacturing organization will view a process as a science problem first, and then as manufacturing process.

Specialized knowledge around how to run the unit operations and properly scale them, how to accurately evaluate performance, plus expertise in designing in-process controls to demonstrate that each step is performing properly, are all reasons why biotech customers, in particular, need to be very choosy about where they outsource their manufacturing. A CMO should have a team of people that has the expertise in specific biologics manufacturing processes that align with their customer base, and they should be able to support it with a strong development background.

5 WHAT IS THE DIFFERENCE BETWEEN PEPTIDE

CHEMISTS AND PROTEIN CHEMISTS?

This question is somewhat facetious, but will stop small molecule specialists in their tracks. Even inside the biologics world, there are significant differences in production of peptides versus large protein therapeutics. Someone who understands the nuances of the large molecule biologics world will answer this question and show that they are a CMO who has lived the process challenges, not just learned them for the initial meeting. The subtle differences between the biologics production of peptide versus protein will give rise to issues that a CMO team that is “learning on the job” has not faced before. (And this question will produce a knowing smile on the face of the large molecule teams — an excellent sign).

Is the CMO asking YOU the right questions? The flow of questions should be a two-way street.

Early on in the selection process, a biopharmaceutical scouting team should take careful note of the questions asked of them by the CMO. Considering the complexity of biologics manufacturing, there can be facets of the manufacturing process that some CMOs simply have not mastered. The type of probing questions posed by the CMO suggests how well they grasp the scope of the manufacturing process. This is a strong indicator that the CMO fully appreciates a client’s requirements and expectations.

To establish a successful partnership with a client, the CMO should thoroughly evaluate the request for proposal (RFP) and meet with the client to clarify any outstanding concerns. There should be an open dialogue with specific

questions around process clarification. Upfront diligence in defining the scope, deliverables and requirements of a program are an indicator that the CMO knows exactly what is being asked of them and they are certain they can deliver. So expect probing, confident questions as an excellent sign. Then, turn it around: Ask how the manufacturing, process, laboratory staff got “into biologics.” The discipline is still less than 50 years old, so finding 30+ year experienced veterans in large molecule processing is not always a given.

From the get-go, is the CMO making suggestions? Are they forthcoming with complex manufacturing issues and strategies to mitigate problems? Look for a CMO that will impress with their knowledge by being engrossed in the process from the very beginning.

CONCLUDING THOUGHTSA CMO that specializes in a particular biologics process as a large percentage of their business will have the cor-rect equipment and unit processes, and investments will continue to be made in equipment that suits the niche they have chosen. This translates to advantages from a re-source allocation standpoint, and advantage to the client.

Even within biologics, there is a huge difference in the equipment needed to make smaller proteins versus large proteins. As a biotech that is looking to outsource manufacturing of therapeutic products, ask questions to ensure the chosen CMO is committed to the process required. This sort of specialized process understanding can mean the difference between success and failure.

Although a large molecule biologics CMO may be chosen to handle manufacturing, the name on the IND is not the name of the CMO. It goes without saying that when an outsourcing partner CMO ships a biologic, above all else, it must be 100 percent compliant. With the complexities inherent in these processes, comes a different approach to identifying and interviewing CMO candidates. A great biologics CMO will be there every step of the way and not only recognize, but also anticipate the issues. Ask these tough questions. The best and most experienced large molecule CMOs can handle it.

ABOUT THE AUTHORAngelo P. Consalvo is a director of manufacturing at Enteris Bio-Pharma. With over 30 years experience, Angelo has been responsible for development of viable manufacturing processes for recombinant peptides and proteins originating from mammalian and microbial expression systems. He served as director of recombinant process development at Unigene Laboratories from 2009 – 2013. In 2013 he joined Enteris BioPharma, where he is heading up the recently launched contract manufacturing business for products produced exclusively in microbial expression systems. Angelo can be reached at [email protected].

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New compounds, delivery methods, Safety and Secu-rity are the current trends driving liquid dose drug manufacturing.

Liquid dose pharmaceuticals are most often formulated as solutions, suspensions or emulsions.1 Solutions are a homogeneous mixture where at least once substance is dissolved into another. Suspensions are heterogeneous mixtures with solid particles floating freely in a solvent. Emulsions involve ingredients which are normally immiscible, meaning that they are unblendable or unmixable. Orally administered drugs are traditionally found in glass bottles and delivered through cups, spoons, and droppers. Parenteral drugs, or non-orally administered drugs, are commonly delivered with a syringe that has been filled from a glass vial or ampoule. Many new advancements have been made to deliver more complex formulations beyond these traditional methods including increased shelf life and better control over the administered dose.

Many new compounds are complex, large-molecule formulations that do not remain stable very long after mixing. Lyophilization, or freeze drying, adds shelf-life to compounds which are unstable as a liquid. In this process, the materials are mixed and filled into a vial, usually in an aseptic, or sterile environment and transported to the freeze-dryers. The freeze-dried product can remain stable much longer which enables extended supply chains and larger inventories where the drug can reliably remain in a status where it is both safe and effective. Often, these products are packaged in a kit with diluent to reconstitute the freeze dried product. In addition to the increase in freeze-dried liquids, there have been advancements that combine delivery methods and packaging.2

Aerosols and foams can be used to deliver inhaled and topical drugs. Aerosols are released as a fine spray which is inhaled or applied topically. Foams are a mass of small bubbles. These products require special manufacturing and packaging equipment to combine the drug substance with a propellant and package them under pressure. Commonly used propellants in the pharmaceutical industry such as tetrafluoroethane or dichloromethane are generally not metabolized by the human body which makes them safe for use in drugs like commonly delivered via a metered dose inhaler.3 Aerosols and foams are commonly self-administered therapies which is another trend in liquid dose manufacturing and packaging.

Self-administered therapies are a driving trend in liquid dose manufacturing. The biggest advancements are unit dose

vials and pre-filled syringes. These delivery methods provide pre-packaged doses of liquid products that a patient can administer themselves. Avoidance of office visits increases the likelihood of patient compliance and reduces costs. Unit-dose-vials produced on blow-fill-seal (BFS) equipment. BFS equipment is a single machine were plastic resin is extruded, blown into a mold, filled and sealed. They can be operated in an aseptic environment for opthalmic products or inhalants that can be nebulized. Pre-filled syringes deliver the product in pre-packaged in a syringe ready for patient dosing. The pre-determined doses ensure a safe dose of the product.

Safety and security are important considerations for any self-administered product. In addition to the product being safe and effective, the packaging must robust and secure. Anti-counterfeit packaging validates that the product came from the proper source. Tamper-evident labels show the consumer that the product has not been compromised after manufacturing and packaging. Additionally, track-and-trace measures will use equipment to apply special labels with coding and, possibly, radio frequency identification (RFID) to ensure that the product can be traced back to the manufacturer.

All drug dosage forms rely upon delivery method and packaging to securely deliver a safe and effective product to the patient. New, life-saving compounds are being developed which require additional manufacturing steps to help them be available on the shelf when they are needed. Innovative delivery methods like aerosols and foams allow drugs to be delivered in novel ways. Self-administered drugs reduce costs and provide for accurate doses. While specialized packaging ensures that the product is what it says it is. All of these factors are driving the trends for liquid dose pharmaceutical manufacturing.

REFERENCES:

Murthy, RSR and Kar, Ashutosh; Pharmaceutical Technology Volume-I, page 3. http://www.newagepublishers.com/servlet/nagetbiblio?bno=002130

Nityanand Zadbuke, Sadhana Shahi, Bhushan Gulecha, Abhay Padalkar, and Mahesh Thube; Recent Trends and Future of Pharmaceutical Packaging Technology; J Pharm Bioallied Sci. 2013 Apr-Jun; 5(2): 98–110. doi: 10.4103/0975-7406.111820; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3697200/

Gold, Dr. Brad; Common Drug Propellants Undergo Insignifi-cant Metabolism by Body, Metrics Scientist Says in AAPS Poster, November 5, 2014 http://metricsinc.com/common-drug-pro-pellants-undergo-insignificant-metabolism-by-body-metrics-scientist-says-in-aaps-poster/

Large Molecules, Drug Delivery, Safety and Security are Driving Trends for Liquid Dose PharmaceuticalsBY LARRY KADIS CEO & PRESIDENT, FEDERAL EQUIPMENT COMPANY

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