As fine-chemical companies, contract manufacturers, and pharmaceutical companies gather in Frankfurt  for CPhI Worldwide, on Oct. 22-24, a fundamental question is on the minds of exhibitors and attendees alike: namely, what is the current and future direction of the industry? To answer that question, Pharmaceutical Technology gained the views of chemical API manufacturers on the key issues shaping the pharmaceutical industry and their impact on supply-demand fundamentals for contract small-molecule manufacturing and the outsourced relationship. Participating in the roundtable were: Susan Daly, PhD, and API technical manager, Aesica Pharmaceuticals; Kurt Hoeprich, global business manager, pharmaceuticals, Albemarle; Brian Scanlan, CEO and president of Cambridge Major Laboratories; Mark Griffiths, CEO, the Dishman Group of Companies; and Andreas Weiler, PhD, head of global strategic marketing, contract manufacturing services and solutions, SAFC. 

 In looking at the market for fine chemicals and contract API manufacturing, what are the key factors affecting supply and demand? How would you assess the current market and the near-term outlook? 

 Demographics, life expectancy, and the fact that the ‘pharmerging’ countries will double their medicine spending within the next five years will increase the global demand of pharmaceuticals. Healthcare cost-saving programs in the developed countries and patent expiries, however, will accelerate the use of generics, so by 2014, 85% of all drugs by volume will be generics. 

Nevertheless, we have seen an increase in approvals of new molecular entities (NMEs) to 30 and 39, respectively in 2011 and 2012 compared with 21 NMEs approved in 2010, with approximately 70% of these small-molecule drugs. We strongly believe that this trend, together with an increase in biological drugs, will continue as we are facing a paradigm shift from general care (i.e., blockbusters) to more specialist care drugs.  

 The trend for Large Pharma to concentrate on their core competencies continues, which increases the opportunity for CDMOs. Large pharma companies continue to divest their sites, and as a result, continue to increase their outsourcing requirements. There are certain additional complexities, such as potent capabilities, which are not typically available in-house to large pharma organizations. There is a growing trend for large pharma to outsource potent drug handling to CDMOs that have the established infrastructure and expertise to manage such complexities. Additionally, the growing importance of the BRIC countries (Brazil, Russia, India, and China) and the Next Eleven (N-11) (Bangladesh, Egypt, Indonesia, Iran, South Korea, Mexico, Nigeria, Pakistan, the Philippines, Turkey, and Vietnam) economies is leading all pharmaceutical companies to develop strategies for these markets. Also, biotechs and virtual companies offer a source of innovation and are a key source of new drug development. Typically, these companies have limited or no manufacturing capabilities in house. The financial environment is now becoming more favorable, allowing smaller companies easier access to more funding opportunities and biotech firms to outsource to CDMOs. 

 At Cambridge Major Laboratories, we definitely see a trend toward increased outsourcing. Whether for cost-containment reasons or to access specific expertise, we know that the outsourcing model is here to stay. What’s really interesting is that in spite of significant offshore investment by Large Pharma and by large CMOs, we notice a trend of demand returning to the United States. The cost advantage once promised by offshoring has eroded, and recent quality issues have generated concern for employee safety, patient safety, and overall project risk. When you factor the increased number of NCEs with permeability and solubility issues and those that require higher containment, the field of choices for API manufacturers that possess these capabilities, to a sufficient degree, narrows significantly. Because nearly two-thirds of drugs from the synthesis stage have low solubility (< 0.1 mg/mL), API manufacturers that offer solid-state chemistry services possess a critical advantage in the current market. Similarly, those with collective experience and expertise in handling high-potency APIs are well poised to take share in the rapidly growing submarket currently experiencing almost double-digit growth. Overall, the current market for contract API manufacturing is robust, and the near-term outlook is positive for companies with a customer-service focus, strong quality record, and sufficient productivity to ensure global cost competitiveness.

There has been a return of venture-capital funding of small and emerging biopharmaceutical companies, which is enabling the funding of innovative research into new therapies. Over the past two years, our early-phase development capabilities have been extensively occupied with new candidates for small and medium biopharma companies. This is encouraging as, even given the attrition rate at the end of Phase II and into Phase III, there will be a number of NCEs being launched from our facilities in the next 18 months. We continue to invest in additional capabilities, such as high-potency high-performance liquid chromatography (HPLC), antibody-drug conjugate capabilities, and semi and fully automated early-phase parenteral fill-finish. Just doing the same thing will not grow our business; we have to innovate alongside our clients.

 The industry as a whole has faced certain large issues, such as pharmaceutical industry restructuring, the increased role of generic drugs, greater strategic importance for emerging markets, and an increased focus on biologic-based drug development. What have been the implications for small-molecule drug development and commercialization, and what other factors are influencing the paradigm for small-molecule drug development and commercialization?

 As a consequence of the upcoming patent cliff and the loss of approximately $120 billion, we have seen many mergers and consolidations within Big Pharma. Cost pressure forced many companies to shift parts of their small-molecule API manufacturing to Asia; others have started to use their empty-reactor capacity to compete in the CMO industry. All this was accompanied by a significant drop in 
small-molecule new drug approvals from 2000 to 2010, creating approximately 40% production overcapacity.

 The increase in new drug approvals over the past two years is mainly driven by innovative therapeutics anticipated for cancer, Alzheimer’s disease, diabetes, orphan diseases, and biological-derived drugs, which will represent one-third of all branded drug sales within the next five years. Many of these new drugs are extremely potent and require highly sophisticated production technologies. In other words, they’re difficult to make and even more difficult to copy, which is the reason they’re a perfect fit for Western CMOs. 

 There is recognition within the industry that biologic-based drug development is increasing and becoming more prominent in the strategies of Large Pharma. Outsourcing of biologic development and manufacture, although a growing market, is not as mature as the outsourcing of small-molecule drug development and manufacture. There continues to be growth in the small-molecule sector, and outsourcing of biologics is not currently forecast to overtake small-molecule development in the short to medium term as large pharma organizations tend to keep biologic projects in-house. 

 To deliver the highest quality products and fully comply with regulatory requirements, the major trend we have observed is the need to efficiently conduct comprehensive process development by adhering to the quality-by-design approach described in guidance documents from FDA. With this approach to development, we commonly exploit design of experiments to ensure a thorough understanding of the process design space and establish validation protocols for robust and reliable commercial-scale production. Albemarle has continued to invest in multi-unit reactor systems and analytical tools to efficiently execute this comprehensive approach to process development and scale-up. Additionally, we see an increasing need to qualify key raw-material suppliers through in-person audits of production facilities, regardless of location. Albemarle’s global presence, which includes a team of sourcing professionals based in China, has facilitated rapid in-person quality audits of key raw-material suppliers. 

It is certainly the case that Large Pharma continues to divest noncore assets, which drives increased overall demand for contract pharmaceutical manufacturing. Emerging markets, such as India and China, have seen strong recent growth due to a rise in demand for generic drugs, and of course, biosimilars are driving expertise-based outsourcing for biologic-based drug development. 

Yet, with respect to proprietary APIs, there is definitely an odd phenomenon in the chemical manufacturing industry. Although the majority of proprietary drugs are developed in North America and North America continues to be the largest pharmaceutical marketplace in the world, the bulk of development and manufacturing of chemical assets do not occur in this region. The pharmaceutical chemistry development industry has evolved in a way that is out of sync with the market at large, but we are starting to see the market swing back into sync. We see regional price differences leveling off, and concerns about quality and security of intellectual property driving demand back to first-world markets and investment in core API infrastructure, particularly in North America. In Europe, excess capacity and the age of facilities drive price competition; however, there is still a lack of quality assets in Europe. Meanwhile, recent facility expansions, commitment to employee and environmental safety, ease of communication, and disciplined project management have resulted in strengthened demand in North America for small-molecule drug development and commercial manufacture.

 I think that Large Pharma has actually always been in the midst of restructuring, certainly in my 30 years in the industry, but the rate of change has increased during the past three years. Where will it end? I guess it will, depending on a complex number of factors that affect Large Pharma’s in varying degrees: R&D output, a rise in costs that affects all of us, regulatory pushback, government pricing policy for new drugs, and access to reasonable patent durations. Ten years ago, Large Pharma set the tone for the outsourced market. I think this has fundamentally changed, and the more ‘aggressive,’ fast-on-their-feet, small and medium biopharm companies certainly set the tone for much of what we do in the Dishman Group and especially at the Carbogen-Amcis boundary. We are constantly challenged to think outside the box by our clients, and this has raised our game as a supplier and innovator, a very rewarding set of circumstances where there is the chance to really form partnerships predicated on mutual need and a desire to focus on the needs of the patient.

 How have the expectations between contract manufacturers and their sponsor companies changed in terms of technical capabilities, geographic/global capabilities, and in managing the outsourced relationship?  

 The ‘old strategic partnership model’ was never really going to work as there was a fundamental need on the part of us (i.e., the CMOs) but a much lower ‘need’ from the outsourcing company. We, as CMOs, fought among ourselves cutting price to compete, and this ultimately benefitted the outsourcing company, not our own businesses. Fundamentally, a partnership relies on elements of mutual need, common goals, and the understanding that both parties are completely open about key elements for each program. In the end, meeting all the deliverables, on time, on quality, and on budget are the key metrics, but great science, project management, flexibility on our part, and an absolute passion for communication get these metrics met. 

 The relationships between sponsor companies and CDMOs have moved from tactical to more strategic relationships due to pharmaceutical companies continuing to reduce their number of suppliers and developing a fewer number of more preferred partner relationships. This continuing trend within the industry will drive consolidation within the contract manufacturing space. 

As regulatory requirements increase and the number of activities an API manufacturer must conduct becomes greater and more complex, we see more strategic relationships developing. We believe this is due to time savings and resource-utilization benefits that can be gained from working with one entity that can conduct comprehensive process development and a full range of validation activities and commercial-scale production while still managing all key raw-material sourcing. In our opinion, there is a push to utilize one supplier for all development needs and commercial manufacturing rather than parcel out numerous tasks to multiple suppliers and service providers.

The increased complexity of new drugs makes it important for sponsors and CMOs to work hand in hand building strategic partnerships, sharing best practices, and developing solutions together with the aim of increasing their productivity and shortening the time to market. 
In the case of some sponsor companies, however, we’re seeing more of a shift away from the partnership model and a main focus on cost savings as the key drivers in their relationships. It will be very interesting to see what model will be more successful in future years. 

We absolutely see trends toward supplier consolidation and outsourcing according to project complexity, and we give a great deal of thought to what makes a partner versus a transactional supplier. At the minimum, a partner should offer the full breadth of capabilities required so that the ability to deliver project results on time is never compromised. For some of our customers, this means the ability to take a compound from preclinical through commercial manufacture at a single site, regardless of whether that site is in North America or Europe. For other customers, this means ensuring that our analytical and quality-assurance departments have equal strength to our chemistry development and manufacturing capabilities, so that we identify and resolve potential issues quickly with timely communication. And for others, it means adopting a service mentality--the ability to remain flexible and responsive in the face of changing demands.  This flexibility is especially important for early-development projects where client requirements or process R&D decisions can change, but it is also important for late-phase projects where continued engagement and optimization adds value.

In looking ahead five years from now, how will the model for contract API manufacturing and fine-chemical manufacturing be the same? How might it be different? What do you think will be the key issues of the future affecting small-molecule drug development and commercialization, including the model for contract manufacturing? 

 Currently, less than 20% of all drugs in the clinical pipeline are innovated by Big Pharma, yet some of these companies have a lot more internal focus. They have their own scientific experts, which can create a challenging environment for a CMO. The remaining 80% (more than 8000) of drugs are originated at virtual, small, and mid-sized pharma companies. Many of those companies have no desire to build up internal capacity or know-how. They are in need of advice and are looking to build strategic partnerships with their CMOs with the goal of increasing productivity and getting their complex drugs to market faster. 

A key issue for the regulatory authorities will be finding a solution to handle an increasing number of new drug approvals with smaller and narrower patient populations. In many cases, there will be increased diagnostic requirements to test the drugs, and in some cases, companies will be seeking fast-track or orphan-drug status. This change will require a refined and strategic approach to approvals, including new resources in the approval process.

 The industry will see more large pharma companies working with fewer, more strategic partners, resulting in further consolidation within the marketplace. The drive toward fewer partners will see Large Pharma looking for CDMOs with a full service of development and manufacturing services for API and formulated products. 

We believe biotechnology and pharmaceutical companies will continue to increase the number of small molecules outsourced for process development, scale-up, and commercial production. Also, we believe developments, such as the Generic Drug User Fee Act, will enable faster and more predictable reviews of applications and supplements and that this will ultimately benefit patients in terms of availability of needed medications that have been produced at facilities that are consistently inspected by FDA. 

The current global CMO landscape is heavily fragmented, and it can be difficult to determine clear points of difference among firms. Five years from now, I think we will be seeing a more consolidated industry where firms have differentiated themselves more clearly in approach to quality, ease of doing business, proprietary expertise, and the ability to deliver solutions in areas of more rapidly growing demand, such as more complex chemistries, high-potency APIs, improved analytical capabilities, and small-volume manufacturing.

 I am surprised that so many of us in the CMO world have managed to survive since 2008, a testament in some way to the tenacity and capability of our subset of the pharma industry. Survival in the future, however, will depend on being diversified in customer bases, technology, and capabilities (i.e., API, formulation, small-molecule, and biologics) as well as having a global presence and most importantly, having the best possible scientists, project managers, and courageous leadership. Analytical capability is becoming a real differentiator. The bar for data supporting the ‘white powder’ has been raised significantly by the regulatory agencies, so having a few HPLC and gas chromatography systems in a laboratory just isn’t going to be enough these days. Having the expertise to interpret data is already key, and this need will increase.

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Industry experts share their views on the outsourcing model and the current and future direction of contract chemical API manufacturing.

Gaining Insights on Contract Chemical API Manufacturing An Industry Roundtable

Process chemists in the fine-chemicals and pharmaceutical industries are tasked with developing optimal routes for manufacturing pharmaceutical intermediates and APIs. Among their challenges, they must develop approaches to improve yield, purity, stereoselectivity, and solid-state properties for a given API while optimizing production economics as a product moves from development to commercial scale. Some interesting recent developments include commercial-scale amide formation and an improved process route for a tetracycline derivative. 


It is well known that amide-formation chemistry can be inefficient and warrants further investigation. This issue has been addressed in the chemical literature, most recently in a study by the American Chemical Society Green Chemistry Institute Roundtable that is particularly relevant to pharmaceutical synthesis (1). The study found that, out of a random selection of drug candidates, amide-bond formation was used in the synthesis of 84% of drug candidates.

The only theoretical by-product of amide formation is water, but examples of this type of reaction are incredibly rare, according to Barrie Rhodes, director of technology development for the CMO Aesica. “Frequently,” he says, “commercial-scale amide syntheses for pharmaceutical manufacture require overly complex stoichiometric coupling agents or reagents.”

Aesica has set as goals the reduction of this complexity in conventional amide syntheses and the development of more sustainable (green) chemical transformations that are practical on a commercial scale. In the pursuit of those goals, the company has partnered with the University of Nottingham for the commercial development of alternative methods in amide-bond synthesis. The partnership’s aim is to revolutionize traditional amide-formation techniques by generating alternative methods for amide-bond formation that will be more eco-friendly and chemically versatile, according to Rhodes.

The new approach should be commercially available to Aesica customers later in 2013. The company is actively seeking commercial opportunities to work with potential compounds that could benefit from the novel technology. “We envisage this new development helping pharmaceutical companies that encounter problems with amide synthesis, and due to the utilization of more sustainable reagents, production costs will be lowered while chemical yields will be increased,” Rhodes notes.

The initial chemistry was developed in 2005 by Simon Woodward, professor of synthetic organic chemistry at the University of Nottingham in the United Kingdom. The coupling reagent of interest is DABAL-Me3, which is an adduct of trimethylaluminum and DABCO (1,4-diazabicyclo[2.2.2]octane). Unlike trimethylaluminum which is very pyrophoric, DABAL-Me3 is a free-flowing solid that can be handled in air (2). In addition to its use in amide-bond formation (3), DABAL-Me3 has been used for the methylation of aldehydes and imines (4, 5), the methylation of aryl and vinyl halides (6), and conjugate additions to enones (7).

With respect to amide bond-formation, DABAL-Me3 can be used to generate amides from unactivated esters and amines that, with conventional routes, require the use of trimethylaluminum or diisobutylaluminum hydride (3). In addition, reactions with DABAL-Me3 tolerate various functional groups, including acetals, alcohols, alkenes, alkynes, ethers, nitriles, hindered esters, and BOC groups. Stereocenters in non-peptidic species are not racemized. Importantly, the preparation of aromatic and aliphatic amides can generally be carried out in an air atmosphere. It should be noted that the rate of the reaction can be accelerated with the use of microwave irradiation, and products can be isolated in 51-99% yield in 8-16 minutes (8).

Preliminary studies on DABAL-Me3 at the university were undertaken using funds awarded by the Engineering and Physical Sciences Research Council (EPSRC) under the Research Development (Pathways to Impact) Funding Scheme. “Since realizing the initial development of our coupling agent in 2005, one of our goals has been to see this novel technology used in larger-scale industrial environments,” remarks Woodward. “We look forward to collaborating with Aesica and seeing the full commercial potential of this novel technology in API manufacture,” he adds.

The chemistry that Aesica is commercializing is more atom-efficient than some other types of amide-formation chemistry and offers a novel synthetic route to make amides from both esters and carboxylic acids, according to Rhodes. Some of the technology is in the very early stages of development and will likely be patentable, so Rhodes is unable to disclose any additional details. He does note that the chemistry is generally applicable and flexible in terms of its ability to prepare amides, and, therefore, any API that either contains amide bonds or goes through an amide intermediate during its synthesis could benefit from this technology. In addition, Rhodes believes that the new amide production technology will enable cheaper and simpler routes to market for many compounds.

This partnership with the University of Nottingham is the Aesica Innovation Board’s (AIB) fourth with an academic institution in less than six months, according to Rhodes. The AIB was established to help bridge the growing R&D gap by identifying early-stage technologies for development into commercial applications.

“The University of Nottingham is renowned for its excellence in chemistry research and has a strong background in green and sustainable chemistry. That, coupled with its interest in open innovation (in that risk and reward are shared) as a model, has been very beneficial. Effectively, the university has the expertise in terms of the technology while Aesica brings its expertise in terms of commercialization and a global network in the pharmaceutical industry,” Rhodes explains.

The partnership for the development of amide bond-formation chemistry is just the start of a hopefully long-term collaboration between Aesica and the university, according to Rhodes. The collaboration builds upon announced plans by the University of Nottingham to establish a Center of Excellence for Sustainable Chemistry, which will be partly funded by an investment from the Higher Education Funding Council for England UK Research Partnership Investment Fund. The Center aims to form creative partnerships with innovative companies to develop new chemical-based technologies that minimize environmental impact and are both energy and resource efficient, according to a university press release. 

“As Aesica further enhances its innovation program, we will seek to develop new technologies, not only with the University of Nottingham, but with other academic institutions as well, in the fields of both API and formulated products manufacture,” concludes Rhodes. 

Process-scale synthesis of tetracycline derivative


  Tetracyclines comprise a group of antibiotics that are recognized as safe and effective and are thus commonly used to treat serious bacterial infections and other less severe conditions such as acne. Unfortunately, because tetracyclines are commonly used, many bacteria have developed resistance to the older versions of these drugs. Recent efforts have thus been directed at developing new tetracycline derivatives.

Scientists at Tetraphase Pharmaceuticals are overcoming this barrier by implementing a new synthetic route first reported by Myers in 2005 (9). This approach involves the coupling of a cyclohexenone intermediate that contains the key tetracycline functionalities with a second functionalized aromatic intermediate via a Michael-Dieckmann reaction, thus enabling the incorporation of a variety of different substituents at various positions in the tetracycline skeleton. Using this methodology, Magnus Ronn, vice-president of CMC at Tetraphase Pharmaceuticals and his colleagues at the company recently reported the successful preparation of eravacycline, a fully synthetic broad spectrum 7-fluorotetracycline in clinical development, in multihundred gram quantities (10). A summary of their work is presented below.

The advantage of this approach to the synthesis of tetracycline analogues is that a single key intermediate can be used to access a wide range of substituted tetracycline active pharmaceutical ingredients (APIs),” says Ronn. This key intermediate is a tricyclic cyclohexenone with three chiral centers  (the synthesis of this compound was reported previously [11]). The enone is reacted with a suitably functionalized phenol bearing an ortho-carboxyphenyl group and a meta-methyl substituent. Other functionalities are included as needed to produce the desired tetracycline analogue.

This aromatic compound, referred to by the researchers as the lefthand piece (LHP), is deprotonated with a strong base to form a benzylic anion, which then undergoes diastereoselective 1,4-conjugate (Michael) addition to the enone moiety when added to the cyclohexenone. The ketone enolate that forms from this step undergoes a Dieckmann-type condensation with the phenyl ester to produce the protected tetracycline compound. To obtain the desired tetracycline analogue, this intermediate is subjected to subsequent silyl-ether cleavage and hydrogenolysis of the benzyl protecting groups with concomitant reductive ring opening of the isoxazole (10). The LHP selected for the preparation of eravacycline is a benzyl-protected phenol with a fluorine atom and a dibenzylamine substituent. It was prepared from a commercially available starting material in seven steps, the synthesis of which will be published in the future (10).

One of the hurdles that the researchers had to overcome in developing the large-scale synthesis of eravacycline was the sensitivity of the Michael−Dieckmann transformation to the reaction conditions, according to Ronn. Not only the order of addition, but the strength of the base was important for the two different deprotonation steps (10). Thus, the researchers reported that it was necessary to first deprotonate the LHP (1.04 equivalents of LHP is used) with lithium diisopropylamide (LDA, 1.13 equivalents) and then add the generated anion to a solution of the cyclohexenone and the weaker base lithium bistrimethylsilylamide (LiHMDS) at -70 °C. The desired adduct was isolated after workup and trituration with methanol in > 90% yield a 98% purity (using high-performance liquid chromatography), even on the 200-g scale (10).

Because both the deprotonation and the Michael−Dieckmann reaction should be performed at -70°C, two cryogenic reactors are required. The researchers reported that attempts to eliminate one of those reactions by raising the temperature of the cyclohexenone solution to -20 °C led to increased production of impurities (10).

To obtain eravacycline, the first step after the Michael-Dieckmann reaction involved cleavage of the tert-butyl silyl (TBS) protecting group. Despite the issues associated with using hydrofluoric acid in commercial manufacturing, the researchers reported that this reagent gave better results than other investigated alternatives and it was thus selected for scale-up (10).

Reductive ring opening of the isoxazoline group and removal of the four benzyl groups using palladium on carbon(Pd/C)/hydrogen to give the 9-amino-7-fluoro-sancycline required extensive investigation by the researchers (10). A mixed solvent system of tetrahydrofuran (THF) in methanol (1:3) was required because of solubility issues. An acid additive was also needed to improve the rate of the hydrogenation reaction, but epimerization at the C-4 position and reduction of undesired groups led to the formation of impurities, including one that was very difficult to separate from the desired product. The reaction was optimized using concentrated aqueous hydrochloric acid (HCl) because it is a stable reagent with a reliable concentration. The palladium on carbon was removed using Celite, and residual palladium was eliminated with the metal scavenger (SiliaBond DMT, Silicycle). The desired hydrochloride salt was precipitated from water/ethanol in approximately 80% yield and high purity (< 2% of the undesired impurities), even on a large scale (10).

Next, the hydrochloride salt of the fully deprotected penultimate intermediate was coupled with the desired side chain to prepare eravacycline. The reaction was carried out in acetonitrile and water. To achieve complete conversion, several charges of the acid chloride were necessary, and it was also found that adjustment of the pH from approximately 3 to approximately 7 after the second charge aided the complete dissolution of the starting material, allowing the reaction to go to completion. After the completion of the coupling, the pH of the reaction solution was brought to pH 6.8 to ensure hydrolysis of any over-acylated compounds to the desired tetracycline product.

Eravacycline was extracted using dichloromethane at pH 7.4. As an added benefit, the researchers found that the undesired C-4 epimer was partly removed in the aqueous layer and when the dichloromethane solution was dried with sodium sulfate prior to evaporation, thus increasing the purity of the tetracycline product (10). Finally, the bis-hydrochloride salt of eravacycline was prepared using an ethanol−methanol mixture containing an excess of hydrogen chloride and precipitated with addition of ethyl acetate.

“While some of the steps presented challenges, this overall route to eravacycline has enabled the production of sufficient quantities of the API for clinical testing. This tetracycline derivative has completed Phase II clinical studies and has been shown to be active against multidrug resistant bacteria and is therefore a candidate as a broad spectrum antibiotic for serious hospital infections. We are continuing to improve the process for future larger-scale manufacturing and are also developing an isolation procedure that will be suitable for commercial production of eravacycline,” Ronn notes.

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Commercial-scale amide formation and an improved process route for a tetracycline derivative are some recent developments in API synthesis.

Advancing API Synthesis

APIs are most conveniently developed and delivered as solid dosage forms that contain a single crystalline form of an API. Cocrystals alter the physical properties of APIs without chemical modification of the API while retaining the benefits of a crystalline solid form.  For compounds that do not form useful salts and still require improved physical properties, such as solubility or stability, cocrystals may provide a viable solution. A cocrystal may thus represent a crystal form with better pharmacokinetic properties, and therefore a better market opportunity. 

In April 2013, however, FDA issued its final regulatory guidance on cocrystals, including the classification of a pharmaceutical cocrystal as a “drug product intermediate.” This classification may help some product development strategies while, at least in the short term, it may limit the ability to use cocrystals efficiently in other cases.

Improved pharmacokinetic properties and more  


  “The selection of a specific crystal form for a given API is a profoundly important step from clinical, legal, and regulatory perspectives: the dissolution rate and intrinsic solubility of different crystal forms is variable and can strongly influence bioavailability; stability to temperature and humidity are critically dependent upon crystal packing; and the unpredictability (i.e., lack of obviousness) of crystal structures and physical properties means that there are legal issues and challenges in terms of obtaining and maintaining patent protection for an API,” says Ning Shan, director of preclinical development at Thar Pharmaceuticals. 

Highly lipophilic APIs have dissolution problems that may be overcome using a cocrystal because the new crystalline lattice being formed often has very different dissolution properties compared to those of the crystals of the API alone, according to Chris Frampton, chief scientific officer of SAFC Pharmorphix. The formation of a new crystal lattice with a pharmaceutically acceptable coformer often enables other issues, such as compaction problems and difficulties with hygroscopicity, to be overcome. In addition, for nonionizable APIs, for which it is not possible to make a salt, the option to form a cocrystal can be advantageous over finding alternative formulation methods or changing the API molecular structure to include the acid or base functionality required for salt formation, which can have an impact on the activity of the API. In addition, increasingly, adds Frampton, cocrystals are also being seen as a lifecycle management tool, because their use can delay or divert generic competition.


    If a cocrystal is to be used, it clearly must have physical properties that offer key improvements over the properties of the API itself. “Cocrystals have been used to create crystalline forms of APIs that were previously known in only amorphous forms, improve melting points, enable improved chemical purity, reduce chemical degradation when exposed to light, remove the risk of hydrate formation in a formulation, and improve the solubility to enable higher bioavailability,” says Scott L. Childs, president and CSO of Renovo Research. For Frampton, improved stability is one of the most desirable attributes of a cocrystal API. “The physical stability, chemical stability, and melting point can all be tuned to achieve a new form that is more desirable than the crystal form of the API alone,” he explains. 

  In addition, the preferred cocrystal will not only meet the physical property improvement requirements, but also contain a “pharmaceutically acceptable” coformer that is nontoxic, has a high weight percent of API compared to coformer, be chemically and physically stable under all relevant conditions, be manufacturable using low-cost approaches in existing production equipment, and remain stable over the shelf life of the product.

Inexperience and need for screening pose challenges


    While cocrystals offer many potential benefits, it is important to recognize that they have not yet been fully embraced or adopted by the industry, according to Childs. There are both skeptics and advocates. It is his opinion that cocrystals are viewed as a “last resort” in some laboratories, and this perception will persist in many minds until FDA approves a product containing a cocrystal that delivers improved performance. “I am convinced, however, that the first FDA-approved cocrystal product is an issue of ‘when’ and not ‘if’,” he asserts. 

Shan adds that the requirement in the FDA guidance that the developer of a cocrystal drug product must provide “assurance that complete dissociation of the API from its excipient occurs prior to reaching the site of action for pharmacological activity” could be a real challenge. He also notes that the prediction of cocrystal structures remains semiempirical, but he anticipates that with more powerful computational equipment, better calculation approaches and estimations will be possible. 

The difficulties that are faced with respect to the selection of appropriate coformers for a given API is a real challenge, agrees Frampton. “The one thing we cannot do is predict the outcome of the properties of cocrystals until they are generated. Although we can recognize that there might be an interaction between the API and a coformer, there is no guarantee that this interaction will lead to cocrystal formation, or if the cocrystals that do form will have desirable properties. A lot of screening is required, and sometimes what we get does not reflect the crystal lattice we intended.” He does note, though, that with respect to melting points, he has found that a lower melting point coformer will tend to reduce the melting point of the cocrystal while a higher melting point coformer will increase it. 

Of course, Frampton also points out that this lack of predictability is necessary to some degree. “As soon as it is possible to predict cocrystal structures, we have a problem. Patent applications for salt forms are already being questioned on the grounds that they are predictable and obvious due to the pKa of the API and the limited list of pharmaceutically acceptable salt formers. The lure of the cocrystal remains the questionable and unexpected successful outcome.”

  New formulating, analytical, and modeling techniques


  There have been some advances in various techniques and technologies that are beginning to address some of these issues. Shan points to the solvent-drop grinding process as a way to manage mechanochemistry issues and advances in computational chemistry that are enabling improved crystal structure prediction. 	

At SAFC Pharmorphix, the ability to perform crystal structure analyses on really small crystals has been very advantageous. “Knowing the crystal structure makes it possible to see how the two materials come together to form a supramolecular complex. Then we can go back to our list of potential coformers, tune them slightly, and follow an iterative process to develop the optimum cocrystal,” observes Frampton. 

Renovo, meanwhile, has developed a new approach to formulating cocrystals that uses the improved cocrystal solubility more effectively. Traditionally, as is commonly done with salts, cocrystals are used in in-vitro and in-vivo pre-clinical studies as “neat” material (pure crystalline powder), according to Childs. This approach is not optimal because cocrystals are highly susceptible to solvent-mediated transformation into the poorly soluble form of the API when dosed as neat material.  

“We have developed our new approach, demonstrated with a danazol cocrystal, that utilizes solubilizing excipients and precipitation inhibitors to create an optimal supersaturation level and controlled dissolution event,” Childs explains. The model system achieved a 10-X increase in the area under the concentration time curve (AUC) in animal studies using the formulation, compared to only a 1.7-X increase in the AUC using the neat cocrystal solid (1).  “The results of this study suggest that the appropriate formulation of cocrystals can be an important part of the cocrystal development process,” he concludes.


While the European Medicines Agency and the Ministry of Health, Labor, and Welfare in Japan have not published any official guides with respect to cocrystal development, FDA’s final guidance was issued in April 2013 (2). The most important aspects of the guidance, according to Frampton, are that FDA determined that a cocrystal is a drug product intermediate, and it defined two types of interactions. First, the coformer used to make the cocrystal is defined as an excipient, which can form a simple physical mixture with the API or interact with the API on the molecular level within the crystal lattice. Frampton compares the latter interaction to that of an API incorporated into a cyclodextrin excipient to enhance bioavailability and solubility, in which the API sits within the barrel of the beta-cyclodextrin. For salt forms, on the other hand, where it is important to know where the proton sits in a complex and if it has been transferred to the API because if that occurs, the salt form is no longer considered to be the ‘same’ API from a regulatory perspective. 

“Many in the industry find it quite surprising that FDA has not regarded cocrystals as new APIs because the properties can vary widely from one coformer to another. It also makes it easier for generics companies to compete with branded products by utilizing these materials,” Frampton comments. “Indeed, the guidance leaves a number of open questions and perhaps some concerns within the pharmaceutical industry about how the use of a cocrystal could impact development timelines, the drug product manufacturing process, and the intellectual property position of a product containing a cocrystal,” adds Childs. 

First, cocrysals are treated like the polymorphs of a drug, rather than as salts. As polymorphs they are considered to be the ‘same’ API, whereas different salts are treated as different APIs from a regulatory perspective. Secondly, drug product intermediates have different regulatory reporting requirements than salts or polymorphs. Finally, there are IP issues. Because cocrystals are considered to be, in effect, the same drug substance, generic-drug companies can introduce them as competitive products that are still considered to be the same API, whereas the use of a different salt would not be substitutable as the same active ingredient.

Shan does point out, though, that a cocrystal still has the same active ingredient as the original drug. “Even so, under the patent protection of the original drug, a cocrystal version of the same drug cannot circumvent the original patent,” he notes. “However, a cocrystal with desired properties can be patented, intellectual-property protected, and marketed, as mentioned previously in the context of lifecycle management.”


“The current perception of cocrystals is analogous to that of amorphous materials during the period when that technology was emerging. While the basic understanding of cocrystals as materials has advanced at a steady pace, there are important questions remaining concerning the regulatory issues, impact of the coformer molecule on toxicology studies, the ability to produce some cocrystals at scale, the cost of production if advanced formulation is needed, and the ability of crystal form IP protection to enable product exclusivity,” says Childs.

“All of these areas have been addressed to some degree in the available literature, but I would caution anyone who thinks that cocrystals will remain an inferior solid form, and that the real impact of cocrystals has yet to be demonstrated. With the appropriate time, effort, and investment, our ability to effectively use cocrystals to create improved pharmaceutical products will reach the point where cocrystals will be a desirable and useful solid form rather than a ‘last resort’,” he continues.

“I envision the ability of cocrystals, in specific situations, to be able to compete directly with amorphous dispersions in terms of efficacy but create a superior product because of the lower risk and improved stability of the crystalline state compared to the amorphous state,” Childs concludes.


  1. 	S.L. Childs, P. Kandi, and S. Reddy Lingireddy, 

Final Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystals

A recent FDA guidance places greater attention on cocrystals as a tool in solid-dosage formulation.

Examining the Role of Cocrystals in Drug Development and Manufacturing

Shellac is a polymer used in coating applications to provide various functional properties. It can be used in film coatings to achieve enteric applications, aesthetic and immediate- release properties, taste masking, and seal coating. The authors describe the background and applications of fully formulated aqueous shellac for film-coating systems.

Shellac is a natural and versatile polymer used for coating applications. It is is used in the pharmaceutical and nutraceutical industries to provide various functional properties. It can be used in film coatings to achieve enteric applications, aesthetic and immediate-release properties, taste masking, and seal coating. It is recognized by the National Formulary (NF) and is classified into categories as orange, de-waxed orange, bleached, and refined de-waxed bleached. Shellac is an approved food additive in the United States and in Europe and is also listed in the

 United States Pharmacopeia, European Pharmacopoeia, Japanese Pharmacopoeia, Food Chemicals Codex,

 and in the European food regulations as E904. It also has generally recognized as safe (GRAS) status as designated by FDA.

Shellac is a resin derived from insects, the Kerria Lacca species (family name Coccidae), also known as lac, which are cultivated in India, Thailand, China, and Vietnam. Shellac is produced from the lac insect’s resinous secretion, which occurs when lac insects attach themselves to the bark of particular host trees and feed on the tree’s sap. The lac insect’s resinous secretion forms in cocoon-like masses on the trees and branches. The cocoon-like masses are physically removed from the host trees. The secretion material harvested is called sticklac, and two crops per year are cultivated or harvested. The sticklac is washed with an aqueous media to remove excess laccaic acid, a red dye, and is filtered and dried. The dried resin is called seedlac because of its seed-like resemblance (1). Seedlac purity is approximately 85-90%, consisting of 5-8% shellac wax and 2-5% impurities. To refine shellac for pharmaceutical use, the seedlac is further processed to the de-waxed grade to increase the purity to the specifications set forth by the NF (2). 

Shellac structurally consists of esters from polyhydroxy carboxylic acids and other polar and nonpolar components within the molecule. The four main carboxylic acid components are: aleuritic (35%), jalaric (25%), shellolic (8%), and butolic (8%). Typically, enteric coatings consist of polymers with acidic functional groups. The acid groups are protonated in an acidic environment making the shellac water-insoluble in the stomach. 

Esterification can be inhibited when using certain plasticizers. A combination of plasticizers and surfactants improves shellac’s flexibility and increases the adhesive structural reinforcement properties of the film. Shellac formulations (e.g., Protect EN, Sensient) have proven successful in functional reproducibility and product stability over time. With the addition of sodium alginate, the enteric film-coating system provides gastric protection with good film adhesion and flexibility for particles, tablets, and capsules. 


Shellac can be used to produce films with targeted functionality to meet desired dosage release within the physiological pH ranges of the digestive tract. 

depicts the pH range of various anatomical regions. 

~ 80.5 to 120 min
      (half emptied: 80.5 min)

, it may be desirable to have coating systems that are designed to release at various pH ranges for targeted drug delivery. However, variability in the pH ranges exists due to the stomach’s physiology and is subject to multiple factors, including age, illnesses, medications taken, and food intake (i.e., fed state). In a fed state, the stomach acidity can rise to a pH of 4, and the stomach empting may be delayed for two to four hours. In a fasted state, gastric empting could occur rapidly in less than one hour. Many pharmaceutical and nutraceutical dosage forms must pass through the stomach before releasing in the lower gastrointestinal (GI) tract. Dosage release from an enteric coating is possible in the more pH-neutral region of the digestive tract due to shellac carboxylic acid deprotonation that allows the shellac to become more water-soluble.

Researchers at the Institute of Pharmacy at Leipzig in Germany coated substrates using an aqueous shellac formulation in combination with various polymers: polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), and carbomer 940, a cross-linked polyacrylic acid polymer (3). This study was designed to understand the effect of enteric properties using different polymers with shellac. The testing results showed cracking of the PVA/shellac films and water was allowed to enter the core. HPMC/shellac film data indicated pore formation resulting in premature drug release. Carbomer 940 resulted in a swelled film leading to increased drug release through the shellac coating. The hydrophilic polymers, PVA and HPMC, used in the study showed variability in disintegration profiles over 3, 6, and 12 months. When shellac was used in combination with sodium alginate, the dissolution stability was maintained both in real time and accelerated studies (3). 

are from the combination of shellac (Protect EN) and sodium alginate. The stability study was performed at room temperature, H2 (25 °C/60% RH), and H4 (40 °C/75% relative humidity [RH]) conditions. Disintegration testing followed 

 indicates passing disintegration results after six months in an accelerated stability study. 

indicates that enteric and seal-coating functionality and stability on ibuprofen release in a strongly acidic environment of the stomach with a weight gain of 3%.

 indicates no release of the Ibuprofen in simulated gastric fluid (SGF), which is characteristic of a true enteric coating where no breaching occurs in the stomach region. The red line in 

 indicates some release when shellac was used without sodium alginate, making the shellac only coating a seal coat but not an enteric coat. Sodium alginate must be present to maintain the enteric properties of the system.


Shellac has vapor-barrier properties that prevent moisture from migrating into and out of a coated substrate. Shellac can act as a particle or core stabilizer and coats easily, providing a strong, hard and adhesive functional film. The adhesive property of shellac is due to the structural orientation of polar groups onto smooth surfaces (4). When shellac is coated onto a surface, the shellac must be applied in thin layers (low-weight gains) to promote efficiently dried film coats. Shellac has a thermal plasticity property that creates soft films when heated and harder films when cooled. This thermal plasticity property of shellac in part is due to the low transition glass temperatures (Tg) of shellac. The typical Tg of shellac ranges between 3749°C (5). The Tg range of shellac is correlated to the acid value content of shellac. The decrease in shellac’s acid value has an increasing effect on the Tg. Strong functional films, therefore, can be formed when coating at low temperatures while achieving desired functional properties. Coating at low temperatures is beneficial when either substrates or cores are sensitive to heat.  

To test the barrier properties of shellac, shellac (Protect EN, Sensient) was applied to arginine base cores at 1, 2, 3, 4, and 5% weight gains using 2428% solution solids (Protect EN, Sensient) and a coating-bed temperature of 32-35°C. Moisture vapor sorption was measured using a thermal gravimetric analyzer (Perkin Elmer). The results in

 show that shellac applied at a 0.5 to 2% weight gain provides the necessary protection against moisture sorption.   

 identifies the actual absorption of water in shellac films at different weight gains. A thin film is adequate to establish a good moisture barrier. The low weight gain confirms the functional property of shellac providing hard, resistant film properties. Counterintuitively, thicker films of shellac result in water retention as indicated by the parabolic curve in 

Shellac has two resinous fractions: hard, or pure, resin and a soft resin (6). The hard resinous fraction of shellac constitutes 70% of shellac’s structure.  The hard resin is derived from four aleuritic acid units (6). The soft resinous fraction of shellac is derived from the erythrolaccin component. The orange/red color of shellac comes from primarily erythrolaccin, which is soft and sticky. The chemical properties of erythrolaccin are a mixture of various hydroxylated fatty acids and esters, including jalaric acid esters.  Controlling the amount of residual erythrolaccin in the shellac may be a crucial part of the shellac purification. Using bleached shellac may provide a solution to overcoming stickiness in shellac films. It is hypothesized that hydrogen bonding between the water and shellac’s free hydroxyl groups, from the erythrolaccin, can create coating problems due to water retention in the film. Slightly tacky films could develop due to excess moisture in the films. When films are completely dry, the shellac film becomes resistant to moisture.

 Shellac as a taste-maskant. WT is weight.

To investigate other functional properties of shellac, a test was performed to determine if shellac could be used as a taste maskant. A bitter drug (ibuprofen) was coated to a 3% weight gain. The coated and uncoated ibuprofen tablets were subjected to dissolution testing at a pH of 5.5 and 6.8.  The pH range of 5.5 and 6.8 was used in alignment with the International Journal of Drug Testing (7) data on the normal pH range of the mouth. This pH range is influenced by patient age. Children have a higher oral cavity pH, and adult oral cavity pH varies with an average of 6.7. The test time period was 60 s, which correlates to the approximate time drug substances are held in the mouth prior to ingestion/swallowing. Timed sample intervals were pulled from the dissolution apparatus and drug-release data were collected using UV-visible absorbance measurements. A UV-visible spectrophotometer (Lambda 35 UV WinLab V6.0, Perkin Elmer) was used with variable (0.5, 1.0, 2.0, and 4.0 nm) bandwidths with wavelength ranges from 190 to 1100nm having scanning speeds of up to 2880nm/min with quartz-coated optics.

 depicts the dissolution response of ibuprofen release at a pH of 5.5 and 6.8.  The response shows when ibuprofen is coated to 3% weight gain, there is no ibuprofen released at a pH of 5.5 to 6.8, thereby suggesting shellac to be a taste-masking functional coating.  

Researchers at the Berlin College of Pharmacy supports the suggested versatility of shellac and have found shellac to have functions as a film former (8). According to Pearnchob et al., shellac-coated tablets showed moisture protection and taste-masking effects (8). Shellac also proved to increase the stability of acetaminophen compared with HPMC-coated systems, irrespective of the storage humidity. Pearnchob et al. found shellac coatings to effectively mask the unpleasant taste of acetaminophen tablets. Ammoniated aqueous shellac was also found to be an effective binder in wet granulations for extended release in compressed matrix tablets. 


Shellac, either in enteric or seal coating forms, can provide new opportunities for functionally diverse coating systems. Shellac based on aqueous ammoniated and plasticized coating products can expand the functionality and stability attributes beyond what is available with other systems. Shellac provides a naturally derived, versatile polymer choice to the pharmaceutical and nutraceutical industries for product function and protection. 


  1. 	Y. Farag and C.S. Leopold, University of Hamburg, Institute of Pharmacy, Department of Pharmaceutical Technology, Bundesstrasse 45, 20146 Hamburg, Germany.
  2.	USP, 

 Page 2192 (Rockville, Md, 2013).
  3.	B. Qussi and WG Suess, 

, 31(1): 99-108 (2005).
  4. 	S.K. Sharma, S. K. Shukla , and D. N. Vaid, Delhi Def Sci J.  33 (3), 261-271 (1983).
  5.	Y. Farag and C.S. Leopold, 

, May: 33-39 (2009).
  6.	A. Tschirch and A. Farner, 

., 237 (1989).
  7.	Karin M. Höld et al., 

.
8.	N. Peamchob, J. Siepmann, and R. Bodmeier,  “

Pharmaceutical applications of shellac: moisture-protective and taste-masking coatings and extended-release matrix tablets


  Beverly Schad* is a technical support manager, Houston Smith is a technical director, Brian Cheng is a formulation scientist, Jeff Scholten is a chemist, Eric VanNess is a technical support manager, and Tom Riley is a formulations manager, all at Sensient Technologies; beverly.schad@sensient.com.
*To whom all correspondence should be addressed. 

The authors describe the background and applications of fully formulated aqueous shellac for film-coating systems.

Coating and Taste Masking with Shellac

The changing development paradigm resulting from FDA’s quality-by-design (QbD) initiative and International Conference on Harmonization (ICH) guidelines requires increased process understanding of the drug substance and drug product throughout development and manufacturing. A lack of information can result in delays in regulatory approval and higher costs. Applying QbD principles leads to greater process understanding, facilitates regulatory approval, and streamlines postapproval changes. Case studies on the manufacture of a bulk powder and the development of a tablet show the application of QbD principles, including defining critical quality attributes, implementing risk assessment, optimizing process development, developing a design space, and performing a criticality analysis.

Quality by design (QbD) is often misquoted, misused, and misunderstood. Pharmaceutical QbD is a systematic scientific risk-based approach to pharmaceutical development that begins with predefined objectives that address product and process understanding and process control (1). Many articles focus on what is required with respect to product quality, safety, and efficacy but successful approaches are not commonly shared. Successful product development relies on consistent application of a proven methodology. The key steps are the same, irrespective of the product or formulation being developed. A proven methodology is described in this article, with the framework shown in 

. These main steps are further described as outlined below. 

CQAs are defined based on the target drug profile. These are quality characteristics of the drug that must be kept within appropriate limits to ensure the desired product quality (e.g., purity, crystalline form, and particle size). 

Risk assessment during the development phase.

 For each CQA, an analysis of the potential critical process parameters (pCPPs) and potential critical material attributes (pCMAs) is conducted. The aim is to evaluate in each process step, operating parameters or raw materials that have the potential to affect a CQA within the known ranges, and therefore, should be monitored or controlled to ensure the desired quality. Because the number of parameters is usually high, a risk assessment based on prior knowledge of the product or process is used to rank the parameters in terms of perceived criticality. The ultimate goal is to keep the development process as lean as possible by focusing the studies on those parameters with a higher likelihood of having a critical impact.

The output of the risk assessment is a qualitative match between CQAs and pCPPs/pCMAs. To confirm the dependences and quantify the effects, a process-development stage is conducted. Usually a statistical approach is followed, through a sequence of design of experiments with different objectives--screening, optimization, and robustness studies. This development stage constitutes the core of the QbD methodology since most of the process knowledge is generated during this stage. Although not mandatory, a model, either statistical and/or mechanistic, is a usual outcome of this stage. Process analytical tools can also be considered at this stage based on the need to improve the CQA monitoring as the process is scaled up.

Design space and normal operating ranges (NOR). 

Once the impacts of the pCPPs/pCMAs are quantified on the CQAs, a feasible operating space can be defined. This space, known as the design space, will consider all the interactions between operating parameters and material attributes and will often be multidimensional. The NOR is established within the design space, and can be thought of as the ranges where the process typically operates. 

After defining the design space and NOR, an exhaustive analysis of the process is conducted at the manufacturing scale. In this study, a failure mode effect analysis (FMEA) of all manufacturing aspects are reviewed, challenging the equipment operating ranges and procedures against the process knowledge gathered in the previous steps. The purpose of this study is to understand and quantify the risk of batch or process failure and to define actions to minimize failures.

 By knowing the feasible operating regions and after evaluating the equipment/procedures at the manufacturing scale and the practical NOR, a final criticality analysis will take place to identify parameters and/or material attributes that will require tight monitoring or control. For example, all parameters for which the corresponding NORs are close to the boundaries of the design space. 

Once the criticality around a process parameter and/or raw material attribute is confirmed, adequate control strategies will be set in place. The ultimate goal is to assure that the operation is always taking place within the design space, therefore, assuring the quality of the final product. For this purpose, and considering the dependence of a control strategy on a given monitoring capability, the final implementation of process analytical technology tools is carried out at this stage. The subsequent steps are mainly focused on the documentation aspects associated with the filing process and will not be addressed in this article. 

 This case study examines the preparation of bulk powder that is subsequently formulated as a tablet. The preparation of the powder was broken down into three stages: synthesis, excipient addition, and spray drying. The spray-drying stage was identified as being potentially crucial for all CQAs, and will be examined in more detail (see 

). CQAs for the bulk powder were determined to be purity, residual solvent level, particle size distribution, and bulk density among others, but will not be addressed in this article. 

 A risk assessment was completed to prioritize and reduce the number of parameters to be investigated in the study. This process is subjective and relies on the experience of the team members involved in the assessment. Having four or more inputs will help reduce bias and enable the top pCPPs to become evident in general (see 

). It is important to recognize that at this point, all process parameters are only potentially critical; confirmation of criticality is only conducted later in the methodology. 

Although identified as being a pCPP, certain parameters may need to be fixed because they impact other aspects of the process such as yield and throughput. In this study, the concentration of the feed solution was fixed and the outlet temperature (T_out), the feed pressure (P_feed), and the spraying nozzle diameter (D_noz) were varied. 

A series of experiments were run as a screening study. Using a statistically valid design of experiments (DOE), eleven runs were made. These trials considered a 24-1 half-factorial design with the centre point run in triplicates (see 

). Once complete, the ranges of a DOE become the knowledge space for your product. Subsequent studies enlarge the knowledge space.

Case studies on the manufacture of a bluk powder and the development of a tablet show the application of QbD principles.

Optimizing Quality by Design in Bulk Powders and Solid Dosage

There are various problems that can arise out of the relationship between CMOs and their clients. The author presents results of a survey of CMOs and biopharmaceutical manufacturers in which respondents describe common mistakes they have encountered. 

As outsourcing becomes increasingly integrated into higher-end, more technical bioprocessing activities, new stresses are added to client-contractor relationships. These outsourcing collaborations are already pressure-filled, high-risk, and high-cost. While clients take into account many factors when selecting the appropriate CMO, the relationship only begins once that contract is signed.  According to CMOs responding to BioPlan Associates’ 10th Annual Report and Survey of Biopharmaceutical Manufacturers(1), there are some significant areas in which the clients themselves prove to be less-than-ideal working partners. Recognizing how the relationship can breakdown on the client’s side can be an important step in reducing risks and ensuring smooth-running projects. 

BioPlan’s study, which included 238 biomanufacturers and 158 suppliers to the industry, set out to discover the most commonly cited mistakes made by CMOs’ biopharmaceutical clients. The study asked CMO respondents to identify which, out of a list of issues, they would consider a very common problem or a somewhat common problem. The most common mistake, according to CMOs, was that clients were not communicating with the CMOs effectively. This problem was cited by every single CMO in the sample. While this is a “soft,” non-technical issue, its ubiquity indicates that it plagues these relationships. Separately, this was seen as a top problem with the biopharmaceutical clients as well. This problem is not, therefore, a one-sided shortcoming.

The second most commonly cited problem (91.7% of respondents) was that clients don’t build-in sufficient time for the project (i.e., unrealistic timeframes). This is a frequent problem in CMO-client collaborations as it is not uncommon for small, inexperienced companies to have unrealistic presumptions. Moreover, companies new to these relationships sometimes simply do not understand a range of issues such as how to achieve high-performance processes, advance from small-scale to clinical manufacturing, how to release clinical grade material, validation requirements, initiate investigational new drug (IND) submissions, and set up and recruit patients for clinical studies. There are often misconceptions regarding the costs for outsourcing of manufacturing, trials, and other tasks. On top of this, all too often some clients’ pre-clinical

 assays need to be repeated with CMO-produced “representative material” (i.e., representative of what will be further developed and go into trials) and the results may diverge from earlier client results.

Besides unrealistic timeframes, a number of other problems were similarly cited by respondents: 

Clients want to contain cost by limited development runs, but still expects successful full-scale manufacturing

Clients expect us to resolve the most difficult scientific or technical problems

Clients expect us to give them our proprietary, internal process development or manufacturing expertise.

  These problems appear to be the most common complaints, but a host of other issues also vex CMOs. More than four in five feel that “Clients don’t recognize the variability in process development,” and “Clients don’t understand their role in regulatory submissions.” In fact, of the 11 problems identified, each was cited by at least half of CMO respondents, and all but one was cited by at least two-thirds. With many companies and their outsourcing project managers likely having less experience both with CMOs and various aspects of bioprocessing than in the past (often due to cutbacks in staff and increased outsourcing), it is not surprising that problems with client communications and expectations are widespread and damaging. 


BioPlan evaluated how trends in client-CMO relationships have evolved over the past few years, finding that these relationships continue to involve problems, and that most have remained steady or even increased in recent years. The top area of complaint in 2013, ineffective communications, jumped to 100% of respondents after gradually rising from 80.4% to 86.1% between 2010 and 2012. Clearly, this problem has become more widespread over the years, reaching its peak this year.

Two other problems show a clear upward trend over the past few years:

Clients expect us to give them our proprietary, internal process development, or manufacturing expertise, cited this year by 91.7%, up from about two-thirds in 2011 and 2012 and 53.6% in 2010 

Clients don’t understand their role in regulatory submissions, indicated to be a problem this year by 83.3% of respondents, up from 69.4% last year, 66% in 2011, and 53.6% in 2010.

These three problems show the most definite multi-year trend. Others appear to have become more pronounced over the past year, but show more variability from one year to the next: 

 Clients want to contain cost by doing limited development runs, but still expect successful full-scale manufacturing, at 91.7% of respondents this year, up from 86.1% last year, but on par with the 92% from 2010  

 Clients expect us to resolve the most difficult scientific or technical problems, also at 91.7% this year, a big jump from 72.2% last year, but again on par with 90% in 2010. 

There are some snippets of good news among the survey results. After gradually rising for a couple of years, complaints about clients not appreciating the differences between small-scale and full-scale manufacturing and just handing off a project without planning for on-going interactions have leveled off this year. Furthermore, fewer respondents this year indicated that clients aren’t planning their tech transfer process or are wanting CMOs to use cell lines or processes that are not suitable for GMP manufacturing. 

Fixing problems requires better communication


  The most common, wide-ranging complaint among CMOs, that clients don’t communicate effectively, extends into many of the other complaints. Part of communicating more effectively is setting and managing expectations, and several of the issues at hand appear to be the result of breakdowns in this area. 

CMOs, for example, should theoretically be able to ease problems associated with clients expecting to contain costs and still achieve full-scale manufacturing. Experienced CMOs will know what they can achieve and what they can’t--and clients should also have a solid awareness of their own weaknesses and pain points. The data suggest that a frank discussion of potential problems at the outset of a relationship can help stave off future issues and establish a more collaborative working environment.

It is unlikely this problem will go away in the short-term. Most CMOs are technical in nature, and their managers are generally scientists and technical experts, often with limited expertise in building customer relations. In contrast, most non-science service industry segments, including hospitality, restaurants, and entertainment, are staffed with people highly trained in customer relations and communication. CMOs are both highly technical organizations and high-risk service providers. Clients in all service industries expect and demand responsiveness, communications, trust, and confidence in their service providers. The CMO industry is no different. Yet, from the past 10 years of BioPlan’s study, there has not been substantial change in how client-CMO relationships have evolved. Given the importance of communication, trust, and competence in this industry segment, any CMO capable of providing all three would likely have a significant competitive advantage. 

10th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production


  Eric S. Langer is president and managing partner at BioPlan Associates, Inc. in Rockville, MD,elanger@bioplanassociates.com, tel. 301.921.5979, www.bioplanassociates.com.  

A CMO perspective on the CMO-client partnership.

Making the Best of a Bad CMO-Client Relationship

Proper risk assessment and risk mitigation are crucial for pharmaceutical manufacturing to ensure product quality. A proposed new standard, the NSF/IPEC 363: Good Manufacturing Practices for Pharmaceutical Excipients, requires application of risk-assessment principles to prevent contamination from personnel, equipment, and facilities. Risk management is also used in supplier qualification, change management, and rework activities. Industry experts share their perspectives on risk assessment and mitigation in excipient manufacture and the excipient supply chain.  

The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) and NSF International, an accredited standards developer of the American National Standard Institute (ANSI), have developed a new American national standard for excipient GMPs, the NSF/IPEC 363: Good Manufacturing Practices for Pharmaceutical Excipients. The proposed standard, which is being finalized, is based on the IPEC-PQG Excipient GMP Guide, a joint initiative between the International Pharmaceutical Excipients Council (IPEC) and the Pharmaceutical Quality Group (PQG). The proposed standard defines GMPs for excipient manufacture for use in drug products and specifies the components of a quality-management system for excipient manufacture consistent with the GMP principles in the IPEC-PQG Excipient GMP Guide. The proposed NSF/IPEC 363 standard requires application of risk-assessment principles to define and justify appropriate GMP controls in order to mitigate risk to prevent contamination from personnel, equipment, and facilities. Risk assessment also is used for supplier qualification, change management, and rework activities. 

To understand how risk-assessment principles have and can be applied across the excipient supply chain, Pharmaceutical Technology moderated an industry roundtable at ExcipientFest 2013, which was held in Baltimore, Apr. 29 to May 1, 2013. Some highlights of that roundtable are provided with  input from the following panelists: Irwin Silverstein, chief operating officer, International Pharmaceutical Excipients Auditing (IPEA); Janeen Skutnik, partner, NSF-DBA, chair of the IPEC Federation, past chair of IPEC-Americas, and former director of quality strategy at Pfizer; Steven Wolfgang, PhD, associate director, Risk Science, Intelligence and Prioritization (acting), FDA’s Center for Drug Evaluation and Research, Office of Compliance, Office of Drug Security, Integrity and Recalls; Dale Carter, global quality director, silica, J.M. Huber Engineered Materials, member of the IPEC-Americas Executive Committee, and immediate past chair of IPEC-Americas; and Meera Raghuram, manager for global regulatory affairs and strategies at Lubrizol and current chair of the IPEC-Americas Regulatory Affairs Committee.  
  
  

 What was the rationale for developing the NSF-IPEC standard and how did it come into being? 

One of the key rationales we had was the IPEC-PQG GMPs that were revised in 2006. In the 2008-2009 timeframe, IPEC, as an organization, decided that it wanted to evolve the guideline to the next level so that we could possibly have it used and referenced by the agency, by other agencies around the world, and take it into a standard, an auditable standard, as opposed to a guideline.  

At that point, we had a discussion with NSF to develop an American national standard. We felt it was an important step forward to create a document that could be used officially as an auditable standard that would be in compliance with the Office of Management and Budget Circular A119, which establishes policies on federal use and development of voluntary consensus standards. This measure is guidance to US government agencies to allow them to refer to consensus-based standards in lieu of developing a standard within an agency of the US government.  

We pulled together experts on excipients, not only from the US and industry, but also from regulatory authorities and public-health agencies in Europe and the US, and of course, key industry representatives who not only worked on the IPEC-PQG original GMPs but also those who have been involved and knowledgeable about excipients for 20, 30, and 40 plus years. It’s been a great process in terms of getting people together and looking at harmonizing expectations. Again, it is not just focused on what’s important in the US, but also what is important globally.  

In terms of the specifics of the standard, certainly anyone familiar with the IPEC guidance will notice a lot of the same key things are emphasized as well as those familiar with ICH Q10 Pharmaceutical Quality System or ISO guidelines. It is focused on a robust, effective quality-management system. It helps you understand what a quality culture is within a company. Whether you’re talking about pharmaceuticals, excipients, or APIs, if a company doesn’t embrace a quality culture, it will always struggle with GMP compliance because if people don’t understand the importance of quality, they’re not ever going to quite get there. The standard helps you assess and look at what the quality culture of a company is by how it approaches all the different elements of a quality-management system. There are expectations for what the appropriate facilities and controls are, what the appropriate documentation is, and what the appropriate personnel and training are. That is something that, time and time again, is very important, not only for excipient manufacturers, but for all parties throughout the supply chain to understand what they’re doing, why they’re doing it, and how it translates to a patient outcome or a patient impact. 

Appropriate test methods and controls are part of an overall process. It is an auditable standard, so it provides a tool for overall supplier qualification. It incorporates all the necessary elements from ICH Q10 

Pharmaceutical Quality System and Q9 Quality Risk Management.  

 How does the proposed NSF-IPEC standard build upon the IPEC-PQG Excipient GMP Guide? 

The IPEC-PQG guide is just that, a guideline, so in certain sections, such as air handling, utilities, personnel protection, and gowning, it would provide several examples of what to do in certain situations. For example, it would say that if you needed a controlled environment, then you had to control it. It was written in a way that those reasonably knowledgeable of what they were doing could look at it and make reasonable decisions and put in their own programs and processes. What the ANSI standard did was it took those examples and translated them into a standard that you could audit. For example, rather than getting prescriptive, it specifies you must do a risk assessment. It took the elements that were already in the guide and said consider these points. The proposed standard then took the points or the examples we gave in the guide to help someone understand and relate them to his/her own process and put them as a kind of a mnemonic for conducting the risk assessment. The standard preloaded your risk assessments by stating the risk questions, ‘What are you trying to prevent, and how are you doing that?’ And in trying to prevent this end, consider these things. The proposed standard  does that throughout by talking about work environment, utilities, control of gowning or personnel, rework, or other aspects that made it into a standard that could be audited.

For the excipient manufacturer, what it does is it puts a little work on you. To convert from being a IPEC-GMP-compliant company into being a company that could be certified under the about-to-be-released ANSI standard, you’re going to have to go back and justify why you did these things. The advantage is now you’ve protected from loss of knowledge through attrition and have the ability to understand from the documented risk assessment what the reasoning was for these programs; it really created a standard that people could implement.

 How is the proposed NSF-IPEC standard compatible with FDA’s expectations and with other agency guidance? 

 In terms of pharmaceutical quality systems, I think there is a lot of compatibility between the standards that are like the ICH guidelines and the approaches that are being recommended in those guidelines and the ANSI NSF 363 standard because you are talking about applying risk-based approaches, establishing quality management systems, and emphasizing the importance of senior management responsibility, which is really part of building the quality culture within an organization. If your senior management doesn’t support it, then, certainly, it’s not going to be supported throughout the organization. In terms of the types of practices that we’ve been trying to encourage finished dosage form manufacturers to apply, we’re seeing a lot of progress in terms of building the same type of approaches throughout the pharmaceutical supply chain, including excipients.  

From a pharmaceutical company perspective, how does the NSF-IPEC standard satisfy the information and documentation that a pharmaceutical company would need?   

 One of the key things is the proposed standard creates a level playing field, which is very important, not just for pharmaceutical companies, but also for excipient manufacturers as well because if there are too many different standards and different expectations, nobody’s expectations are met. The standard creates a clear set of expectations, so everybody’s on the same page as to what is important to the quality of an excipient, which is something very important for a pharmaceutical user.  

 From the perspective of excipient manufacturers, how does the proposed NSF-IPEC standard provide needed flexibility for the excipient manufacturer while providing the needed documentation and information that the excipient user might need in its requirements?

 From my perspective, what the standard allows you to do, using the risk-assessment model, is to describe what you do and to justify it. It allows you to make the same safe product and then add to it some of the quality and consistency requirements needed for drug products and explain that and communicate it in a controlled way because there is a common standard. The excipient manufacturer is not being audited by different standards from the pharmaceutical industry.   

From an excipient manufacturer’s perspective, we have always used risk assessment to make informed decisions, but where the gap was may not have been always documented. For example, we may ask, ‘Why are we doing this?’ The answer may be ‘We have always done it this way. We have done it this way for the past 20 years and it has worked well.’ What the standard does is it forces you to look at the quality performance, customer requirements, and the safety of the excipients and document why you are using certain controls or why you may not need certain controls in certain places. There is a large advantage to implementing and having a consistent standard across the board.

Industry experts share perspectives on risk assessment and mitigation in excipient manufacture and the excipient supply chain.