Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

The science- and risk-based approach in quality by design (QbD) entails greater product and process understanding as a means to ensure product quality. These concepts are embodied in ICH guidelines Q8 (R2) 

Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) 

(1-4), which offer a lifecycle approach to continual improvement to drug manufacturing.   
  
  


ICH Q11 focuses specifically on the development and manufacture of drug substances. It specifies that a company can follow “traditional” or “enhanced” approaches or a combination of both in developing a drug substance (4). In the traditional approach, set points and operating ranges for process parameters are defined, and the drug-substance control strategy is typically based on process reproducibility and testing to meet established acceptance criteria (4). In an enhanced approach, risk management and scientific knowledge are used more extensively to identify and understand process parameters and unit operations that affect critical quality attributes (CQAs) (4). The enhanced approach further includes the development of appropriate control strategies applicable over the lifecycle of the drug substance that may include the establishment of design space(s) (4). Manufacturing process development should include, at a minimum, according to ICH Q11:

Identifying potential CQAs associated with the drug substance so that those characteristics having an impact on drug-product quality can be studied and controlled

Defining an appropriate manufacturing process

Defining a control strategy to ensure process performance and drug-substance quality (4).

An enhanced approach to manufacturing process development would additionally include: 

A systematic approach to evaluating, understanding, and refining the manufacturing process, including identifying--through prior knowledge, experimentation and risk assessment--the material attributes (e.g., of raw materials, starting materials, reagents, solvents, process aids, intermediates) and process parameters that can have an effect on drug-substance CQAs

Determining the functional relationships that link material attributes and process parameters to drug-substance CQAs (4). 

The enhanced approach, in combination with quality risk management, is used to establish an appropriate control strategy. Those material attributes and process parameters important to drug-substance quality should be addressed by the control strategy. The risk assessment can include an assessment of manufacturing process capability, attribute detectability, and severity of impact as they relate to drug-substance quality (4). For example, when assessing the link between an impurity in a raw material or intermediate and drug-substance CQAs, the ability of the drug-substance manufacturing process to remove that impurity or its derivatives should be considered in the assessment (4). The risk related to impurities can usually be controlled by specifications for raw material/intermediates and/or robust purification capability in downstream steps. It is important to understand the formation, fate (whether the impurity reacts and changes its chemical structure), and purge (whether the impurity is removed via crystallization, extraction, etc.) as well as their relationship to the resulting impurities that end up in the drug substance as CQAs (4). The process should be evaluated to establish appropriate controls for impurities as they progress through multiple process operations (4).


  In March 2011, the European Medicines Agency and Food and Drug Administration launched a three-year pilot program for a parallel assessment by both agencies of certain quality and chemistry, manufacturing and control (CMC) sections of new drug applications submitted to FDA and marketing authorization applications (MAAs) submitted to EMA that are relevant to QbD, such as development, design space, and real-time release testing. The objective of the pilot, which is scheduled to end Mar. 31, 2014, is to ensure consistent implementation between the European Union and the United States of ICH guidelines Q8, Q9, Q10, and Q 11 and to facilitate sharing of regulatory decisions (5-7). 

In August 2013, the agencies reported that the first EMA-FDA parallel assessment of QbD elements of an initial MAA was successfully finalized as well as some consultative advice procedures. In a question-and-answer format, EMA and FDA reported on their expectations as they relate to quality target product profiles (QTPPs), CQAs, classification of criticality, and application of QbD in analytical method development (7). 

With respect to the QTPP, the agencies specified that they expect applicants to provide the QTPP, which describes prospectively the quality characteristics of a drug product that should be achieved to ensure the desired quality, safety, and efficacy of the drug product. With respect to CQAs, the agencies expect applicants to provide a list of CQAs for the drug substance, finished product, and excipients when relevant. This list should also include the acceptance limits for each CQA and a rationale for designating these properties as a CQA. Furthermore, there should be a discussion of how the drug substance and excipient CQAs relate to the finished product CQAs based on prior knowledge, risk assessment, or experimental data. The basis of the control strategy is to ensure that the drug substance and finished product CQAs are consistently within the specified limits (7).

Another issue was whether the agencies would accept a three-tier classification of criticality for process parameters. The agencies responded that ICH Q8 (R2) specifies that a critical process parameter is one whose variability has an impact on a CQA and needs to be monitored or controlled to ensure the process produces the desired quality. EMA and FDA cited a regulatory submission in which the applicant proposed an approach to risk assessment and determination of criticality that included a three-tier classification (“critical,” “key,” and “noncritical”) for quality attributes and process parameters. Using this classification, a “critical” factor was defined as a factor that led to failure during experimentation. A factor that had not led to failure within the range studied, but still may have an impact on product quality, was considered as a “key” factor. The agencies said that they do not support the use of the term “key process parameters (KPP)” because it is not ICH terminology and there is differing use of the term “key” among applicants. Although FDA and EMA said they are amenable to this terminology in the pharmaceutical development section to communicate development findings, they are not in describing the manufacturing process, process control, and control of critical steps and intermediates, where the description of all parameters that have an impact on a CQA should be classified as critical (7).

The agencies further specified that process manufacturing descriptions be comprehensive and describe process steps in a sequential manner, including batch size(s) and equipment type. The critical steps and points at which process controls, intermediate tests, or final product controls are conducted should be identified (7). Steps in the process should have the necessary detail in terms of appropriate process parameters along with their target values or ranges. The process parameters that are included in the manufacturing process description should not be restricted to the critical ones; all parameters that have been demonstrated during development as needing to be controlled or monitored during the process to ensure that the product is of the intended quality need to be described (7).

The agencies also commented on QbD as it relates to analytical methods using risk assessments and statistically designed experiments to define analytical target profiles (ATP) and method operational design ranges (MODR) for analytical methods (7). “There is currently no international consensus on the definition of ATP and MODR,” noted the agencies. “Until this is achieved, any application that includes such proposals will be evaluated on a case-by-case basis” (7). The agencies noted, however, that an ATP can be acceptable as a qualifier of the expected method performance by analogy to the QTPP as defined in ICH Q8 (R2), but the agencies would not consider analytical methods that have different principles (e.g., high-performance liquid chromatography  and near-infrared [NIR] spectroscopy) equivalent solely on the basis of conformance with the ATP. “An applicant should not switch between these two types of methods without appropriate regulatory submission and approval,” they said. The agencies also noted that similar principles and data requirements could apply for MODRs. For example, data to support an MODR could include: appropriately chosen experimental protocols to support the proposed operating ranges/conditions and demonstration of statistical confidence throughout the MODR. Issues for further reflection include the assessment of validation requirements as identified in ICH Q2 (R1) throughout the MODR and confirmation of system suitability across all areas of the MODR (7). The agencies further indicated that future assessment of the pilot program will include other lessons learned in areas such as design-space verification, the level of detail in submissions for design space and risk assessment, continuous process verification, and continuous manufacturing.


  A review of recent literaure reveals some interesting applications of QbD in drug-substance development and manufacturing. For example, scientists at Bristol-Myers Squibb reported on a process-modeling method using a QbD approach in the development of the API ibipinabant, a cannabinoid receptor 1 antagonist being developed to treat obesity (8). In its development, the molecule had volume requirements of 6 kg for toxicology studies and formulation development, which later increased to 175 kg for late-stage clinical trials. The researchers used mechanistic kinetic modeling to understand and control undesired degradation of enantiomeric purity during API crystallization. They implemented a work flow, along with kinetic and thermodynamic process models, to support the underlying QbD approach and reported on the use of risk assessment, target quality specifications, operating conditions for scale-up, and plant control capabilities to develop a process design space (8). Subsequent analysis of process throughput and yield defined the target operating conditions and normal operating ranges for a specific pilot-plant implementation. Model predictions were verified from results obtained in the laboratory and at the pilot-plant scale (8). Future efforts were focused on increasing fundamental process knowledge, improving model confidence, and using a risk-based approach to re-evaluate the design space and select operating conditions for the future scale-up (8).

Scientists at Merck & Co. reported on their work in applying QbD to set up an improved control strategy for the final five steps in the production route of a legacy steroidal contraceptive, which has been produced for more than 20 years within its facilities (9). A generic ultra-high-performance liquid chromatography method was developed according to QbD principles to create a range of proven acceptance criteria for the assay and side-product determination for the final five steps in the production route of the API (9).

Scientists at Eli Lilly reported on a systematic approach consisting of a combination of first-principles modeling and experimentation for the scale-up from bench to pilot-plant scale to estimate the process performance at different scales and study the sensitivity of a process to operational parameters, such as heat-transfer driving force, solvent recycle, and removed fraction of volatiles (10). This approach was used to predict process outcomes at the laboratory and pilot-plant scale and to gain a better understanding of the process. The model was also used further to map the design space (10). 

In other work, scientists reported on the application of latent variables-based modeling to a reaction process in a small-molecule synthesis based on continuous-flow hydrogenation (11). In another study, scientists reported on using a QbD approach for designing improved stability studies (12). Also, scientists at UCB and the Institut des Sciences Moléculaires de Marseille in France recently reported on the feasibility of using online NIR spectroscopy as a process analytical technology tool to monitor in real time the API and residual solvent content to control the seeding of an API crystallization process at industrial scale. A quantitative method was developed at laboratory scale using statistical design of experiments and multivariate data analysis (13). 

Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)

(2012). 
  5.	FDA, “FDA, EMA Announce Pilot for Parallel Assessment of Quality by Design Applications,” Press Release, Mar. 16, 2011.
  6.	EMA, “European Medicines Agency and US Food and Drug Administration Announce Pilot Program for Parallel Assessment of Quality by Design Applications,” Press Release, Mar. 16, 2011. 
  7.	EMA, “EMA-FDA Pilot Program for Parallel Assessment of Quality-by-Design Applications: Lessons Learnt and Q&A Resulting from the First Parallel Assessment,” Press Release, Aug. 20, 2013. 
  8.	S.B. Brueggemeier et al., 

16 (4) 567-576 (2012). 
  9.	J. Musters et al., 


  17 (1) 87-96 (2013).
  10.	I. Figueroa, S. Vaidyaraman and S. Viswanath, 

, online, DOI: 10.1021/op4001127, July 22, 2013. 
  11.	Z. Shi, N. Zaborenkdo, and D.E. Reed, 
  

 7 (3-4) 
  205-213 (2012).
  13.	C. Schaefer et al., J. 

 online, DOI.org/10.1016/j.jpba.2013.05.015. May 20, 2013. PT

Articles

The adoption of quality by design in small-molecule drug development and manufacturing continues to evolve as the industry seeks ways to augment process understanding for APIs.

Quality by Design in APIs

Cambridge Major Laboratories (CML), a provider of API development and manufacturing services, and AAIPharma Services, a provider of pharmaceutical analytical testing, product development, and manufacturing services, announced earlier this month their intent to merge. Patricia Van Arnum, Executive Editor with 

 discussed the merger with Brian Scanlan, CEO and president of CML. 

: Can you explain the strategic rationale for the acquisition? 

 On an immediate level, this merger of equals provides the opportunity for both CML and AAI to offer greater flexibility and more value-added services to our clients. By providing access to a more comprehensive suite of services, we can deliver greater overall value as well as accelerate the drug-development process.

 And yet, this merger has the potential for strategic advantage beyond just expanded capabilities. First, both organizations are best-in-breed in their respective markets. They are strong organizations with track records of growth, technical excellence, and profitability. Second, size matters. Both organizations are of similar sizes and cultures, which is imperative as we look forward to a combined organization. Third, our combined entity provides local strength and global reach. Our new offering provides significant assets in North America, where the majority of innovation is based, but we retain our established presence in the Netherlands, where we have been serving the European market for years. Last, but not least, are the synergies obtained by combining strength in analytical chemistry across the combined organizations. Few, if any, integrated CMC [chemistry, manufacturing, and controls] competitors have equally balanced strength across the entire service offering of API, to analytical chemistry, to finished dosage form. 

: In terms of a business model, the resulting combined company offers API manufacturing, formulation development, and finished product manufacturing. Typically, chemical development and API manufacturing are provided by one contract service provider, and formulation development and finished product manufacturing by another. What are the benefits of this combined model and what differentiation do you hope to provide? 

 Beyond the strategic rationale and immediate benefits previously described, we feel there are a few additional key points of differentiation that will ensure a unique and successful service offering.

First is world-class analytical chemistry that spans the continuum from drug substance through drug product. We believe that analytical chemistry is critical to successful and seamless transition from API into finished dosage form. Parallel development of methods that may be suitable for both API and dosage form can speed overall development. Strong analytical capabilities that enable rapid development of methods and structural elucidation of low-level impurities such as genotoxic compounds are critical.

 Second is combined solid-state/preformulation services to de-risk drug development. Combined characterization services, such as CML’s solid-state chemistry and AAI’s preformulation expertise, enable identification of optimal approaches to enhance solubility and improve the quality of outcomes for overall dosage-form development. The combination of drug substance- and drug product-focused scientists working together will create a new, powerful paradigm in solid-state chemistry.

 Can you provide an overview of the manufacturing facilities (type of manufacturing and location)of the combined company? 

 [It would be as follows]: API development (preclinical, clinical, small-scale commercial) in Germantown, Wisconsin and Weert, the Netherlands; API large-scale clinical and commercial manufacture in Germantown, Wisconsin; finished dosage form development in Wilmington, North Carolina and Charleston, South Carolina; solid-dose manufacture in Wilmington, North Carolina; parenteral manufacture in Charleston, South Carolina; and analytical development and testing in  Wilmington North Carolina, Edison New Jersey, and St. Louis, Missouri.

: What will be the management structure of the combined company? 

 Both entities possess experienced leadership teams that have combined to form an integrated team with direct accountability for a 100-day integration plan. We expect to announce the senior leadership organizational structure very shortly. Cambridge Major Laboratories Inc. and AAIPharma Services Corp. are merging under the ownership of American Capital. Each will retain its name and headquarters at the time of closing, and we expect to announce a new company name in 2014. The combined company will have approximately 800 employees. 

Brian Scanlan, CEO and president of Cambridge Major Laboratories, discusses the rationale behind the company's merger with AAIPharma Services.

Cambridge Major Laboratories Discusses Strategy on its Merger with AAIPharma Services

As pharmaceutical companies intensify their product development and commercialization of biologic-based drugs, they are also investing in biologics manufacturing capacity. Roche and Sanofi are the latest companies to announce investments in biologics. 

Roche plans to invest CHF 800 million ($879 million) within its global manufacturing network to increase production capabilities for its biologic medicines over the next five years. The investment will be spread across sites in the following locations: Penzberg, Germany; Basel, Switzerland; and Vacaville and Oceanside, California in the United States. The investment will support increasing demand for Roche's licensed biologic medicines, such as RoACTEMRA (tocilizumab), Kadcyla (trastuzumab emtansine), and Perjeta (pertuzumab) as well as provide a manufacturing foundation for 39 investigational biologic medicines in the Roche pipeline. 

Biologic manufacturing capacity will be increased at sites in Vacaville and Oceanside with a planned investment of approximately CHF 260 million ($285.6 million). In Penzberg, Roche will invest approximately CHF 350 million ($384 million) toward increased manufacturing capacity and equipment refurbishment.  In addition, Roche will construct an antibody-drug conjugate (ADC) production facility in Basel, Switzerland through an investment of more than CHF 190 million ($209 million), which is expected to create 50 jobs. This investment will provide additional capacity and flexibility to support Roche’s first approved ADC, Kadcyla, and a further eight ADCs in clinical development. 

Genzyme, a Sanofi company, will invest $80 million to build a new downstream processing facility for Fabrazyme (agalsidase beta) to support anticipated growth in global demand over the coming years. The new plant, which will be located adjacent to the new Fabrazyme cell-culture manufacturing site in Framingham, Massachusetts, will expand purification capacity.

Pfizer is investing $130 million in two of its Irish manufacturing sites: $100 million at its Grange Castle site in Dublin and $30 million in the Ringaskiddy site in Cork, according to a July 11, 2013 press release from IDA Ireland, Ireland’s industrial development agency. The $100-million investment in Grange Castle is for additional mammalian-cell manufacturing capacity with the addition of a new production line, scheduled to be operational in 2015, when the first process validation batches will be made. In 2011, Pfizer invested $200 million in the Grange Castle site to develop a new suite to expand the manufacturing process for an invasive pneumococcal vaccine, according to IDA.

Bristol-Myers Squibb is spending approximately $250 million to expand its large-scale biologics manufacturing facility in Devens, Massachusetts. The expansion will introduce biologics development and clinical-trial manufacturing capabilities to the site while adding approximately 350 employees. The Devens site is home to the company’s large-scale bulk biologic manufacturing facility. Construction of the Devens site was completed in 2009. It was the company’s largest single capital investment ($750 million) and provided the company with large-scale bulk biologics production capacity. In May 2012, the company received FDA approval to manufacture its arthritis drug Orencia (abatacept) at the Devens facility. The new $250-million investment will be used to construct two new buildings: one for process development and one for clinical manufacturing. Together, the two buildings will add approximately 200,000 ft2 of laboratory and office space to the Devens site. 

Novartis is constructing a new biotechnology production site in Singapore with an investment valued at more than $500 million. The new facility will focus on drug- substance manufacturing based on cell-culture technology. The site is expected to be fully operational in 2016. It will be colocated with the company’s pharmaceutical production site in Tuas, Singapore. In the future, Novartis expects its Singapore site to be a technological competence center for both biotechnology and pharmaceutical manufacturing. 

In 2012, GlaxoSmithKline (GSK) announced it was investing more than £500 million ($767 million) in the United Kingdom across its manufacturing sites, which included selecting Ulverston in Cumbria as the location for the first new GSK manufacturing facility to be built in the UK in almost 40 years. GSK will locate a new £350-million ($538 million) biopharmaceutical manufacturing facility in Ulverston, Cumbria. Detailed planning and design of the new facility is underway with an anticipated start date for construction of 2014-2015, dependent on portfolio timing and obtaining necessary planning and related consents. Once construction starts, it is likely to take at least six years before the plant is fully operational, according to GSK. 

Roche's plans for a major biologics manufacturing expansion is the latest investment by Big Pharma

Tracking Biologics Manufacturing Investment by Big Pharma

Antibody drug conjugates (ADCs), which consist of a cytotoxic small molecule linked to a monoclonal antibody, are drawing the large pharmaceutical companies and contract manufacturers. AstraZeneca, Roche, and SAFC are among the latest companies to invest in ADC technology. 

This week, MedImmune, the global biologics R&D arm of AstraZeneca, announced it had acquired Spirogen, a privately held biotechnology company focused on ADC technology for use in oncology. MedImmune has also entered into a collaboration agreement with ADC Therapeutics to jointly develop two of ADC Therapeutics’ antibody-drug conjugate programs in preclinical development. 

MedImmune will make an equity investment in ADC Therapeutics, which has an existing licensing agreement with Spirogen. MedImmune will acquire 100% of Spirogen’s shares for an initial consideration of $200 million and deferred consideration of up to $240 million based on reaching predetermined development milestones. Existing out-licensing agreements and associated revenue streams are excluded from this acquisition. MedImmune will also pay $20 million for an equity investment in ADC Therapeutics, which will be matched by Auven Therapeutics, the majority shareholder in both ADC Therapeutics and Spirogen. The collaboration agreement will include an upfront payment with predetermined development milestones for two programs from a defined list and a cost- and profit-sharing arrangement with MedImmune representing the majority share. ADC Therapeutics will also have the option to copromote one of the products in the US. 

As part of a larger biologics manufacturing investment, Roche plans to construct an antibody-drug conjugate (ADC) production facility in Basel, Switzerland through an investment of more than CHF 190 million ($209 million). This investment will provide additional capacity and flexibility to support Roche’s first approved ADC, Kadcyla, and a further eight ADCs in clinical development. 

Sigma-Aldrich's custom-manufacturing services business unit, SAFC Commercial is expanding two of its manufacturing facilities in the United State: The company is  investing in commercial-scale manufacturing capacity for ADCs at its facility in St. Louis, Missouri and is expanding its high-potency API (HPAPI) manufacturing and storage capacity at its facility in Verona, Wisconsin. Additional commercial-scale manufacturing capacity has also been designed to accommodate future growth in demand for ADC production. 

Earlier this month, Carbogen Amcis announced an investment of $4-million to expand its cleanroom clinical-supply facility at its Bubendorf, Switzerland. The Bubendorf facility features a new 100-m

 ADC cleanroom suite for the development and production of ADC clinical material under cGMP and contains Grade D and Grade C areas to allow aseptic and safe handling of highly potent material at occupational exposure limit values (OELs) below 1 µg/m

 at 8-hour time weighted average (8h-TWA). In 2012, Carbogen Amcis and ADC Biotechnology (ADC Bio) partnered for ADC development and manufacturing services. 

In January 2013, Lonza announced plans to invest CHF 14 million ($15 million) to expand ADC manufacturing capacity at its site in Visp, Switzerland. The expansion of the ADC facility will double the company's existing large-scale manufacturing capacity in Visp. The expansion is expected to be completed in the second quarter of 2014. 

In October 2012, Fujifilm Diosynth Biotechnologies formed a strategic alliance with Piramal for ADC production, whereby the two parties will offer contract development and manufacture of ADCs. Piramal offers ADC production at its site in Grangemouth, Scotland. Piramal recently invested $2.5 million at is Grangemouth site to upgrade one of its ADC manufacturing sites from clinical phase to commercial grade. The upgrade gives Piramal two commercial grade ADC suites at the Grangemouth facility while retaining clinical phase manufacturing capacity in other suites on site. 

AstraZeneca and SAFC are the latest companies to expand positions in antibody drug conjugates (ADCs).

Pharma Companies and CMOs Invest in ADC Technology

A review of financing trends in the global and US life-sciences sectors for the first nine months shows mixed results. On the plus side, initial public offerings (IPOs) are up significantly this year on a global basis and in the United States, rebounding from anemic levels in 2012. Venture-capital funding, however, was flat through the first nine months of 2013, and global and US partnering deals declined slightly. Also, on a global basis, mergers and acquisitions (M&A) increased more than 10%, but M&A activity for US-based targets declined slightly. 

Year-to-date global public financings for life-sciences companies were up 15.9% above the same period in 2012, and up 10% for US public companies, according to a recent analysis by Burrill & Company. Globally, capital raised through IPOs is up 232% and follow-on offerings are up 129% in 2013 compared to the same period in 2012. Through the first nine months of 2013, there were 46 life-sciences IPOs compared with 28 IPOs in the same period in 2012, notes the analysis. The 46 IPOs thus far in 2013 raised $6.1 billion compared to $1.8 billion raised from the 28 IPOs in 2012 on a global basis. In the United States, 39 IPOs raised $5.9 billion through the first nine months of 2013 compared with only 12 IPOs that raised only $871 million in 2012, representing a nearly 583% increase. 


On the venture capital front, privately held life sciences companies raised $9.2 billion globally through the first nine months of 2013, about on par with the amount raised in the same period in 2012, according to the Burrill & Company analysis. US financings, at $7.3 billion, were slightly above the $7 billion raised year to date in 2012. Theracos, a pharmaceutical research and development company that develops therapeutics to treat inflammatory disease, metabolic disorders, and depression, completed a $93 million financing, the largest financing of September 2013. 

Globally, life-sciences companies completed $98.1 billion in M&A through the first three quarters of 2013, an increase of nearly 12% compared to the same period a year ago, according to the Burrill & Company analysis. M&A involving US targets is down 4.3% through September 2013 year to date. Most of the activity in September focused on deals outside of innovative therapeutics, noted the Burrill & Company analysis. Private-equity firm Kohlberg Kravis Roberts said it will pay nearly $1.7 billion to acquire Panasonic’s healthcare unit. After the deal, it will own 80% Panasonic Healthcare, which makes and sells blood glucose monitoring devices for diabetics and information technology equipment. Medical-device company Stryker said it will pay nearly $1.7 billion for privately held Mako Surgical, which makes robotic-assisted tools for orthopedic surgery. The biggest therapeutics deal during September was Japanese pharmaceutical company Otsuka’s $886-million acquisition of Astex Pharmaceuticals to bolster its therapeutics pipeline, notes Burrill & Company. The deal gives Otsuka Astex’s fragment-based drug-discovery platform, a pipeline that includes several mid-stage cancer drug candidates, and several partnered programs. Astex’s Dacogen, a drug for myelodysplastic syndromes and elderly acute myeloid leukemia, is sold by Eisai and Janssen. 

Although the global life-sciences partnering activity was down 5% for the first nine months of 2013 compared to the same period in 2012, it was up 5.5% in September 2013 compared to the same period a year ago. The report notes that AbbVie, which has been actively seeking to boost its pipeline as it prepares to lose US patent protection on its blockbuster rheumatoid arthritis drug Humira in 2016, entered into two licensing agreements during the month. It licensed from Ablynx next-generation treatments for rheumatoid arthritis and lupus in a deal worth up to $840 million. Ablynx will get $175 million upfront for rights to its mid- stage candidate ALX-0061. AbbVie also expanded its partnership with Galapagos, which is focused on a next-generation candidate to succeed Humira, to cover new drugs for cystic fibrosis, noted the analysis. Galapagos will get $45 million upfront and up to an additional $360 million in milestones if the partnership succeeds in producing a small-molecule treatment for the debilitating respiratory disease. 

Global biotechnology financing through the first nine months of 2013 shows that initial public offerings are on the rise while venture-capital funding stays relatively flat.

Tracking Biotech Financing

The market for biopharmaceutical contract fill-and-finish services reached $1.2 billion in 2012, an increase of 33% over the past two years, according to an analysis by the market research firm High-Tech Business Decisions. This growth results from the underlying growth in the biopharmaceutical market, expansion of services offered by fill-and-finish contract manufacturing organizations and the greater use of contract manufacturing organizations by pharmaceutical and biotechnology companies (1). Contract manufacturing organizations with traditional aseptic, small-molecule filling capacity have expanded their capabilities to meet the filling challenges of temperature sensitive and fragile protein drugs. The biotechnology industry continues to use fill-and-finish contract manufacturers to provide expertise, filling capacity and lyophilization as they focus on drug development and API manufacturing. 

The analysis notes that long-term prospects for biopharmaceutical fill-and-finish contractors remain strong with growth opportunities in new presentations that offer improved convenience for both patients and healthcare providers. Other growth opportunities include new services associated with special handling of niche products and smaller dosage volumes. As a result of these growth opportunities, this study projects the worldwide market for biopharmaceutical fill-and-finish contract manufacturing will continue to expand through 2017, reaching $1.6 billion. 

"Biopharmaceutical products are becoming increasingly complex requiring special technologies and handling. Capacity utilization rates at contract manufacturing organizations have improved somewhat from two years ago," said William Downey, president of HighTech Business Decisions, in a High-Tech Business Decision release (1). "The investment in new fill capacity by contract manufacturing organizations will be modest over the coming years, thereby keeping industry utilization rates stable. New opportunities exist as the industry evolves to be more flexible with broader offerings and increased capabilities." 

1. High-Tech Business Decisions, "Biopharmaceutical Fill-and-Finish Contract Manufacturing Study Shows Market Growth and New Opportunities," Press Release, Jan. 17, 2013. 

A recent market analysis offers a promising outlook for contract fill-finish and lyophilization services.