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Combine Mechanistic Modeling and DoE to Streamline QbD

BioPharm International, September 2010 Issue (PDF)

Drug safety has come under fire, prompting the US Food and Drug Administration to take a closer look at its program for establishing Risk Evaluation and Mitigation Strategies (REMS). Charges of safety problems with GlaxoSmithKline's diabetes treatment Avandia (rosoglitazone) prompted advisory committee members to request a restrictive REMS to keep the drug on the market. Recent scrutiny of new anti-obesity therapies indicates that manufacturers will need to present fairly extensive REMS plans to get on the market in the first place. And the ongoing debate over devising a class-wide REMS for long-acting opioids reflects the difficulties in imposing safeguards on prescribing widely used therapies associated with dangerous abuse. 

Although manufacturers are willing to implement costly and cumbersome programs to meet FDA postmarketing safety requirements, doctors, pharmacists, and other healthcare providers are alarmed by the proliferation of new requirements for drug prescribing and dispensing. The most restrictive REMS programs are intended to apply only to those very high-risk products that cannot come to market without special safety controls, but healthcare providers, as well as manufacturers, feel that the program is being overused, raising costs and interfering with patient treatment. Health providers regard all the new educational and patient registration programs as a significant burden on their operations and on the healthcare system. Similarly, payers are concerned about added costs, while consumers are caught between their desire for access to treatment and the need to avoid adverse events.  

These issues have been debated at recent advisory committee meetings to evaluate proposed drugs, as well as at a two-day FDA public meeting in July on the REMS program. The shape and scope of REMS requirements has become a central topic related to revising the Prescription Drug User Fee program (PDUFA), and significant changes are likely to be included in the user fee renewal legislation slated for enactment by 2012.  

At the July public meeting, Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research (CDER), acknowledged that the REMS program established by the FDA Amendments Act of 2007 (FDAAA) "is not perfect" and that the FDA is looking for guidance from all stakeholders on "how we might remodel our house." The FDA also published a draft guidance in October 2009 on what information manufacturers should include in REMS proposals, and the FDA is reviewing comments on this plan.  

Everyone at the meeting acknowledged the importance of REMS in ensuring safe drug use, while highlighting the unintended consequences of added postmarketing requirements at both ends of the REMS spectrum: more diverse medication guides, as well as a growing number of highly restricted REMS with Elements to Assure Safe Use (ETASU). The general complaint is that there are too many REMS of all kinds, and that the FDA should more clearly explain the need for special risk management requirements. So far, the FDA has approved more than 120 REMS, including 15 with ETASU.  

Pharmacists, physicians, and healthcare leaders outlined a host of burdens and costs imposed by multiple REMS requirements. Physicians cited multiple educational and training programs that they consider redundant and unnecessary. Oncologists have been particularly vocal in opposing added educational requirements, noting that they are well trained in using highly toxic chemotherapies. Pharmacists described how training, tracking compliance, and patient counseling takes time and interferes with pharmacy operations.  

Probably the most objectionable REMS feature for pharmacists and providers is the limited distribution systems for high-risk therapies that permit prescribing by only certain well-informed specialists and dispensing by specialty pharmacies that can verify appropriate use and patient understanding of risks. Retail pharmacists complain that such systems steer patients away from regular pharmacies, while hospitals and health plans cite added costs and difficulties in obtaining therapies from restricted sources.  

Pharmaceutical and biotechnology companies would like the FDA to shoulder more responsibility for explaining the need for educational and distribution requirements to providers. The Pharmaceutical Research and Manufacturers of American (PhRMA) proposes that the FDA spell out in action letters on new drugs why a REMS is needed, what risks are being addressed, and why other risk management tools are insufficient to protect patients.  

Another industry goal is to streamline the process for making modifications in established REMS by reducing those changes that require prior approval. The policy creates unnecessary delays and wastes FDA resources, said Andrew Emmett of the Biotechnology Industry Organization (BIO). He proposed a tiered approach to REMS modifications that would allow sponsors to merely notify FDA of administrative and technical changes and limit prior approval to those revisions that affect the main goals, timetable, or implementation system of a REMS.   

A main change sought by manufacturers is to separate MedGuides from the REMS program. Before FDAAA was enacted in 2007, MedGuides were considered part of labeling, and not related to specific risk management plans. Manufacturers preparing MedGuides now also have to establish program goals, monitor how well pharmacists and providers distribute the information, and develop timetables for assessing the plans. There's a lot of paperwork for both the industry and the FDA. Pharmacists say there are too many different MedGuides for patients, sometimes different ones on the same drug for pharmacists and physicians. In some situations, such as with kidney dialysis, patients have to review the same risk information at every monthly treatment session, a requirement that physicians find burdensome and ineffective. But pulling MedGuides out of REMS requires legislation, as would a move by the FDA to establish a single document for describing drug benefits and risks.  

Woodcock acknowledged that paper MedGuides are not the optimal way to provide patients with information and said that the FDA plans to develop a patient information leaflet that is more informative and uses modern communication science. A number of stakeholders support that approach, urging the FDA to devise templates or standardized formats for MedGuides to reduce provider and patient confusion, and to better focus on the information that patients really need. 

Although manufacturers welcome provider support for curbing the scope and number of REMS, they are leery about third parties playing a more prominent role in REMS development and approval, a main goal of pharmacists, physicians, and health plans. At the public meeting, providers called for a more transparent process for REMS development so that doctors and pharmacists would be aware of upcoming risk management programs and have an opportunity to weigh in early on specific proposals.  

It's not clear, though, how or when the FDA could consult third parties on REMS proposals. Before approving a drug for market, confidentiality restrictions prevent the FDA from indicating that a REMS is even under discussion, explained Jane Axelrad of CDER. John Jenkins, director of CDER's Office of New Drugs (OND) queried: "How can we meet early with sponsors to discuss REMS and avoid delay, when consumers see early agreement on REMS lacking in transparency?"  

An added issue is whether REMS programs erect barriers to generic drug development and follow-on biologics. There is general agreement that generic and innovator products should use a shared risk management system to avoid unnecessary multiple approaches, but achieving that goal raises issues about who controls the risk program and how costs should be shared. 

FDAAA specifies that a REMS should not block generics from coming to market and includes provisions providing considerable relief for generics makers in REMS implementation. But generics makers complain that limited distribution systems required by highly restrictive REMS programs prevent innovators from releasing products for bioequivalence testing needed to develop generic versions of the drug. Health plans and payers fear similar problems for developers of follow-on biologics, which generally involve more risky therapies that will be subject to more restrictive REMS requirements. 

 is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, 

Regulatory Beat

Too many REMS cause headaches for doctors and the industry.

REMS Program Challenges Manufacturers, Providers

This article presents a label-free platform for protein characterization and quantitation based on localized surface plasmon resonance (LSPR) on a nanostructured metallic film. With recent advances in manufacturing techniques, the reproducibility of nanostructured thin films has allowed the transition of LSPR from academic interest into the first system commercialization for practical use in research, bioprocess, and diagnostic applications. The nanostructured gold films exhibit a distinct color caused by the absorption of certain wavelengths in the spectrum of white light. The film color changes as biomolecules or other chemicals come into contact with the LSPR surface, enabling precise quantitation of biomolecular interactions. This article reviews the sensitivity and dynamic range of LSPR. It also explains how LSPR signals can be amplified through enzymatic reactions to achieve greater and faster sensitivities than published results for ELISA end-point analyses.

Stained glass has been displayed in the windows of churches all across Western Europe since Medieval times. It was only in 1857 that Faraday

  formulated a scientific explanation for the coloration of the stained glass. As it turns out, the stained glass colors are based on the sands used by the ancient artisans. Unknown to them, different sands contained various quantities of metal salts or minerals (such as gold chloride, gold oxides, cobalt, and silver compounds) which, when melted into glass, resulted in distinct colors ranging from reds and blues to yellow. We now understand that the metal minerals decomposed in the melt and the metal ions aggregated into nanometer-size inclusions. These glass colors are based on wavelength absorbtion of light by the electronic oscillation modes of the metal nanoparticles, called localized surface plasmons.

Basic studies using colloidal solutions showed that colors and wavelengths absorbed can be tailored by the metal's nature, size, and local environment surrounding the metal colloids.

  Using colloidal solutions to monitor binding events for label-free bioanalyses has become routine.

  However, the transition from the academic laboratory to commercialization has been awaiting manufacturing techniques that can replicate what researchers have achieved in Eppendorf tubes.

  With the emergence of powerful metrology tools that can explore the nanoworld, the relationship between the nano and the macro realm finally could be mastered. Today, stable metal films with precise nanostructuring and tunable absorption can be routinely manufactured using a wide range of surfaces. These films are at the core of a new commercial technology, termed 

(LSPR). This article aims to introduce the salient features of LSPR technology and show how LSPR is useful for protein characterization and quantitation.  

Unlike surface plasmon resonance (SPR), a sister technology that uses flat gold thin films surrounded by sophisticated instrumentation, LSPR technology resides in the sensor itself and requires only elementary components.

  An LSPR instrument schematic is shown in Figure 1A. White light from a tungsten halogen bulb is directed onto the nanostructured LSPR film. The light interacts with the localized surface plasmons so some wavelengths are absorbed by the film. The reflected light therefore has certain wavelengths missing and is analyzed by a spectrometer. Figure 1B compares the absorptions of a gold nanostuctured LSPR film (red) and a regular gold thin film (dark yellow). The insets are camera images of both films. The regular gold thin film absorption is featureless and can be described by Rayleigh scattering (~1/λ, in which λ is the wavelength of light).

  In contrast, the nanostructured LSPR film exhibits strong absorption near 550 nm that is the linear superposition of Rayleigh scattering and localized surface plasmon absorption. The LSPR has a natural width of ~80–100 nm, but its maximum position, or λ

, can be tracked in real time with a resolution of a few picometers (Figure 1C).  

Figure 1. Description of the LSPR technology. A) An instrument is composed of a source of white light, the LSPR film, and a spectrometer to read the reflected light. For convenience, in this configuration of an instrument, the light arrives at 90Â°  through optical fibers. The reflected light is sent to the linear array CCD spectrometer (Ocean Optics, USB 2000, with SONY 2048 pixel chip that cover 430â730 nm range) using optical fibers for analysis. B) Absorption spectra of a regular flat gold surface (dark yellow) and the LSPR nanostructured film (red), along with a true color of both films. Absorption is related to the reflected signal through Abs = âlog10 (ref/normalization). The peak position Î»max is computed in real time by a proprietary algorithm. With current hardware, the standard deviation on the peak position is ~6 pm. C) Sensorgram showing the binding and elution of human IgG on a Protein A surface in real time at 3 Hz. D) To test the robustness and reproducibility of the LSPR technology, the same experiment is performed 8 times on four surfaces simultaneously. By computing the shift of the IgG injection after 60 sec, the coefficient of variation (CV) of the 32 readings is ~2.1%. 

, is sensitive to the nature of the interface between the nanostructured gold surface and its environment. For example, in Figure 1C, the LSPR surface is used for the label-free and real time detection of a human IgG antibody binding to immobilized Protein A. Before injection of the antibody, the LSPR signal λ

 = 0. When the antibody is injected, the resonance starts to red-shift, and reaches 3,200 pm after 3 min. After a brief rinse with phosphate buffered saline (PBS), the solution pH is lowered to pH 2 so the interaction between the antibody and the Protein A surface is disrupted. This produces a sudden decrease of the LSPR signal indicating that the antibody has been removed from the surface. When the pH is re-established to its PBS value, the LSPR signal returns to its original value, i.e., Δλ

 = 0, an indication that the sensor has been regenerated. Traces such as this one, also called sensorgrams, represent raw LSPR data. Unlike SPR, LSPR does not require correction for bulk effect signals that occur during injections and rinses. This is a result of the plasmons' localized nature and the fact that they extend and sense only 20–30 nm from the surface. Regular surface plasmons of thin films sense changes up to 200–1,000 nm away from the surface.

To illustrate the performance of current LSPR technology, a 4-channel biochip is used to monitor channels simultaneously in real time when the same human antibody is injected. Figure 1D superimposes the sensorgrams when 8 cycles and binding-regeneration are performed. Analysis of reproducibility is performed by computing the shift in λ

 after an arbitrary 60 sec time lapse after the injection. For these 32 independent repeats, the shift reading yields a coefficient of variation (CV) of ~2.1%. A CV of similar magnitude is measured across channels and across different sensors of the same batch. This underscores the apparent consistencies possible for both the manufacturing and biofunctionalization of the nanostructured films. 

Label-free techniques are powerful tools in bioprocess monitoring for quality management applications and in R&D for applications such as antibody screening, epitope binning and mapping, and affinity and kinetic studies. LSPR technology fits into these categories based on recent published results.

  Concentration monitoring and kinetic analyses, two applications of LSPR technology, are discussed below. 

The high degree of binding reproducibility traces can be used to evaluate dose response or the titer of a particular analyte. In Figure 2A, the response of a Protein A biosensor is measured when exposed to different concentrations of human IgG ranging from 7 μg/mL to 10 mg/mL. There are three overlapping repeats at 500 μg/mL. For quantitation, the LSPR sensor shift is read as a function of the analyte concentration at arbitrarily set check times. Figure 2B reports the reading after 25 and 120 sec for each concentration. The readings can be fit with a logistic model as shown by the dashed lines through the data points. This approach establishes a calibration curve for the sensor or batch of sensors, and is used for determining  the test antibody concentration by comparing the shift produced by the test antibody with the calibration curve.  

Figure 2. Examples to illustrate the depth of the LSPR detection. A) Dose-response of a Protein A surface for human IgG binding, ranging from ~7 Î¼g/mL to 10 mg/mL. 60 Î¼L of IgG is introduced at 30 Î¼L/min to the LSPR surface, followed by a rinse of PBS. The green (25 sec) and blue (120 sec) arrows indicate reading time for generating the calibration curves in panel B. B) Shifts after 25 sec (green line) and 120 sec (blue line) are plotted against the IgG concentrations. The dashed line represents a fit to the logistic model and is used as a calibration curve. C) Illustration of the influence of the matrix on the performance of the LSPR sensor. The binding properties for a Protein A/IgG binding are measured for IgG spiked in PBS and in cell culture media of non-expressing cells at an identical concentration (performed at a customer site). There is a close relationship between the two media, indicating only a minimal perturbation of the media on the performance of the LSPR sensor. D) Illustration of the LSPR capability to compute kinetic parameters. The model used here has caboxybenzene sulfonamide (CBS) on the surface and bovine carbonic anhydrase II (CAII), a 29 kDa molecule, in solution at concentrations of 100, 33.3, 11.1, 3.33, and 1.11 Î¼g/mL. The gray line is the response of CAII on a reference surface lacking CBS on the surface. Fits with Scrubber 2 software to yield a KD of ~1.5 Î¼M, consistent with results reported using SPR techniques.9â10 

Figure 2C compares the dose-response for human IgG measurements performed in PBS and crude media, and indicates only a marginal difference. In fact, LSPR technology has been used to quantify the amount of IgG expressed by Chinese hamster ovary cells and in media obtained from a fermenter within a few percent of the value obtained by HPLC. More generally, LSPR technology is compatible with various matrices, including crude media, whole blood, cell lysates, and other complex buffers containing up to 10% dimethyl sulfoxide (DMSO).  

Similarly, LSPR technology is particularly useful for kinetic analyses because in injection and rinse steps there is negligible bulk effect, which minimizes the need for data manipulation, a potentially major source of variance. Figure 2D represents the kinetic data for the binding and dissociation of bovine carbonic anhydrase II, a 29 kDa protein, to immobilized sulfonamide ligands. Various repeats show that the responses can be reproduced, and allow the kinetic parameters to be computed using Scrubber 2 software, designed for data analysis and used for SPR. The rate constants (k

) are compatible with values reported in the literature using SPR.

FROM LABEL-FREE TO LABELED DETECTION FOR ENHANCING SENSITIVITY

During bioprocessing, detection of host-cell protein, Protein A amounts leached from purification columns, and absence of live mycoplasma are critical for batch validation. These tests currently are performed with methods orthogonal to label-free techniques, and often rely on ELISA assays performed by a third-party laboratory. While results are being determined, production is in a stand-by mode. 

Although label-free LSPR does not require sample pretreatment, its sensitivity is restricted to the 10–200 ng/mL range of detection dependent on the protein being analyzed. To bridge the gap between label-free and labeled technology, LSPR detection can be enhanced with an enzyme-labeled protein capable of selectively binding to the antigen of interest, such as the low level contaminants mentioned above. With a single reading platform, it becomes possible to expand levels of detection into the pico- to femtogram range for an assay time <30 min. The principle of LSPR-labeled detection is illustrated in Figure 3A. An enzyme, such as alkaline phosphatase, is used to convert a substrate into an insoluble form. After deposition on the LSPR surface, the plasmon peak position red-shifts by between 20 and 100 nm (Figure 3B).  

Figure 3. A) Illustration of the label-free and labeled assay implementation using an LSPR surface. In the labeled case, an enzyme is linked to a specific protein. Similar to an immunoassay, the enzyme is used to convert a soluble substrate into an insoluble product. As soon as the product deposits on the surface, the LSPR color changes. After 2 min of reaction with an estimated 2 nm of product deposited on the surface, the color of the surface becomes blue and corresponds to a shift of 50â100 nm with respect to the original plasmon. B) The proof that color change is specific to a LSPR surface becomes evident based on the comparison of LSPR and regular gold sensors for the detection of various amounts of alkaline phospahatase. Although LSPR sensors show a significant dose-response, the regular gold sensor shows minimal response. C) Use of label-free and labeled LSPR for the detection of residual Protein A (Pro A), in a background of 5 mg/mL IgG. In the left panel, residual Pro A is spiked in a solution of 5 mg/mL IgG; Pro A is detected label-free in real time to ~10 ng/mL or 2 ng/mg-IgG of Pro A; in the right panel, the sandwich antibody is labeled with alkaline phosphatase, and its plasmon is read. After addition of the substrate and 2 min of incubation, the LSPR array is read again to screen for a positive response. The graphs on the right represent a control surface exposed to BSA (lacking exposure to Pro A) and a surface exposed to 10 pg/mL or 2 pg/mg of IgG of Pro A. Spectroscopically, the positive surface displays a 44 nm shift, whereas the control shifts by only 6 nm. 

The color shift is caused by insoluble substrate being deposited onto the sensor surface, whereby the nanostructured surface acts as a transducer. The presence, not the color, of the precipitate is measured. For example, the reduction rate of nitro-blue tetrazolium (NBT) by alkaline phosphatase (0.002–0.007 OD/min)

  corresponds to a deposit on the surface of 2–5 nm/min. On the other hand, the LSPR surface can detect <0.1 nm NBT deposition, because that amount would cause a measurable index of refraction change at the surface of ~10

  This is why detection is faster than the traditional ELISA when the same type of experiment is performed on the LSPR surface. 

The particularities of the nanostructured LSPR surface are illustrated in Figure 3B. Antigen and alkaline phosphatase have been immobilized in parallel on both the LSPR and regular gold surfaces. After 2 min of substrate conversion, there is a minimal change on the regular gold chip at an even higher antigen dose, while clear and distinct coloration appears on the LSPR chip. A real case scenario for the detection of residual Protein A, in a 5 mg/mL IgG background, was undertaken to demonstrate the feasibility of this approach. Although the label-free detection can detect down to ~10 ng/mL of Protein A in a solution with 5 mg/mL IgG (Figure 3C, left), the labeled method was able to detect down to ~10 pg/mL of Protein A. The labeled-approach currently is a semiquantitative end-point assay, but there are indications that it can be recast into a real time quantitative assay as the technology advances. 

Monitoring through LSPR requires only a white light source and a spectrometer. The platform also is largely insensitive to temperature and ultra-precise alignment and therefore can be assembled at a fraction of the cost of conventional SPR. Because of its engineering simplicity, LSPR is amenable to miniaturization for certain point-of-use assays. Academic laboratories already have reported palm-size prototypes based on LSPR.

  The emergence of a commercial LSPR platform that reads the absorption of white light by a nanostructured thin film holds great promise for basic protein science and for applications such as quality control and quality assurance. It permits label-free quantitation of biomolecules at the ng/mL level, yet makes contaminant detection in solution at femtogram to picogram levels possible, using the addition of labels that provide notable improvements over current ELISA testing by enhancing the sensitivity and speed of assay responses. LSPR technology is equivalent to current state-of-the art SPR instruments in terms of data quality, sensitivity, and dynamic range, while also being scalable relative to throughput. In its current inception, the LSPR instrument can read eight channels simultaneously with future modules enabling a greater number of channels.  

 are both senior scientists at LamdaGen Corporation, Menlo Park, CA, 650.235.5971, 

1. Faraday M. Experimental relations of gold (and other metals) to light. Philos Trans R Soc London. 1857;147–5. 

2. Mie G. Beiträge zur Optik truber Medien, speziell kolloidalet Metallösungen. Ann Phys. 1908;25:376–445. 

3. Kreibig U, Vollmer M. Optical properties of metal clusters. Springer Series. In: Materials Science, vol. 25. Berlin: Springer; 1995. 

4. Xia Y, Halas NJ editors. Synthesis and plasmonic properties of nanostructures. MRS Bulletin. 2005 May;30(5):329–408. 

5. Anker JN, Hall WP, Lyandres O, Shah NC, Zhao J, van Duyne RP. Biosensing with plasmonic nanosensors. Nat Mat. 2008;7:442–53.  

6. Englebienne P. Use of colloidal gold surface plasmon resonance peak shift to infer affinity constants from the interactions between protein antigens and antibodies specific for single or multiple epitopes. Analyst. 1998;123:1599–1603. 

7. Knoll W. Interfaces and thin films as seen by bound electromagnetic waves. Ann Rev Phys Chem. 1998;49:569–638. 

8. Willets KA, van Duyne RP. Localized surface plasmon resonance spectroscopy and sensing. Ann Rev Phys Chem. 2007;58:267–97. 

9. Day YSN, Baird CL, Rich RL, Myszka DG. Direct comparison of binding equilibrium, thermodynamic, and rate constants determined by surface- and solution-based biophysical methods. Prot Sci. 2002;11:1017–25. 

 10. Jecklin MC, Schauer S, Dumelin CE, Zenobi R. Label-free determination of protein-ligand constants using mass spectrometry and validation using surface plasmon resonance and isothermal titration calorimetry. J Mol Recognit. 2009;22:319–29. 

 11. Virella G, Thompson T, Haskill-Strowd R. A new quantitative nitroblue tetrazolium reduction assay based on kinetic colorimetry. J Clin Lab Anal. 1990;4:86–9. 

12. Neuzil P, Reboud J. Palm-size biodetection system based on localized surface plasmon resonance. Anal Chem. 2008;80:6100–3. 

Features

Use it label-free, or add labels to detect contaminants in solution.

Label-Free and Labeled Technology for Protein Characterization and Quantitation

All companies in the biopharmaceutical and pharmaceutical sectors must comply with regulatory demands. When considering how to achieve regulatory compliance, even small companies, virtual or not, should consider implementing a quality management system (QMS).  

There is, arguably, a common sense business rationale for companies to reach their compliance goals through the introduction of a well designed and easy to operate QMS. There are two business drivers that must be explored. The first is risk mitigation. The second is the need for small organizations to be as efficient as possible in today's challenging financial landscape. 

A well designed QMS can, and should, be an integral part of a business's risk management policy. In both biopharmaceutical and pharmaceutical organizations, particularly those that outsource significant elements of their business, risk management is not an optional add-on, but is a key tool to ensure their growth during the early days of their organizations. Now, it is also an expectation of the regulators that organizations will quantify and manage risks in their supply chains. This is described in ICH Q9. 

A well designed QMS will also ensure that correct alignment across the organization is achieved, so everyone truly understands and delivers what is expected of them. If those processes are well designed and linked through a compliant electronic QMS, small companies will be able to maximize the system's benefits. There is significant cost and risk to a company in this sector having an inefficient and ineffective QMS, and the absence of such a system will likely cause business failure. 

At this point, it is useful to explore why the QMS has not been implemented by all small biopharmaceutical and pharmaceutical companies. There is no single reason, but rather a combination of causes that have caused this. Many organizations do not have a clear vision of how to develop and set up a QMS. In addition, because they typically are R&D-led organizations, they do not have the expertise to introduce a QMS. 

These factors can cause organizations to make the wrong decisions in how they develop and introduce a QMS; then, when the QMS does not deliver the expectations of the business, the QMS is blamed in a self-fulfilling prophecy. If this is the case, the chances of convincing the management team to re-deploy a new QMS diminishes. 

KEY STRATEGIC ELEMENTS OF AN EFFECTIVE QMS

An effective and efficient QMS needs the backing of the organization's entire management team. Otherwise its introduction will not be aligned to the core aims of the business. 

ICH Q10 describes the management team's responsibilities in the QMS. ICH Q10 has been globally accepted by regulatory agencies as the best top-level design for a QMS in the biopharmaceutical and pharmaceutical sectors. It clearly defines what is expected of the management team in a successful QMS. These requirements include: 

 to ensure that the QMS is effective and achieves the quality objectives. 

 to describe the quality strategy, including regulatory compliance. 

 to define and communicate the quality objectives, ensure resources are in place, and establish and review performance indicators. 

 for all types of resources and their appropriate application. 

 in a timely manner, appropriately done, and in the correct flow, including clearly defined escalation processes. 

 of the QMS  for suitability and effectiveness, and periodic reviews. 

If these elements are built into the QMS from the start, the strategies embodied in the QMS will be clearly aligned throughout the business. This allows the business to ensure that the main objectives of having a QMS—compliance, risk management, and productivity—are delivered by the organization through the application of the QMS. 

The management team must consider how to embed the QMS in the organization and how the quality function can be organized and deployed to keep the QMS effective and compliant. 

A review of various regulatory requirements can cause confusion regarding actual QMS requirements. These requirements are best defined in the FDA's quality system inspection technique (QSIT):  

The elements required of these systems are described further in detail. The organization then can assess what elements are necessary for their business operations at their current stage of development. If an element is not necessary, a statement is made in the documentation of the QMS. This ensures that all necessary areas are considered as the organization develops and the QMS stays aligned to the business. The organization also must consider elements not described in the QSIT documentation such as EU-driven requirements for clear quality (technical) agreement between the company and its suppliers. 

Selecting appropriate elements from a well-designed and compliant electronic system (e-system) is the most effective way to allow the QMS to develop as the business grows and its needs change. Ideally, an e-system would be populated with generic documents that could be individually tailored as required to meet the needs of the organization. Regular updates to the generic documents should be made annually to ensure continued compliance with changes in regulation and incorporation of best practices to the QMS.  

At this point it makes sense to consider what a simple system really means. The documents in the QMS must effectively describe the key processes being used by the organization, but in a nonbureaucratic manner. The application of common sense goes a long way to ensure that documents and associated systems are well designed and effective in their application. The organization should develop a hierarchy of documents starting with policies at the top, which lead to the necessary procedures in the QMS. 

There must be a solid and concerted disciplined approach to prevent the number of documents from increasing as the business develops. Adding documents will be necessary, but each one must be carefully considered to prevent the QMS from becoming unwieldy and disorganized.  

Of course, a proactive training strategy is a key element of the application of a simple, well-designed QMS, and the development of the QMS must be done hand in hand with a well thought out training strategy. The organization also must consider whether there is a need for a cultural change as the QMS is deployed. The key to a successful QMS is the people who operate it—therefore, the culture, training, and organizational structure must embody the best approach to gaining staff engagement and alignment to the business strategy. 

In both the biopharmaceutical and pharmaceutical sectors, a simple well-designed quality management system (QMS) can be a real business asset to an organization. It can ensure that the organization stays productive as it grows and develops. Effective application of a QMS will not only ensure compliance with regulations and ensure that the needs of the customers are met, but also will reduce risks and allow the organization to achieve and maintain a competitive level of productivity. 

This can most effectively be done through a compliant e-system that contains well-written documents that clearly describe the processes used in the organization. A strong training strategy must accompany the introduction of the QMS, and the organization also must consider if there are any cultural or organizational elements that must be built into the implementation strategy for the QMS. This can be facilitated by a well-designed QMS that ensures correct alignment and engagement of the whole organization.  

 is the associate director of quality and compliance and 

 is the managing director, both at Pharmaceutical Development Services, Ltd., Nottingham, UK, +44.115.9124277,  

Compliance Notes

What small biotechs need to know about quality management systems.

Quality Management Systems for Small Biopharmaceutical Organizations

On March 23, 2010, some four decades after the modern US healthcare reform debate began, comprehensive reform provisions were signed into a law. Among thousands of pages of legislative text are the most extensive and potentially farthest-reaching amendments to the statutory provisions governing biologics in the 65-plus-year history of Section 262 of the Public Health Service Act (PHSA), pursuant to which the US FDA approves biologic license applications (BLAs). Those PHSA amendments—set forth in Title VII, Subtitle A, of the healthcare reform law and known as the Biologics Price Competition and Innovation Act (BPCIA)—are the culmination of a 14-year debate. That debate began in earnest in 1996, when the FDA adopted its original comparability guidance and, three weeks later, issued its pioneering approval of the first comparable biologic, Biogen Idec's Avonex (interferon  β-1A). In licensing Avonex, the FDA allowed Biogen to rely on the results of a clinical trial of another company's interferon β product manufactured from a different cell line in a different facility in another country—reliance that the FDA's expert reviewers determined was scientifically justified based on Biogen's demonstration that the products were "biochemically and functionally equivalent"—without requiring Biogen to conduct any clinical trials on Avonex.  

Fourteen years later, the BPCIA is designed to leverage what has long been recognized as the next logical step—flowing directly out of the Avonex comparability determination and hundreds of other comparability determinations that the FDA subsequently rendered—by establishing a new regulatory pathway for biosimilars. Thus, under the BPCIA, a biosimilar is a biological product demonstrated to be "highly similar" to a reference biologic from another company that the FDA previously licensed. By adopting this approach to biosimilarity, Congress could be considered to have codified the FDA's longstanding comparability standard. For many years, comparability has been 

"[A] conclusion that products have highly similar quality attributes before and after manufacturing process changes and that no adverse impact on the safety or efficacy, including immunogenicity, of the drug product occurred. This conclusion can be based on an analysis of product quality attributes. In some cases, nonclinical or clinical data might contribute to the conclusion."

Against this historical regulatory backdrop, the BPCIA establishes a biosimilar pathway that adds explicit, albeit waiveable, mandates to the BLA-licensure provisions of the PHS Act for the first time in their 66-year history. Most notably, the law establishes an express requirement that a biosimilar application include "a clinical study or studies (including the assessment of immunogenicity...)." This contrasts with the very broad, longstanding statutory regime, which was in place throughout the biotech revolution and that was aptly summed up in the Federal Court decision affirming the FDA's comparability determination for Avonex: 

"Biogen and FDA acknowledge FDA's past insistence upon clinical trials of each drug being considered for approval, but they contend that no statute or regulation requires it and submit that the use of data on "comparable" drugs is within FDA's discretion.... Neither the PHSA itself nor FDA's regulations issued under the PHSA provide that the clinical study offered to demonstrate the safety, purity and potency of a new biological product shall have been conducted on that very product.... FDA conceded that it had never before approved a new biological drug on the basis of a clinical study of a "comparable" drug, but FDA demonstrated by reference to public documents that the principle of comparability was not unknown and that, in fact, it had been previously applied in other situations."

Under the BPCIA, the statutory regime that the FDA must apply to a "highly similar" biosimilar differs significantly from the very broad and straightforward provisions governing traditional BLAs, which  make no reference to clinical trials or other studies, and simply require a demonstration of safety, purity, and potency to secure BLA approval for an originator biologic. Although Congress greatly amplified the detail of the requirements for what must be included in a biosimilar application, Congress nonetheless delegated scientific responsibility for implementing those requirements to the FDA. In doing so, Congress established what can be, on a product-by-product basis, a self-implementing pathway and one that, in all cases, defers to the expert scientific judgment of the FDA's career reviewers in the same review divisions having responsibility for the counterpart reference biologic BLA. 

From a regulatory science perspective, therefore, what remains to be seen is whether, and if so, to what extent, the provisions of this new pathway governing 

 biosimilars will affect comparability determinations for biological products regulated under traditional BLAs. Even before enactment of the new law, some signs seemed to be emerging that pre- and post-manufacturing change comparability assessments may be subjected to regulatory requirements that could approach those now codified for biosimilars. For example, in connection with Myozyme (alglucosidase alfa) for use in patients with Pompe disease, when the sponsor sought approval for product made at a significantly higher scale after completing a comprehensive comparability exercise, the FDA's initial review uncovered problems indicating the products were not comparable. The FDA's subsequent review found insufficient data to establish clinical comparability between the products. The FDA then requested that the sponsor submit a new BLA with clinical data to support separate licensure of the large-scale product as a new product, for which a new brand name, Lumizyme, was required, albeit with the same international nonproprietary name (INN), alglucosidase alfa.

Traversing the 16-year history between the approvals of Avonex and Lumizyme, it would not be appropriate to suggest that either of them, or any of the comparability assessments in between, are necessarily harbingers of things to come. However, it certainly is clear from these and many other regulatory precedents that demonstrating comparability remains a sponsor's burden and one that needs to be met case-by-case on a data-driven basis. More broadly, depending on how the FDA evaluates biosimilar applications for highly similar biologics in the future, the biosimilars provisions of the BPCIA ultimately could become the foundation for one of the most transformative regulatory paradigm shifts in the years to come. 

In the regulatory pathway itself and in the provisions delegating its implementation to scientific experts at the FDA, Congress established a regulatory pathway that generally enables sponsors to pursue development and approval of biosimilars that they have demonstrated to be highly similar to a previously licensed biologic.  

It is not reasonable to apply that same conclusion, however, to the remaining nonregulatory BPCIA provisions. That is because much of the rest of the BPCIA is disproportionately focused on patent rights, including unprecedented disclosures to enable enforcement of patent rights, and unparalleled limitations on the exercise of patent rights. Unlike the relatively straightforward regulatory pathway-related provisions, which consume about three pages of legislative text, the patent provisions take double that amount of space to codify what can only be considered a convoluted process. Indeed, simply mapping out the patent challenge and enforcement process reveals that it is Kafkaesque in its disorienting complexities. 

Unfortunately, in the years of legislative debate leading up to enactment of the BPCIA, the emphasis from an intellectual property (IP) perspective was on provisions granting nonpatent exclusivity to originators who pioneer the development of innovative biologics. As if exclusivity were the only issue on the table, stakeholders on all sides of the debate often concentrated their advocacy on the period of years: Should it be 5 or 20, 7 or 14, 10 or 11 or 12? Reasonable arguments were presented on various sides of the issue, and Congress ultimately determined that 12 years was an appropriate nonpatent exclusivity period to incentivize R&D for biologics. 

What was lost in the undue focus on this exclusivity period is that Congress codified an exclusivity regime unlike any other that preceded it. One of the most significant distinctions is that it provides for a flat 12-year period (plus pediatric exclusivity when attainable) running from the date of the original approval of the first BLA for a biological product. In practical terms, this means that, as of the day of enactment, there already were several dozen biologics that do not receive any nonpatent exclusivity, including blockbusters like Amgen's Enbrel, Epogen, and Neupogen; Genentech's Rituxan and Herceptin; and J&J's Procrit and Remicade. Moreover, Congress codified detailed provisions (so-called "anti-evergreening" prohibitions) that prevent exclusivity from being granted to slightly modified biologics that are not truly innovative. 

The intensity of the debate around the exclusivity provisions was matched only by the equally intense support among most stakeholders for a patent-challenge process tied to the FDA's regulatory review process. A general consensus emerged among most stakeholders that early patent challenges should be encouraged, but there was no comparable emphasis on adopting a mechanism for concluding litigation. The result was a proverbial patent thicket—ironically, one that presents unique challenges for biotech patent holders and biosimilar sponsors alike. 

For a biosimilar sponsor, the law imposes an unprecedented mandate to turn over its complete BLA and its entire manufacturing process to its direct competitor within 20 days of filing of the application by the FDA. This disclosure occurs some six-to-nine months before patent litigation is initiated in Federal court with attendant judicial oversight of the process. 

For biotech patent holders, the law effectively compels patentees to put their entire patent estate at risk prematurely—when a biosimilar application is filed and potentially long before it enters the market—and imposes unprecedented limitations on enforcement of their rights for any patent not put at risk. These results flow from just a few of the many intricate aspects of the new law's patent-challenge process. First, there is a mandate that the reference BLA holder "shall" provide the biosimilar sponsor—within 60 days of receiving its application and manufacturing process—a list of all patents under which the BLA holder believes a patent-infringement claim reasonably could be asserted against a party making, using, offering to sell, selling, or importing into the US the biosimilar product. Second, to encourage full disclosure of a comprehensive patent list, the new law provides that the owner of any patent not disclosed on a timely basis, i.e., on the initial list or a supplemental list provided within 30 days of a later-acquired patent being issued or in-licensed, is statutorily precluded from enforcing that patent-infringement litigation against the biosimilar applicant. Finally, even for timely disclosed patents, if the statutory timelines are not followed (with litigation initiated before expiry of the relevant 30-day statutory window) or if timely litigation is dismissed without prejudice, the sole and exclusive remedy for infringement is a reasonable royalty. Consequently, biotech patentees confront a real Hobson's choice—either list and risk all patents or "hold back" one or more patent(s) having substantially diminished value. Like so much else in the law's intricate patent provisions, these unparalleled curbs on patent rights create an unlevel playing field for biotech-patent enforcement and are likely to trigger any number of legal and constitutional challenges that will divert resources to a potential plethora of lawsuits spawned by this convoluted new patent-challenge process. None of these outcomes is good for any segment of the biopharmaceutical industry, and all of them represent unsound IP public policy. 

The fundamental flaw in the BPCIA's patent-challenge provisions and the one repeatedly underscored both by the Federal Trade Commission in recommending against their adoption and by the one stakeholder that consistently opposed their enactment is that for the first time in the history of the biotechnology industry, biotech patent challenges are tied directly to the initiation of the regulatory review and approval process.

  This ill-considered approach, however, applies only to biosimilar applications; it does not apply to traditional BLAs. In addition to codifying an overarching disparity across patent-enforcement regimes in the biotechnology industry, the approach creates perverse incentives. Sponsors that otherwise might submit biosimilar applications may undertake the additional regulatory burden of submitting a traditional BLA to avoid the unprecedented requirements and inherent complexities of the biosimilar patent-challenge provisions. Like any other traditional BLA applicant, such a sponsor then would have much greater control over its own destiny in terms of any patent disputes. It could take steps to defer litigation until the postapproval phase, or it could potentially initiate an action during the preapproval phase. 

Such choices generally have always been available to traditional BLA sponsors in connection with hundreds of patent disputes that have arisen among traditional BLA sponsors and between those sponsors and other patent holders. A fair number of those disputes have been settled or resolved through alternative-dispute-resolution mechanisms like arbitration, while others have resulted in published opinions. The latter category can be quite useful in elucidating the newly created disparity in patent-enforcement regimes across biologics sponsors. 

For example, there is the "other" Avonex litigation, the patent lawsuit amongst Biogen, Schering Corporation, and Berlex

While Biogen's BLA was pending at the FDA, the agency and Biogen focused on BLA review and approval, and patent litigation ensued at the end of that review.

  Although Biogen ultimately prevailed on its non-infringement claim, it is worthwhile to consider whether the outcome might have been altered if, when the FDA accepted Biogen's BLA, Biogen had been statutorily compelled—without any discovery request, without any ability to meaningfully object, and without any court oversight—to turn over its complete BLA and its entire manufacturing process. Similarly, when Schering Corporation and Biogen were joined in patent litigation against Amgen on a Biogen patent licensed to Schering Corporation, that suit was initiated after the BLA (now held by Intermune) for Amgen's Infergen (interferon alfacon-1) was approved by the FDA.

  Amgen ultimately prevailed, but it is not unreasonable to ponder how the course of that case might have been affected if Amgen had been statutorily compelled to disclose its trade secrets in its BLA and manufacturing process at the time of BLA filing. Equally worth considering is the patent litigation that Genentech filed against Boehringer Mannheim after the FDA approved a new thrombolytic to compete against Genentech's Activase.

  Although the various reteplase infringement lawsuits ultimately were resolved under unique circumstances (after Roche acquired Boehringer Mannheim, sold US marketing rights to Retavase to Centocor, and then joined Genentech's board),

  it undoubtedly would have been a  fascinating situation if Boehringer Mannheim had been required preapproval and immediately post-filing to turn over its entire BLA and complete manufacturing process to Genentech. 

The prospect of statutorily compelled precomplaint discovery linked to the FDA regulatory review process is merely a hypothetical prospect in these historical cases, and the question of its impact is by definition rhetorical. Nonetheless, given the patent estates and biologics at issue, these cases can be informative case studies for visualizing the impact of such a preapproval patent-resolution process. That process and its unprecedented draconian penalties are the new norm for patent disputes involving biosimilars. 

The inclusion of these patent provisions creates the single greatest hurdle to the realization of the potential that otherwise would be achievable through the regulatory pathway Congress enacted. They are deterring, and probably will continue to discourage, any number of biosimilar applications that could meet the requirements of the new regulatory pathway but that either will be submitted as BLAs or simply will be abandoned. For as long as such perverse outcomes persist, the competitive impact of biosimilars will not be fully realized. The biopharmaceutical industry will not be fully subjected to the market-based competition that can both enhance access to lower cost high-quality biologics and also motivate R&D of the next generation of biologics. Moreover, the US healthcare system as a whole—which was the focal point of the broader law in which the BPCIA was enacted—will not benefit from the savings that otherwise could be achieved. As Europe has demonstrated, biosimilars that are equally as safe and effective as their originator counterparts are producing substantial savings. In the current economic climate, there is an imperative for the US to achieve that same economic outcome and the public health benefit of expanded access to biologics. It can be accomplished through a straightforward fix that, for patent-enforcement purposes, reverts to the 

, eliminates patents from the PHSA entirely, and puts all BLA sponsors on the same footing. 

The views presented in this article solely represent the author's personal opinions and do not constitute the views of his law firm or any of its clients.

is the managing partner at Engel & Novitt, LLP, Washington, DC, 202.207.3303, 

1.  International Conference on Harmonization. ICH harmonized tripartite guideline: Q5E comparability of biotechnological/biological products subject to shanges in their manufacturing process. 70 Fed. Reg. 37861–62. 2005 Jun 30. See also FDA Guidance concerning demonstration of comparability of human biological products, including therapeutic biotechnology-derived products. 61 Fed. Reg. 18612–13. 1996 Apr 26. 

2.  Berlex Laborat ories, Inc. v. FDA, 942 F. Supp. 19, 25 (D.D.C. 1996). 

3.  US Food and Drug Administration. Dockets. Available from: 

http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4389s1-01-FDA.pdf

http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4389b1-04-Genzyme.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125291s000TOC.cfm

4.  Federal Trade Commission Report. Emerging Health Care Issues: Follow-on biologic drug competition 2009. Jun; 52–63. Available from: 

http://www.ftc.gov/os/2009/06/P083901biologicsreport.pdf

http://www.ftc.gov/os/comments/healthcarecompissues/537778-00009.pdf

http://www.ftc.gov/os/comments/healthcarecompissues/537778-00032.pdf

5.  Biogen, Inc. v. Schering AG, 954 F. Supp. 391 (D. Mass. 1996). See also Biogen, Inc. v. Berlex Laboratories, Inc., 318 F.3d 1132 (Fed. Cir. 2003). 

6.  Schering Corp. & Biogen, Inc. v. Amgen Inc., 969 F. Supp. 258 (D. Del. 1997). See also Schering Corp. & Biogen, Inc. v. Amgen Inc., 222 F.3d 1347 (Fed. Cir. 2000). 

7.  Genentech, Inc. v. Boehringer Mannheim, 47 F. Supp. 2d 91 (D. Mass. 1999). 

8.  Kleid DG. Patent Litigations. In: Scientist and patent agent at Genentech: An oral history conducted in 2001 and 2002 by Sally Smith Hughes for the Regional Oral History Office. The Bancroft Library. University of California, Berkeley; 2002. Available from: 

http://content.cdlib.org/view?docId=hb1t1n98fg;NAAN=13030&doc.view=frames&chunk.id=div00167&toc.depth=1&toc.id=div00047&brand=calisphere

An in-depth analysis of the patent provisions of the new legislation.

Biosimilars Approvals in the US: The Path Forward

In recent editorials, I have discussed two major issues involved in biosimilars: intellectual property protection (see more "Biosimilars Approvals in the US: The Path Forward") and the comparability standard. Now, let's consider the third holy grail of biosimilars: interchangeability.  

Under the new US biosimilars legislation, the FDA will decide whether or not to designate a biosimilar as 

 with its reference product. Under such a designation, the biosimilar may be substituted for the reference product without involving the prescribing physician. The stakes surrounding this determination are high. If a biosimilar is 

 designated as interchangeable with its reference product, the manufacturer will achieve little market penetration without actively promoting it to doctors. Most generics manufacturers, who don't even have a sales force, clearly are not prepared for that task. 

In the current regulatory environment, it seems likely that the FDA will be cautious in designating biosimilars as interchangeable. Yet in 1996, the FDA was the first to establish comparability as the standard for interchangeability for innovator biologics following manufacturing changes. In such cases, product labels don't change, and physicians and patients do not know that a manufacturing change has occurred. This brings us back to the standard used to approve a biosimilar. Given that comparability already is the interchangeability standard used by the FDA for innovator biologics, how can a biosimilar approved based on this same standard 

Meanwhile in Europe, where the first biosimilar was approved in 2006, the law is silent on interchangeability. However, at least 15 countries have prohibited automatic substitution at the pharmacy level. Yet some countries have allowed it 

 through the use of tenders and other purchasing arrangements. (In Poland, for example, based on one year's bid, children were switched from Genotropin to Omnitrope, and then following the next year's bid, they were all switched back.) 

There are other recent examples of regulators encouraging drug switching that are unrelated to biosimilars. Following news that the supply shortages of Genzyme's Fabrazyme (agalsidase beta) will continue for months, the EMA's Committee for Medicinal Products for Human Use (CHMP) recently recommended that physicians consider switching patients on low doses of Fabrazyme to alternative Fabry treatments, such as Shire's Replagal (agalsidase alfa). These switches are between products that could never pass the comparability test because they have different active ingredients.  

Here in the US, too, regulators have facilitated drug switching by providing patient access to Replagal under a treatment protocol. Previously, the FDA did the same for VPRIV (velaglucerase alfa), another Shire drug that addresses a Genzyme product shortage. Of course, these latter substitutions involve the physician, and are in response to a critical drug shortage. Yet it is interesting to see that regulators do not seem to feel that the risks involved are high, in spite of known major differences between the products.  

Thus, the interchangeability of biologics has been routine in the US for almost 15 years, as every FDA comparability determination results in a "new" postmanufacturing-change version of a product being treated (by the FDA, the innovator, and physicians) as fully substitutable with the premanufacturing-change product. Furthermore, the FDA, EMA, and physicians have felt it appropriate to substitute certain non-comparable products that have never even been compared in clinical trials. Thus, as the US enters the world of biosimilars, we should keep in mind the full extent of interchangeability that has been going on in this space for years. 

From the Editor

The third holy grail of biosimilars: interchangeability.

Biosimilars, Part 3: Interchangeability

After your R&D team has had a "Eureka!" moment, the first order of business is to engage in process development and production of the product for clinical supply. Perhaps that moment came a few years ago and now you need to ensure that you can supply enough product to meet commercial demand. Do you choose to 

 or retrofit your own manufacturing plant or do you 

 via outsourcing to a contract manufacturing organization (CMO)? This complex decision shouldn't be made lightly because it could affect nearly everything about your business, including your company's financial situation, intellectual property position, and business and product goals. 

In 2009, many small- to medium-sized biopharmaceutical companies struggled to raise funds for their product development and manufacturing projects, while large, financially stable companies reigned in spending and reassessed their pipelines. The building of new manufacturing facilities decreased, possibly reflecting changes in business philosophies as well as a reduced ability by the pharmaceutical and biotech companies to progress with construction.

  At the same time, the global CMO market declined to approximately $2.6 billion, a reduction from years past.

  In general, CMOs saw a drop in requests for proposal, more sensitivity to pricing from potential clients, and there was (and continues to be) increased level of competitiveness amongst CMOs. At least one CMO closed its doors (QSV Biologics). Mergers and acquisitions also changed the landscape of the CMO business, as CMOs of all sizes and capabilities were integrated into larger pharmaceutical or biotech companies (Watson Pharmaceuticals/Eden Biodesign; Merck/Avecia; Recipharm/Cobra).  

Today, the business environment seems to be on the rebound: interest in pipelines including biologics remains strong, and for companies considering outsourcing, CMO capacity is broadly available (though, perhaps because of the acquisitions of 2009, capacity may not remain readily available). Process economics continue to improve through leaps in productivity and the acceptance of new production technologies. There is a wider array of product types requiring cGMP manufacture, including the emergence of biosimilars as originator product patents expire. But the industry has learned some valuable lessons as a result of the tumult of 2009. Companies remain cautious when evaluating requirements for risk sharing, product quality compliance, and business partner compatibility. Cost-containment is still paramount and everyone is looking to manage their project budgets efficiently.  

When deciding whether to build your own capacity or buy it from a CMO, prioritization of what is most important to you as a company should be key. Although your available budget and the return on investment must be considered, your choice shouldn't be made on potential costs alone. Several factors should be weighed before you make your choice:  

 Are you willing to put some (or all) of the responsibility for product development and manufacturing into the hands of a trusted partner?

 Can you assemble a team to execute various project tasks, or do you require support from an external source for things like basic process development and manufacturing, or for specialized activities like fill-and-finish?

Manufacturing scale and production forecast:

 How much of your product will you need to complete your clinical trials or to support commercial demand? Will your company have available capacity at the proper production scale to meet your needs?

 What technologies will be required to manufacture, test, and finish your product? Do you already have the appropriate science and equipment in place? Do you have the budget and time to obtain the required technology, or is partnering with a CMO the best option?

 Is there pressure from investors or the market to achieve a clinical or commercial milestone by a particular date? How will the required project tasks fit with the expected timeline? Will building or retrofitting a facility fit with the timeline, or do you need to use a CMO to achieve your milestones?

Geography/cultures/currencies/ communication:

 Does closer necessarily mean better? Are currency exchange rates critical to your project budget? Are you prepared to communicate across various time zones and possibly cultural influences?

 What is your target market and will you need to include several locations around the globe in your plan to submit a regulatory filing? Do you need to have your own facility and RA staff in the same location as the clinical sites? Is there a CMO out there that can fully support your regulatory plans?

 Does your company wish to control its IP completely, or are you willing to share your know-how with a trusted CMO partner? Will you grant a license to a business partner who will take your product through to commercialization, or do you prefer to maintain control, including manufacturing, throughout the product's lifecycle?

Number of products and their development/clinical phase:

 You should plan for success, but the "what ifs" of failure also need to be considered. Do you have one or two products in the early phase of development, or is your portfolio well balanced with products in all stages of clinical development and clinical trials? It does not make sense to build a new facility if your pipeline cannot support it.

If you have the option to build a facility from scratch ("greenfield") or to retrofit an existing space, you must carefully scrutinize what is available to support the production of your product. A greenfield facility will be fit for purpose from the beginning, but various challenges may arise for a company that choses to build, including keeping to the construction budget and timeline; employing people with the proper background to ensure that the facility is fit for purpose; and training staff to install, validate, and operate equipment. On the other hand, it may be more difficult to retrofit an existing space because the existing space must be able to accommodate the new equipment while perhaps maintaining (and re-validating) some of the legacy infrastructure (e.g., clean-in-place and steam-in-place skids, utilities, tanks, water supply). Any compromises in facility design will need to be weighed against planned production and regulatory requirements.  

If you do decide to build, consider that there are several manufacturing technologies to choose from:  

Disposable, single-use, or limited-use manufacturing equipment:

 Some of the benefits of these components and systems include a low initial capital outlay, fast installation, and reduced routine operating costs, because these can reduce or eliminate the requirement for cleaning or cleaning validation. Although the use of a completely disposable production train is not common, biotechnology companies are beginning to investigate this as an option.

  For particular types of products such as viral vaccines, disposables are indispensable.

 Stainless-steel systems are proven for manufacturing products reliably and reproducibly; the technology is common, so process transfer between manufacturing sites (internal and external) is relatively straightforward, and these systems can support various types of products. But consideration should be given to budget and timeline requirements for installation because they tend to be expensive and time-consuming to order, install, and validate. Cleaning will be a continuous challenge for the lifetime of the system.

Hybrid systems consisting of disposable and stainless-steel components:

 This option seems to be the most popular for manufacturing biopharmaceutical products.

  Systems can be designed to meet your facility and product requirements, using a "best of both worlds" approach. 

Before making your decision to build or retrofit, consider that regardless of the equipment you choose to install, maintenance and materials supply will be a continuous endeavor. Planning for time and costs to operate and maintain these systems should be included in your overall product lifecycle design. 

An alternative to building or retrofitting a facility is to partner with a CMO. Indeed, innovator companies have started looking at the strategic benefits of engaging CMOs to support their products throughout their lifecycle: in general, it is likely that the CMO's facility and quality systems already meet regulatory requirements, including international regulations; an innovator company can choose a CMO in a particular location (or locations) as there continues to be significant CMO business development in Singapore, Israel, Japan, and the BRIC countries (Brazil, Russia, India, and China); CMOs are differentiating themselves by increasingly offering specialized technologies and services, and several major CMOs are engaging the innovator companies by exploring alternative business models. In addition, companies have access to CMOs that are already prepared to not only manufacture a myriad of products, but also provide you with technologies and personnel already in place to "hit the ground running" in support of your project needs. 

One of the benefits of working with a CMO is that in some instances the IP holder for a particular expression system is the CMO (for example, G-Pex/Catalent; GS/Lonza; BI-HEX/Boheringer Ingelhiem; CHEF-1/CMC Biologics), or a technology may be available to the CMO (SURE (Selexis), UCOE (Millipore)/Eden Biodesign) and accessing it through the CMO may allow your company to obtain preferential business terms. Discussion of available options that may be most appropriate for the production of your product should be based on your company's supply requirements (current and future); your available budget; any target product delivery date(s); and your company's risk tolerance and regulatory strategy.  

There are a few areas of specialization that commonly are outsourced by innovator companies, including those who have their own internal manufacturing capability. These include:  

 This usually includes highly specialized analytical techniques such as mass spectrometry, amino acid analysis and post-translational modification analysis. Because these analytical methods usually require expensive equipment and highly skilled technicians, many companies choose to engage the services of an external contract testing house.

This can include vial fill and lyophilization, combination products, and transdermal patches. 

Viral product production: There are several product types in development requiring specialized knowledge and expertise. Examples include viral vaccines, gene therapies, and cell culture products comprising or made using baculoviruses, adenoviruses, or a wide variety of other viruses. Some innovator companies choose to outsource the production of these types of product because of constraints in their existing facility (e.g., segregation of production suites and air handling units), technical expertise, or regulatory requirements.

Before making the decision to buy, get to know your potential CMO partner. Ask questions and be prepared to answer some too. You should understand and then share what your expectations are for working with your chosen CMO, and you should have an understanding of how its capabilities stack up against your internal capabilities and project requirements.  

How current economic conditions affect your build-or-buy decision.

BioPharm International-09-01-2010