The Pharma & Biopharma Outsourcing Association (PBOA), a non-profit trade association established to advance the interests of contract manufacturing organizations (CMOs), contract development manufacturing organizations (CDMOs), and other service providers, has elected Peter Bigelow to serve as chairman of the board of trustees.

Bigelow will work with the board and with PBOA President Gil Roth to develop the PBOA's agenda, represent the association in its regulatory, legislative, and business mission, and serve as liaison between the Board and the member companies. He will serve an initial term of two years, effective immediately. 

PBOA was formed in 2014 by CMOs/CDMOs to advance their regulatory, legislative and business interests. 

"CMOs and CDMOs are the companies that help the pharma and biopharma industry develop and manufacture drugs and other treatments safely and cost effectively. Until now, they haven't had a trade association to represent their needs and interests. The PBOA will ensure that their voice is heard, that they have a seat at the table, and that the industry can move forward and mature," said Roth.

Peter commented, "The strategic importance of outsourcing partnerships has grown immensely in the pharmaceutical development and manufacturing industry. The PBOA represents a great opportunity for the industry to make progress on key issues. I am very pleased to be a part of this new and exciting organization."

Bigelow is the president of xCell Strategic Consulting, a consulting firm to the pharmaceutical industry. He recently served as interim president of the Qualitest Pharma division of Endo Health Solutions, Inc. Prior to founding xCell, he served as the resident of North America commercial operations at Patheon and also held the role of CEO.

He previously spent 14 years with Wyeth, where he was responsible for global supply of Wyeth’s Consumer Healthcare products and held a variety of senior engineering and operations roles for the prescription drug business. In addition, Bigelow spent 14 years at SmithKline Beecham (now GlaxoSmithKline) doing international project work in Europe and the Far East and operations experience with injectable product manufacturing.

PBOA members represent large and small molecules, APIs, and finished dosage forms, and incudes single-site and multi-national companies. The association's founding members are Afton Scientific, Coldstream Laboratories, Cook Pharmica, Gallus BioPharmaceuticals, Halo Pharma, Hospira One 2 One, Jubilant HollisterStier, Metrics Contract Services, Patheon, Inc., Therapure Biomanufacturing, and WellSpring Pharma Services. Initial general members are AAIPharma Services/Cambridge Major Laboratories, Coating Place, Confab and DPT Labs. The advisory committee is chaired by Jim Miller, president of PharmSource.

In a statement, the PBOA will work to advocate and represent its industry before regulatory, governmental, and legislative bodies, keeping members informed of relevant developments; educate pharmaceutical and biopharmaceutical companies, the general public and other stakeholders on the value that CMOs/CDMOs bring to the development and manufacture of therapeutics; and advance common industry goals and interests and support members through industry research, analysis and knowledge sharing.

Activities will include outreach with FDA, Congress and industry associations, holding workshops and webinars for member companies and other CMOs/CDMOs, establishing special interest groups to pursue focused goals, building Business Solutions partnerships with vendors that serve the industry, and developing baseline standards to streamline the client auditing process.

The PBOA's Board of Trustees includes Roth and representatives from the founding members:

• Karen Blair, vice-president, Hospira One 2 One
  • David Flowers, director, business development, Jubilant HollisterStier
  • Nick Green, president, chief executive officer, Therapure Biomanufacturing
  • Tedd Green, president, Cook Pharmica
  • Sally Langa, vice-president, sales and marketing, Halo Pharma
  • Laura Parks, senior vice-president, corporate operations and strategic initiatives, Patheon, Inc.
  • Sam Ricchezza, vice-president, business development , WellSpring Pharma Services
  • John Ross, executive vice-president, Metrics Contract Services
  • Tom Thorpe, president, Afton Scientific
  • Mike Ultee, chief scientific officer, Gallus BioPharmaceuticals
  • Chris Verbicky, director of business development and marketing, Coldstream Laboratories

Pharma & Biopharma Outsourcing Association (PBOA)

Articles

Business

Industry veteran Peter Bigelow to guide PBOA Board.

Outsourcing Association Elects Chairman

Following the recall by FDA in 2008 of heparin due to contamination of raw material from China, the pharmaceutical industry realized that greater management and control of the supply chain was needed to properly protect patient safety. The result: creation of the Rx-360 Consortium, an industry group focused on sharing information and developing processes to enhance the integrity of the healthcare supply chain that complements the efforts of regulatory agencies. Five years later, Rx-360 has established itself as a resource for the industry by providing valuable information and tools related to supply chain security and quality. The organization is currently working to expand its efforts to pharmaceutical markets in developing regions of the world.


  The biggest success for the Rx-360 Consortium, according to Rx-360 chair Brian Johnson, who is also senior director of supply chain security at Pfizer, is that the group is viewed as an industry thought leader in supply chain safety and patient safety. He notes that the group has established a very effective mechanism for raising awareness of counterfeiting, product diversion, theft, and other harmful activities and is now seen as a key source of supply chain intelligence. In addition, Rx-360 has published numerous white papers and developed other supply chain security tools that it shares for free on its 

. The Consortium also hosts free training webinars on key supply chain security topics. “Our goal is to help everyone in the supply chain increase their ability to protect the integrity of the supply chain,” Johnson says.

A key accomplishment for the group has been the development of the Joint Audit program, which allows multiple companies working with the same business partner to participate in a standardized audit without sacrificing product or process confidentiality. “The program is designed to significantly reduce audit costs, standardize the audit scope, expand the number of audits conducted, and ultimately reduce supplier audit fatigue while maintaining a high quality standard,” observes Johnson. “With this program,” he adds, “it is possible for pharmaceutical companies to more effectively allocate their limited resources and achieve greater reach into the supply chain.” In June 2014, Rx-360 announced a strategic partnership with BSI Supply Chain Solutions to streamline the audit process and ensure supplier compliance with quality and security standards through verification audits.

These various initiatives are, however, only part of the reason Rx-360 is viewed as a thought leader by both industry members and regulators, according to Johnson. The Consortium’s commitment to sharing and communication of information is just as crucial. “Rx-360 was founded on a culture of transparency and openness, and our activities are all driven by the need to ensure patient safety. It is necessary to be inclusive, transparent, and open, and to communicate about all issues so that problems can be identified and resolved. Patient safety is not a competitive advantage,” he asserts.


  Recent projects either completed or initiated by Rx-360 cover numerous aspects of supply chain security and involve various approaches to providing information and assistance. White papers made available on the website are written by subject-matter experts and provide tips and suggestions for dealing with challenging issues. One recent example focuses on responding to the problem of cargo theft, which has been an issue for pharmaceutical manufacturers in Italy. The thefts generally involve organized crime and hijacking. The white paper discusses steps that companies can take to reduce their exposure to these types of incidents. Also in 2014, a white paper describing tools and techniques for managing the supply chain and maintaining supply chain integrity was published. According to Johnson, two to three such papers are prepared each year.

Back in the US, Rx-360 pursued an educational campaign targeting the medical community on why purchasing drugs from known, validated sources is critical. Counterfeit, substandard, and diverted medicines represent a serious patient safety risk and can enter the legitimate supply chain via healthcare providers purchasing from unknown sources, according to Johnson. The issue was clearly highlighted when fake Avastin was found in the United States on two separate occasions in 2012. “Education and awareness within the medical community about safe buying practices is an important part of the battle against fake medicines,” he notes. Also in September 2014, the Consortium announced its support for FDA’s “Know Your Source” campaign, which encourages healthcare professionals to verify the source of their prescription drugs and utilize suppliers licensed in-state.

In Africa, Rx-360 has been working to provide information on effective pharmaceutical distribution practices. “It is often a significant challenge to get safe medicines to people in need in Africa due to the lack of proper distribution infrastructure and awareness of the storage and handling needs of many drugs. We have developed materials on good distribution practices (GDP) and are providing them to pharmaceutical companies and distributors through a series of GDP Workshops in Africa in order to help address the shortcomings and increase the likelihood that key medicines will be delivered safely,” he explains.

In the serialization space, Rx-360 is focusing on issues that are not being addressed by other groups. In particular, a working group has been established to look at potential data architectures for serialization that will enable the smooth movement of drug products from one market to another. The Traceability Data Exchange Architecture Work Group, established in August 2014, is a collaborative work group set up to support serialization and track and trace legislation that is evolving globally. “The focus of the group,” says Johnson, “is to develop conceptual models for the interoperable exchange of information needed to comply with global regulations.” The group is expected to have a white paper available by the end of 2014 for discussion at industry forums. The workgroup is tri-chaired by Lloyd Mager of AbbVie, Peggy Staver of Pfizer, and Brian Rezach of Actavis.


  With the numerous successes that Rx-360 has achieved in its first five years, Johnson believes the group is positioned to expand its efforts in a variety of ways. He first notes that globalization has led to increasing complexity in the supply chain, with raw materials manufactured in one part of the world, drug substance produced in another, final drug products packaged in a third and then distributed globally. “As a group, Rx-360 was initially focused on the US and European Union, but we do realize that emphasizing markets that are already highly regulated will not solve the problem. Therefore, we are increasing our efforts around the world, with the ultimate goal of covering the entire globe,” comments Johnson. 

The first initiative was launched in 2013 when the Asia Working Group was established in China. This group is doing a lot of the same work that Rx-360 is doing in the US, but from an Asia/China perspective and with the hopes of influencing supply chain integrity in the region, according to Johnson. The Consortium is also in the process of establishing a similar working group in India. Rx-360 is in discussions with a number of stakeholders and is building momentum for achieving the critical mass needed to formally launch the group.

The Consortium is also focused on expanding participation in the organization by groups involved in the pharmaceutical supply chain other than drug manufacturers and their direct suppliers. “There are a lot of people involved in the supply chain, including distributors, carriers, service providers, and others, and we want to engage with all of these groups in order to be able to evaluate supply chain security issues in a truly holistic manner,” Johnson states.

Driving volume in its Joint Audit program is another major goal for Rx-360. With a larger number of companies participating in the program, the number of available audit reports will increase. As a result, pharmaceutical manufacturers will be able to rely on the joint audit program for lower risk audits of reliable suppliers, and focus their resources on higher risk sources, according to Johnson. “We want this program to be as successful as possible for the industry, and thus we are committed to increasing the volume of audits,” he says.

Finally, Rx-360 is also looking to expand its user base and leverage its knowledge of supply chain security for the benefit of related industries. One of the first efforts is the Medical Device Initiative, which was launched in May 2014 to identify and address the supply chain quality and security needs of medical device companies. The Medical Device Working Group was created to integrate the goals and priorities of the medical device industry into the existing supply chain security programs of Rx-360, according to Johnson. 

Featured Content

Supply chain security and quality group Rx-360 driven by patient safety.

Mission: Close Gaps in the Supply Chain

The number of CMOs is shrinking due to acquisitions, exits, and compliance problems. Additional capacity is being lost as more CMOs pursue proprietary products to gain a better return on their assets. And unlike 15 years ago, when the industry first took off, there isn’t a lot of available capacity to bring into the industry.

Industry consolidation by way of acquisitions is a long-term trend that will run for at least several more years. The emergence of larger CMOs that can achieve economies of scale and offer serious alternatives to in-house networks is a positive development for the industry, and a clear sign of maturity.

Exits from the CMO industry are a more recent development that seems to be picking up momentum. Examples of CMOs leaving the industry in the past year include the contract manufacturing units of Bayer and Boehringer-Ingelheim; Pharmalucence; and SCM Pharma (see  

). There have been two principal drivers of these developments: growing demand for captive manufacturing capacity, and regulatory compliance difficulties.

Boehringer-Ingelheim   Contract Manufacturing*

The demand for captive or in-house capacity stems directly from the acceleration of new product development. Global bio/pharmaceutical companies have rebuilt their pipelines in the past five years, largely through acquisitions and in-licensing, and need capacity to launch new products. Older facilities are being retooled to handle some of the new products, even as new facilities are being built, especially for biologics.

The demand for injectables capacity, in particular, is strong. It is being driven by the development of innovator biopharmaceuticals and biosimilars, but demand from generic-drug manufacturers is also high, thanks to rising prices and shortages of important drugs. This trend is underscored by Sun Pharmaceutical’s decision to take Pharmalucence out of the contract manufacturing business immediately after its acquisition in August. Ten years ago, many injectables manufacturers in India promoted themselves as contract manufacturers; today most of them are using their capacity to support their own generic injectable product lines and hardly mention contract manufacturing.

Exits resulting from quality problems are another important factor. The compliance problems at Ben Venue Laboratories, which resulted in the decision by Boehringer-Ingelheim to withdraw from the CMO business and ultimately close the facility, are well known. In two recent cases, quality problems resulted in a major client taking over the CMO to safeguard its interests. Allergan took over Exemplar Pharmaceuticals, a manufacturer of inhalation products, when Exemplar had problems with a new product Allergan was planning to launch from its site. More recently, Shire Pharmaceuticals took over SCM Pharma to maintain production of a commercial product after SCM lost its GMP license from the Medicines and Healthcare products Regulatory Agency (MHRA).

An important factor in the shrinkage of the industry is the lack of readily available capacity to replace it. The bio/pharmaceutical contract manufacturing industry emerged at a time when global bio/pharmaceutical companies were shedding manufacturing facilities as their blockbuster products neared the patent cliff. Large bio/pharma companies welcomed the opportunity to offload assets onto CMOs, often start-ups formed by site management teams, and avoid costly severance and site cleanup costs. CMO investors welcomed the chance to get productive assets for a nominal amount, with their risk further reduced by contracts to manufacture legacy products.
  Today, the global bio/pharma companies have shed or shuttered most of their unneeded facilities, and there simply isn’t much capacity available on the sidelines. Even if facilities were available, most CMOs wouldn’t want them (unless they were for injectable or bio/pharmaceutical products) because they already have substantial underutilized capacity.

For CMOs, the reduction of the number of competitors and capacity, even at the margin, is a good thing. The tighter capacity can mean better pricing and margins, as buyers have less opportunity to play suppliers off against each other.

The possibility that a CMO might exit the business, however, can have serious implications for bio/pharma companies that depend on CMOs. Generally speaking, unless the CMO goes out of business altogether, product supply should continue through the term of the contract. The client could then be faced with a costly supplier search process and re-qualification at a new CMO.

That eventuality underscores the need for thorough due diligence beyond just a GMP compliance audit. Bio/pharma companies need to understand their CMOs’ corporate strategies and financial condition as well as on GMP. Is the parent company or investors committed to the CMO business for the long term? Does the CMO have the financial resources to sustain itself through difficult times? The due-diligence process may require conversations with the CEO and CFO as well as business development and quality assurance staff.

Risk management plans should incorporate the possibility of a CMO choosing or being forced to exit the business. Sound companies will continue to honor supply contracts, and may even pay for tech transfer if they really want the client products out of the facility However, if a bio/pharma company has concerns about the CMO’s near-term ability to supply its product, it should have a viable second-source strategy or a large buffer stock to protect itself.
  Exits are part of the consolidation process that comes with industry maturity. The CMO industry should welcome the exits of weaker or less committed participants, because it strengthens the industry overall.  But clients need to stay aware, especially during the selection process, that their CMO may be forced or choose to leave the business, and should practice careful due diligence to protect themselves.


Jim Miller is president of PharmSource Information Services, Inc., and publisher of 

, tel. 703.383.4903, Twitter@JimPharmSource, 

Outsourcing

As the number of CMOs shrinks due to acquisitions, exits, compliance problems and a switch to proprietary products, the capacity available to industry is reduced.

CMO Exits Reduce Pharma Manufacturing Capacity

The European Union has been given a leadership role in a   World Health Organization (WHO) pilot project on the sharing by regulatory authorities across the world of assessment   work on the marketing approval of generic medicines. It is a move that has been welcomed by European generic-drug manufacturers, but it is also a move that will highlight the EU’s own difficulties in establishing a harmonized, collaborative approval system for generic drugs among its 28 member states, as well as two other non-EU European states--Norway and Iceland--who comply with the EU licensing system. It will also throw the spotlight on the slow progress in achieving widespread use in Europe of the active substance master file (ASMF) scheme, which would speed up the quality and safety assessment of active ingredients.

The three-year pilot project, which is part of the WHO’s two-year-old International Generic Drug Regulators Pilot (IGDRP) to promote international convergence in generic-drug regulation, aims to provide a model for a permanent system among regulators for sharing work and information on the assessment of generics. Within the pilot scheme, the EU will share with non-EU regulators its assessment reports on the approval of generic drugs within its decentralized licensing procedure, which accounts for the vast majority of marketing authorizations of generic medicines in Europe. The scheme is being led by the EU’s Coordination Group for Mutual Recognition and Decentralized Procedure-Human (CMDh), which runs the decentralized system on behalf of the national medicines agencies.

“(We) strongly support the International Generic Drug Regulators Pilot,” Beata Stepniewska, deputy director general and head of regulatory affairs at the European Generic Medicines Association (EGA), Brussels, told

. “[The pilot will] enable cooperation between regulators and the industry to increase efficiency while maintaining the highest level standards based on the EU regulatory procedure,” she added.

In addition to the EU, the scheme will also initially involve Australia, Canada, Taiwan, and Switzerland, whose medicines agencies are members of the Heads of Agency Consortium. This consortium already has a generics working group that has been drawing up work-sharing arrangements in the approval of generic medicines. Other members of the IGDRP, including Russia, Brazil, China, Japan, Korea, Mexico, New Zealand, Singapore, and South Africa, may join the pilot scheme later.

“The EU leadership is a quite natural (choice), due to its long experience of managing marketing authorization procedures involving multiple partners,” said Stepniewska. “The decentralized procedure, introduced 10 years ago, was a significant improvement, although there are still some areas that can be improved (further).”


The impetus behind the IGDRP program, which includes EU involvement in exploring work sharing in ASMF activities and inspection of bioequivalence and bioanalytical operations, comes from the need to ease the burden on regulatory agencies dealing with an increasing number of generic-drug applications.

“Regulatory authorities must now also contend with more sophisticated generic-drug products and complex global production and distribution chains,” said Mike Ward, international programs manager, Health Canada’s therapeutics products directorate, in an article on the pilot project (1)

The EU’s decentralized procedure gives generic-drug companies the option of gaining marketing approval for their products in individual member states. They can also obtain authorization in groups of countries under a mutual recognition process under which approval in one country is accepted by the licensing agencies in other states.

The procedure has been a pioneer in work sharing of assessments. “One of the key elements of the decentralized procedures is the concept of work sharing between member states receiving the same application for a marketing authorization,” a spokesperson for the CMDh told 

. “As such, the elements identified by the IGDRP, like using resources for an already-assessed application, are in this way not an issue for the individual member states of the EU as the concept of work sharing is already working well.”

There are, however, problem areas where more uniformity in approaches is needed. These areas include measuring of bioequivalence, the contents of the summary of product characteristics (SmPCs), which should be consistent with the product information on the reference medicine, and dealing with information updates, especially resulting from process variations.


Generic-drug companies also have the option of having their products approved through the EU centralized approval system run by the European Medicines Agency (EMA). The EMA also arbitrates on disagreements within the CMDh on mutual recognitions and gives scientific opinions on 
assessment issues arising from the decentralized process.

There has been a sharp drop, however, in numbers of marketing applications for generic drugs through the centralized process mainly because of restrictions on duplicates or more than one authorization for a drug. The decline has stemmed from a decision four years ago by the European Commission to tighten the rules for centralized approvals in the interest of “transparency and predictability” (2).

The restrictions, which came into effect in 2011, were mainly aimed at large international generic-drug companies wanting to market drugs with, for example, different names, variations in excipients, and fewer indications. The Commission allowed duplicate applications from companies with the same ownership but placed restrictions on, for example, the use of different drug names, manufacturing sites, and excipients. Now the number of generic-drug and hybrid-drug applications under the centralized system has dropped by more than half since the restrictions were introduced. In 2013, they totalled 20 against 45 in 2011.

“[The Commission’s action] effectively reduced the interest of generic companies to use the centralized procedure,” explained Stepniewska. “(It) does not reflect how generic companies operate in the EU 28 national markets. This is really not satisfactory for generic manufacturers, as a lot of them would love to use the centralized procedure, especially in view of significant amount of reference products authorized centrally.”

Ironically, the international generic-drug companies that would like to make more use of the centralized procedure are also those most supportive of the IGDRP initiative, because it also has the potential for providing a means for gaining accelerated access to more markets.


An important tool for speeding up the assessment process is the use of ASMFs, which enable the valuable know-how of the manufacturer of the active substance to be protected. At the same time, it allows the applicant or marketing authorization holder to take full responsibility for the medicine, including the quality of the active ingredient.

An ASMF is divided into two parts--an ‘open’ part for the applicant that does not contain any confidential information and a ‘closed’ section detailing the intellectual property on the manufacturing process, which provides the basis for the regulatory authority’s assessment of the API’s quality and safety.

Since the publication of the EMA’s first guideline on the ASMF procedure in 2005 (3), the pharmaceutical industry, particularly generic-drug producers, has had difficulties grasping the ASMF process. The section on the ASMF in an EMA question-and-answer document (4) has had to be revised a number of times so that it now extends to seven pages with nine subchapters. With respect to international information sharing, the EU’S ASMF guideline poses problems. Unlike with the other active ingredient drug master file systems, the EU’s ASMF excludes excipients.

The EU has also not yet finalized its own procedure for work sharing of ASMF assessments. At the moment, the same ASMF can be assessed by different EU member states, which can result in duplication of work. This duplication can result in “inefficient use of assessor resources and inconsistent decisions being made on the same date,” according to a statement by the EMA/CMDh Working Group on Active Substance Master File Procedures (5).

 The working group was established in 2011 to set up a work-sharing system through a harmonized use of ASMF assessments. “The experience gained by the joint working group will certainly be of benefit to the IGDRP pilot,” an EMA official told 

. In 2013, the working group announced it was launching its own pilot scheme with the objective of rolling out a work-sharing procedure through a stepwise approach. The aim was to begin with a “new ASMF” covering an active substance that had not been assessed. It would extend through the whole lifecycle of the API, in particular its updates derived from variations in processes, which has been a big complication for holders of ASMFs for the generic-drug market.

A challenge for this pilot scheme and, above all, for the major IGDRP EU-led pilot project is that they both require pharmaceutical companies to volunteer to take part in them. The success of the initiative to set up a permanent international information and work-sharing model will depend on the support of the industry right from the beginning.

“Regarding the IGDRP project itself, it is too early to assess how many companies will be interested in participation,” said Stepniewska. “The level of interest may not be even visible at the beginning as the regulatory strategy for [imminent] applications has already been established and may not be easily changeable.”

28 (1) (2014). 
  2.	European Commission communication ENT/F/2/RSR re:  Handling of Duplicate Marketing Authorization Applications (Brussels, March 2010).
  3.	EMA, CPMP/QWP/227/02 

Guideline of Active Substance   Master File Procedure

 (London, April 2005).
  4.	EMA, EMA/339324/2007 

Pre-authorization Procedural Advice for Users of the Centralized Procedure

 (London, 2007).
  5.	EMA, EMA/252320/2011 

Mandate of the Working Group on   Active Substance Master File Procedures


Sean Milmo is a freelance writer based in Essex, UK, 

Regulatory

The European Union takes the lead in a global pilot project on the marketing approval of generic medicines, highlighting the challenges of achieving consensus among different nations.

WHO Promotes International Collaboration for Generic Drug Approvals

Analytical instruments and methods are producing more information, enabling more rapid development drug therapies. Experts from contract testing laboratories and service organizations shared their perceptions of analytical testing advances, and challenges still ahead with 

: What emerging technologies or practices do drug sponsors expect your organization to provide?

: In addition to developing clinical candidates that do not have special regulatory designations, drug sponsors expect us to be able to execute accelerated development programs to support their clinical development candidates that have expedited, breakthrough, or orphan designations while maintaining the highest quality standards. In terms of emerging technologies or practices, drug sponsors expect some degree of familiarity with the use of bioavailability and solubility enhancement approaches and an expertise in dry-granulation processes.

: Several analytical areas have been evolving over the past few years that our sponsors look for us to understand and put into practice. One area is cleaning verification and making sure we are up to date with all of the global regulatory requirements. Another area is the use of Phase-specific analytical method qualification/validation and being able to do analytical work following the quality-by-design principles. 

: Sponsors expect CROs to lead implementation of technology and best practices that help them stay current with changing regulatory requirements. Within the past year, older elemental wet chemistry methods were replaced with ICP-MS [inductively coupled plasma mass spectrometry] and ICP-OES [inductively coupled plasma optical emission spectrometry] for United States Pharmacopeia monograph testing per the ICH Q3D [Guideline for Elemental Impurities] revised requirements on specific quantification of heavy metals. Other growth areas (sponsors expect expertise, working practices, or instrumentation) are extractable/leachable testing, following new regulations on container closure; and in-vitro release test (IVRT).

: Mass spectroscopy capabilities are increasingly expected to be a more commonly available asset in contract analytical labs for supporting routine stability or development/validation studies, and not just for characterization studies. Quantitative mass spectrometry, in particular, is required for these services. 
Development/optimization of analytical methods, particularly when performed for bioassays, is expected to include experimental design to test/define method limits, reduce variability, and support a conclusion of method robustness.

: It is very important for a service provider to maintain existing technologies but also to keep up to date with developing equipment and methodologies. Mass spectrometry, for example, has evolved from a research tool to a technique that is often now expected in QC [quality control] environments. Quality is perhaps the single most important aspect of all practices demanded by drug sponsors. 

New test methods deliver more information

: What scientific or technical advances have positively or negatively impacted drug-development processes in this market segment?

: Generally, the ability to automate analytical processes has made significant impact on precision and speed. ;A move towards UPLC technology allows for increases in the rate of analytical testing in the field of liquid chromatography, although, due to the increased efficiency, such development can lead to an often unwanted re-evaluation of the product composition.

: Industry acceptance of IVRT has reduced the number of in-vivo studies used to demonstrate bioavailability or bioequivalence and has helped drug developers better predict the outcome of product release attributes 

. Enhanced chromatography technologies improving method sensitivity and selectivity have allowed drug developers to identify potential degradation products and impurities earlier in the development process.Technology advancements have helped formulators to develop better delivery systems earlier in the product development lifecycle.

: Growing application and acceptance for using reporter gene assays that improve the generation of signals relevant to a product’s mechanism of action has expedited the ability to develop and validate potency assays for biological products. This results in improving the sensitivity in assessing product comparability, whether across lots or in determination of stability, as well as in demonstrating the degree of sameness between an innovator and a proposed biosimilar. 

: Sponsors would like to have one month of stability on the clinical batch to be filed in their IND [investigational new drug application] and they do not want this to slow down their submission.  To accomplish this, the goal is to put the CTM [clinical trial material] batch on stability as quickly as possible, which in a number of projects puts analytical method qualification on the critical path. Formulators have become more proficient at developing final clinical drug product, which in turn puts more pressure on analytical work. 

: On a positive note, a renewed interest in the use of bioavailability and solubility enhancement in formulation development has allowed drug substance candidates that previously would not have been considered for clinical development to achieve sufficient bioavailability to be advanced into further development. 

: Are you seeing shifts in demand for particular types of services? 

: Xcelience is seeing a shift in certain service areas. In particular, sponsors desire a better evaluation and understanding of their active drug substance. They want to have a full understanding of what properties of their API are critical to their drug product. This also applies to excipients that will be utilized in the drug product.  The concept of quality by design should now be a focus of the analytical work and not just a focus of formulation development.

: One trend is a continued demand for extractable/leachable (E/L) studies for broad array of dosage forms and products as a requirement for drug development and commercialization. In addition, E/L studies now are being extended to manufacturing process equipment and intermediate storage containers. Service requests performed by our biopharmaceutical services department are growing rapidly, particularly in support for follow-on biological and biosimilar products. Included in this is an increasing emphasis on a product’s functional characterization. 

: We are seeing an increase in demand for dry granulation services, especially in roller compaction, large molecular characterization, and an increased interest in the development of dosage forms specially designed for pediatric administration.

: Demand for heavy metal testing, extractable/leachable testing, IVRT for all types of products, and purity/characterization analyses for large molecules have increased. Since large molecules are difficult to characterize using singular analytical techniques, a variety of test methods, from size-exclusion chromatography, gel electrophoresis and Western Blot, to particle characterization using laser diffraction and fragmentation analysis using mass spectrometry may be employed. These challenges have increased demand for specialized analytical services.

: In the specific area of biopharmaceutical testing, there has been an unmistakable expansion into services that allow higher order structures to be defined. Such techniques are now applied in characterization of primary products as well as for comparability studies such as in the testing of in biosimilars. 

Addressing technical challenges
PharmTech

: What pressing technical challenges have you seen in this market segment? What actions has your company taken to resolve the challenge? What actions does your company suggest?

: Common technical challenges often relate to instrumentation limitations. The use of currently available instrumentation generally involves sacrificing sensitivity for broad application, or vice versa. 
Most service providers actively attend relevant conferences and events (such as Pittcon) and engage frequently with instrument developers to stay current on instrumentation technology and attempt to employ these technologies to specific analytical challenges. 

: Because of the aggressive development timelines associated with today’s drug product market and a renewed interest in drug-product candidates with expedited, breakthrough, and/or orphan designations, we have seen a decrease in the amount of time and effort available to fully assess their product and process design space to support process performance qualification (PPQ). To address this growing trend, we incorporate QbD [quality by design] into our development strategy and have established what we term “QbDLite,” which is an abbreviated yet thorough assessment of our client’s design space to support PPQ.

: One technical challenge is the increasing expectation for the contract lab to evaluate impurities at trace levels as instrumentation capabilities become enhanced. However, this is often thwarted by obstacles caused by product matrix complications. Another area is the growing interest in the effects of aggregates on product performance, particularly regarding the impact on a product’s potency. Both the generation and evaluation of aggregates and their effects on product performance promise to increase the technical demands on the biopharmaceutical services team. Evaluating various sample prep cleanup options and automation are two of the approaches we are taking to address this. We are recommending that our clients initiate earlier and more extensive characterization of degradation conditions, and investigate the changes to a product’s physicochemical characteristics, as well as performance changes that might occur.

: A challenge is the use of mechanical calibration for dissolution apparatus. This speeds up the process and provides for fewer failures than using the traditional tablets procedure for calibration. It takes some training to get analysts used to operating this way but is well worth the effort. Labs are being pushed to get the data faster whether it is for a batch release or for stability samples. To meet the ever-tighter timelines, it is necessary to evaluate all processes used in lab and become more efficient. The answer is not just [to] hire more people.

: One of the many technical challenges lies in definition of biotherapeutic impurities. Such studies often demand a multidisciplinary approach in terms of technology and expertise. SGS is able to respond to such requirements by maintaining a broad base of scientific experts and diversity within laboratory instrumentation, which is continually updated.

: What advances do you see developing in science or technology in this market segment in the next five years?

: In the next few years, it is foreseeable that we will see more seamless integration of mass spectrometry with biological samples in aqueous buffers. In addition, routine, bench-top NMR [nuclear magnetic resonance] for impurities identification and characterization will be more commonly used. Plug-and-play mass detectors will be more routinely applied to LC [liquid chromatography] and GC [gas chromatography] covering wide mass ranges.

: We see increased interest in anti-counterfeiting measures to address the growing global pharmaceutical manufacturing activities that can result in compromised global supply chain.  In addition, we see the growing importance of assuring patient compliance through the use of advanced technology approaches, including those that can sense and signal the administration of dosage units to patients.  There are also new advances in tablet presses that allow for unique dosage-unit configurations that were not possible even a few years ago.  These advances can result in the design of bisected compressed powder tablets that maintain sustained release delivery even after bisection or the ability to form dry-coated dosage units containing multi-particulates.

: High throughput and sensitive analytical instrumentation will continue to advance.  Using a combination of scientific expertise with the latest technologies will continue scientific advancement for analytical techniques.  It is important for scientists to remain engaged in the development of new technology and ensure that the technologies developed are fit for the purpose they are intended. 

: Traditionally, there has always been a demand for increased rate of testing and this will continue with advances in automation and application of technologies such as UPLC. In the biopharmaceutical-testing field, advances in sensitivity and miniaturization will become critical, particularly with the evolution of individual patient therapies. Techniques such as  FTIR [fourier transform infrared spectroscopy]  may also advance to allow non-destructive, continuous screening, which may find application in, for example, stability programs.  


New assays, as well as advances in mass spectrometry and chromatography, give analytical testing laboratories tools to provide drug sponsors with additional information.

Analytical Testing Advances Deliver More Data

Due to its high ionization potential, electron affinity, and electronegativity, fluorine is a highly electron withdrawing substituent. In addition, fluorine-carbon bonds are much stronger than carbon-hydrogen bonds. Consequently, incorporation of fluorine atoms into APIs results in changes in polarity that often affect not only the reactivity of neighbouring groups, but also the acidity, basicity, protein binding affinity, and lipophilicity of these molecules. As a result, fluorination can significantly impact the bioavailability of drug substances. Introducing fluorine into complex intermediates can be a challenge, however, and generally requires special expertise. Finding contract manufacturers with GMP fluorination capabilities can, therefore, also be a challenge.


The initial reagents used for the fluorination of organic compounds, such as potassium fluoride (KF), hydrogen fluoride (HF), antimony trifluoride (SbF

) itself, generally require harsh reaction conditions. These reagents are also typically gases that are aggressive. Some are also explosive and/or toxic.

Although still widely used in many industries, their application to API synthesis has been somewhat limited. Reagents that are more commonly used in the pharmaceutical industry still present handling issues. They also tend to be costly and often are not appropriate for the introduction of fluorine in the presence of functional groups. Such reagents include poly[4-vinylpyridinium poly(hydrogen fluoride)], 1-fluoro-2,4,6-trimethylpyridinium triflate, cyanuric fluoride, and tetrabutylammonium hydrogen difluoride.


The search for less aggressive, easy-to-handle, nontoxic fluorinating reagents has been underway for many years. Initially improved reagents such as (2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), which are both from Air Products, have been more widely used in API synthesis. Diethylaminosulfur trifluoride (DAST) is another common reagent.

Deoxo-Fluor and DAST are nucleophilic fluorinating reagents that have improved properties compared to the harsher chemicals mentioned previously. They rapidly deoxofluorinate alcohols, aldehydes, and ketones under mild conditions to yield the corresponding fluorinated compounds with high efficiency and selectivity. The reaction involves the nucleophilic replacement of oxygen with fluorine, with hydroxyl groups converted to C-F substituents and carbonyl groups to CF2 moieties.

Selectfluor, also known as F-TEDA-BF4, is a general-purpose, site-selective electrophilic fluorinating agent that rapidly fluorinates a wide range of organic molecules under mild conditions with high efficiency and selectivity and, in many cases, has been used as an alternative to FClO

OF. Recent examples of reactions achieved with Selectfluor include the iron-catalyzed free radical Markovnikov hydrofluorination of unactivated alkenes (1) and the synthesis of monofluorinated benzylic substrates (2), the silver-catalyzed decarboxylative fluorination of aliphatic carboxylic acids (3), and the chemoselective, metal-free introduction of a fluorine atom into various aromatic and aliphatic compounds (4).


More recently, solid fluorinating reagents have been introduced to the market: Xtal-Fluor-E from Manchester Organics (in partnership with OmegaChem) and Fluolead from UBE Industries.

Xtalfluor reagents include (diethylamino)difluorosulfonium tetrafluoroborate (Xtal-Fluor-E) and difluoro(morpholino)sulfonium tetrafluoroborate (Xtal-Fluor-M). These fluorinating agents are easily handled crystalline solids with enhanced thermal stability (i.e., higher decomposition temperatures with lower exothermic heat and higher onset temperatures for self-accelerated decomposition) (5). They do not generate free HF and are compatible with glass equipment. In addition, they generally produce fewer elimination side products, and thus provide greater selectivity than more traditional nucleophilic fluorinating reagents, such as DAST and Deoxo-Fluor (6, 7).

Fluolead (4-tert-Butyl-2,6-dimethylphenylsulfur trifluoride) is also a crystalline nucleophilic fluorinating agent useful for deoxo-fluorination reactions. Its reactivity is comparable to that of SF

, but it has high thermal stability, can be handled in air, does not fume, and reacts slowly with water.  In addition to converting alcohols and carbonyls to CF and CF

 groups, Fluolead converts carboxylic acid (COOH) substituents to trifluoromethyl (CF

) groups and can fluorinate sulfide compounds (8-11). While these reagents are easier and safer to work with, their higher cost can still pose a challenge for commercial-scale use.

I) has also risen recently, according to Anthony Nigro, manager of product development for Halocarbon Products. Conventionally, the trifluoroethyl group has been introduced using trifluoroethylamine, which is a weak base that requires strongly acidic reaction conditions and thus can only be used for substrates that can withstand exposure to strong acids. Trifluoroethyliodide is much more reactive, and this reagent can even be used in later stages of pharmaceutical syntheses. “Convergent synthetic strategies, which require the introduction of fluorine substituents much later in the synthetic sequence, are gaining in popularity, as are direct fluorination techniques. This trend is one of the drivers for the interest in trifluoroethyliodide,” notes Nigro. He adds that the iodide does not require any special equipment or handling and is a cost-effective reagent.

I include the Pd-catalyzed 2,2,2-trifluoromethylation of organoboronic acids and esters (12) and the synthesis of β-trifluoromethylstyrenes via a domino Heck coupling reaction (13).


While the search for fluorinating reagents that are inexpensive, safe, and mild for use with complex intermediates in large-scale manufacturing processes continues, pharmaceutical companies must continue to achieve fluorination using currently available reagents that meet the cost and reactivity constraints of their systems. In the past, it was common for drug manufacturers to perform these types of reactions in-house, but that is not the case today, according to Nigro. “Most pharmaceutical companies have streamlined their operations and generally outsource the production of intermediates that require specialized chemistries and synthetic techniques. Fluorination often falls under this category given the physical and chemical characteristics of most cost-effective fluorinating reagents,” he explains.

There are few contract manufacturers with expertise in fluorination chemistry and not all of them can produce pharmaceutical intermediates under GMP conditions. “There is a need in the marketplace for contract manufacturers that have the necessary skills and expertise to both perform fluorination chemistry and meet GMP requirements,” says Nigro.

. 134 (33), 13588-13591 (2012).
  2. 	S. Bloom et al., 

15 (7), 1722-1724 (2013).
  3. 	F. Yin et al.,

. 134 (25) 10401-10404 (2012).
  4. 	Y. Amaokaet al., 

, Accessed 8/21/2014.
  6. 	A. L’Heureux et al.,

. 75 (10) 3401-3411 (2010).
  7. 	A. L’Heureux et al., 

 153 (1) 57-60 (2013).
  8. 	T. Umemoto et al.,

. 132  (51) 18199-18205 (2010).
  9. 	R. P. Singh and T. Umemoto, 

 76 (9) 3113-3121 (2011).
  10.	T. Umemoto and Y. Xu, “Substituted Phenylsulfur triflouride and other like fluorinating agents”, US patent 7,265,247 B1, Sep. 2007.
  11.	T. Umemoto and R. P. Singh, “Substituted Phenylsulfur triflouride and other like fluorinating agents”, US patent 7,381,846 B2, June 2008.
  12.	Y. Zhao and J.Hu, 

 51 (4) 1033-1036 (2012).
13.	G.A. Olah et al., 


Cynthia A. Challener is a contributing editor at 

API Synthesis & Manufacturing

Fluorination can significantly impact the bioavailability of drug substances, however, safer fluorinating reagents and access to GMP fluorination capabilities remain challenges.

GMP Fluorination Challenges Limit Use in API Synthesis

The Brazilian economy is being impacted by internal and external factors, and forecast figures are being quickly revised downwards. Market research released by Brazil’s Central Bank revised average analysts’ projections for economic growth in 2014 down to 0.70% from 0.90% four weeks earlier (1). In June 2014, the Hong Kong Trade Development Council (HKTDC) stated that the local economy was projected to grow by 1.8% in 2014. Projection figures keep slipping on a weekly basis (2).

The HKTDC research identifies moderation in local industrial production and a slower inflow of foreign capital as reasons for Brazil’s economic boom cooling off after recording growth levels of 7.5% in 2010. The research shows, however, that because there are signs of worldwide economic recovery and sustained commodity demand, the economy could see growth of approximately 2.1% in 2015, “as the world economy improves” (2). 
After hosting the World Cup in 2014, the country’s presidential election in October 2014, and the planning of the Summer Olympics in 2016, the economic situation has become unstable, unpredictable, and uncomfortable for companies, consumers, and investors. These players all await political, social, and economical clarification to go forward with start-ups, investments, and acquisitions, including the pharmaceutical sector. Analysts believe the sector will continue its growth pattern, however, due to the country’s strong domestic demand and large foreign reserves as well as wide potential for growth as the Brazilian population ages and becomes wealthier.

Growth linked with wealthy and aging population


Specialist Rodrigo Leifert, intelligence analyst at São Paulo-based consulting company Tendências Consultoria Integrada, told 

 that the sector’s growth is directly linked with how much the population earns and how wealthier it becomes as it ages, needing and wanting more pharmaceutical products and services. Leifert expects pharmaceutical production to grow approximately 3.8% in 2014, and to maintain a similar growth pattern for the next five years, considering Brazil’s Statistics and Geography Institute (IBGE) projections for the sector.

“Brazil’s pharmaceutical sector might not grow as strongly as years before, but should continue growing at positive figures,” he told 


. According to Leifert, one of the reasons why the growth patterns for the sector slowed down is that during the World Cup, there were fewer working days. He said the scenario started to deteriorate in the beginning of 2014’s second quarter, as fewer working days meant less production of pharmaceuticals.

The analyst expects this year’s figures will reflect uncertainty amid the political scenario while 2015 might show a few adjustments to the political and economic scenario. In 2016, Brazil could see benefits from adjustments and definitions, Leifert said. “It will all depend on how Brazilian families adjust to the scenario and how they cope financially,” he said. Leifert explained that, when it comes to the pharmaceutical sector, how well families do financially directly impacts the growth of the sector. Leifert believes most pharmaceutical projects will be resumed after political definitions are unveiled following presidential elections in October.

Renato Tamarozzi, executive director of the Brazilian Association of Pharmaceutical Commerce (ABCFARMA), is also optimistic for the future of retail sales. Tamarozzi told 

 that he expects retails sales of pharmaceutical products to grow approximately 12% in 2014 and believes the two-digit pattern should continue for the next five years. Tamarozzi explains that there is a positive trend related with the sector’s growth, which is the access and globalization of health information for both patients and doctors.

“An informed patient will tend to take better care of his own heath, while a doctor who has more access to information (on health and drugs) will tend to write more prescriptions,” said Tamarozzi. That alone, added to an aging population, could increase sales by meeting “restrained demand,” he says.

Tamarozzi says Brazil’s growth potential in terms of retail sales could lie in the poorer areas of the country, as these needy areas tend to grow faster than the richer southeast where access to pharmaceutical drugs is easier and the competition is fierce.

“Larger retail groups are present in only 450 municipalities, from a total of 5.564 municipalities in Brazil … [therefore], we cannot say that larger retail groups have consolidated the local market,” said Tamarozzi. Difficulties regarding regulatory issues and bureaucracy, however, many times end up slowing retail growth in the country. “Structural, political, and bureaucracy issues directly affect retails sales,” he adds.


Brazil had total revenue of $25.4 billion in 2013, up 17% from the previous year, making Brazil the sixth largest pharmaceutical sales market globally, according to Emerging Markets Information Service. Brazil’s pharma market is expected to move up the ladder a bit more by 2016.

According to public information offered by Marketline from April 2014, population growth and economic stability produced a robust pharma market in recent years, helped also by import tariffs on pharma products, which aided the local industry (3). According to the research, the performance of the market is expected to accelerate during 2013-2018, driving the market to a projected value of $24.2 billion by the end of 2018.

Public figures from Visiongain’s Brazilian Pharmaceutical Market Report predicted that the country’s pharma market would reach $41.3 billion in 2017, with fast expansion, and by 2024 would contribute strongly to world medical revenues (4). The research stated that manufacturers of generic and biosimilar drugs would stand to profit. The study concludes that patients, healthcare providers, and pharma companies would benefit from progress in Brazil, citing population size as the biggest driver. The research indicates that the generic-drug segment would continue growing and projects that the southeastern region of the country, with approximately 40% of the national population, would contribute with over half of pharmaceutical market revenues.


Hellen Berger is a business correspondent based in São Paulo, Brazil.

The Brazilian economy is being impacted by internal and external factors, and forecast figures are being quickly revised downwards.

Pharma Industry Growth Slows in Brazil

Technologies, such as high-throughput screening and single-use systems, are facilitating the development and manufacture of large-molecule drugs.  Representatives of contract service organizations that develop biologic-based drugs discussed technology trends with the editors of 

Sandles (Fujifilm Diosynth Biotechnologies)

: The introduction of high-throughput screening technologies across R&D means that it is much easier to demonstrate rapid and scalable process development. For instance, our recently purchased ambr250 (TAP Biosystems) aids in rapid selection of upstream fermentation conditions. This initial screening timeframe reduction takes process development further off the critical path to in human trials and consequently means the drug development process is reduced with an increased data set to justify forward-working decisions and satisfy regulation.

: Alternative technologies to extend the half-life of biologic drugs are being developed. This has positively impacted the drug-development process by giving more choice. However, the new technologies have yet to be approved by the FDA for use in commercial drugs. A sponsor would have to license a new technology. PEGs are already approved and easy to use. A lot of the emerging technologies would require specialist expertise and be more complex to set up. 

: The wider use of antibody drug conjugates (ADCs) and the introduction of improved, potentially safer ADCs in particular, will undoubtedly have a positive impact on this market. There are currently only two with FDA approval: Brentuximab vedotin for the treatment of Hodgkin’s and anaplastic large cell lymphoma, and trastuzumab emtansine … for the treatment of HER2+ breast cancer. The current ADC pipeline is large, with more than 100 ADCs currently in clinical trials; this effort underscores the industry’s belief that ADCs will help create safer, effective biotherapeutics.

: For mammalian cell culture there is an increasing demand for single-use technologies and is expected as the norm in this sector. The environmental and financial outcomes are favorable over stainless steel at smaller scales of production; however, at larger scale stainless steel is still a very prominent option. Using single-use means up to 90% less water is needed for cleaning purposes per batch, meaning a reduced contamination risk and cost is incurred against stainless steel.

: Drug sponsors have come to expect CMOs to offer the GMP manufacture of larger volumes of product at competitive prices. CPS has invested in a facility for the manufacture of mPEG alcohols in Mexico and a site at Mirfield, UK that can provide large-scale, multi-metric tonne GMP manufacture of activated mPEGs for biologic drugs. Increasingly, drugs being PEGylated are higher dose, which in turn requires larger-scale production of PEGs for half-life extension. 

: Industry expectations of CMOs for technologies include disposable technologies and single-use systems. A broad, in-house analytical capability is also an expectation. In all cases, however, the bioprocessing technology needs to be scalable to commercial scale. 

: We have seen increasing demand for biologics and biosimilars development, where we have proven cell line technology and have recently launched new manufacturing facilities in Madison, Wisconsin. ADCs are also attracting much interest. Catalent is developing the oral delivery of vaccines to treat the flu, pneumonia and HPV through our Zydis Bio technology platform.  Further innovations for oral macromolecule delivery include our OptiGel Bio technology that may overcome the traditional hurdles by enhancing permeability combined with targeted delivery.

: What pressing technical challenges have you seen in this market segment? What actions has your company taken to resolve the challenge? 

: We are finding that customers are expecting material that represents scalability to be produced at much faster rates. Fujifilm has the technology to meet these demands with both microbial and mammalian cell culture expression systems. We have added extra HTS [high throughput screening] capability for upstream and downstream process development to further reduce time to clinic for our customers. 

: One challenge is the perception that PEGs can be expensive, potentially immunogenic and may accumulate in the body. Producing PEGs in larger volumes brings costs down and there has been no evidence of adverse events in patients. Other technologies used for increasing half-life have not yet been FDA-approved. Therefore, PEGs remain the preferred half-life extension technology. 

: The most pressing technical challenges are mostly on a case-by-case basis, and more often than not, related to the specific biological product in question. Having technologies that allow for solutions that will scale with the process to commercial scale, as part of the CMO toolbox, remains an important capability. Analytical resources and reliable analytical methods are key to any challenge and its solution.

: Technical challenges include ‘big picture’ ones, such as finding more efficient ways to purify protein and better ways to grow cells to obtain higher titers, cleaner starting material, etc., but also smaller, less exciting ones, such as standardization of single-use connectors and films that will also fundamentally effect the industry.

Specialized manufacturing advances expected

: What advances do you see in science or technology in this market segment in the next five years?

: We expect to see more and wider deployment of single-use technology as the benefits become widely recognized. 

): There will be an increase in technologies able to prolong the half-life of biologic molecules. Companies who are looking for an appropriate half-life extension technology will screen several technologies to determine which is best. PEGs is likely to remain a significant technology but probably not the only one in regular use. There will be increasing development and use of mono-disperse PEGs and use of PEGs in new areas such as nanoparticles and niche formulations. 

: Bioprocessing is becoming less of a unit operation and more continuous. Technologies that provide for continuous processing upstream and downstream are at the forefront for the next five years. Being able to process highly concentrated proteins without having to go through a lot of buffer exchange unit operations will impact time on plant, buffer-prep, and QC resources and ultimately affect [cost of goods sold] COGS.

: Look for breakthroughs in efficiency in manufacturing and for new technologies, such as ADCs with advanced linker technologies, to drive safer, better treatments.  Many of these products will be more complex than current biologics, leading to more extensive characterization and testing. We also expect to see more countries looking within their own borders for biologics manufacturing as they want to control manufacturing of these products due to concerns about supply chain of these products.

Technologies, such as high-throughput screening and single-use systems, are facilitating the development and manufacture of large-molecule drugs.

PTSM: Pharmaceutical Technology Sourcing and Management-11-05-2014