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A Single-Use System for Safe Freezeâ€“Thaw

BioPharm International, December 2010 Issue (PDF)

When I was first hired by a biotech manufacturing site as a member of the leadership team more than 10 years ago, I was very concerned about what I'd gotten myself into. I had just left a successful career as a performance turnaround specialist in the semiconductors industry and I felt ready to tackle whatever I found in biotech. Yet I was concerned, because I had a sense that something wasn't right with my new industry and I couldn't quite describe what it was.  

I had a couple of positions I needed to fill quickly, so I called an old semiconductors buddy to interview for one of them. He had the skill set we needed for the role, but what I really wanted was to have him make the rounds in my new company to see if he picked up on my feeling about biotech. He was a straight-shooting operations-minded veteran and I wanted his take on the situation. 

The interview process included long discussions with the heads of manufacturing, quality, and technical services. At the end of his day of interviews, we went to dinner to debrief—just the two of us. Once he had settled down with a drink, I asked what he thought. He set down his pint and wiped his old-school mustache with the back of his hand. Then, true to form, he cut to the chase. He shook his head, sighed, and said, "Chris, these guys are really smart . . . but they don't know how to make stuff." 

That was almost 10 years ago but it's one of my favorite quotes. It suggests a problem at the operating principle level that continues to plague many in our industry. In the early days at my new site, it was what I was picking up on in my interaction with the talented group of people I had just joined. These individuals were technically brilliant, personally driven, and supportive of their peers, but something was missing. They didn't know how to "make stuff."  

It wasn't a shortcoming of this particular biotech. Frankly, they led the league in everything important at the time. Instead, this was a shortcoming of a technical industry still early in its lifecycle. In the early days, technology companies have implicit operating principles around excellence in science and engineering. But as companies mature, too many of them fail to draw the line and formally enter the realm of those who "make stuff." To make the transition effectively, it's important to understand the operating principles for making stuff well. 

The technology companies that have learned how to make stuff well have adopted four such operating principles, which I will explain. 

RECOGNIZE PERSONNEL MANAGEMENT AS A REAL JOB

The highest priority for a company that is focused on execution is personnel management. Across technical industries, there is a tendency to hire and promote based on technical expertise and to largely ignore management skills. It's easy to see how this happens. Most companies fail to recognize that competence is domain-specific and that top performance as a scientist or engineer says nothing about one's ability to manage people. Most companies still look at good technical performance as an indication of some sort of enlightenment that results in the person being great at everything. This extrapolation of technical competence into non-technical areas is a problem. Believing that technical competence is an indication of managerial competence is the same as assuming that golfing great Phil Mickelson must also be a great singer. If we look to the companies that are good at making stuff, they identify a core set of management skills and make sure everyone has them.  

The hard part is acknowledging that something non-technical can have a significant impact. In biotechnology, we still have a cognitive bias away from non-technical solutions, so it's difficult for many site heads and leaders to acknowledge the impact of management skills. 

A majority of managers in our industry do very little personnel management in their current roles. Instead, they are called on to continue carrying out their roles as technical experts and individual contributors while also having a group report to them. When I begin working with a client's managers, one of the first things I hear is that the manager doesn't have time for things like one-on-one meetings with direct reports. In other words, a majority of biotech employees have no meaningful connection with their bosses. This in turn means that our teams are not engaged and our organization is underperforming.  

When a company recognizes that it is in the business of making stuff, then it focuses on execution, which is tied directly to the effectiveness of the individual manager. For a company that wants to be operationally excellent, there is no priority higher. 

Focus on your core competencies and be willing to outsource everything else. Biotech companies continue to face cost pressures, and along the way, they explore outsourcing. However, we are not yet realizing all the benefits of a robust outsourcing strategy because we forget to tell our people how to operate in a new way. I hear two comments from biotech managers that reveal this problem.  

One: "I don't like using contingent workers or consultants because at the end of the day all of the expertise walks right out the door." 

Two: "It's better to do the work with full-time staff, because the quality is always better." 

Both of these statements show a lack of understanding of outsourcing. Companies that have learned the secrets of making stuff know that the object is to find the combination of in-house resources and outsourcing that yields the lowest cost and highest quality as fast as possible. So the question isn't whether outsourcing can do that for you. The question is whether you can do that with outsourcing. The answer depends on your ability to execute. When I am helping clients with outsourcing strategies, someone will always say to me, "But sometimes outsourcing ends up costing more." I always acknowledge that there is no magic in it. "You can screw this up just like anything else," I reply. "It's about execution." When companies focus on what they can do with outsourcing, they get a different result. Instead of managers standing around and hoping everything goes well or talking in the lunch line about how they wish they had more full-time staff to work with, they go out and get better at working with contingents. When a manager is good at working with contingents, she recognizes that she needs to manage the outsourcing company behind the workers too. The manager needs to be clear with expectations and feedback for the service provider. This seems simple but it's not getting done. Instead, client companies sit back and assume that the company that employs the contingent will handle everything. 

Focus on managers and provide training in how to manage contingents. Then, hold the managers accountable for hitting the budget target. When contingents are used just like full-time staff, waste ensues. The contingents spend time in unnecessary meetings and blend into the local pace of work. Then, when you do the math on the hourly rate you end up seeing that it costs more. The point is, companies need to clarify their expectations for managers and hold them accountable for running the business. There is a learning curve involved. To get good at making stuff, a company must move through that learning curve and drop its reluctance to outsource aggressively. 

IT'S NOT JUST ABOUT SCIENCE; YOU MUST COMPETE TO WIN

This one seems obvious, which is why it doesn't get the attention it deserves. The best operational companies are full of team members that know what it means to work in a competitive business. Here's a quick example. If you're in a company that has multiple manufacturing locations or outsourced manufacturing sites, consider how transparent your company is about comparing one site to the others. The best companies get to the point where they don't try to tell their team members that the objective is to have one big, non-competitive family. Instead, they make it clear that in a competitive business environment, you are either aggressively competing or you are waiting to be defeated. That applies at the company level and it applies at the intra-company site level too. 

Some companies are good at discussing competition when it's about their product versus someone else's. But they resist encouraging internal competition. The argument is that they don't want to lose sight of the big picture, which is about "all of us" winning. The truth is, we can't compete with other companies if we're not comfortable competing internally. There is a first violin chair in an orchestra and all of the violinists would like to sit there. Along the way, they play their part to the best of their ability. But make no mistake: They want the first chair. Acknowledging the need to compete drives behavior change.  

The primary behavior change comes from understanding that you have to improve to survive. You simply can't stay the same and be around in a couple of years. When managers understand this and hold their teams accountable for behaving this way, performance improves. Instead of complaining about how uncertain everything is and longing for the imagined days before cost pressure, people get to work and find a way to improve. Or, they go work somewhere else, and that's okay too. The companies best at making stuff understand that their objective isn't to retain all staff; it's to retain the right staff. By helping everyone understand that they must continue to improve to remain competitive, a company focuses energy in the right place and drops the waste involved in any other perspective.  

A friend of mine joined a financial services company about 10 years ago because he was interested in becoming a stock broker. The head of the office hired John and explained the he would pay him a salary for six months as John learned the business and got some clients of his own. Thereafter John would need to generate his own fees from managed assets.  

Like all new brokers, John entered the world of cold calling. The brokerage house knew that the name of the game with young brokers was for them to make lots of calls. That way, they would learn what worked and what didn't. So John and the other newbies were measured by the number of calls they made in a day. In the early days, John told me about how many calls he was making in a day. Ever supportive of my friends, I think I said something like, "Gosh, that's quite an existence you've carved out for yourself John."  

My sarcasm aside, John learned how to do it. After a few months, he began bringing in significant investment dollars and developed a successful career as a broker. But not everyone was like John. After John had been there for four or five months, one of his co-workers was still coming by his desk and saying things like, "100 calls already this morning, man. Can you beat that?" The problem was, the guy had brought in very little money. He was still counting calls when the successful people were counting dollars. 

This mistake also shows up in biotechnology. How are your metrics for closing nonconformance investigations? Are you getting really good at closing investigations quickly? How about those metrics on closing work orders? Are you getting better at processing unnecessary paperwork?   

I've worked with organizations that ran Six Sigma projects to get better at something they didn't need to do. I've also worked with multiple clients that found a way to check for errors before the actual check so they didn't need to record an error but instead could just take the time to do it over again. Hurray! 

If you're going to be among the best in the world at making stuff, be careful what you get good at. The more efficient we get at unnecessary, non-value adding activity, the easier it is to institutionalize. Once waste gets in that deep, your team begins describing it as "the way we've always done it." Worse, the unnecessary process grows like a vine through something that is actually required and then disentangling everything is nearly impossible. 

The biopharmaceutical industry is full of smart people. Being smart, however, is not enough. To be successful in manufacturing, companies must understand how to become good at "making stuff." To do so, they must understand and adopt the four key principles described here. If they follow those, operational excellence will come. 

 is the CEO of the Driscoll Consulting Group, 303.725.4473, 

Features

To achieve manufacturing excellence, biopharma companies must adopt four key operating principles.

Getting Better at Making Stuff

Commercializing therapeutic proteins involves a series of processes aimed at maintaining safe and efficient protein drug solutions before final patient administration. Common operations include important steps such as pre-formulation, drug product formulation, sterile filtration, freezing, thawing, and freeze-drying intended to stabilize the protein drug before fill-and-finish, and during storage and transportation. Freeze–thaw operations used in the biotechnology industry still are generating debates regarding safety problems because methods to freeze and thaw samples can affect the purity, activity, safety, and efficacy of the final product. This article presents a Quality by Design (QbD) approach to define a safe freeze–thaw space where a protein's quality is not affected by the freezing or thawing method used.

Freezing is a process step used by most biopharmaceutical companies to store proteins. Yet little attention is generally given to this important step, even though reports suggest that processes for freezing protein solutions require detailed precautions.

  During freezing, the physical environment changes dramatically, which can significantly affect the protein quality. Moreover, freeze–thaw variations can exist in or between batches, and heterogeneous processes raise serious validation concerns. Cryoconcentration has been recognized as the most likely and important stress for biopharmaceuticals during freezing, and occurs at two levels.

 At the microscopic scale, when water molecules of the bulk buffer crystallize, an unavoidable dehydration of the amorphous phase occurs, called amorphous phase cryoconcentration.

  Although highly concentrated, the amorphous phase quickly reaches its frozen glass transition temperature (Tg'), below which the high viscosity prevents molecular interactions, leading to product loss.  

At the macroscopic scale, a bulk-scale or progressive freeze concentration may result from back-diffusion of solutes from the solidification front to the remaining unfrozen solution.

 This redistribution of solutes in front of the advancing surface of ice can lead to product and solute concentration in the liquid phase for an extended period of time and may be detrimental for product stability (e.g., oxidation, aggregation, denaturation). 

To limit the cryoconcentration effect, Sartorius Stedim Biotech has developed the Celsius Control Freeze Thaw (CFT) technology: a single–use system for controlling the freezing and thawing rate at manufacturing- and laboratory-scale.

  With this system, the ice crystal growth rate in the direction of the heat flux is sufficient to prevent back-diffusion of solutes from inter-crystalline space into the liquid bulk, thus minimizing the bulk-scale cryoconcentration.

In this article, we evaluate the suitability of the laboratory-scale Celsius S3 system as a screening tool for determining a safe freeze–thaw space where a protein's quality is not affected by the freezing or thawing method used. 

To define the freeze–thaw space for each studied molecule, a two-factors, two-levels face centered composite surface response was applied as described in Table 1. The two factors investigated were freezing and thawing rates and the response was the aggregates content as determined by size exclusion high throughput liquid chromatography (SE-HPLC). These screening conditions were generated by Minitab factorial designs to identify significant main effects and interactions among the two variables.  

Table 1. Two factors, freezing and thawing times, were studied for their damaging effects on proteins 

This approach was applied to four different molecules: an interferon (IFN), two monoclonal antibodies (MAbs), and an Fc-fusion protein. To increase the reliability of the statistical output, each condition was performed twice.  

Freeze and thaw cycles were run using the Celsius S3 system and the 30-mL Celsius-Pak bags equipped with a thermocouple, allowing aseptic temperature measurements during freeze–thaw operations.  

The Celsius S3 system is a laboratory–scale tool specifically designed for scale-up and scale-down freeze–thaw studies. The system, shown in Figure 1A, includes a freeze–thaw module, an orbital mixer, a temperature control unit, and a data-acquisition system for temperature control and recording. The 30-mL single-use bags, filled to the nominal volume with protein samples, were placed in the Celsius S3 module between a pair of heat-exchange plates within which circulates a heat-transfer fluid (HTF) as shown in Figure 1B. This setup reproduces the freezing and thawing conditions encountered at large scale because it uses the same freezing distance and the same material of construction as the production-scale Celsius-Paks. This configuration allows for a controlled freezing process based on bidirectional crystal growth along the general direction of the heat flow.

Figure 1. A) Laboratory-scale Celsius S3 system B) Celsius-Pak insertion inside the S3 module. 

The thermocouple used to monitor the temperature of the sample was located 1 cm below the liquid level at the last point to freeze (LPTF) of the container (Figure 4). Then, by monitoring the temperature of the product and that of the HTF, it was possible to generate the typical temperature profiles of the freezing and thawing processes for each molecule and condition studied. 

All freezing and thawing parameters of the Celsius S3 system were defined using the Cryopilot 5.0.1 software. This custom-built software allows control and monitoring of the sample, the HTF temperatures, and the mixer unit. To generate the necessary freezing and thawing times required by the DoE listed in Table 1, a freeze–thaw program was created for each studied condition by changing the temperature set point of the HTF during time as represented by the dashed line in Figure 2.  

Figure 2. Temperature profile of the freezing phase for the best case point (2 h freezing and 2 h thawing) generated with the S3 system. Solid line: interferon; dashed line: set point; dotted line: heat-transfer fluid temperature. 

A freezing process begins by cooling the liquid down to its transition temperature (approximately 0 °C in this study). The system then releases its latent heat of solidification at nearly constant temperature, creating a temperature "plateau" whose duration indicates the rate of ice crystal growth. This phase is the most crucial part of a freezing process because the rate of crystal growth will determine the importance of the cryoconcentration effect, and therefore, the product stability. In this study, we defined the freezing time as the plateau duration.  

Figure 2 shows a temperature profile of the DoE "best case" point with a freezing plateau of 2 h. By lowering further the temperature after the 2 h plateau, the products' temperature profiles drop down very quickly with the same slope as the HTF temperature profile, indicating the end of freezing. The temperature set point with a "stair shape," and especially the short pulse of low temperature at –45 °C at the beginning of the freezing process (i.e., between 2 and 3 h), was implemented to limit the undercooling effect typical of low salt solutions. This pulse was necessary to give enough energy to start the nucleation, thereby avoiding a delay in the freezing process.  

Undercooling lowers the liquid temperature below a solution's freezing temperature while maintaining its liquid form. A liquid below its standard freezing point will crystallize in the presence of a nucleus around which a crystal structure can form. However, lacking any such nucleus, the liquid phase can be maintained all the way down to the temperature at which homogeneous crystal nucleation occurs. The homogeneous nucleation can occur above the glass transition where the system is an amorphous (non-crystalline) solid and will occur very quickly (Figure 3).

  Undercooling occurs randomly and cannot be completely eliminated. It can indirectly affect protein quality and can clearly generate differences in batch-to-batch or sample-to-sample preparation, creating unwanted heterogeneities in the process. Therefore, a limitation or a partial control of the undercooling effect can reduce the risks of eventual sample damaging.  

Figure 3. Description of the undercooling phenomenon 

With the Celsius S3 system, the thawing phase cannot be defined by a clear plateau.  In fact, if during the freezing process the heat exchange has an outside–inside direction resulting in a precise LPTF, thawing occurs in the opposite direction, resulting in a growing liquid zone without a well-defined point (i.e., there is no "last point to thaw"). Therefore, the thawing time is defined as the time to melt the whole product.  

Figure 4. Description of the freezeâthaw process occurring in the bag. (LPTF: last point to freeze) 

For this study, the end of thawing was determined by a small drop on the thawing profile (Figure 5). At the end of the thawing phase, the remaining ice starts detaching from the wall's container and moves to the surface of the liquid toward the temperature probe (located in the center of the container at the LPTF), resulting in a small drop in the temperature. In other words, the thawing time was defined as the time period covering the beginning of thawing, i.e., when the HTF set point is switched to the target thawing temperature, up to the small drop of temperature previously described. Finally, for each thawing time required by the DoE, a specific thawing temperature set point was defined.  

Figure 5. Temperature profile of the thawing phase for the best case point (2 h freezing and 2 h thawing) generated with the S3 system. Solid line: interferon; dashed line: set point; dotted line; heat transfer fluid temperature. 

The impact of freeze and thaw on different molecules, an IFN, an Fc-fusion, and two MAbs was investigated using a DoE approach as outlined in Table 1. Two parameters, i.e., freezing time and thawing time, that are known to have a major damaging impact on proteins were studied.

  The formation of high molecular weight (HMW) species, which has been described as the most probable protein-degradation pathway during freeze–thaw cycles was then monitored by SE-HPLC.

Figure 6. DoE surface response representation of the interferon dimer reduction expressed as a percentage of a reference freezingâthawing procedure under non-controlled conditions (as explained in the text). For each experimental condition dimer, content was measured and divided by the dimers content of the reference. 

The amount of these multimeric forms (i.e., dimers for IFN and aggregates for the Fc-fusion and MAbs) generated during freezing or thawing was compared to the HMW species content generated during a standard freezing procedure that used a simple and uncontrolled freeze–thaw system, which requires >10 h for freezing and >10 h for thawing. The difference expressed in percentage of multimeric content between the reference procedure and the freeze–thaw conditions of the DoE, was then used as response for the DoE. The output of the study carried out on the IFN is summarized in Figure 6, which describes the DoE results modeled and analyzed by the Minitab 15.1 software. The R

  value of 97.2% indicates the high validity of the model. The P value for freezing time was 0.067, higher than the typically chosen a-level of 0.05, indicating that freezing rate does not significantly affect the reduction of a dimer compared with the uncontrolled system. On the other hand, the P value of the thawing time was 0.001, well below the a-level, indicating that the thawing rate has a strong impact on protein quality and that a dimer content reduction has to be expected. Figure 6 clearly points out that a maximal dimer content reduction, up to 18%, can be achieved for very short thawing times of <3 h. However, despite this strong decrease in dimer content, the observed value was still above specification limits.  

Figure 7. Temperature profile of the 2 h/2 h freezeâthaw condition (solid line) and kinetic study of the interferon dimer conversion during incubation at high temperature (triangle). 

When the product is thawed using the fastest condition, a thawing plateau of 2 h and incubated at a higher temperature (>29 °C) for an additional few hours, up to 56% of the formed dimers were converted to the more active monomeric form (Figure 7). These findings clearly indicate that dimers are preferentially formed during freezing and that they are then partially converted into monomers during thawing. The conversion rate is visibly temperature dependent, and the higher the temperature, the faster the dimer conversion.  

Figure 8. Kinetic study of interferon (IFN) formulated with a protecting agent. Solid line: temperature profile of the incubation. Square: IFN dimer conversion during incubation at high temperature. 

In an additional experiment, the IFN was formulated in the presence of a protecting agent aimed at limiting the dimer formation during freezing, and a fast freeze–thaw cycle (with a thawing plateau of 2 h) was applied. After complete thawing, the sample was immediately incubated at +7 °C for a few hours to stop any conversion activity and the dimer content was measured. A conversion kinetic study was then started by incubating the sample at +29 °C during a period of 6.5 h. The results are summarized in Figure 8 and indicate that almost complete conversion is obtained after only 2.5 h incubation. The obtained value of <1% of dimer content aligns with the specification in use for this product.  

Figure 9. Fc-fusion protein aggregate content measured for each DoE condition. Ref. represents the initial sample before any freezeâthaw cycles. 

As previously mentioned, a similar approach was carried out on an Fc-fusion protein and two additional MAbs. However, in these cases, no significant difference in terms of aggregate content was observed (Figure 9). It means that a well-controlled freezing procedure such as the Celsius system might not be necessary, and a simpler and cheaper system such as the Flexible Freeze Thaw containers (Celsius FFT) may be more appropriate. The Celsius FFT concept combines a flexible container with a semi-rigid polymeric protective shell (Figure 10). The contribution of the protective shell is predominant in the absorption of stresses resulting from processing or handling conditions (i.e., protection against impact and vibration). At low temperatures, the physical properties of plastic materials may change sufficiently to introduce brittleness that can reduce the capacity of the bag to absorb shocks leading to possible bag, port, tubings, or connector breakage. The FFT system is designed for freezing and thawing protein solutions in conventional and commercially available equipment (e.g., laboratory and walk-in freezer, cold room, temperature controlled cabinet, or water bath), facilitating its implementation in existing facilities and eliminating the high capital costs associated with specialized technologies.  

Figure 10. Celsius FFT system: a single-use bag encapsulated inside a protective polymeric shell. 

Protein quality during freezing or thawing is governed by several well known chemical and physical phenomena linked to the way that the protein is frozen or thawed.

  It is mandatory to characterize as much as possible the impact that these different process parameters may have on the protein quality. Traditional freeze–thaw approaches are based on stability studies, carried out during process development, which use simple and uncontrolled procedures to freeze and thaw the sample protein. These small-scale freeze–thaw systems are a simple reduction of the container used for freezing the sample at process scale (usually the scale down is based on the surface or volume ratio, which is kept constant between scales).

 Therefore, the freezing and thawing velocities (probably the two main parameters affecting protein quality) are clearly faster compared with a larger scale that involves larger volumes and therefore larger freezing path lengths.

 In this study, we have shown the possibility of characterizing the stability of the protein over a range of process parameters typical of a manufacturing scale. Scale-down studies were designed to capture a fully controlled freeze–thaw scenario when short freezing and thawing times, as well as very long freezing and thawing times (typical of uncontrolled freeze–thaw large-scale systems) can be generated. After the design space was created, it was easier to define the most appropriate freeze–thaw solution to be used at manufacturing scale.  

Finally, the same freeze–thaw QbD approach can be applied to formulation studies where small scale-down models, representative of the manufacturing scale, are needed.

  In this case, factorial screening of different excipients stabilizing the molecule can be carried out using the freezing and thawing times as block parameters, including the direct effect of the freezing or thawing procedure in the formulation study. Formulation development studies also are critical for protein therapeutics development and can clearly benefit from this freeze–thaw QbD approach. Indeed, in process development, intermediates and final drug substance formulation are defined using buffer and additives screening approaches. To select the best candidates, storage and freeze–thaw has to be taken into account. In this context, the Celsius S3 concept can be used to test several formulations in parallel, allowing good throughput, good knowledge of the freeze–thaw procedure, and good scalability for the transfer to the production site. 

 is an assistant scientist DSP & Preformulation, biotech process sciences, 

is a vice president of the Center of Expertise Manufacturing and head of biotech process sciences, and 

is a bioprocess and innovation DSP specialist, Centre of Expertise Manufacturing, all at Merck Serono SA, CH, Switzerland.  

is an application  specialist, fluid management Technologies, Sartorius Stedim Biotech SA. 

 1. Rathore N, Rajan RS. Current perspectives on stability of protein drug products during formulation, fill and finish operations. Biotechnol Prog. 2008;24(3):504–14. 

 2. Singh SK, Rathore N, McAuley A, Rathore AS. Best practices for formulation and manufacturing of biotech drug products. BioPharm Int. 2009;22(6):32–48. 

Apply a DoE strategy to test several formulations in parallel.

Safe Freeze–Thaw of Protein Drug Products: A QbD Approach

Market consolidation and the importance of size have been regular themes in the past year. A major deal in the early-development segment has once again underscored the primacy of these trends in the evolution of the pharmaceutical outsourcing sector.  

The big deal is the 10 year services relationship between Covance (Princeton, NJ) and Sanofi-Aventis (Paris, France). The arrangement, which has a potential value of as much as $2.2 billion, has several key components. The key aspects are:   

Covance will acquire the research and development sites (R&D) of Sanofi-Aventis in Porcheville, France, and Alnwik, United Kingdom, for $25 million and maintain employment at those sites for 300 employees for at least five years.

Covance will receive a five-year take-or-pay contract from Sanofi-Aventis worth at least $350 million for services to be provided from the two acquired facilities.

Covance will receive from Sanofi-Aventis a 10-year, take-or-pay contract worth at least $850 million for additional services, including discovery, chemistry, Phase 2–4 clinical research, and postapproval services.

Covance will be designated as the sole provider of central laboratory services to Sanofi-Aventis for a 10-year period, with potential business valued at up to $1 billion during the 10-year period.

The Porcheville and Alnwick sites host a variety of early-development activities, including drug metabolism, toxicology, and bioanalytical testing. The sites also have capabilities for CMC development, including early-phase small-molecule active pharmaceutical ingredient (API) development and manufacture, preformulation, formulation, and radiolabeling.  

The deal with Sanofi-Aventis certainly is a big one for Covance. In two to three years, when the deal fully kicks in, Covance could generate $200 million or more in revenue. That gain represents a six-fold increase in the revenues that Covance will generate from Sanofi in 2010 and is equivalent to 10% of Covance's total revenue for all of 2010. Moreover, the deal protects Covance's preclinical margins at the two acquired sites by guaranteeing $350 million of billings for the first five years. That guarantee is extremely important because there is a glut in preclinical testing capacity, which has hurt pricing and forced preclinical contract research organizations (CROs) to operate facilities with high fixed costs at low levels of use. 

In fact, what has been particularly impressive in both the Sanofi-Aventis deal and the deal Covance struck two years ago with Eli Lilly (Indianapolis, IN) has been Covance's apparent ability to negotiate extremely favorable terms for itself. For one, it has been able to get very large take-or-pay or exclusivity agreements for relatively small initial outlays and very low risk. In good times, these arrangements often yield greater-than-guaranteed volumes, and in bad times they provide a degree of revenue certainty. 

Covance also has used these deals to leverage the relationship beyond its core strengths in preclinical toxicology and central laboratory services to other R&D services where it is not necessarily a standout player, including Phase 2–4 clinical research and other analytical services. In addition, the facility acquisitions have enabled Covance to gain valuable new capabilities, including API development and formulation capabilities in the Sanofi-Aventis deal. 

Covance's deals with Sanofi-Aventis and Eli Lilly are remarkable because of their large size and the broad scope of services they encompass. What does Covance bring to the table that is so convincing to its large pharmaceutical partners?  

For one, Covance probably is the only CRO in the industry that has the scope of services and the scale of operations to offer such a comprehensive R&D package to a top 10 global pharmaceutical company. Other CROs can offer the combination of central laboratory and other clinical research services, and there are a few nonclinical CROs that can offer a comprehensive discovery and preclinical development package. However, no other CRO can offer a combined preclinical and clinical offering with such a large worldwide network of operations. 

Further, we can assume that Covance has demonstrated a high level of operational prowess across its service offerings. Clients wouldn't be signing up for such large fixed commitments unless they were getting good performance from existing dealings with Covance and were convinced it could deliver. Finally, it has a strong balance sheet and a long record of profitability. 

This Covance-Sanofi deal is impressive, but is it really strategic? It doesn't seem to be a game-changer for Sanofi. After all, Sanofi spends $6 billion per year on R&D. When Covance is billing Sanofi $200 million or more per year, that level will only amount to about 3.5% of Sanofi's total R&D and less than 10% of its preclinical and clinical expenditures. Furthermore, we can assume that much of the work now guaranteed to Covance has been outsourced to other CROs, so by itself, it probably means only a marginal increase in overall outsourcing activity. Sanofi is benefitting from saving the financial and political costs of closing two redundant facilities and garners some potential contract-management savings by reducing the number of CROs it is working with in this area.  

As a truly strategic deal, this one falls short of some others we have seen, notably those struck by Lonza (Basel, Switzerland) to provide biologics development and manufacturing services for Novartis (Basel) and GlaxoSmithKline (London, UK). In both those cases, Lonza is effectively substituting its own expertise and facilities for its clients' capabilities and taking principal responsibility for some very strategic elements of its clients' pipelines. The Covance–Sanofi deal doesn't seem to go that far. 

Although the clinical research arena has seen more preferred-provider deals in recent years, it's not clear whether we will see many more of the size and scope of Covance's deals with Sanofi and Lilly. There have been several proposals floated by major pharmaceutical companies, but most have come to naught. A big part of the problem has been that the pharmaceutical companies haven't been willing to guarantee a sufficient volume of work to the CRO to justify the cost and risk of acquiring the facility. It takes a serious corporate commitment and senior executive leadership to do a deal like this, and few major pharmaceutical companies seem to be there yet. 

is president of PharmSource Information Services, Inc., Springfield, VA, 703.383.4903, 

Outsourcing Insights

Covance's deal with Sanofi-Aventis demonstrates the power of scale and scope.

Winning Big

Shortly after becoming editor in chief of this publication in November 2005, I realized that I made an excellent choice, because I had entered a fascinating field replete with passionate people. Five years later, I know a lot more of the details of why the topic is so interesting and the crowd is so good, but the overall assessment is the same: biotech, and bioprocessing more specifically, is a great place to be.  

In spite of that, I couldn't resist the opportunity to switch gears and embark on a new adventure. I am departing 

 to take on a new role here at Advanstar, as the editorial director of the Analytical Science group, which includes 

The great news is that Michelle Hoffman will be taking over the editorial leadership of 

 For the past three years, Michelle has been at the helm of 

 to her responsibilities, with the title of editorial director.  

For those of you who know Michelle from her work at 

, you don't need me to tell you that no one could be better qualified for the job. For those of you who don't know Michelle, please allow me to introduce her.  

 in 2007, Michelle served as editor-in-chief of 

. She also served as the senior science editor for Harvard Medical School followed by almost a decade as the associate editor (life sciences) for 

 magazine. In addition, she was formerly a member of the news staff at 

During her business career, she has been a member of the launch teams of two biotech startups, Quantum Genomics (functional genomics) and Karyogen (drug discovery). Michelle also analyzed new ventures at BD Technologies (part of Becton Dickinson) as a member of the business development group.  

She was trained in molecular biology at Brown and Harvard and holds an MBA from the University of North Carolina at Chapel Hill, where she specialized in corporate finance and entrepreneurship. 

I have seen first hand the excellent work that Michelle has done at 

and the IVT journals. I can't wait to see what happens when she applies her sharp intellect, keen sense of publishing, and her science expertise to 

 I also can't wait for her meet the wonderful 

Before all that happens, however, I have one important final step to take: expressing my gratitude to this great community. To all of you who have provided me with advice and guidance over the past five years—as well as contributions in the form of articles, webcasts, and interviews—I would like to extend a simply stated and heartfelt 

Saying good-bye is always difficult, but in today's digital world, it's not completely necessary. We may not have the opportunity to see each other in person at conferences, but it's easy to stay connected through online communities and even using old-fashioned methods like e-mail and the phone. So let's stay in touch! 

From the Editor

Biotech, and bioprocessing more specifically, is a great place to be. But it's time for a new adventure.

New Adventures

How do life-saving biopharmaceuticals reach people who can't afford to pay for them? Often, it is through public–private partnerships that link companies with governments and international institutions, such as the World Health Organization. In some instances, not-for-profit companies also are involved. These collaborations bring together organizations that sometimes are adversaries in endeavors that have great societal and scientific benefit. They also can further the business goals of the participants.  

In biopharmaceuticals, many of the public–private and cross-sector alliances focus on public health responses to diseases of poverty, such as malaria and tuberculosis. Others distribute preventative vaccines. Most simply, the public sector provides money that the patients cannot. The private sector provides the drug and other technical support at significantly reduced prices, sometimes without making a profit at all. In addition to getting access to the medicines, there can also be an economic development benefit in the communities being served when local residents get jobs distributing and administering the medicines or otherwise participating in the network of activity it takes to produce and use a drug.  

One such alliance is the Novartis Malaria Initiative, which began in the mid 1990s as a partnership with the Chinese Academy of Military Medical Sciences under Novartis predecessor Ciba-Geigy. The Novartis Malaria Initiative is a network of strategic supplier partnerships that extend from China to Kenya that have enabled Novartis to meet skyrocketing demand, diversify supply sources, and reduce the cost of manufacturing by >50%. It has saved an estimated 800,000 lives to date, created economic opportunity in Africa, and helped its Chinese partners implement internationally recognized good manufacturing practices (GMPs). This complex, multi-sector, global alliance has earned Novartis formal recognition for its social responsibility.  

Public–private partnerships also are used to help attract companies to specific locations. Tax credits, investment, infrastructure, and access to technology all are incentives that governments use to attract companies to their locale. In turn, the local economy benefits through the creation of jobs, funding for innovative research, and increased business activity. What makes these partnerships possible is that none of the individual entities could achieve the purpose on their own, and each participant benefits from the results in a unique way.  

Aligning this diverse range of interests makes managing public–private partnerships quite challenging. In two-party collaborations, gaining alignment among internal stakeholders, then between the partners is a significant component of an alliance professional's job. Complexity increases exponentially as new participants are added to the public–private partnership and it becomes a collaborative network. Alliances and collaborative networks seem deceptively simple, but it takes a tremendous amount of diplomatic and strategic skill to achieve an objective that all partners can buy into. The principles of alliance management can guide leaders in deploying policies, processes, and tools that will reduce complexity and achieve great value.  

Despite the management challenges, cross-sector collaborative networks, including public–private partnerships, effectively are tackling complex problems such as diseases of poverty. So far, the major biotechs have not had a big presence.  

Collaborative networks of cross-sector alliances are a necessary and desirable component of societal response to complex problems. They stretch the management abilities of the best and require innovation on many levels to succeed. It remains to be seen what role biologics may have in treating other neglected diseases and public health concerns. If the major biotech firms find value in participating in public health-oriented public–private partnerships, alliance professionals stand ready to provide innovative management practices along side of innovative therapies. 

 is the president and CEO of the Association of Strategic Alliance Professionals, 

is the president of The Rhythm of Business, Inc. and a member of the executive committee of the Association of Strategic Alliance Professionals, 

Final Word

Managing partnerships for the greater good.

Public–Private Partnerships: Life-Saving Mechanisms of Action

The slow pace of economic recovery and continued high unemployment were the top issues fueling the Republican landslide in last month's Congressional and state elections. In addition, fear and confusion over President Barack Obama's healthcare reform plan ignited a "throw-the-bums-out" attitude across the nation that eroded the Democratic majority on Capitol Hill.  

With new leaders controlling the House of Representatives, and Democrats holding a narrower majority in the Senate, Republicans will be looking to deliver on promises to cut government spending and to repeal or revise Obamacare. That will not be an easy task, as many provisions of the Affordable Care Act (ACA) are highly popular, such as tax credits for small businesses, closing the Medicare drug benefit doughnut hole, and requiring insurers to cover patients with pre-existing conditions. There's strong support for approving biosimilars that will be more affordable for patients, a provision championed by consumers and biotech manufacturers alike.

To satisfy candidates who successfully ran against Obamacare, the new House leaders are gearing up for a vote to repeal health reform early next year. But this will largely be a symbolic gesture because it's unlikely to pass the Senate or override Obama's veto. Insurers and biopharmaceutical companies want to extend coverage to the 30 million uninsured, and the individual mandate is key to preventing consumers from waiting until they are sick to purchase health insurance. The worst-case scenario for biopharmaceutical manufacturers is that the promised expansion in healthcare coverage evaporates, leaving companies with added fees and rebates, and considerable uncertainty about reimbursement for new therapies that are costly to develop.  

Instead of wholesale repeal, the new Congress will be looking to challenge specific provisions in the ACA. Medical product makers and insurers would like to roll back the billions in added taxes designed to cover expanded coverage, but that will be costly to the government. One piece of low-hanging fruit is a cumbersome tax-reporting provision that requires businesses to file 1099 forms with the IRS for payments worth more than $600 during the year. Small business is livid over the policy, and even Obama says it should be modified. 

A prime target for biopharmaceutical companies is to eliminate or modify the Independent Payment Advisory Board (IPAB), which has broad powers to set payment policy for Medicare and recommend changes in private-sector payment systems. Doctors and other providers are leery of IPAB's authority to implement rate cuts, and manufacturers fear the Board will propose lower acquisition costs of drugs—particularly high-cost therapies—without weighing how these treatments can help lower healthcare costs overall. Congress is supposed to start funding IPAB in 2012 so it can be up and running in 2014, but that may not happen. 

A main Republican strategy is to starve the implementation of IPAB and other new programs they don't like. House Republicans plan to block appropriations needed by the Department of Health and Human Services (HHS), the Internal Revenue Service, and other agencies to establish new ACA initiatives. This strategy is part of the plan of Rep. John Boehner (R-OH) presumptive House speaker, to make hefty reductions in federal non-defense discretionary spending. 

Cutting the federal budget will not be any easier for Republicans than for Democrats, particularly because Congress first has to deal with some high-cost issues. Medicare fees for physicians will drop by 30% on January 1, 2011, unless legislators extend that deadline for another year, a move calculated to cost about $275 billion. And Bush-era tax breaks, which Republicans champion, also expire Dec. 31 unless renewed or extended before then.  

Big curbs on government spending could create problems for biotech companies. Reducing federal outlays to 2008 spending levels, as Boehner proposes, would be devastating to the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), and various health and social programs. NIH would lose about $3 billion, almost 10% of its current budget, and new FDA initiatives would fall by the wayside. 

At the same time, Republicans may be more responsive to industry concerns about what they deem excessive regulation and supportive of negotiations to renew prescription drug user fees, a top priority for the Biotechnology Industry Organization (BIO) in the coming year. Republicans are less likely to worry about user fees making FDA too dependent on industry, but to cut the budget, they may want to tap manufacturer fees to cover more FDA activities than has been the rule.  

The Republican takeover of the House puts them in charge of the key committees with oversight of health and biomedical programs, and the new leaders plan to be much less friendly to the Obama administration health officials who run them. The new leaders of the House Energy and Commerce Committee are eager to grill HHS Secretary Kathleen Sebelius and her top aides on healthcare reform cost estimates and the effect of specific new policies on employer coverage, premiums, and benefits. The panel also plans hearings on FDA policies and what new initiatives should be added on to user fee renewal legislation.  

Rep. Darrell Issa (R-CA) is in line to chair the House Oversight and Government Reform Committee, where he will be able to issue subpoenas to access desired government documents. At hearings this fall on the FDA's handling of Johnson & Johnson's recall of faulty over-the-counter medicines, Issa criticized the FDA for taking too long to shut down the noncompliant J&J plant and for withholding information sought by committee investigators.  

Although Democrats retained control of the Senate, there will be changes in key health-related committees. Sen. Orrin Hatch (R-UT) will be the top ranking Republican on the Senate Finance committee, where he will continue to play a lead role in revising healthcare and crafting relevant pharmaceutical regulatory policies. He replaces Sen. Charles Grassley (R-IA), removing a long-time critic of pharma and the FDA from that position. The Senate Health, Education, Labor, and Pensions (HELP) committee lost two long-term members because of retirement: Chris Dodd (D-CT) and Judd Gregg (R-NH). Chairman Tom Harkin (D-IA) and Mike Enzi (R-WY) will be lead players in crafting FDA user fee renewal legislation.  

With Congress unlikely to repeal the ACA, opponents of the law are looking to the courts to do the job; several states are challenging as unconstitutional the main tenet of health reform—the individual mandate for purchasing insurance. A case filed in Virginia challenges the individual mandate directly, while a group of 20 states have filed a case in Florida that opposes the federal government expansion of Medicaid, as well as the individual mandate and insurance market reforms. The federal judges hearing these cases decided recently that the issues deserve further consideration, even though another federal judge dismissed a similar case in Michigan in October 2010. With the more conservative jurists in the south likely to disagree, the issue most likely will end up before the Supreme Court in another year or two—but before the individual mandate is scheduled to go into effect in 2014. All sides—including insurers and payers—agree that without a requirement that everyone obtain healthcare coverage, insurance market reform may be unsustainable.  

All of these developments create uncertainty about the prospects of reimbursement for new biomedical therapies, which discourages outside investment in sciences, noted Mark Heesen of the National Venture Capital Association at the October Mid-Atlantic BIO meeting. He and others will be looking to see if Republican leaders are more supportive of policies likely to stimulate small business growth and to address the effect of government regulation on emerging companies. 

Washington editor, Chevy Chase, MD, 301.656.4634, 

Regulatory Beat

Changes on Capital Hill create uncertainty for healthcare reform, drug regulation, and biomedical research.

Biotech Manufacturers Face New Political Landscape

Enhanced process and product understanding are the basic tenets of Quality by Design (QbD). Although significant advances have been made, appropriate characterization and management of raw materials remain a concern for the regulatory authorities. Because of the large number of raw materials that typically are used in biotech processes, a QbD-based approach for raw material management must be based on scientific knowledge and risk analysis. This strategy will ensure that adequate characterization is performed on those raw materials that have the most effect on process consistency and product quality. Part 1 of this article presented an approach for raw material management following QbD principles. In Part 2, we discuss how to conduct risk assessments for biotech raw materials, along with examples of risk assessment tools that can be used. 

The contribution of raw materials to product quality, safety and process performance is considerable, in part because of the potential to introduce contaminants. It is therefore important in designing processes and selecting raw materials that careful thought be given to understanding their purpose and suitability for the intended use. Raw materials also are a major source of variability, and steps must be taken to minimize any negative effects arising from materials and their sources. There essentially are two parts to this: prevention through assessment, inspection and control of incoming materials; and intervention, in which processing conditions are modified to account for variability, sometimes through continued monitoring of materials and their effect on process performance.  

 series discusses how to conduct risk assessments, handling risk communication to stakeholders, and give examples of applying risk assessment tools for analyzing raw materials in biotech processes. 

TOOLS FOR RISK ASSESSMENT, EVALUATION, AND COMMUNICATION

There are a number of different risk assessment tools available in a range of detail and complexity, and it is important to use a methodology suited to the purpose of the assessment. The approach begins with identification of risk factors through brainstorming, in which ideas are recorded with minimal critical appraisal; or Fishbone or Ishikawa diagrams, which offer a more structured approach. These can be used either to map the process generally, working backwards from the endpoint and identifying all possible risks at a given point, or to structure the evaluation around a given sent of questions at each point (e.g., the 6M's: material, method, measurement, machine, man, and mother nature).

  After they are identified, risks can be analyzed by a variety of tools, such as preliminary hazard analysis (PHA), failure mode effects analysis (FMEA), failure mode effects criticality analysis (FMECA), What-if?, fault tree analysis (FTA), event tree analysis, cause consequence analysis, hazard and operability analysis (HAZOP), and hazard analysis and critical control points (HACCP).  

A comparison of some risk assessment tools is given in Table 1. PHA scores risk based on severity and occurrence on a five-point scale, with the highest scores representing the greatest risk. FMEA adds detection to the scoring system. By adding the extra scoring category, it is relatively simple to advance a PHA assessment to FMEA, which may become appropriate as more information is known. Additional criteria may be added to distinguish between risks to more or fewer critical quality attributes (CQAs), bringing it to a FMECA assessment. HAZOP assessments commonly are used to evaluate risk to operators or environmental risks.  

Table 1. Comparison of different risk assessment tools			

The next stage of the risk assessment is risk evaluation, in which the calculated risk index rating is compared to established criteria to determine high-risk items and whether additional information is required, and what mitigation activities are required to bring risk to an acceptable level. 

Finally, communication is an important part of any risk management plan. It is essential that the outcome of the risk assessment is communicated to stakeholders and management and the recommendations for further mitigation or acceptance of residual risk are taken at the appropriate level.  

Before performing a risk assessment, it is necessary to establish a list of CQAs from the target product profile (TPP) of the molecule in question to establish what is being affected by the material in question.

  These can be product related, such as aggregates, deamidated isoforms, incorrectly folded product, or different glycoforms; or process related, such as DNA, host cell protein, cell culture medium components, or purification components.

  Drug product materials also may include materials of construction, dimensionality, labels, and instructions. A more detailed list of product quality attributes, and a discussion of quality attributes is given elsewhere.

A risk assessment is also a valuable exercise in knowledge management, because it brings together cross-functional teams from quality, manufacturing, and early- and late-stage development. Teams should assemble internal and external knowledge, and information from 

, animal, and human clinical studies. The quality of the risk assessment can be highly dependent on the team composition and dynamics, and it is critical to have experienced team members and facilitators available to ensure that all voices are heard. It is strongly recommended to run the meeting face-to-face. It is also recommended that the team begin with the most critical operations near the end of the process and work backwards, because these are the most effective. Lastly, teams should benchmark their scoring against the outcome of previous assessments for similar products and materials to ensure a consistent view of risk. 

Risk assessment examples of materials commonly used in antibody purification are provided in this section. The risk assessments that follow are not specific to any product or material, but represent risks that may be present in a class of materials. No specific supplier is identified or scored in the examples, but they are mentioned where there may be general concerns over the source. 

The purpose of upstream processes is to express the product of interest. Materials are chosen to maximize productivity and consistency without impairing quality. The process also must be protected from adventitious agents, which could result in the loss of a batch, but are unlikely to affect quality because no product would reach patients. A hypothetical scoring of selected materials used for upstream unit operations is given in Table 2. 

such as hydrolysates and yeast extracts are added to cell culture media at various points from thaw to production. They affect growth, titer, cell viability, and product quality, and are a known cause of variability. Functional performance testing is required at great cost to distinguish between lots. Complex nutrients may be a source of viral contamination, resulting in a high severity score: S = 9. This usually is controlled by suppliers, resulting in a lower occurrence score: O = 3. Viral contamination would be observable in the bioreactor, with a detectability of D = 3. Complex nutrients also contain immunogenic materials which typically are removed by downstream processing, so occurrence in the final product is low, and removal of host cell protein can be considered a surrogate marker for the presence of high molecular weight (immunogenic) material, so detectability is good for that parameter as well.  

, which can result in differences in product variants (glycosylation, protease activation) caused by inherent variability and the presence of trace elements. These variants may have similar clinical properties; there may also be variability in titer, cell viability, and filterability, resulting in a lower severity score (S = 7). Such lot-to-lot variability has been observed (O = 5). The variability in product performance is clear if cell growth is affected, but variability in product quality may not be observed until further downstream. Detectability is good (D = 3) and in many cases, downstream purification is likely to remove the variants. 

are used as peripheral filters to protect the main process streams from microbial contamination. They may be 0.45 or 0.22 μm filters that can be used elsewhere as sterilizing filters. Guard filters have contact with process fluids and may be a source of leached materials. Severity scores are low (S = 3), and occurrence and detection levels also are low because contact times are limited and filters typically are characterized for leachable materials. The low risk attached to such filters mean that it is relatively straightforward to qualify alternate sources. Complex nutrients and growth media, on the other hand, may require more extensive qualification, but because a disruption in supply could have severe consequences on process performance and product quality, it is important to consider and qualify alternate sources.  

The main purpose of downstream processes is to achieve the desired levels of product purity; the secondary objective is minimizing product loss. Product variants, process by-products such as host cell protein and DNA, and process materials such as media components have to be removed and the product transferred to the final formulation. Purification typically is through a combination of chromatography and filtration steps, but may include other process steps (precipitation, partitioning, and crystallization) as appropriate. Hypothetical scoring for a downstream step is provided in Table 3.  

Table 3. Selected downstream materials			

generally are innocuous, although there may be some risk for leachables, notably after long-term storage. These usually are characterized by the supplier, and the information is available as a regulatory support file or drug master file. Solvents (ethanol, benzyl alcohol) frequently are used as preservatives, and this also represents the major risk for residual solvents later in the process. Ethanol is a class 3 solvent and represents a low severity (S = 3). Solvent is present in the material as shipped and after storage, but not in the material as used, because resins are washed by a validated washing process before use. Additional consideration should be given for affinity resins where the ligand leaches into the process and specific removal steps may be required for its removal. Protein A is not particularly toxic and is used in approved FDA processes, but does have biological activity as a superantigen,

  which would increase the severity score (S = 5) and require specific removal steps and controls, but is detectable (D = 3). Resins are the primary agent for product purification and poor performance would have a high impact on product quality and yield (S = 7). However, they are not the final step and typically are used in combination with other purification steps. Resin quality is good, and poor performance is seldom observed (O = 3), and normally is detected (D = 3) by changes in purity or yield. Column performance can be tracked by in-line procedures such as transition analysis to monitor continued fitness for purpose. Resins are not interchangeable because the base matrix and resulting profile of impurities from nonspecific binding will vary, depending on the source. Because this represents a single point of failure, supplier selection is critical, and risk may be managed by using different suppliers at different points in the process or in different processes. This is highlighted by the recently published case study from Toro, et al.

  The authors' company received a supply chain notification from a supplier of an ion-exchange resin. Laboratory experiments performed thereafter showed minor differences in the chromatographic profile and pressure drop across the column at different flow rates. The new resin was therefore deemed comparable to the old resin. However, when packed in 20-cm radial columns, significant differences were noticed in the packing properties of the old and the new resins.  

Particle size analysis through a laser-diffraction particle size analyzer showed that the average size for the new resin was 126.9–141.7 mm versus 127.2–130.1 mm for the old resin. Thus, the difference in particle size could not be the reason for the difference in packing behavior. Per the authors, "Since we received the SCN sent by our chromatography media supplier, a significant amount of time and resources have been allocated to identify differences caused by that simple change in the supplier's resin liner source." They further state, "That investigation is ongoing, as is additional experimentation on our part." This case study exemplifies the problems faced when changes are made in critical raw materials.  

are used for maintaining sterility of process streams, concentration, buffer exchange, and virus removal. Filters usually are made of non-interactive materials, and the chief concern, as with guard filters, is the presence of leachables. The effect on the process depends on the specific purpose of the filters; where product passes through the filter there is minimal contribution to the process, but where product is retained, there is the potential for product losses (S = 5). Occurrence and detectability scores typically are low. In the case of viral filters, there are no specific detection methods for viruses. However, filters are validated for viral clearance and if the filter remains integral after use, this can be taken as evidence of successful performance. 

are used as buffers and cleaning agents. These are well defined and typically well understood. However, problems may arise from handling issues such as clumping or deliquescence, which could affect dispensing, extraneous matter, insoluble materials, and filterability (S = 3). Compendial materials generally are intended to have minimal interaction with product, but the presence of trace components may result in undesirable adducts or modifications. These usually are not of concern until the final stages of the process where there are no remaining steps between the product and the patient. Final formulation and packaging processes transform drug substance to drug product. All remaining product components (active pharmaceutical ingredient, packaging, delivery systems, instructions, labels, and secondary packaging) should be viewed as high risk because of their proximity to the final product. 

This article presents an approach for managing raw materials in the QbD paradigm. It should be understood that risk assessments are limited by what is known at a given point in time. In a recent example, it was noted that the distribution of peaks on a column in the purification train showed differences after a process transfer from one site to another. Although it caused no difference in product functionality, the cause of the variability was sought. After investigation, the two sites were found to be using different sources for a media component. Further investigation showed that the two sources differed in their content of a trace metal ion, which was a cofactor for an enzyme whose activity could explain the differences in peak distribution. Continuous monitoring of processes and the use of techniques such as multivariate data analysis are prerequisites for continuous improvement and superior process performance.

The authors would like to thank Jennifer Mercer, Amgen Inc., Thousand Oaks, CA, for her review of the manuscript and her helpful comments.  

, is a biotech CMC consultant and a faculty member at the Indian Institute of Delhi, India, +91-9650770650, 

 is a scientific executive director in process development at Amgen Inc., Thousand Oaks, CA. 

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2. ASTM Standard E-2476. Standard guide for Risk Assessment and Risk Control as it Impacts the Design, Development, and Control of PAT Processes for Pharmaceutical Manufacture. ASTM International. West Conshohocken, PA; 2009.  

3. Rathore AS, Winkle H. Quality by Design for pharmaceuticals: regulatory perspective and approach. Nature Biotechnol. 2009;27:26–34. 

4. Rathore AS. A roadmap for implementation of Quality by Design (QbD) for biotechnology products. Trends Biotechnol. 2009 Sep;27(9):546–53. 

5. Rathore AS. Follow-on protein products: scientific issues, developments and challenges. Trends Biotechnol. 2009 Dec;27(12):698–705. 

6. CMC Biotech Working Group A-Mab: a Case Study in Bioprocess Development. 2009. Available from: 

http://www.ispe.org/cs/explore_by_topic/pqli_resources

http://www.casss.org/displaycommon.cfm?an=1&subarticlenbr=286

7. Low D, Phillips J. 2009. Evolution and integration of Quality by Design and process analytical technology. In: Rathore AS, Mhatre R, editors. Quality by Design for biopharmaceuticals. Hoboken, NJ: Wiley Interscience; 2009. p. 255–86.  

Evaluate and communicate risk to stakeholders.

BioPharm International-12-01-2010