 Anniversary issue, the editors interviewed biopharmaceutical industry experts about the biggest changes the industry has seen in the past 40 years and the challenges still to be addressed (see “

The New World of Biopharmaceutical Manufacturing

” in the July issue). Here, these experts share their perspectives on the advantages of single-use (i.e., disposable) technology and on some of the changes the industry is seeing in biopharmaceutical facility design.

 spoke with Eric Langer, managing partner at BioPlan Associates; John Boehm, chairman of the Bio-Process Systems Alliance (BPSA) and Colder Products Company Bioprocessing Business Unit manager; Parrish M. Galliher, chief technology officer, Upstream, GE Healthcare Life Sciences; Sabrina Restrepo, associate director in the Sterile & Validation Center of Excellence, Global Technical Operations at Merck; Helene Pora, PhD, vice-president, Single-Use Technologies, Pall Life Sciences; Eva Heintz, global market manager, Healthcare, at Solvay Specialty Polymers; and, for facility design, Par Almhem, at ModWave.

 What has been the biggest advantage of single-use systems for biopharmaceutical manufacturing to date?

 Single-use technology saves lives, saves money, and saves the environment. The flexibility and reliability of single-use technology enable drug manufacturers to develop new therapies more quickly. Single-use technology lowers capital expenditures for facility construction and improves operational costs by increasing process flexibility, delivering faster campaign turnover and higher product yield. Single-use technology consumes less water, utilities, and chemicals with a smaller carbon footprint than traditional stainless-steel processing, creating a greener manufacturing platform. All these advantages demonstrate the potential of single-use technology in maintaining or improving sterility assurance and the quality of final drug product.

 In my opinion, the biggest advantage single-use systems have brought to biopharmaceutical manufacturing is flexibility. Now, it is possible to create sterile, closed systems with ready-to-use or steam-sterilized components that can fit into a diversity of facilities and allow for faster implementation and manufacturing times.

 In many cases, the biggest advantage is the increased speed to market for products manufactured using single-use systems. Single-use systems allow for more flexibility in development; less time and resources are spent in cleaning and validating activities, which therefore increases speed to market.

The biggest advantage of single-use technology remains the absence of cleaning and cleaning validation-critical to the operation of traditional stainless-steel systems-which saves time and money. And because you are replacing the product contact layer every time the equipment is used, you remove the risk of contamination from previous batches. Additionally, single-use systems provide greater flexibility in footprint, at all scales-users can arrange and rearrange equipment as needed. 

The benefits of single use continue to expand and unfold as the industry applies it more extensively. The benefits compared to stainless-steel facilities include reduced capital cost, reduced facility footprint, and no steam-in-place (SIP) or clean-in-place (CIP) facilities. Reduced time to build allows delaying the decision to build. Faster turnaround between batches, faster turnaround between different products, and reduced chance of cross contamination between different batches are benefits that also enable multi-product manufacturing.

 Annual Report of Biopharmaceutical Manufacturing continues to show consistent trends in single-use device adoption. The top three critical reasons given in the 2017 survey, which are driving the implementation of single-use devices are:

		a reduction in capital investment in facility and equipment

	Other factors include: ‘reduced time to get facility up and running,’ ‘decreased risk of product cross-contamination,’ and the ‘flexibility of a modular approach.’ Essentially, single-use devices are being increasingly seen as strategic tools to reduce costs and speed up both operations and facility construction.

 What have been the most significant changes in facility design for biopharmaceutical manufacturing in the past 40 years? Past five years?

Since the early 1980’s, biomanufacturing facility design has historically been dependent upon the level of segregation and separation across processes. These designs take into account flow patterns for the product, materials, operators, and waste; they are designed to ensure protection of the product, and they have been complicated by open (i.e., exposed to the environment) processing operations. To achieve this protection, the process is spread across multiple cleanroom suites with multiple heating, ventilation, and air conditioning (HVAC) zones. 

	In contrast to simpler microbial or yeast-based facilities, mammalian cell-culture facilities require additional considerations for clearance of potential virus and aerosols across the process. Virus reduction by the process steps from cell culture to bulk drug substance (BDS) is so high (10–20 logs) that a minor upstream aerosol or spill could cross-contaminate the BDS. As a result, mammalian cell-culture facility design requires more complex, multiple cleanroom segregation and separate HVAC systems. 

	In the past 5–10 years, cleanroom facility layout, design, and operation costs have come under new scrutiny as manufacturers continue to hunt down inefficiencies and reduce costs. Cleanrooms are expensive to build and maintain, and they come with high gowning and labor costs. In the past 10 years, better designed closed systems and single-use technology have become more popular. Truly validatable and robust closed systems potentially require less stringent cleanroom environments or isolators and could relieve segregation requirements from upstream to downstream operations.

	Because of these trends, open architecture facilities (or ballrooms) are being considered more often to cut capital and operating costs, with an acceptable low risk of adulteration of the product. Implementing single-use is easier in ballrooms as it facilitates the logistics of carrying in the single-use assembles and carrying them out after the batch is complete.

	The rebirth of modular facilities is another result of the trend towards single-use manufacturing, because the modules lack the expensive stainless steel piping and infrastructure. As a result, modules are simpler, lighter, and cheaper to build and ship to the facility location.

 A number of significant changes have occurred during the past 15 years.  While not an exhaustive list, the following are some of the changes I consider most significant:

		Use of isolators limiting the requirements on cleanrooms while reducing risk of contamination, thereby improving product quality

		A move to single-use and closed systems, reducing requirements on the facility as well as utility supply, while increasing flexibility in operation and lowering investment cost

		An increasing focus on flexibility and efficiency, rather than on capacity, which was the primary focus of facility design in earlier years

		Globalization (building in low cost areas) and, increasingly, market-driven localization to build in-country-for-country production

		An increasing use of modular systems (process skids, modular cleanrooms, and modular suites and buildings).

	A key driver for these changes has been cost. For a long time, the challenge in biopharma manufacturing was capacity to manufacture a growing number of blockbuster products. The key was to supply the market and cost was the secondary priority. The increasing cost pressure on pharmaceutical companies has completely changed this, and cost is now a major factor. While maybe not a dominant driver, regulatory changes are influencing how facilities are being designed and built; the increasing use of isolation technologies is a good example of this influence. Moving forward, regulatory agencies are increasingly supporting continuous manufacturing.

	Technology, market, and political trends are also drivers of change. Single-use systems, isolators, and modular systems are all technology improvements that have significantly contributed to this change. Blockbusters are giving way to smaller-volume products, increasing the need for flexibility. And with dramatically increasing yields in biologics drug substance manufacturing, the need for the ‘mega-factories’ has been significantly reduced. In addition, many countries are requiring an increasing share of products to be manufactured locally.

: What types of design do you expect will be used for new facilities in the near future?

: I think the trend towards smaller, more flexible, often modular, facilities will continue. Trends towards more potent products, increasingly personalized medicine, and new technologies (e.g., continuous manufacturing) will continue to drive the need for speed and flexibility. Some production systems will likely even be at bench-top scale. At the same time, we will likely see a few (but only a few) large-scale facilities being built.

	An interesting question is how the continued consolidation will impact these trends. Will the focus be on retrofitting existing assets (which seems likely) rather than building new facilities? That would mean that innovative ways of refurbishing and repurposing existing facilities could play an important role.

Smaller closed system and single-use facilities will be more abundant as in-market, for market distributed manufacturing spreads across the globe. Increases in efficiency to reduce costs and drug prices in emerging territories will further reduce scales as high-productivity technologies and continuous processing are applied more extensively across the process.

 How do you expect facilities to increase capacity (e.g., mobile manufacturing pods/trailers, continuous manufacturing, modular facilities)?

We see companies considering all of the above when planning their 5–10-year horizon. Scaling out (adding multiple lines of the same scale) is becoming a more popular way to add capacity because it reduces up-front capital risk and avoids scale-up risk. It can be added when the need arises, which allows companies to build the right size at the beginning and grow (or not) as the market grows.

I think we will see a wide range of alternative solutions. For larger-scale production, continuous manufacturing has significant advantages and will likely be replacing traditional batch systems. For small-volume products (with individual doses as the extreme example), the trend will likely be towards modularity, repeatability, and short cycle times. Operational efficiency will be even more crucial.

Articles

Feature

The advantages of single-use systems become clear as they become more broadly implemented.   

Single-Use Technologies Transform Biopharmaceutical Facilities and Manufacturing Equipment

	Maintaining data integrity is essential for all biopharmaceutical manufacturing operations. 

 interviewed Dan Nelson, Customer Experience Team member at DataNinja, which provides real-time manufacturing and quality software for the life-science industry, for insight on best practices in maintaining manufacturing data integrity. 

 What do you see as the most important considerations for manufacturing data integrity?

 There are really two main reasons why biopharmaceutical manufacturers care about data integrity: protecting the business and enabling the business. If manufacturing data are missing or inaccurate, then the firm is in violation of GMP regulations; it may mean that the quality of the product cannot be trusted. In serious cases, bad data integrity could lead to an FDA-mandated shutdown of production. I’d say just about every biopharmaceutical manufacturer understands this concern. So, out of fear, they invest heavily in business-protecting activities to ensure data integrity. These investments usually occur in the form of additional manual document reviews, more rigorous quality documentation, hiring more personnel, implementing electronic systems, and so on.

	Many companies thus view data integrity as a law-mandated, paper-intensive, cost center. Stereotypes are changing, however, as innovative companies are leveraging technology to turn data integrity into a business-enabling profit center.

	There are massive amounts of data collected during production, including machine usage; historian data; timestamped, in-process measurements; and materials usage. Forward thinking-manufacturers use these data for business optimization efforts. 

What are some examples of business enabling or optimization activities? 

 Once the business feels protected, it can progress to the next level, where the concern starts to become more about data accessibility. A thought process, for example, may be ‘Now we have production yield and quality data that are reliably collected, and we can trust their integrity. How might we leverage that data to minimize variability?’

	At a large contract manufacturer in Salt Lake City, Utah, for example, one quality manager took it upon her team to try and identify the root causes of batch yield variance. They meticulously went through batch production records, one filing cabinet at a time, to aggregate datasets of the suspected yield variability drivers. When they compared yield data to all the other datasets they discovered that one of their main suppliers was under filling, and that was the most significant correlation to batch yield fluctuation. 

	The practice of dataset correlation analysis is common. It’s how the hard, but often extremely valuable insights are earned. In all industries, the innovators compete with data. 

	Biopharmaceutical manufacturers are leveraging data integrity to answer their toughest operational questions, such as the following:

		Which piece of equipment is causing the most packaging deviations?

		How can I get more timely and accurate financials from manufacturing?

	More life-science manufacturers are stepping away from paper batch records. A paperless system lowers the cost of collecting data and increases the ability to analyze and profit from it.  It enables you to find correlations that otherwise would have been impossible or not cost effective to capture with a paper-based system. 

	Ideally, what you are after is a system that meets all your business-protecting requirements while simultaneously leveraging that data integrity for business-enabling activities. For example, with such a system in place, you could connect an initial entry on an electronic batch record to historian sensors and then process a financial transaction in your ERP [enterprise resource planning system], all in real time. 

 What are the benefits of electronic data systems for improving data integrity? 

 First, electronic systems improve accuracy. With an electronic system, you get real-time verification of operator data entry, instead of catching mistakes/missed entry in the final quality control review. Operators receive immediate feedback if they do anything that could cause a deviation. 

	Second, electronic systems make data searchable. Instead of burying loads of useful manufacturing data in a filing cabinet, an electronic system stores it in a database ready for value-adding insights to be extracted from data trends. No need to type in critical data points. Your analysts can get straight to discovering insights. 

 What are the data integrity risks associated with computerized systems and how can these be mitigated? 

 The data integrity risks associated with computerized systems fall into two main buckets: data loss and data manipulation. Loss of any manufacturing quality data is potentially catastrophic. Because of redundant database architectures and modern cloud applications, computerized systems are superior to paper in terms of total data loss. Computerized systems have their own unique weakness when it comes to data loss; there are more variables that can result in partial data loss. When it comes to paper, all you have to worry about is completion and having a grasp on the physical document. With computerized systems, you might have to deal with Internet disruptions, hardware failures, or human error (e.g., pressing log-out, instead of save). The risks are best mitigated with redundancy, audit trail robustness, and auto-saving. 

	Cloud redundancy can mitigate risk. If lightning stuck your server room and everything there was instantly destroyed, how would it affect your data integrity? Modern computerized applications merge government-level security with cloud agility. So, data are securely stored with multiple redundancies and ensured with multiple failover locations.

	Audit trail robustness is also crucial. With manual, paper-based systems, it’s crucial to know what was done and who did it. We have all reviewed records with an initial missing. It’s a major pain. There is a calculable probability that given the hundreds of initials required on each batch, one out of ‘x’ batch records will be missing an initial. Computerized systems combat this threat by tracking user actions based on user credentials. If a user completes documentation, the system records who did it along with a timestamp automatically.

	Auto-saving is important. A computerized system should not threaten your work based on whether or not you press a save button. This risk should be mitigated with auto-saving functionality. If you don’t have auto-saving, then you’d better focus your efforts on training. 

 How can manipulation of electronic records be detected and prevented?

 Detection of data manipulation has got to be built into the computerized system. Advanced computerized systems leverage MD5 hash encryption to verify that original data integrity remains intact. The MD5 hash is like a digital seal that is uniquely generated based on the contents of the electronic record. If data in the record were manipulated, the MD5 hash would reflect the change and detect the manipulation. Computerized systems for biopharmaceutical manufacturers must comply with FDA’s 

 21 Part 11 regulation for electronic signatures.

	The risk of data manipulation is mitigated through validation and access. It’s hard to manipulate pen on paper; it looks obvious when something appears to be overwritten. How can you trust that computerized systems contain no data manipulation? First, limit access. Make it impossible for people entering the data to manipulate it, whether in person or through a co-worker. Put in place total separation of powers so that there is no way someone could get someone else to manipulate data post-electronic signature. In regulatory jargon, this means you want your computerized system to be ‘open’.  

Electronic systems allow biopharma manufacturing companies to meet data integrity requirements and optimize practices.

Data Integrity Best Practices

	Despite decades of effort to design packaging that helps people take the right dose of the right prescription at the right time, the number of prescriptions that are not taken as directed has been stuck around 50% since at least 1993 (1, 2). Sometimes the reason for lack of compliance, or what increasingly is referred to as “adherence,” is financial. The patient can’t afford the medication, so the prescription goes unfilled. But more often, lack of compliance is due to difficulty accessing and dispensing the proper dose and remembering dosing times. 

	“The severity of medication non-adherence has been so well documented that the healthcare industry is taking a much more serious look at how to improve patient behavior,” reports Ward Smith, director of Marketing at Keystone Folding Box Co. “People are starting to recognize compliance is a really important factor in determining the outcome for the patient,” agrees Graham Reynolds, vice-president and general manager of Global Biologics at West. Reynolds explains: “Non-adherence has significant financial consequences. The patient ends up in the hospital or back in the hospital and puts additional strain on the healthcare system. From a pharmaceutical company perspective, non-adherence is widely recognized as a cause for a significant loss of revenue; a number recently estimated at $600 billion.”  

To improve adherence, many compliance packaging designs have been introduced. The Pharma Compliance Pack from August Faller Group features an integrated sliding mechanism (see 

). As doses are taken, perforated tabs are removed to provide access to the next dose(s) on the blister card. “The patient can directly see which tablets he/she already took,” says Tanja Feldmüller, head of Marketing  and Innovation at August Faller. 

	Keystone’s child-resistant Key-Pak and Ecoslide-RX packaging also calendarize medication dosing. “This type of packaging has been documented to improve medication adherence,” says Smith. He notes, however, that it appears to be less effective for patients on multiple medications. “…if a patient takes more than five medications; all of the packages (blisters and bottles) can become overwhelming,” he explains. 

	Some patients on multiple medications resort to pill minders with compartments for each day and/or various times of day. However, this solution can be problematic. Filling errors can result in missed doses or overdoses. Sensitive medications can be exposed to detrimental environmental conditions, and product information is separated from the dose. 

	“No one solution seems to exist to solve non-adherence,” says Smith. As a result, there’s growing interest in more holistic approaches that integrate packaging with interactive devices, software, rewards programs, and personalized support. 

	An example of a more holistic approach is a smart, wireless pill bottle from AdhereTech. Used primarily for specialty medications like cancer drugs, each bottle contains a wireless cellular chip and numerous sensors. It collects adherence data in real-time, analyzes the information, and populates a secure dashboard. If a dose is missed, the system sends an automated alert via phone call or text message to the patient, caregiver, or pharmacist. The bottle itself offers alerts via blinking lights or audible chimes.

	 The smart bottles are child-resistant and supplied free to patients and pharmacies through programs sponsored by pharmaceutical companies. When the prescription is dispensed, the pharmacist inputs the necessary information into the system, and the bottle is ready for use. Sensors detect when the bottle is opened and reclosed and can monitor other attributes such as the contents of the bottle, battery level, and signal strength. “If the bottle is in an area with no cellular coverage, the bottle holds data on up to 180 doses for later transmission,” says Josh Stein, CEO and cofounder of AdhereTech. The pharmacist can access the compliance dashboard and intervene if the patient needs help. Results to date show the wireless pill bottle boosts adherence up to 20%, while persistence (the time on therapy) jumps to 30%. 

	Another smart packaging option, the iCap closure from TimerCap, is Bluetooth-enabled with red, yellow, and green lights to visually indicate medication status. Each time the cap is opened, the onboard timer stops and returns to zero. The cap also collects data for real-time or email transmission. Compatible with Android, iPhone, and Apple Watch devices, the child-resistant, push-and-turn closure is sold as a kit with two caps, two bottles, two batteries, and the MediSafe iConnect app. Various colors make it possible to differentiate medications. The Medi-Safe iConnect app moves setup of the iCap closure to a Smartphone or other device, minimizing energy consumption and maximizing battery life. In addition to tracking adherence, the MediSafe iConnect app can monitor almost two dozen measurements including glucose levels and weight. The iCap not only helps patients take their medication as prescribed, but also can track and detect opioid abuse and diversion. 

	With the iCap, the pharmaceutical company sees firsthand when a patient takes a medication. “That knowledge helps fix side effects and other issues and determine why a drug works for some and not others,” says Larry Twersky, CEO of TimerCap. As a result, healthcare providers have a better chance of knowing how a particular drug will work for a patient. 

Smart labels equipped with a near-field communication (NFC) chip and/or QR code also can support adherence (see 

). “NFC has multiple advantages compared to a QR code, such as a very high security level for authentication purposes, the possibility to individually change or protect specific information or the enhanced convenience to read the tag with your Smartphone,” says Gene Dul, president of Schreiner MediPharm US. “However, the advantage of including both [code and chip] is that online information is also available to those users that do not have an NFC-enabled Smartphone available.” Labels also can be equipped with other features such as anti-slip varnish, hologram for authentication, or a temperature indicator that changes color when a certain ambient temperature is reached. 

	Medication management tools from Compliance Meds Technologies (CMT) can be tailored to the needs of various settings such as senior care, addiction treatment, and clinical trials. Tools include the CleverCap LITE; the CleverCap PRO; an optional mobile app called Companion App CMT; and secure, cloud-based reporting/analytics portals. The devices are distributed through the pharmacy, incorporated into existing medication vials/bottles, shipped directly to enrolled patients, or given out by a participating doctor.

	Moses Zonana, founder and CEO of CMT, described how the integrated technology works. “The CleverCap PRO … detects when a pill is dispensed and can control the dose, ensuring the patient receives the right dose at the right time. The information is automatically transmitted through cellular 3G networks into the CMT Reporting, Analytics, and Engagement System. Devices can generate visual and sound alerts at predefined timeframes or operate under silent mode. The CleverCap LITE does everything the CleverCap PRO does except it doesn’t actually track at the individual pill level of granularity or control dosage. It tracks when the vial/bottle is accessed or is not properly reclosed to provide an extra layer of security.  

	“We have observed regimen adherence levels of 95% using CleverCap PRO and regimen adherence levels of 96% using CleverCap LITE. In the majority of our programs, there is an intervention layer in addition to the technology layer, which allows us to obtain those types of successful results. These interventions may incorporate nurse support groups and incentives for better medication habits.”  

		National Council of Patient Education and Information, 

Accelerating Progress in Prescription Medicine Adherence: The Adherence Action Agenda 


	Hallie Forcinio has reported on packaging as 

 Packaging editor for more than 20 years. Her first article for the publication, in March 1993, looked at patient compliance, which continues to be a concern today. Tel 216.351.5824, editorhal@cs.com. 

	This article is excerpted from H. Forcinio, “

A staggering percentage of people do not take their medication correctly, but pharmaceutical packaging aims to improve patient compliance using new technology to address reasons for non-adherence.  


Equipment and Processing Report-07-19-2017

Single-Use Technologies Transform Biopharmaceutical Facilities and Manufacturing Equipment

Data Integrity Best Practices

Solid-Dosage Packaging Improves Patient Compliance