Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

Organic chemists are tasked with optimizing synthetic routes for pharmaceutical compounds. Catalysts, both chemical catalysts and biocatalysts, play a crucial role in improving reaction efficiencies and conditions, increasing yield, and achieving desired stereoselectivity. Fine-chemical companies, contract manufacturers, and other researchers are advancing this field for producing pharmaceutical intermediates and APIs. 


  Codexis, a company specializing in biocatalysis, recently reported on its development of industrial  biocatalysts for sulfide oxidation and Baeyer-Villiger-type monooxygenations (BVMO). These BVMO enzymes can be used to improve methods to manufacture chiral sulfoxides, which are important molecules for pharmaceutical synthesis. Codexis used these enzymes to develop biocatalytic processes for producing esomeprazole and armodafinil to improve enantiometric purity and reduce sulfone impurity, according to an Oct. 3, 2013 Codexis press release. The enzyme and API manufacturing processes are currently being scaled up for commercial supply. Codexis’ BVMO enzymes are commercially available as a screening kit that process chemists can use to develop new biocatalytic oxidation processes. 
  
Earlier this year, Codexis partnered with Purolite, a provider of ion-exchange, catalyst, adsorbent, and specialty resins, to develop and market immobilized enzymes for the pharmaceutical industry. The enzymes are immobilized through binding to inert resins to allow for easier separation from a reaction mixture, and immobilization allows the enzymes to be used under different reactions conditions and re-used at a commercial scale. The collaboration is focused on immobilized transaminase enzymes. 

Codexis also partnered earlier this year with the CMO AMRI in a nonexclusive, two-year agreement focused on identifying and implementing new and improved manufacturing routes for select APIs. Codexis is providing its directed evolution technology for enzyme discovery and optimization, and AMRI is providing process development and manufacturing capabilities, including using AMRI’s proprietary microbial strains.

Johnson Matthey Catalysis and Chiral Technologies (JMCCT) business unit, which provides heterogeneous, homogeneous, chiral, and biocatalytic technologies, is expanding its existing specialty ligand-manufacturing capability to include commercial-scale manufacturing up to 100 kilograms. The expansion is largely focused on the Buchwald ligands from the Massachusetts Institute of Technology. The Buchwald ligands offered by JMCCT are a class of dialkylbiaryl monophosphine ligands, which are used for the

 generation of active catalysts for coupling reactions in the manufacture of pharmaceuticals and specialty chemicals. The XPhos and SPhos ligands are used for Suzuki-Miyaura reactions, in particular with hindered aryl substrates and heteroaryl halides. In addition, the combination of Buchwald ligands, such as XPhos, SPhos, RuPhos, and BrettPhos with several palladium catalyst precursors, such as Pd(OAc)

 generation of active catalysts. These catalysts can be applied in carbon-carbon, carbon-nitrogen, carbon-oxygen, carbon-sulfur, and carbon-born bond formations, including the Suzuki-Miyaura, Negishi, Sonogashira, Buchwald-Hartwig amination and carbonyl alpha-arylation reactions.

The biocatalysis company evocatal is relocating to Monheim, Germany, to a facility that doubles the company’s laboratory and production area to add additional capacity for research, process development, and production. The expansion adds new industrial fermenters to optimize the manufacture of biocatalysts up to the 100-L pilot scale. In addition, the new location will house multipurpose equipment for the synthesis of fine chemicals up to the kilogram scale. 

Almac recently reported on its collaboration agreement with DSM Pharmaceutical Products in biocatalysis, which includes the successful transfer of enzymes for enzyme screening, process development, and scale-up manufacture. The agreement grants both companies access to their enzyme platform technologies, services, and expertise for API manufacturing. Almac is bringing expertise in enzyme identification, scale-up, and implementation into early-phase projects, and DSM is providing commercial-manufacturing expertise, which gives Almac a preferred partner for large-scale production. Since forming their agreement in 2012, Almac and DSM have initiated and completed multiple projects in the fields of ketoreductases, transaminases, bio-oxidations, and hydrolases. Almac also recently completed a knowledge transfer partnership with Queens University Belfast to develop, improve, and embed bioprocesses.


Researchers at Max-Planck-Institut für Kohlenforschung in Mülheim an der Ruhr, Germany recently reported on their work in immobilizing various catalysts on nylon and applying them in pharmaceutical synthesis among other reactions. Working in collaboration with scientists from the Deutsches Textilforschungszentrum in Krefeld, Germany and Sungkyunkwan University in Suwon, Korea, the researchers at the Max-Planck-Institut für Kohlenforschung in Mülheim an der Ruhr developed a process for immobilizing different organic catalysts on textiles with the help of ultraviolet light. The fabric acts as a support for the substances on which a chemical reaction occurs.

The researchers used three organic catalysts: a base (dimethylaminopyridine, DMAP), a sulfonic acid, and a catalyst that functions as both an acid and a base, according to a Sept. 13, 2013 Max-Planck-Institut für Kohlenforschung press release.  To attach the catalysts to the nylon fibers, the chemists irradiated the textile to which a catalyst was applied with ultraviolet light for five minutes. All three catalysts converted approximately 90% of the source materials to the desired products. 

Compared with other ways of immobilizing catalysts, organotextile catalysis has several advantages. In particular, it provides the reagents with a larger surface than other supports, such as plastic spheres or foils, with the larger surface enabling a more efficient reaction. Moreover, the nylon is flexible and inexpensive. In the approach for  immobilization of organocatalysts on the textile nylon using ultraviolet light, the catalyst and the textile material require no chemical modification for the immobilization (1). All of the prepared textile-immobilized organocatalysts (a Lewis basic, a Brønsted acidic, and a chiral organocatalyst) showed “excellent” stability, activity, and recyclability for various organic transformations, according to the researchers (1). They reported good enantioselectivity (> 95:5 enantiomeric ratio) that was maintained for more than 250 cycles of asymmetric catalysis. The researchers asserted that textile organocatalysis may be beneficial for various fields by offering inexpensive and accessible functionalized catalytic materials (1).

In another development, researchers at Boston College in Massachusetts reported on the enantioselective silyl protection of alcohols promoted by a combination of chiral and achiral Lewis basic catalysts. The researchers noted that catalytic enantioselective monosilylations of diols and polyols provide alcohol-containing molecules in high enantiomeric purity, but that these transformations require high catalyst loadings (20-30 mol%) and long reaction times (2-5 days) (2). To resolve those challenges, the researchers used an achiral cocatalyst structurally similar to a chiral catalyst. A combination of Lewis basic molecules served as an achiral nucleophilic promoter and the other molecule performed as a chiral stereoselectivity base. On the addition of 7.5-20 mol% of a commercially available N-heterocycle (5-ethylthiotetrazole), reactions typically proceeded within one hour, with high product yields and enantiomeric ratios (2). In certain examples, there were no reaction in the absence of the achiral base, but the presence of the achiral cocatalyst facilitated product formation in high enantiomeric purity (2). Overall, the new approach reduced the reaction time to less than an hour, down from a period of two to five days, reduced catalyst loading, and produced a more efficient transformation for enantioselective alcohol silylation, according to a July 2013 Boston College press release. 

“The use of cocatalysts can be tricky, especially in procedures intended to deliver handedness in the molecules you want your reaction to produce,” said Amir Hoveyda, the Joseph T. and Patricia Vanderslice Millennium Professor of Chemistry at Boston College, in the Boston College press release. “What we’ve shown is that in this procedure, you can take two cocatalysts, which on the surface are competing with one another, and effectively keep them from interfering with one another.”

Hoveyda and Boston College Professor of Chemistry Marc Snapper have worked since 2006 on this method of catalysis. These catalysts, originally developed in their laboratories seven years ago, are valued for producing reactions that offer a high level of enantioselective purity. The relatively slow reaction time of two to five days was a key problem, but which was mitigated by applying a computational approach. The researchers used the cocatalyst model involving two Lewis base molecules, adding an achiral molecule to an already present chiral molecule. These cocatalysts operated in concert, with the chiral molecule activating alcohol and the additional achiral molecule (from commercially available 5-ethylthiotetrazole) activating silicon. Identification of the positive influence of ethylthiotetrazole proved to be the key component of the discovery, giving the team the ability to fine-tune the reaction and effectively control the interplay between the cocatalysts. Together, the Lewis bases served as a closely related Brønsted base to allow the catalyst to work faster while retaining high enantioselectivity.


  1.	Ji-Woong Lee, Science 341 (6151) 1225-1229 (2013). 
  2.	A. Hoveyda,

Articles

Fine-chemical companies, contract manufacturers, and researchers advance chemocatalysis and biocatalysis.

Applying Catalysis to Optimize API Synthesis

AstraZeneca received a mixed decision regarding US patent litigation for its asthma drug Pulmicort Respules (budesonide). A US federal appeals court has reversed and remanded for further proceeding a trial-court decision that generic-drug company defendants involved in the litigation did not infringe a US patent (US Patent No. 7,524,834) protecting the drug. That patent covers sterile glucocorticosteroids and sterile formulations containing glucocorticosteroid and use thereof in the treatment of an allergic and/or inflammatory condition of the nose or the lungs (1). The US federal appeals court, however, upheld the trial-court’s decision that another patent (US Patent No. 6,598,603) protecting AstraZeneca’s Pulmicort Respules in the US is valid. That patent provides a method of treating respiratory diseases (e.g., pediatric asthma) in a continuing regimen with not more than one daily dose of the drug budesonide using a nebulizer (2).

Pulmicort Respules is one of AstraZeneca's key drugs with 2012 revenues of $866 million. The trial-court decision dates back to earlier this year. On Apr. 1, 2013, the US District Court for the District of New Jersey ruled that AstraZeneca’s patent (US Patent No. 6,598,603) protecting Pulmicort Respulses in the US was invalid. The court further ruled that the generic-drug company defendants involved in the litigation did not infringe AstraZeneca’s second patent, US Patent No. 7,524,834.

AstraZeneca had filed patent-infringement lawsuits against the generic-drug companies Apotex Inc., Apotex Corp., Watson Laboratories (a subsidiary of Watson Pharmaceuticals; Watson Pharmaceuticals acquired Actavis in 2012 and later took the Actavis name), Breath Limited (a UK-based subsidiary of Watson), and Sandoz Inc., for infringement of US patents directed to methods of use and formulation and form of the active ingredient (budesonide) for Pulmicort Respules. At the trial, AstraZeneca contended that the defendants’ generic budesonide inhalation suspension products and their use would infringe the claims of the two AstraZeneca patents should those defendants market their generic products in the US. The defendants denied that they would infringe and asserted that each patent was invalid under US patent laws.

Two of the manufacturers, Apotex and Watson/Breath, had received FDA approval. A third manufacturer, Sandoz, received FDA approval while the appeal was pending. None of these manufacturers launched their generic products. Apotex was previously enjoined from launching a generic product. On May 24, 2013, AstraZeneca announced that the US Court of Appeals for the Federal Circuit issued a temporary injunction blocking the generic-drug manufacturers from distributing generic versions of Pulmicort Resuples in the US during the pendency of AstraZeneca’s appeal. Under agreement with AstraZeneca, Teva Pharmaceutical Industries has a generic version of Pulmicort Respules product on the market. 

AstraZeneca said "it has full confidence in the strength of its intellectual property rights protecting Pulmicort Respules," according to an 

 statement. The patents protecting Pulmicort Resuples in the US expire in 2018, with pediatric exclusivity extending into 2019.

1. A.K. Karlsson et al., "Sterile Powders, Formulations and Methods for Producing the Same (US Patent 7,524,834), Apr. 28, 2009. 

2. B. Andersson et al., "Treating Respiratory Diseases" (US Patent 6,598,603), July 29, 2002. 

A US court of appeals rules on patent litigation for AstraZeneca's asthma drug Pulmicort Respules (budesonide).

AstraZeneca Receives Mixed Decision on US Patent Litigation

	As the pharmaceutical industry prepares for changes to compendial and regulatory standards for elemental impurity analysis, QA/QC and laboratory scientists are tasked with adapting their operations to include data management, analysis, and reporting based on inductively coupled plasma–mass spectrometry (ICP–MS). Understanding the necessary technical controls to implement and manage analytical operations is crucial to ensure regulatory compliance. 

 will present a live educational webcast, 

“Achieving Regulatory Compliance When Moving to ICP-MS for Elemental Impurity Analysis,”

 on Wednesday, November 6, 11:00 AM to 12:00 PM EST to provide insight from leading industry experts on ICH, USP, and EMA guidelines for elemental impurity analysis and best practices and strategies to optimize the analytical workflow, data management, and data reporting when using ICP-MS.

will be Mark Alasandro, PhD, Director of Pharmaceutical Analysis and Microbiology, Allergan, past chair of the PhRMA Stability Working Group, and member of the AAPS Steering Stability Focus Group Committee and Planning Committee; and Linda Doherty, PhD, Senior Product Manager, Software and Informatics Division, Agilent Technologies. Viewers will be able to ask questions of the panelists to gain further insight into compendial and regulatory requirements for elemental impurity analysis and on how to optimize analytical workflow, data management, and data reporting when using ICP-MS in elemental impurity analysis.

	For additional information and to register for the 

 on Wednesday, November 6, 11:00 AM to 12:00 PM EST, click 

As the pharmaceutical industry prepares for changes to compendial and regulatory standards for elemental impurity analysis, QA/QC and laboratory scientists are tasked with adapting their operations to include data management, analysis, and reporting based on inductively coupled plasma–mass spectrometry (ICP–MS).

Regulatory and QA/QC Focus Elemental Impurity Analysis

	Regulatory compliance is of paramount importance to pharmaceutical and biopharmaceutical companies, which must be continually prepared for inspections by FDA, EMA, and other health authorities to meet requirements for good clinical practices (GCP) and good manufacturing practices (GMP). 

 will present an educational webcast on Thursday Nov. 7th from 1:00 to 2:00 PM EST, 

“Ensuring Preparedness for Regulatory Inspections,”

 which will provide insight on inspection trends and practical advice on how to best prepare for GCP/GMP inspections, examine the key information/documentation sought by regulators, and ways to achieve operational efficiency for providing access to that information.

	Successful GCP/GMP inspections can be achieved only through well-controlled laboratory, manufacturing, and quality systems with efficient access to related documentation and information. Often, technical limitations in content-management systems result in unsuccessful inspections. This 60-minute 

 will examine the approaches taken by regulatory authorities in GCP/GMP inspections and how properly executed document-management systems and advances in electronic data-management system technology can better prepare companies for successful GCP/GMP inspections.

will be: Robert Schiff, PhD, RAC, CQA, FRAPS, President and CEO, of Schiff & Company; Steven Scribner, Principal Consultant,
	Documentum for Life Sciences, EMC Corporation; and Adam Kelch, Product Manager, Documentum for Life Sciences, EMC Corporation. Viewers can ask questions of the panelists to gain further insight into how to meet regulators’ expectations and requirements for successful GCP/GMP inspections and how to optimize laboratory, manufacturing, and quality systems  to provide efficient access for related documentation and information to ensure successful inspections.

	Additional information and to register for the 

 webcast, “Ensuring Preparedness for Regulatory Inspections,” for Thursday Nov. 7th from 1:00 to 2:00 PM EST may be found 

Regulatory compliance is of paramount importance to pharmaceutical and biopharmaceutical companies, which must be continually prepared for inspections by FDA, EMA, and other health authorities to meet requirements for good clinical practices (GCP) and good manufacturing practices (GMP).

Preparing for Regulatory Inspections

Formulation scientists tasked with developing oral formulations often face many challenges such as drug instability in the acidic and alkaline environments of the gastrointestinal (GI) tract and unsatisfactory absorption variations of compounds with poor physicochemical properties such as low solubility or low permeability. The primary function of the GI tract is to digest and absorb nutrients and water while at the same time impede the entry of potentially noxious luminal contents such as harmful pathogens and toxins. This function is accomplished by the establishment of intestinal barriers formed by a continuous sheet of polarized columnar epithelial cells that separate the external luminal environment from the internal environment of the body and exhibit selective absorption (1-3). Oral formulations must, therefore, be able to withstand the hostile acidic environment of the stomach and the high enzymatic activity in the small intestine, circumvent the inherently impermeable intestinal epithelial barrier and the binding capacities of the resident mucus and  luminal contents, escape the efflux system that pumps substances back into the lumen, and evade first pass metabolism by the liver (3). Pharmaceutical Technology spoke with Anshul Gupte, PhD, senior formulation scientist, and Michael DeHart, PhD, development scientist, from the CDMO Metrics, about the strategies used to enhance oral absorption and the challenges in developing oral formulations for poorly permeable drugs. 

 What factors influence drug absorption in the GI tract? 

Characteristics of the drug that influence absorption include particle size, solubility, lipophilicity, stability, ionization state (pKa), and polymorphism. Sometimes these characteristics work against each other to improve absorption. For example, a drug that is more lipophilic may increase permeability, but may result in lower solubility, thereby, decreasing the overall absorption. To overcome deficiencies of absorption due to drug properties, the dosage form may help improve absorption by altering the disintegration and dissolution time, increasing residence time in the intestine, and providing delayed release in the lower intestine instead of the stomach. 

The absorption of the drug through the GI tract is governed by either a simple passive diffusion or active transport with the aid of transporters located in the GI tract. For most drugs, passive diffusion is the mode of transport. The amount of drug absorbed is dictated by the gradient created across the membranes in the stomach and the small intestine as well as the chemical structure of the drug molecule itself such as the size and degree of ionization. Size and absorption usually have an inverse relationship. Most drugs are weak acid or bases, therefore, the pH of the stomach and the intestinal tract affects the degree of ionization of the drug, which directly affects the solubility of the drug in the GI tract. The stomach has a pH of between 1 and 2 while the intestine has a pH ranging from 4 to 8. With this environment, the intestine provides a wide pH range for drugs to exist in their ionized state, which increases their solubility compared to the more lipid-soluble, un-ionized state. 

Most of the absorption takes place in the intestine mainly because the intestine offers much greater surface area for drug uptake. The residence time of the drug in the stomach may vary depending on the time for gastric emptying. The latter is affected by food uptake, other drugs, and other factors. Due to the acidic nature of the stomach mucosa and the presence of enzymes such as pepsin, drugs may be degraded before they are absorbed. The presence of fatty foods can also lead to increased gastric emptying time, which can lead to degradation or reduced absorption of some drugs. 

Lipinski’s rule of five has been used as a preclinical tool to assess the bioavailability of a drug. According to Lipinski’s rule of five, the molecular weight of the drug has to be below 500 Da for it to be a good candidate for oral absorption. Additionally, Lipinski’s rule of five states that the drug molecule should have less than five hydrogen-bond donors and not less than 10 hydrogen-bond acceptors. The log P for the drug should ideally be less than 5. A balance between the polarity and lipophilicity of the drug is necessary so that the drug has sufficient solubility in the gastric media as well as permeability through the gastric mucosa. 

To optimize drug absorption, pharmaceutical scientists employ formulation strategies such as salt formation to increase drug solubility, micronization or particle size reduction to increase surface area, inclusion of surfactants and emulsion system to alter wetting and dispersibility, and addition of buffer systems that alter the microenvironment pH. Spray drying and conversion of the drug into its amorphous, and thus, more soluble form is well established. In the case of a moderately or highly permeable drug, the disintegration and subsequent dissolution from the formulation are critical rate-limiting steps. In the case of an immediate-release formulation, the disintegration of the dosage form is the critical step for the drug to be in solution and subsequently absorbed. The dissolution of the formulation in the fed and fasted gastric media and intestinal media is usually studied in vitro to establish a relationship for the drug 

. Additionally, the drug could be formulated into sustained-release, delayed-release dosage forms. 

What strategies are used to increase oral absorption of poorly permeable drugs?

Creating an esterified prodrug is the most common way of increasing permeability for a highly soluble drug. Prodrugs are reversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug. Common functional groups that are employed for prodrug formation are amine, hydroxyl, sulfhydryl, and carboxyl moieties. A few examples of the drug/esterified prodrugs are acyclovir/valacyclovir and melagatran/ximelagatran. Esterification of these drugs eliminates an ionized functional group and increases the lipophilicity of the drug molecule. When developing prodrugs, the pharmaceutical scientist must be careful that the increased permeability due to increased lipophilicity doesn’t result in reduced solubility, whichcould offset any increase in absorption due to increased permeability.

Another approach is to use polymers that, in general, mask the inherent hydrophilic nature of the API and hence, lead to enhanced absorption. Liposomes, nanoparticles, and microspheres are all polymer-based delivery systems that generally incorporate a hydrophilic compound inside a lipid membrane. Mucoadhesive polymers can be used to increase the residence time in the GI tract. Specific molecular weights and combinations of polyethylene oxide, for example, have been shown to exhibit excellent adhesive characteristics 

Other methods include the formation of bile salt complexes or using cyclodextrin inclusion complexes, which allows poorly soluble drugs to be combined with cyclodextrins, thereby, creating a soluble complex. Developing self-emulsifying drug-delivery systems (SMEDDS) is another strategy to increase oral absorption of a poorly soluble drug. These systems are typically administered as soft gelatin capsules. The drug is dissolved in the oil phase, and through careful selection of surfactants, SMEDDS are able to promote GI absorption by inhibiting bile secretion. In addition, the surface area of cells exposed to certain surfactants is increased.

What are the challenges when developing oral formulations for poorly permeable drugs? 

One challenge is that a drug would be soluble in the gastric media, but would not get absorbed along the GI tract and is subsequently eliminated from the body. One must consider the permeability change over the entire length of GI tract. Another factor to consider is whether the drug is a substrate for the active transport system in the gastric mucosa. The strategy of creating SMEDDS can be undertaken by those companies that possess soft gelatin capsule technology. In some cases, there may be benefit of a delayed-release formulation. 

 The two biggest hurdles in formulation development for a poorly permeable drug are cost and time. Using newer technologies or equipment that have not been fully tested and validated as a commercial option poses a risk. Therefore, proven methodologies such as the addition of functional excipients, particle size reduction, modified-release tablets, or enteric coatings may offer the most practical option to increasing permeability. 

What are some recent advances in oral absorption enhancement strategies? 

Spray drying to generate amorphous material to increase bioavailability is becoming more prevalent. Spray drying is a fast process where the drug molecule and a stabilizer, usually a polymer, can generate a wide range of particle sizes to improve solubility (BCS II and IV) or permeability (BCS III and IV). The spray-dried amorphous material generated from spray drying can then be processed into tablets or capsules with specific release profiles. Other techniques that generate amorphous material to improve absorption are hot-melt extrusion, freeze drying, and supercritical fluid drying. Each of these techniques has their own advantages and disadvantages. 

A more recent advancement in increasing oral absorption is the advent of chronotherapeutics. Chronotherapy uses the body’s natural, circadian rhythms to improve absorption of drugs. For example, blood flow, active versus resting state, and gastric mobility are a few things that change throughout the course of the day that could influence drug absorption. To effectively target the circadian rhythms of the body, several techniques have been developed to offer pulsatile drug release. To achieve the pulsatile-release profile, tablets are generally formulated with multiple layers that contain a combination of immediate-release, extended-release, and delayed-release matrixes. The one-step drug coating (OSDrC) Optidose technology, a proprietary technology of Catalent, can manufacture multiple layer tablets and a tablet-in-tablets with multiple core placement to achieve almost any desired pulsatile-release profile. In a similar fashion, capsules containing beads with various polymer coatings can effectively deliver a drug using the body’s circadian rhythms. 

, 4 (2) 144-151 (1999).
  2. 		P.D. Ward, T.K. Tippin, and D.R. Thakker,

, 3 (10) 346-358 (2000). 
  3. 		T.Y. Ma and J.M. Anderson, “Tight Junctions and the Intestinal Barrier,” in 

, L.R. Johnson, Ed. (Academic Press, Burlington, MA, 4th ed., 2006) pp 1559-1594.

Formulation scientists tackle the challenges of improving drug absorption across the gastrointestinal membrane.

Evaluating Strategies for Oral Absorption Enhancement

A recent analysis of the Chemical Pharmaceutical Generic Association (CPA), which represents Italian generic API manufacturers  points to strong growth for the pharmaceutical contract research and manufacturing services (PCRAMS) industry. The overall world PCRAMS industry, which includes revenues from both contract research organizations (CROs) and contract manufacturing organizations (CMOs), was valued at $72 billion in 2012, up from $21 billion in 2000. Contract manufacturing accounted for  two-thirds of the  2012 market, or $47 billion, and contract research the remaining $25 billion, according to the CPA report, 

Of the global contract manufacturing business, contract manufacturing of APIs and intermediates accounted for the largest sector for contract manufacturing  at 64% or $30 billion. Contract manufacturing of finished dosage forms accounted for 9.6% or $4.5 billion, according to the CPA analysis.  Development of finished dosage forms accounts for approximately 15% of the contract manufacturing market, or $7 billion, and packaging/labeling and other services  represent the remainder or $5.5 billion. 

Of the  market for contract manufacturing of APIs and intermediates, custom synthesis (mainly focused on new, branded APIs) accounts for 40% or $12 billion, and toll manufacturing  for  the remaining 60% or $18 billion. For purposes of the analysis, “custom synthesis” denotes when a company outsources the manufacturing of an intermediate or API without indicating the operational modalities. “Toll manufacturing” denotes when the production of the intermediate or API is carried out by the external suppler according to operational modalities established by the sponsor company. 

Overall, the global PCRAMS market is forecast to grow at an average of 13.6% yearly over the next five years to reach $136 billion by 2017 from $72 billion in 2012. The global CRO business is expected to increase from $25 billion to $43 billion in 2017, representing average yearly growth of 11.4%, according to CPA. The global CMO business will increase from $47billion in 2012 to $93 billion in 2017, an average of 14.6% in yearly growth, according to CPA estimates.  

Asia Pacific will show the strongest growth in the global PCRAMS market, with particularly strong growth for India and China. The share held by India in the world PCRAMS market will nearly triple in the next five years, and by 2017, India will be the second largest market for PCRAMS, accounting for 21.3% of the global market compared to only 8.3% in 2012. India will only be surpassed by the United States, which is expected to hold almost 25% (24.9%) of the global PCRAMS market in 2017 compared to a share of 33.7% in 2012. Just as the US market’s share in the global PCRAMS market will decline so will the share of Western Europe from 25.0% in 2012 to 17.1% in 2017. China’s share of the global PCRAMS  market will increase from 12.2% in 2012 to 19.2% by 2017, according to the CPA analysis. 

Overall growth in the market for pharmaceutical contract research and manufacturing is strong although growth in established markets erodes at the expense of emerging markets.