A significant proportion of new drugs under development contain high-potency active pharmaceutical ingredients (HPAPIs), which is leading to explosive growth in demand for their production. The cytotoxicity of HPAPIs, however, presents handling challenges and requires heavy investment in specialized containment to ensure that employees and their environment are protected from exposure. This article examines the planning, equipment, and facility design of chemical and biologic HPAPIs as well as biologic–HPAPI conjugate manufacture. It also outlines the efforts made by the pharmaceutical industry to develop voluntary standards for HPAPI production and handling.  

During the last decade, the demand for HPAPIs has grown rapidly, mainly as a result of advances in clinical pharmacology and oncology research. There is particular interest in HPAPI–antibody conjugate technology, which uses monoclonal antibodies to selectively deliver HPAPIs to specific cancer tumors. When conjugated to the antibody, the HPAPI targets cancer cells specifically and thereby spares nontarget cells many of the toxic effects. Wyeth's "Mylotarg" (gemtuzumab ozogamicin) is an example of such a drug. It  is commercialized for treating acute myeloid leukemia, and numerous other antibody drug conjugates are in preclinical or clinical trials.  

Compared with the overall  growth in the pharmaceutical market of about 7% per year, HPAPIs are estimated to have an annual growth of 12% (1, 2). They account for about 12% of the total pharmaceutical market, and this share is set to rise strongly (3). Although this emerging market is attractive, it presents a significant challenge for pharmaceutical manufacturers to upgrade existing facilities that are set up to handle only nonpotent APIs—the challenge being the major cost associated with the specialized containment needed to ensure that employees and their environment are protected from exposure. Many contract manufacturers are also building new facilities that are designed specifically for the manufacture of HPAPIs, which require an investment of millions of dollars beyond typical GMP (good manufacturing practices) production facilities. This investment may include specialized facilities for HPAPI–antibody conjugations that incorporate both potent-compound handling and biologics processing capabilities. 

The definition of an HPAPI varies depending on the literature; however, APIs deemed to be potent may fall into the following categories (4):

1. A pharmacologically active ingredient or intermediate with biological activity at approximately 150 μg/kg of body weight or below in humans (therapeutic daily dose at or below 10 mg) 

2. An active pharmaceutical ingredient or intermediate with an occupational exposure limit (OEL) at or below 10 μg/m

3. A pharmacologically active ingredient or intermediate with high selectivity (i.e., ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental effects, or reproductive toxicity at low doses

4. Or, by default, a novel compound of unknown potency and toxicity. 

The potency of pharmaceutical chemicals is often characterized by OELs in μg/m

; the lower the value, the more potent the chemical and the greater the level of containment that is required. Currently, there is a significant increase in the number of APIs going through development and clinical trials, and into the production environment with OELs well below 10 μg/m

. These processes require specialized containment to ensure that employees and their environment are protected from exposure. Figure 1 shows a facility design of a typical kilo-laboratory (using glassware) for HPAPI handling. The main features are as follows:  

Figure 1 (FIGURE 1 IS COURTESY OF SAFC.) 

Room pressure differentials designed for containment (with monitoring and verification), with the main HPAPI-handling area at negative pressure to surrounding rooms 

Airlocks and vestibules around manufacturing and laboratory spaces to provide gowning and degowning areas and proper pressure differentials

Restricted access to ensure that only the necessary trained employees enter the HPAPI-handling areas

HVAC (heating, ventilation, and air conditioning) systems designed for single-pass air—no return, with temperature, humidity, and particulate controls 

Misting showers as part of degown and exit vestibules to rinse personal protective equipment (PPE) and gowning prior to removal 

Filtration and capture of contaminants, with safe-change filters, both point source (within the isolator, ventilated enclosure) and the general HVAC exhaust system

Preventive maintenance and change-control procedures to ensure that equipment and systems continue to operate properly and according to design specifications.

Several factors need to be taken into consideration when planning a facility as outlined below:   

Cleanability, decontamination, and product changeover

Controlling employee activity in the facility to minimize exposure potential

Flexibility (i.e., does the design allow for easy reconfiguration?). 

Operating an HPAPI facility means that a number of systems, policies, and standard operating procedures (SOPs) must be put in place to protect staff. Additionally, manufacturers must ensure all employees handling HPAPIs be  adequately trained. Senior management must support the implementation of such systems, which includes providing the necessary funding for these systems. There should be regular reviews of material safety data sheets, toxicological literature, and relevant occupational safety and health literature for knowledge regarding the compounds used. These reviews should also include information on PPE and engineering processes. 

 To develop and monitor handling programs and training, it is recommended that a committee be established to take responsibility for HPAPI-handling programs. Ideally, this committee would comprise a mixture of senior management, handling staff, experts, occupational health professionals, and senior scientists. The committee should put together a general company policy and a range of SOPs for potent-compound handling, including details of which staff members have access and are able to handle HPAPIs, training-program requirements, development of SOPs, evaluation, categorization, and updating procedures and processes. For each step, specific written instructions for equipment use and unit operations must be in force, though this could be applied through the use of SOPs. 

  One of the primary concerns when handling potent compounds is employee exposure, which could potentially result in undesired health effects and/or sensitization. It is vital to set up an appropriate employee medical surveillance and monitoring program. An occupational physician should work closely with the committee, regulatory authorities, and any relevant health and safety bodies. Another significant issue is the ability to clean contaminated surfaces to an established, acceptable and safe level set out by GMP or industrial hygiene guidelines. Cleaning verification and validation procedures are critical and should include a viable deactivation solution in the cleaning process whenever possible.  

  Response plans must also be in place to ensure employees react appropriately to an unplanned event. These plans should include employee training for emergency response, communication plans, and an ongoing evaluation of the program. Involvement of local authorities in the planning and training for emergency response is also important.  

  It is vital that HPAPI-handling systems and equipment are tested and verified to meet the necessary isolation requirements. For example, isolation equipment may be expected to meet a containment capability of  less than 1 μg/m

. The capability of equipment, systems, and procedures to contain and isolate materials under expected operating conditions must be verified as a critical component of the overall HPAPI-handling program. This process typically requires the use of both air and surface industrial hygiene sampling methods to confirm proper isolation following a detailed sampling plan. In many cases, sampling and testing methods for products in early preclinical or clinical testing have not been developed. Therefore, surrogate products such as lactose or naproxen sodium, are frequently used to complete the equipment testing. 

  When considering the manufacture of an HPAPI, there must be close evaluation of the compound for potential toxicity, potency, and hazards. The Occupational Safety and Health Administration ensures that employees are provided a safe and healthful working environment, but there is no official guidance about safely manufacturing potent APIs. As a result, the industry has begun policing itself. There are currently two commonly used programs—a five-tiered system such as the one used by Merck & Co., and a more frequently used four-tiered system similar to the one developed by SafeBridge Consultants. 

The compound is placed into a potency category based on the available data and evaluation process (see Table 1). The following are attributes that may be considered for each category of compound using the SafeBridge rating system: 

 Low potency, higher dosage levels, minimal reversible acute and chronic health effects, good warning properties, no "genic" effects, not a sensitizer, slow absorption, no medical intervention required following exposure

: Moderate acute and chronic toxicity, reversible effects, weak sensitizer, fair warning properties, moderate absorption rate, no "genic" effects, may require medical intervention

 Elevated potency, high acute and chronic toxicity, effects may not be reversible, moderate sensitizer, poor or no warning properties, quick absorption rate, suspected or known "genic" effects, moderate to immediate medical intervention required

: High potency, extreme acute and chronic toxicity, irreversible effects, strong sensitizer, poor or no warning properties, quick absorption rate, known "genic effects," higher degree of medical intervention required, may affect sensitive subpopulations.

This categorization system is referred to as performance-based exposure control limits, which link compound toxicity and potency to procedures for safe handling practices (5). This system was set up in the late 1980s by pharmaceutical manufacturers for handling development projects where insufficient data was available to establish OELs. SafeBridge recommends Category 3 as the default categorization when very little or no information about a compound is available. This requires handling of the material as a potent compound with sufficient engineering controls for containment. 

 Engineering controls should be used as the primary source for containment and isolation of potent compounds. Although PPE is also used, it is secondary employee protection for exposure control. The category assigned to the compound defines proper handling procedures as follows:  

 General laboratory practices and gowning; open handling can be completed for ~ ≤ 1 kg, local ventilation for > 1 kg; no containment.

 General laboratory practices and gowning, open handling can be completed for ~ ≤ 100 g,  local ventilation for > 100 g; containment for high-energy, dust-generating operations (milling) 

 Additional gowning and respiratory protection when handling powders; no open handling of powders, additional facility controls for containment, closed-system solution transfers

: Full gowning and PAPR (powered air purifying respirator)/supplied-air respiratory protection, no open handling, full containment of all solutions and powders, deactivation solutions for cleaning, specialized facilities. 

Potent-compound handling systems should ideally incorporate five levels of cascading protection,  the first two being the primary methods of product isolation as follows:  

 closed-system glassware and reactors, α/β  valves

: glove-box isolators, ventilated laminar flow enclosures, rapid-transfer ports, local exhaust ventilation, closed-system cleaning via clean in place

: air pressurization, high number of air changes, single-pass air, restricted access, airlocks, safe-change filters, misting showers

 Saranex coveralls and hoods, PAPR or supplied air, proper glove selection, chemical suits when needed for solvents and reagents 

: training, procedures and policies, education, health monitoring.

Companies handling HPAPIs should also consider being certified by a third-party organization such as SafeBridge. This certification process allows for all aspects of the potent compound-handling program to be evaluated against current industry expectations by independent experts. As an added benefit, certification can also lead to continuous improvement and evaluation programs designed to ensure advancement of the HPAPI-handling systems. Even if the company chooses not to go through the certification process, they still may choose to have an evaluation by third-party experts as an effective means of identifying gaps or opportunities for improvement in the HPAPI program. 

The development and manufacture of high-potency active pharmaceutical ingredients (HPAPIs) requires significant planning, extensive employee training, proper equipment, and facility design as well as implementation of the necessary procedures to safely handle the compounds. The capital investments are significant, and the knowledge gained through experience is invaluable. Robust systems must be employed in all aspects of the HPAPI-handling program, from initial project evaluation through equipment cleaning, to disposal of process wastes. As the number of potent compounds in pharmaceutical development continues to increase, so will the opportunities for HPAPI manufacturers, especially for companies with capabilities in growing niche areas such as HPAPI–antibody conjugation. 

 is director of regulatory affairs at SAFC Pharma, 645 Science Drive, Madison, WI 53711, tel. 608.233.3115, fax 608.233.6873, 

Articles

The author explains the planning, equipment, and facility design requried for manufacturing HPAPIs and specialized requirements for handling these compounds.

High-Potency APIs: Containment and Handling Issues

While contract manufacturers of active pharmaceutical ingredients (APIs), pharmaceutical intermediates, and finished products gather for CPhI Worldwide in Frankfurt later this month, the outlook for contract services is positive. Several large contract manufacturing organizations (CMOs) report healthy sales gains so far in 2008 and are proceeding with expansion plans in developmental and CGMP (current good manufacturing practices) capacity.  

IMAGES COURTESY OF SAFC. BACKGROUND MOLECULES: CHAD BAKER/GETTY IMAGES			

Lonza shows growth in small molecules and biologics

Lonza (Basel, Switzerland), one of the largest CMOs for small-molecule and biologics manufacturing, reported strong growth in the first half of 2008. Sales in its exclusive synthesis and biopharmaceuticals businesses increased 19.2% to CHF 765 million ($697 million) for the six-month period ending June 30, 2008. Capacity utilization in these businesses was approximately 90%, with a slightly higher level in biopharmaceuticals. The company also reported that restructuring measures initiated at its facilities in Baltimore, Maryland; Riverside, Pennsylvania; and Braine-l'Alleud, Belgium, facilities are all on track and contributed to improved profitability.  

 Led by gains in its small-molecule business, sales in Lonza's exclusive synthesis business increased to CHF 364 million ($331 million) in the six-month period ending June 30, 2008, up from CHF 242 million ($220 million) in the same period of 2007. The company is proceeding with several expansions. A small-scale, multipurpose CGMP API plant in Nansha, China, completed additional product validations during the first half of 2008. Construction of a corresponding large-scale API plant in Nansha is on schedule, and Phase I is expected to be completed in the second half of 2008. Further expansion phases in Nansha are in the planning stage, according to the company.  

Lonza also expanded its technology portfolio with the addition of commercial-scale antibody drug conjugate capabilities and successfully completed commercial CGMP batches. The commercial-scale capabilities complement laboratory-scale and small-scale pilot-plant capabilities. Lonza is also expanding its fine-chemicals complex in Visp, Switzerland,  for large-scale production of high-potency APIs (HPAPIs).  

 Based on increased demand for mid-scale microbial manufacturing capacity, Lonza is expanding its microbial production facility in Hopkinton, Massachusetts, with the addition of a high-titer 2000-L manufacturing train. The new plant is scheduled to come on stream in March 2009. Lonza brought on line two large-scale microbial lines (15,000 L) at the company's Visp, facility, in 2007, and the lines are now fully operational. 

 In May 2007, Lonza broke ground for a facility for biopharmaceutical manufacturing technologies, support systems, and warehouses in Portsmouth, New Hampshire, where the company has large-scale mammalian cell-culture manufacturing capabilities. Lonza also added a 5000-L bioreactor to the existing facility. The company added a 500-L train at its mammalian manufacturing facility in Slough, England. Lonza began construction for a second large-scale mammalian facility in Singapore in 2007. The facility is scheduled to be completed and fully operational in 2011. A second large-scale mammalian manufacturing facility is scheduled for completion and operation in 2009.  

 Lonza says it is expanding its contract- manufacturing business model to accommodate "pipeline agreements," in which the company and its pharmaceutical and biotechnology clients have the option to jointly develop and manufacture a pipeline of both chemical and biological products, an expansion from single-product agreements. Also, to focus on high-value-adding steps, the company is evaluating its outsourcing activities for low-value starting materials and intermediates.  

SAFC (St. Louis, MO) has invested $45 million in high-potency expansions during the past 18 months. In late 2007, it began operations of a new 600-ft

  HPAPI conjugation suite at its St. Louis, manufacturing facility. The suite is designed for producing early-stage clinical supplies and has capabilities to expand production into commercial scale in multikilogram quantities. The company invested $4.5 million to expand CGMP capacity on a pilot-plant and kilo-laboratory scale at its facility in Madison, Wisconsin. This investment follows a $12-million, 38,000-ft

  HPAPI expansion at its Madison facility, which was completed in 2006. SAFC is investing $29 million for a new facility for large-scale production of bacterial and fungal fermentation-derived HPAPIs in its Jerusalem, Israel, facility. The expansion is scheduled for completion in 2009.  

Covance expands drug-development services			

SAFC is proceeding with a $12-million expansion of its viral-product manufacturing facility in Carlsbad, California. The expansion is scheduled to be operational in the second half of 2009. The new suites will add 8000 ft

  of manufacturing space and enable 100-L batch production in stirred-tank bioreactors and 1000-L batch manufacturing in disposable bioreactors. These investments follow a $10-million expansion of commercial-scale API manufacturing and storage capacity, respectively, at its Arklow, Ireland, and Buchs, Switzerland, facilities in 2007.  

To build its contract-manufacturing activities, Dr. Reddy's Laboratories (Hyderabad, India) completed two key acquisitions in 2008: Dow Chemical's (Midland, MI)  Dowpharma small-molecules business associated with its Mirfield and Cambridge, United Kingdom, sites, as well as BASF's (Ludwigshafen, Germany) manufacturing facility in Shreveport, Louisiana, and related contract-manufacturing business for finished pharmaceuticals. The acquisition of the Dowpharma small-molecules business includes customer contracts, associated products, process technology, intellectual property, and trademarks as well as the transfer of the Mirfield and Cambridge facilities. Dr. Reddy's will also have a nonexclusive license to Dow's "Pfenex Expression Technology" for biocatalysis development.  

The BASF acquisition includes relevant business, customer contracts, related abbreviated new drug applications and new drug applications, trademarks, as well as the Shreveport facility and related contract manufacturing activities. It also includes a tolling and supply agreement.  

DSM (Heerlen, The Netherlands), which provides contract development and manufacturing services for small molecules, biologics, and solid-dosage and sterile products, reported gains in its pharmaceuticals business. Sales increased nearly 4% from EUR 425 million ($627 million) in the first half of 2007 to EUR 444 million ($652 million) in the same period in 2008. DSM recently added aseptic fill–finish manufacturing services for injectable cytotoxic products. The aseptic cytotoxic capabilities include flexible commercial scale fill–finish services for liquid and lyophilized products in vial sizes as large as 65 mL. In early 2007, DSM completed an expansion to its sterile parenteral manufacturing facility in Greenville, North Carolina. It added a clinical-trial-material manufacturing suite capable of manufacturing large- and small-molecule liquid and lyophilized products for Phase I–III clinical trials. 

Aptuit adds chemical development services

In December 2007, Aptuit (Greenwich, CT) completed the acquisition of the chemical and pharmaceutical development) business of Evotec (Hamburg, Germany). Aptuit gained an API facility in Oxford, England, and a recently expanded parenteral (injectable vials) fill–finish facility in Glasgow, Scotland.  

The Evotec acquisition is the latest move by Aptuit to strengthen its contract drug-development portfolio. Acquisitions in 2007 include SSCI, a solid-form research firm, and EaglePicher Pharmaceutical Services, which provides small-molecule synthesis capabilities, including HPAPIs. 

Aptuit is also building its global footprint in India. In 2007, Aptuit and Laurus Labs Limited (Hyderabad, India) formed a new contract drug-development company, Aptuit Laurus (Hyderabad), as part of a phased acquisition. The deal positions Aptuit in the growing market for pharmaceutical outsourcing in India. 

Aptuit Laurus will consist of a 160,000-ft

  research and development facility in Hyderabad, a large-scale manufacturing plant currently under construction in Pharma City, Vishakhapatnam, and Aptuit's existing informatics development and support group in Bangalore. 

Aptuit says it plans to invest approximately $100 million during the next several years to build upon Aptuit Laurus's development, manufacturing, and informatics capabilities with the addition of a complete suite of development services, including medicinal chemistry, preclinical services, solid-state chemistry, consulting, clinical packaging and logistics, Phase I–IIa research, and large-scale dosage-form manufacturing. When these investments are completed, Aptuit Laurus will mirror the capabilities of services offered by Aptuit in North America and Europe. In addition, the new company plans to offer expanded services in discovery and clinical research and access to large-scale manufacturing at the backend of the product-development life cycle. 

Patheon makes select investment and restructures

In secondary manufacturing, Patheon (Toronto) is expanding its Manati, Puerto Rico, facility to add a dedicated high-potency and controlled-substance manufacturing area. Patheon will invest a total of $2.8 million for a new 3386-ft

  area that will include three manufacturing suites, air-lock containment areas, and humidity-controlled air systems. The construction project is expected to be completed by October 2008.  

Earlier this year, Patheon opened a new early-phase development facility in Milton Park in Oxfordshire, United Kingdom. The 13,500-ft

 , leased facility contains newly constructed formulation laboratories and a fully equipped analytical laboratory. The Milton Park operations will focus on the early-phase development of solid, semisolid, and oral liquid dosage forms. The facility includes GMP manufacturing areas for the production of materials for Phase I–II clinical trials. Patheon's "Quick To Clinic" programs, which accelerate molecules to clinical trials while minimizing API requirements, will be supported at the site.  

These expansions follow recent restructuring. In April 2008, Patheon completed the sale of its York Mills facility located in Toronto for Can $12.5 million ($12.3 million). Patheon is transferring commercial production and development services undertaken at its York Mills facility primarily to its Whitby facility. A smaller portion of activity will be transferred to the company's Mississauga, Ontario, and Cincinnati, Ohio, facilities. Patheon is decommissioning the York Mills facility and has leased back the facility for as long as two years to facilitate this process. 

In February 2008, Patheon completed the sale of its Niagara-Burlington commercial-manufacturing business  to Pharmetics (Laval, Quebec, Canada), a privately owned contract manufacturer of vitamins, herbal products, supplements, and over-the-counter (OTC) pharmaceutical products. Pharmetics acquired the assets, including equipment, facilities, and land, at Patheon's facilities in Fort Erie and Burlington, Ontario. Collectively, the two sites currently serve 14 clients, manufacturing and packaging about 60 OTC pharmaceutical products in a range of dosage forms, including tablets, liquids, and powders.  

Catalent Pharma Solutions (Somerset, NJ) will double its bioreactor capacity by adding a 1000-L bioreactor train in its Middleton, Wisconsin, facility by 2009. The expansion is in response to increased client demand for production to support clinical trials in Asia, Australia, Europe, and the US.  Catalent supplies biotechnology companies with proteins made by its "GPEx" system, which produces stable, high-yielding mammalian cell lines for protein production. 

Catalent also added a Phase I sterile vial-filling suite in its Research Triangle Park, North Carolina, facility, which complements the existing clinical and commercial manufacturing capabilities in its nearby North Raleigh facility. The new suite is designed to meet increasing market demand for early phase sterile-product development and manufacturing services. It will be equipped to fill vials with most highly-potent compounds, traditional small-molecule drugs and biologics, and controlled substances. Catalent has Phase I capabilities in blow–fill–seal and in prefilled syringes at its facilities in Woodstock, Illinois and Limoges, France, respectively. 

Cook Pharmica (Bloomington, IN), the biopharmaceutical contract-manufacturing division of Cook Medical, will invest $80 million in an 80,000-ft

  expansion for parenteral formulation and fill–finish capacity. The expansion is scheduled to come on line in early  2010. The company also plans to open a new office and warehouse this year in Shanghai, China, for its customers in Asia.  

Earlier this year AMRI (Albany, NY) opened its first 

 biology laboratory in Singapore and completed a 10,000-ft

  laboratory expansion for medicinal-chemistry discovery services, more than doubling the capacity of its Science Park III facility. The 

biology group will test compounds synthesized by AMRI's Singapore-based medicinal-chemistry teams to provide potency data using cell-based or biochemical assays. AMRI anticipates hiring roughly 70 additional chemists and biologists to staff the Singapore facility during the next three years. 

These moves complement AMRI's recent activity in Asia. In 2007, the company acquired the assets of Ariane Orgachem in Aurangabad and Ferico Laboratories in Navi Mumbai, India, giving the company two API and intermediates facilities in the country. AMRI also acquired additional land for expansion and plans to invest approximately $15 million to increase and upgrade manufacturing capabilities during the next several years. 

Cambridge Major Laboratories (Germantown, WI) is  expanding its large-scale API manufacturing with a new 120,000-ft

  manufacturing facility. The facility is designed for multiple GMP manufacturing suites capable of producing multiton quantities of APIs. The facility will initially feature six manufacturing suites with reactors as large as 2000 gallons. The facility will have complete isolation and containment, several vessels for hydrogenation and cryogenic reactions, and the potential to accommodate additional manufacturing suites to the 4000-gallon scale. Completion is scheduled for August 2009. 

Carbogen Amcis's (Bubendorf, Switzerland) Indian subsidiary, Carbogen Amcis India, plans to open a high-potency facility in Bavla, India. The facility will be located on the Bavla site of its parent company, Dishman Pharmaceuticals and Chemicals (Ahmedabad, India). The facility's design and operation is modeled after Carbogen Amcis high-potency operations at its Bubendorf, facilities. The facility is expected to be operational by the first quarter of 2009. 

Carbogen Amcis is part of Dishman Pharmaceuticals and Chemicals. Dishman acquired Carbogen Amcis in 2006 as part of a broader strategy to increase its global presence by acquiring Western fine-chemicals and pharmaceutical assets. In 2007, Dishman acquired Solvay Pharmaceuticals's (Brussels) fine-chemicals and vitamin businesses for an undisclosed sum. The deal included Solvay's Veenendal, The Netherlands, facilities, as well as the intellectual property rights for fine chemicals, vitamin D, and vitamin D analogues. In 2006, Dishman acquired I03S, a company specializing in ozone chemistry. In 2005, it acquired the UK-based contract research company Synprotec. 

Earlier this year, Hovione (Loures, Portugal) purchased a 75% stake in China's Hisyn Pharmaceutical. The acquisition includes development laboratories in Shanghai and a 22,000-m

  API plant. Hovione's relationship with Hisyn started with the supply of intermediates, but this facility will now produce Hovione's two largest volume products, according to Hovione. 

The outlook is fairly optimistic as contract manufacturing organizations (CMOs) gather at CPhI Worldwide in Frankfurt. CMOs are expanding capacity for small-molecules, biologics, and finished-product manufacturing.

Expansion Activity of CMOs

Olefin metathesis provides an efficient method for the construction of carbon-carbon double bonds. Significant progress in catalyst development and applications has been made during the past 15 years (1–5). One recent advancement in olefin-metathesis catalysts has been reported by the group of Prof. Warren E. Piers with their synthesis of novel 4-coordinate metathesis catalysts possessing an open coordination site  

-heterocyclic carbene ligand (see Figure 1) (6, 7). These novel, 4-coordinate metathesis catalysts directly mimic the active 14-electron olefin-metathesis catalytic species and negate any prior ligand dissociation step that is necessary with the original 5-coordinate Grubbs- and Hoveyda-type catalysts. Piers' catalysts are active at low temperatures, which makes them particularly useful in inhibiting double-bond migrations (8–12). These new catalysts have contributed to the increasing importance of olefin metathesis as highly functional-group tolerant and as a user-friendly synthetic methodology. 

Figure 1 (ALL FIGURES ARE COURTESY OF THE AUTHORS.) 

Olefin metathesis in pharmaceutical applications

In recent years, olefin metathesis has been increasingly used by the pharmaceutical industry to synthesize biologically active molecules. Notably, K.C. Nicolaou's group described the syntheses of a variety of complex biologically active molecules using olefin metathesis as the key step (5, 13). Merck reported the synthesis of a NK-1 inflammation drug candidate in which double ring-closing metathesis (RCM) was used to build a key spirocyclic intermediate (see Figure 2) (14). Eisai reported the use of both RCM and cross metathesis (CM) in the synthesis of pladienolide (see Figure 3) (15).  Eisai showed that cross-metathesis was successful when the traditional Julia–Kocienski coupling failed to produce the desired product  

Figure 2 (ALL FIGURES ARE COURTESY OF THE AUTHORS.) 

This article describes the latest progress in olefin-metathesis catalyst technology for applications in both the pharmaceutical and fine-chemical industries and highlights the discovery and use of the new 4-coordinate, 14-electron Piers' olefin-metathesis catalysts. 

Figure 3 (ALL FIGURES ARE COURTESY OF THE AUTHORS.) 

During the past 15 years, major progress has been made in advancing ruthenium olefin-metathesis catalysts. The majority of these new metathesis catalysts were based on ligand modification of well-defined and widely employed Grubbs and Hoveyda ruthenium catalysts (see Catalysts 3, 4, 5, Figure 4) (16–18). Most recently, metathesis catalysts (see Catalysts 6 and 7, Figure 5) were developed to address the need for the highly efficient synthesis of hindered olefins, particularly for RCM reactions forming tetrasubstituted cycloalkenes (see Figure 5) (19, 20). 

Figure 4 (ALL FIGURES ARE COURTESY OF THE AUTHORS.) 

Two recent, excellent examples of olefin metathesis from the Stoltz group demonstrate the usefulness of Catalyst 6 (see Figure 5)  for natural-product synthesis. Catalyst 6 was successfully used for a key RCM step in the synthesis of elatol, a natural product from chamigrene, which has broad antimicrobial activity (21). In another recent example, the Stoltz group reported the synthesis of (–)–Cyanthiwigin F where Catalyst 6 completed both a RCM and CM step in the same reaction flask (22). 

Figure 5 (ALL FIGURES ARE COURTESY OF THE AUTHORS.) 

The metathesis catalysts shown in Figures 4 and 5 are typical 5-coordinate ruthenium olefin-metathesis catalysts. The first step in the metathesis reaction involving these catalysts is the dissociation of the donor ligand  

 generating the catalytically active 4-coordinate, 14-electron species. This 14-electron species binds an olefin, forms a metallocyclobutane ring, and productively undergoes a cycloreversion to yield the new olefinic product. Efficient dissociation of the donor ligand and olefin binding are key for fast initiation of these catalysts.  

Piers' catalysts are another new addition to the ruthenium olefin-metathesis catalyst family. Piers' catalysts adopt a pseudo-tetrahedral geometry and possess an open coordination site  

 to the phosphine (see Catalyst 1, Figure 1) or the  

-heterocyclic carbene ligand (see Catalyst 2, Figure 1)  (6, 7). This open coordination site eliminates the need for any ligand dissociation prior to olefin coordination. As such, olefin binding and activation is anticipated to be more facile with Piers' catalysts.  

Catalysts 1 and 2 are highly active for the metathesis of terminal olefins. For example, Catalyst 2a reacts with ethylene at –50 °C (8). Kinetic studies on the initiation of metathesis with  

–isopropoxystyrene as a test substrate indicated that the initiation rate of Catalyst 2a (see Figure 1) at –10 °C is similar to the initiation rate of the Grubbs catalyst (see Catalysts 3 and 4, Figure 4) at 35 °C (6). Piers' catalysts offer the additional advantage of running metathesis reactions at lower temperatures when the substrates may be temperature sensitive or to suppress double-bond migration. 

Use of Piers' olefin-metathesis catalysts

The Piers' group is developing these novel catalysts and, along with Materia, is exploring their use for a range of industrial applications, including ethenolysis, RCM, CM, self-metathesis, and ring-opening metathesis polymerization (ROMP). In general, Catalysts 1 and 2 (see Figure 1) are more active than the Grubbs catalysts (see Catalysts 3 and 4, Figure 4) for the metathesis of terminal olefins. In addition, Piers' catalysts are very active at low temperatures, and thus, are of interest to those applications where low temperatures are desired. Not too surprising, Catalysts 1 and 2 are somewhat slower for metathesis reactions involving only internal olefins such as the CM of internal olefins, which is likely due to the steric bulk of the cationic PCy

The high efficiency of Piers' catalysts for metathesis involving ethylene and other terminal olefins is particularly valuable for the industrially significant ethenolysis and RCM reactions described below.  

Ethenolysis involves the CM of ethylene and an internal olefin to generate terminal olefins. The ethenolysis of soybean oil to produce 9-decenoic acid is of significant interest to the chemical industry as an antimicrobial agent and as a monomer for polymer-industry applications (24–26). More recently, reports on the synthesis of additional biologically active molecules involving CM reactions of ethylene with internal olefins have been published as well (27). Given the high reactivity of Piers' catalysts with ethylene, we were interested in exploring their use for the ethenolysis of seed oils. This use is important as natural seed oils represent a renewable source of olefinic raw materials that can provide atom-efficient and environmentally friendly products. The affordability of these olefinic sources, coupled with their worldwide availability and inherent functionality, has already contributed to their use in several areas (24). Olefin metathesis offers new and exciting opportunities for the conversion of these unsaturated seed oils into commodity chemicals that can have wide-ranging applications. 

Ethenolysis can be complicated by secondary metathesis reactions (secondary processes generate undesired internal olefins) and by the self-metathesis of internal olefins. For an ethenolysis of methyl oleate model reaction, see Reaction 1, along with a competing self-metathesis process, see Reaction 2. 

Piers' Catalyst 1b (see Figure 1) demonstrated very good selectivity for the desired ethenolysis products, while Piers' Catalyst 2b (see Figure 1) led to the formation of significant amounts of self-metathesis products, and thus, low ethenolysis selectivity.  

The same trend was observed for Grubbs Catalysts 3 and 4 (see Figure 4) (28). The catalytic performance of Piers' Catalyst 1b and Grubbs Catalyst 3 for the ethenolysis of methyl oleate were compared at 20 °C and 40 °C, using toluene as the solvent and 0.02 mol% catalyst under 150 psi ethylene (see Figure 6). Data points were taken at 2 h (29). As shown in Figure 6, Catalysts 1b and 3 showed similar efficiency at 40 °C. At 20 °C, however, Catalyst 1b is much more active than Catalyst 3. 

Figure 6 (ALL FIGURES ARE COURTESY OF THE AUTHORS.) 

RCM is one of the most used metathesis reactions for the synthesis of biologically active molecules. Studies in the Piers' group and at Materia have shown the advantage of Piers' catalysts. The high efficiency of Piers' Catalyst 2a (see Figure 1) for RCM at low temperature (0 °C) was initially reported by Piers and coworkers (6, 7). Using RCM of diethyl diallymalonate as a model reaction (see Reaction 3), they have shown that Catalyst 2a (see Figure 1) outperformed Catalyst 1a (see Figure 1) as well as the other olefin-metathesis catalysts. 

Figure 7 (ALL FIGURES ARE COURTESY OF THE AUTHORS.) 

Results from Piers' work are shown in Figure 7 (6). Using 1 mol% catalyst and dichloromethane as the solvent, the reaction reached > 90% conversion within 2 h with Catalyst 2a while it took 4 h for the reaction to reach the same conversion with Catalysts 1a as well as with Schrock's catalyst (see Catalyst 8, Figure 8) (8). As shown in Figure 7, Grubbs Catalyst 4 and Grubbs fast-initiation Catalyst 9, which incorporate more labile 3-bromopyridine ligands, offer much lower conversion under otherwise identical conditions. Piers' catalysts possessing other noncoordinating counteranions (i.e., Catalysts 2b, 2c, 2d) display similar efficiencies under the same conditions (6, 7). 

Figure 8 (ALL FIGURES ARE COURTESY OF THE AUTHORS.) 

The use of Catalyst 2a for RCM of other substrates was further explored at room temperature by the Piers' group (6). Toluene was used as the solvent and the results from their publication are shown in Table I. These results indicate that Catalyst 2a is highly efficient for the RCM of a range of substrates at room temperature. For the formation of di- and trisubstituted 5-membered and 6-membered cycloalkenes (see Entries 1, 3, 4, Table I), the reaction went to completion in less than 10 min using 1 mol% catalyst loading. Disubstituted cyclopentene can be efficiently synthesized at lower catalyst loading (0.1 mol%, see Entry 2, Table I). For the formation of the more hindered trisubstituted cyclohexene (see Entry 5, Table I), the reaction went to completion within 1 h with 1 mol% catalyst loading. A higher catalyst loading (5 mol%) was used to drive the reaction to a high conversion for the formation of challenging 7-membered cycloalkene (see Entry 6, Table I), with the reaction reaching 85% conversion in less than 10 min. 

Building upon Piers' initial results, the authors explored the use of the Piers' Catalyst 2b for the RCM of heteroatom containing substrates.  

-Boc-diallyamine was selected as the model substrate, and RCM experiments were conducted at 30 °C and 50 °C with the use of only 0.05 mol% catalyst loading (see Reaction 4). Multiple solvents were screened. Toluene and methyl  

-butyl ether (MTBE) were found to be the best for this reaction ( 

-Boc-diallyamine concentration was 1M, and reaction time was 8 h). The results for Catalyst 2b are compared with the standard olefin-metathesis catalysts (see Catalysts 4 and 5, Figure 9).  

Figure 9 (ALL FIGURES ARE COURTESY OF THE AUTHORS.) 

Catalyst 2b gave complete conversion in both toluene and MTBE at 30 °C, while ~90% conversions were produced at 50 °C in both solvents. Catalyst 5 reached complete conversion at 50 °C in toluene, but ~90% conversion under the other reaction conditions. Catalyst 4 performed poorly under these conditions, yielding < 50% conversion under all conditions tested.    

Catalyst 2b was efficient at 30 °C due to its fast initiation and stability at this temperature. The lower yields at 50 °C are presumably due to catalyst degradation. Catalyst 5 performed well at 50 °C in toluene but was less efficient in MTBE and in both solvents at 30 °C. The poor performance of Catalyst 4 was attributed to its slow initiation under these conditions. 

When comparing Catalysts 4 and 5 under the same reaction conditions and in the presence of terminal olefins, the authors observed that Catalyst 5 initiates faster and has a faster reaction rate but has a poorer lifetime (Catalyst 5 is often inactivated within 1 h) compared with Catalyst 4. Conversely, Catalyst 4 initiates slower and has a slower reaction rate but has a much better lifetime (Catalyst 4 is active up to 8 h). It is presumed that Catalyst 5 cannot stabilize the methylidene, as a 4-coordinate complex, which leads to catalyst degradation. Catalyst 4 can stabilize the methylidene by having the PCy

 ligand bind to the ruthenium center, thereby forming a stable 5-coordinate complex, which can then dissociate the PCy

 ligand, allowing the methylidene to re-enter a productive metathesis cycle. Research is underway to understand why Catalyst 2b is more efficient at lower temperatures compared with Catalyst 5. 

Newly developed Piers' catalysts (see Catalysts 1 and 2, Figure 1) have been shown to be highly efficient for several olefinmetathesis processes, including ethenolysis and RCM. The high proficiency of these catalysts is attributed to the unique 4-coordinate structure, which allows for more facile catalyst initiation compared with the 5-coordinate Grubbs and Hoveyda-type catalysts. The high activity of Piers' catalysts observed even at low temperature makes them ideal candidates for applications where low temperatures are desirable. Investigations into the scope of these catalysts, along with the recently reported catalysts containing a less sterically encumbered phosphonium alkylidene for more diversified substrates and processes is ongoing at Materia (30). It is also anticipated that new catalysts derived from ligand modification of Catalysts 1 and 2 may offer improved efficiency and broader substrate scope in pharmaceutical applications. Particularly, the development of chiral Piers-type catalysts may offer opportunities for improved enantioselectivities in asymmetric olefin-metathesis processes due to the low temperature efficacy of these catalysts. 

The authors would like to thank Warren E. Piers (University of Calgary, Canada) for allowing us to use results from his publications. The authors would also like to thank Tim Champagne, PhD (Materia), Kevin Kuhn (California Institute of Technology), and Andy Nickel, PhD (Materia) for reviewing this manuscript and for their helpful discussions.  

,* is director of fine chemicals R&D, all at Materia, Inc., 60 N. San Gabriel Blvd., Pasadena, CA 91107, tel. 626.584.8400, fax 626.584.1984, 

 To whom all correspondence should be addressed. 

 1.  Handbook of Metathesis, R.H. Grubbs, Ed., Vol. 1–3 (Wiley-VCH: Weinheim, Germany, 2003).  

 2.  A.H. Hoveyda and A.R. Zhugralin, "The Remarkable Metal-Catalyzed Olefin Metathesis Reaction,"  

 3.  Y. Schrodi, and R.L. Pederson, "Evolution and Applications of Second-Generation Ruthenium Olefin Metathesis Catalysts,"  

The authors describe the Piers' catalysts and detail latest progress in olefin-metathesis catalyst technology.

Highly Efficient Olefin-Metathesis Catalysts

Strategies for securing the supply chain is of growing importance to the pharmaceutical industry. These efforts have largely focused on anticounterfeiting measures and related track-and-trace technologies to ensure the chain of custody of a finished drug product from a pharmaceutical manufacturer to distribution points engaged in the sale of the product. As the technical and regulatory considerations for electronic pedigree (ePedigree) begin to evolve, the industry is also evaluating strategies to exchange information and improve the audit trail earlier in the supply chain for raw materials and other pharmaceutical ingredients. 

Under the Food and Drug Administration Amendments Act (FDAAA) of 2007, which was signed into law on Sept.  27, 2007, the Secretary of the Department of Health and Human Services (HHS) is required to develop standards and identify and validate effective technologies for purposes of "securing the drug supply chain against counterfeit, diverted, subpotent, substandard, adulterated, misbranded, or expired drugs." The law further requires the Secretary to develop a standardized numerical identifier to be applied to a prescription drug at the point of manufacturing and repackaging at the package or pallet level sufficient to facilitate the identification, validation, authentication, tracking,  and tracing of the drug no later than 30 months from the enactment of FDAAA (1). 

To meet these legislative requirements, FDA sought public comment on the standards and technologies for ePedigree of prescription drugs. During the public comment period, which ended May 19, 2008, the agency requested information on radio-frequency identification (RFID) technologies, encrypting technologies, and nanotechnologies and their strengths and weaknesses for identification, validation, track and trace, or authentication. The agency also requested information on the utility of these technologies in ePedigree, the cost of their implementation and use, their interoperability, and the development of related standards (1, 2).  

FDA is in the process of analyzing the information provided and is researching several options received. The agency says it is working toward meeting the March 2010 deadline for developing a standardized numerical identifier, but cannot provide specific deadlines for developing standards for validation, authentication, and track-and-trace systems as well as  addressing promising technologies, but says it "will work toward meeting these goals as quickly as it can."  

In addition to FDA, states such as California and Florida are moving forward with state requirements for ePedigree. California enacted a drug-pedigree law that mandated serialization, electronic pedigree, and track-and-trace systems in 2004, with an initial effective date of Jan. 1, 2007. Additional state legislation  in 2006 moved the effective date to Jan. 1, 2009. Earlier this year, the California Board of Pharmacy, the state agency primarily responsible for implementing the state's ePedigree law, exercised authority delegated to it by the 2006 legislation to further extend the effective date for the implementation of the ePedigree requirements to Jan. 1, 2011 (3). 

In providing comment on FDA's request for information on ePedigree technologies and standards, the California State Board of Pharmacy identified two possible technologies: 2D (data matrix) barcodes and RFID tags. The board recommended RFID be the industry standard and that 2D barcodes only be used as a backup technology (3). In terms of standards, the board recommended that the Global Trade Item Number (GTIN) developed by GS1/EPCglobal, two organizations involved in developing industry-driven standards for the electronic product code (EPC) to support the use of RFID. The board specified that GTIN is already in use and approved by the FDA for marking pharmaceutical products (4). "We particularly encourage adoption of the SGTIN-96, which is the version applicable to serialization of drug products using RFID tag technology as the data carrier," said the board in its comments (4).  

In recommending RFID, the California State Board of Pharmacy said RFID tags are less easily counterfeited or duplicated than are other data carriers, including 2D barcodes. "This is true not only because the technology itself is not as easily replicated as e.g., a printable 2D barcode, but also because RFID (EPC) tags are typically given a unique identifier (e.g., Tag ID) by the tag manufacturer that confirms its authenticity and additional level of security from widespread duplication or  counterfeiting," said the board in its comments (3). The board also noted that RFID is a non-line-of-sight technology, which allows unit-, case-, and pallet-level tags to be read  from varying distances and through several levels of packaging (3).  

For these reasons, the board sees RFID as more readily adaptable. RFID technology would "permit mass serialization and item-level track and trace of drug products throughout the US supply chain without requiring either: a significant disruption of present practices and a dramatic increase in processing times due to the opening of every case or container; or interference on such a large scale that mass serialization/item-level tracking mandates lose much of their salience," said the board (3).  

RFID may have other advantages such as the extensibility of RFID (EPC) tags for optimizing capabilities such as by adding extra data to the tag, adding sensors for temperature, pressure, light, allowing for the distinctions between "active" (smart) and "passive" (dumb) tags, and permitting a variety of frequencies, read ranges, and sizes to be used. The board noted that there are already marketable products that incorporate RFID tags into or under labels and into or under packaging materials (3).  

 In addition to California, Florida enacted its own electronic pedigree requirements in 2006 that duplicate the paper-based records within an EDI (electronic data interchange) transaction (5). 

As federal and state authorities evaluate ePedigree standards and technologies, industry members point to the need to unify ePedigree requirements. "Congress should pass legislation that would enable FDA to establish industry-wide implementation dates for federal pedigree standards," said Mike Rose, vice-president of supply-chain technology at Johnson & Johnson (New Brunswick, NJ) in testimony before the US Senate Committee on the Judiciary in June 2008. "The FDA should be encouraged to work with state and international regulators to develop effective, practical pedigree and track and trace standards for the United States and globally." He added that the complexity of multiple pedigree laws may result in fraudulent or counterfeit pedigrees, which underscores the need for federal standard ePedigrees (6).  

The ePedigree movement reached an important milestone in 2007 with the ratification of the EPCglobal Drug Pedigree Messaging Standard. The standard provides a data format that complies with all state and federal government regulations and allows trading partners to send and receive data in a secure, interoperable manner, using existing data-transfer technologies. The standard's security mechanisms ensure that data cannot be forged without easy detection, while interoperability provisions ensure that pedigrees are understandable by all trading partners, regardless of ePedigree vendor (7). 

Proposed legislative requirements for ePedigree

As the regulatory authorities access ePedigree, Congress is also taking action. Earlier this year, Reps. Steve Buyer (R-IN) and 12 additional members of the US House of Representatives introduced a bill, "Safeguarding America's Pharmaceutical Act of 2008" (H.R. 5839) to establish federal requirements for a closed-loop, track-and-trace pedigree system using item-level serialization. The bill specifies that no state or nonfederal body can establish a pedigree system separate from the federal standards (8). As of press time, the bill had been referred to the House Committee on Energy and Commerce.  

In late July, the House Committee on Energy and Commerce also issued a revised discussion draft to the Food and Drug Administration Globalization Act of 2008. The revised discussion draft provides additional requirements for quality risk-management plans and for electronic statements for the chain of supply of a drug. The purpose of the discussion draft is to be provide a basis for debate on possible legislation, which is not yet introduced. The committee issued the original discussion draft in April 2008. 

 The revised discussion draft proposes registered establishments that are involved in the "manufacture, preparation, propagation, compounding, or processing of a drug" to provide the HHS Secretary, upon request, "an electronic statement identifying each prior sale, purchase, or trade of the drug, including each prior sale, purchase, or trade of its ingredients and raw materials." The electronic statement would include the date of the each such prior sale, purchase, or trade, the names and addresses of all parties to each such transaction, and any other information required by the Secretary by regulation (9). 

Although ePedigree requirements for pharmaceutical ingredients is now only a subject of discussion, consideration on how to electronically secure the custody of a drug earlier in the supply chain to include raw materials and other pharmaceutical ingredients is of growing importance. "In order to ensure paperless compliance throughout the pharmaceutical supply chain, manufacturers need a better way to improve business processes and maintain end-to-end visibility, enable product authentication, and ensure data integrity across all transactions," says Robert Pease, director of marketing of Hubspan (Seattle, WA), a provider of on-demand integration tools and services.  

Connectivity and interoperability between suppliers and their customer are two issues to consider when trying to create an custody-tracking solution. "Companies face the need to share data and increase visibility within the supply chain but are reluctant to increase their investment in technology," says Pease. "Making an additional investment in eCommerce infrastructure often means increased costs and resource drain as a result of building an in-house solution or burdening existing systems for connecting a company with its trading partners."  

Enterprise-resource planning (ERP), EDI, enterprise application integration (EAI), and other business-to-business applications may be used to link systems together. As the complexity of the supply chain increases, however, a supplier has to consider how these systems can be linked. "Companies may find themselves having to decide among undesirable alternatives," says Pease. These alternatives may include the following:   

Change business relationships, discontinue and/or restrict distribution, or assume additional risks 

Continue existing supply-chain relationships while adding manual processes that increase costs and delay delivery

Implement complex, expensive hardware and software solutions that require dedicated information technology resources that may not scale. 

"No company wants to disrupt business processes, introduce delivery delays, increase operating expenses, and potentially reduce revenue," says Pease. "Organizations' legacy systems such as EDI and flat-file transfer are no longer enough. Low-level connections that only transfer batch files between applications and trading partners are giving way to smart networks that incorporate diverse integration functionality that provide  integration with business processes and ERP systems," he says.  

Instead, Pease points to the value of software-as-a-service (SaS) delivery model. SaS is a delivery model for business-processes integration among trading partners. Figure 1 outlines a custody-tracking solution. The hosted, managed service allows suppliers to send and receive documents electronically without having to make an additional investment in e-commerce infrastructure or upgrading existing systems. The product custody data is transmitted straight to their respective backend systems. The solution can be delivered as a portal or as a fully integrated service to translate and validate data to make it readily usable by in-house systems. To maintain data integrity throughout the supply chain, the offering should provide a central repository to ensure the safety of data so that the products' custody information can be tracked across the supply chain, without impacting trading partners' IT infrastructures and business processes, explains Pease. 

The SaS model is an alternative to deploying cross-enterprise integration software or developing an in-house solution. Rapid deployment, accessibility, flexibility, and scalability are advantages of such an approach, says Pease. A typical deployment may be operational in several weeks. All participants should be able to communicate 

a single connection and may use a platform using business-to-business applications, EAI, ERP systems or a secure portal for tracking transactions. The solution can also add process-automation features such as generating e-mail notifications in the case of incomplete or incorrect transactions. Transactions can either be resubmitted or corrected manually via the secure portal. The system also creates an audit trail and a searchable archive of critical data. 

Specialized vendors are offering applications to assist in meeting ePedigree and supply-chain requirements. For example, SupplyScape (Woburn, MA) introduced in June 2008 Nexus-enabled applications and services to its product serialization and supply-chain optimization solutions. Nexus is a network-based data-sharing and collaboration platform to facilitate interoperability within trading networks. 

Axway (Scottsdale, AZ) offers its "Synchrony" supply chain integrity suite as a solution for supply-chain management among life-science companies and its trading partners. The product includes capabilities for data-integrity assurance, ePedigree, business-activity monitoring, and trade- activity management, and track-and-trace functionality. 

In July 2008, rfXcel (San Ramon, CA) release its "Everest" track-and-trace platform for ePedigree and serialization compliance and business analytics. In January 2008, Acsis (Marlton, NJ) released "PharmaTrak 2.0," a preconfigured, serialized track-and-trace solution developed for pharmaceutical manufacturers, co-manufacturers, and distributors The software is designed to manage serialized drug products in warehouse and distribution centers to support the ability to generate ePedigree documents, automate product movement and transfers, as well as support track, trace, and product authentication through the supply chain.  

 1. FDA, "Standards for Standardized Numerical Identifier, Validation, Track and Trace, and Authentication for Prescription Drugs; Request for Comments" (Docket No. FDA-2008-N-0120), 

 2. FDA, "Technologies for Prescription Drug Identification, Validation, Track and Trace, or Authentication; Request for Information" (Docket No. FDA-2008-N-0121), 

 3. California State Board of Pharmacy, "Response of the California State Board of Pharmacy, Docket No. FDA-2008-N-0120, Standards for Standardized Numerical Identifier, Validation, Track and Trace, and Authentication for Prescription Drugs; Request for Comments" (Sacramento, CA, May 12, 2008), available at http://

 4. California State Board of Pharmacy, "Response of the California State Board of Pharmacy, Docket No. FDA-2008-N-0121 Technologies for Prescription Drug Identification, Validation, Track and Trace, or Authentication; Request for Information" (Sacramento, CA, May 12, 2008), available at http://

 5. P. Faber, "RFID Strategy—Pharmaceutical EPedigree—Biggest Supply Chain Topic of 2008," 

 6. M. Rose, "Testimony before the Senate Judiciary Committee" (Washington, DC, June 17, 2008), available at 

http://judiciary.senate.gov/pdf/08-06-17Mike_Rose_Testimony.pdf

 7. P. Spellman, "EPedigree to the Next Degree," 

 8.  G. Koroneos, "Congress to Consider National ePedigree Standards," 

 (online), Apr. 30, 2008, available at http://

pharmexec.findpharma.com/pharmexec/News/Congress-to-Consider-National-ePedigree-Standard/ArticleStandard/Article/detail/512999

 9. House Committee on Energy and Commerce, "Revised Discussion Draft of the Food and  Drug Administration Globalization Act of 2008" (Washington, DC, July 24, 2008), available at 

http://energycommerce.house.gov/FDAGlobalAct-08/RevisedFDAGA.DraftDrugSafetyTitle.072908xml.pdf

EPedigree, track-and-trace technologies, and other tools for optimizing supply-chain management are of increasing importance to the pharmaceutical industry. The author examines the current regulatory and legislative framework for ePedigree for finished drug products as well as proposals to require electronic statements for pharmaceutical ingredients.

Epedigree in the Pharmaceutical Supply Chain

The control of the crystal particle size of an active pharmaceutical ingredient (API) is necessary when the final product's performance depends on well defined and, ideally, engineered mesoscopic particles. The size of the particle and the crystal form of the API can influence behavior such as dissolution rate in a biological system. This influence is of particular importance because more than 40% of new molecules being developed are poorly water soluble. 

The technology available for particle engineering to improve therapeutic performance has grown rapidly in popularity and sophistication and has created a need for technology that can tailor particles for various applications. The need for improved and efficient drug delivery systems for many new drugs has become apparent, especially when the drugs are administered in a particulate form (1). 

In respiratory drug delivery, effective deep-lung deposition is achieved with 1–5-μm particles. Pulmonary administration of various drug substances, particularly small molecules, whether for systemic or local delivery, is especially appealing because of the thin alveolar epithelium wall's large surface area and absorption ability. Local delivery of therapeutics to the lung is an appropriate method for treating conditions such as asthma, chronic obstructive pulmonary disease (COPD), infections, and disease states such as cystic fibrosis. Other important therapeutics areas that pulmonary delivery can address include those where a rapid onset of action is required (e.g., diabetes, neuropathic pain, migraine), and systemic action of peptides, proteins, and oncolytics. 

Size reduction, or "top-down," destructive methods for preparing mesoscopic particles such as fluid-energy milling, also known as micronization (including jet milling and fluidized-bed jet mills), achieve the target size range, but the high energy required for such processes often damages the crystal's surface. This damage leads to highly charged and cohesive particles, which result in the chemical and physical instability of the drug. A significant proportion of micronized particles may be too fine and of an unsuitable shape for a given use. These qualities lead to undesirable surface polymorphological transformation, which may form amorphous structures that are undesirable for applications such as inhaled treatments. In addition, the particle properties can vary from batch to batch, thus causing problems in downstream processing and product formulation. Micronization can also generate considerable heat, which may be incompatible with the material of interest (e.g., a low-melting solid API). 

The authors discuss advanced sonocrystallization particle-engineering techniques for manufacturing mesoscopic particles.

Pharmaceutical Technology-09-01-2008

High-Potency APIs: Containment and Handling Issues

Expansion Activity of CMOs

Highly Efficient Olefin-Metathesis Catalysts

Epedigree in the Pharmaceutical Supply Chain

Power Ultrasound and the Production of Mesoscopic Particles and Aqueous Dispersions

Industrial Applications of Whole-Cell Biocatalysis

Manufacturing Considerations for Sourcing GMP Fermentation Services