Expanding Excipient Portfolios

Excipients play an important role in pharmaceutical formulations by adding functionality or facilitating the processing of a drug product. Several excipient manufacturers are planning or recently expanded production capacity, have made acquisitions, or have partnered to broaden their product portfolios and related service offerings.

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Company activity

Ashland Specialty Ingredients recently added low-viscosity, pharmaceutical-grade polyvinyl pyrrolidone (PVP) capacity for its Plasdone excipients at its manufacturing facility in Calvert City, Kentucky. PVP is a synthetic polymer used as a tablet binder. Ashland currently produces PVP at its manufacturing facilities in Calvert City, Kentucky, and Texas City, Texas.

Patricia Van Arnum

In January 2012, Ashland also announced that it planned to expand production of Polyplasdone crosslinked polyvinylpyrrolidone (PVPP) at its manufacturing facility in Texas City. The company plans to complete the addition of a new PVPP production unit at the site by late 2013. Polyplasdone PVPP is a synthetic polymer used as a tablet disintegrant and drug-dissolution aid. The company says it expects steady growth in PVPP driven by an industry need for formulation ingredients that improve the dissolution of poorly soluble drugs and growth in emerging markets generated by increased demand for generic-drug products and consumer demographics. In August 2011, Ashland acquired International Specialty Products, an excipient producer and manufacturer of the Plasdone and Polyplasone products.

In October 2011, Ashland Specialty Ingredients launched three new commercial grades of Benecel hypromellose (HPMC) excipients for the formulation of matrix tablets. These commercial grades (HPMC K250 PH PRM, HPMC K750 PH PRM, and HPMC K1500 PH PRM) of intermediate-molecular-weight polymers are designed to provide more predictable controlled-release profiles compared with blending legacy grades of HPMC. HPMC is used in hydrophilic matrix systems. Molecular weight plays a key role in dictating drug release, so formulators select specific molecular weight grades based on drug solubility and desired release profile, which often required blending different grades of HPMC. The new grades eliminate the need for such blending.

Meanwhile, Univar formed an agreement with Dow Corning in March 2012 for the US distribution of its silicone-based products, including pharmaceutical excipients, process aids, and fluids for siliconization. The agreement includes the United States and Puerto Rico and is an extension of the companies' existing partnership in Canada. Univar will sell a range of Dow Corning branded products, including simethicones, dimethicones, medical antifoams, and specialty fluids. The products are used in a variety of end-use applications, formulations, and manufacturing processes.

BASF launched a new packaging system, PeroXeal, last October, to protect its pharmaceutical excipient, Kollidon, which is based on polyvinylpyrrolidine, against contact with oxygen and subsequent oxidation. The system makes it possible to reduce the level of peroxide of Kollidon, thereby making the excipient suitable for use in oxygen-sensitive formulations. The PeroXeal packaging system consists of a multilayered and heat-sealed plastic film used as inner packaging material. The new packaging has been introduced for most Kollidon products at the company's Ludwigshafen and Minden, Germany, sites. BASF will offer all grades of the Kollidon line with the new technology starting by the end of 2013.

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Also in October, BASF and Colorcon formed a collaboration for the development of future film-coating systems using BASF's Kollicoat SmartSeal 30D and new Colorcon preformulated additives. Colorcon developed a preformulated additive system for use with Kollicoat SmartSeal 30D to enable efficient preparation and application of this polymer in taste-masking applications. The preformulated additive lowers the number of materials to be dispensed by 50% and reduces the preparation time by almost 40%, according to the companies.

BASF launched Kollicoat Smartseal 30 D, an aqueous dispersion of a film-forming polymer with taste-masking and moisture-barrier applications in 2011. The excipient is highly impermeable to water vapor, which helps preserve the potency of sensitive active ingredients, according to the company. The polymer is stable in saliva and specifically soluble in gastric juice. These properties allow for effective protection from unpleasant taste in the patient's mouth and rapid release and onset of active ingredient action in the stomach.

Also in 2011, Dow Polyglycols, Surfactants & Fluids, a business unit of Dow Chemical, announced it is expanding capacity for Carbowax Sentry solid-grade polyethylene glycols, which are used as pharmaceutical excipients, APIs (i.e., laxatives) and in personal-care products. The company announced the expansion last October with the expansion slated to begin in 2012 to support global supply.

In late 2010, the chemical company Celanese launched VitalDose, an ethylene vinyl acetate (EVA) polymer-based excipient for controlled-release pharmaceutical applications. The EVA-based excipients can be used in the design of transdermal, subcutaneous implant, and mucosal insert dosage forms.

On the acquisition front, DMV–Fonterra Excipients GmbH & Co. KG, the 50–50 joint venture for pharmaceutical excipients between the Dutch dairy company Royal Friesland Campina and the New Zealand dairy company Fonterra, acquired the business and assets of Brahmar Cellulose Private Limited (BCPL) in 20011. The move positions the company in pharmaceutical microcrystalline cellulose and sodium carboxyl methylcellulose.

Evonik completed the acquisition of SurModics Pharmaceuticals, a subsidiary of SurModics, in late 2011. The acquisition gives Evonik ownership of SurModics' parenteral dosage forms services and bioresorbable polymers business. The new business includes two facilities for the development and manufacturing of polymers and drug-delivery systems in Birmingham, Alabama. Formulation approaches used with the bioresorbable polymers include bioresorbable microparticles, nanoparticles, liposomes, implants, and other polymer-based configurations. Evonik is a producer of functional pharmaceutical excipients, which includes coatings and matrix systems for controlled release of APIs in tablets and other oral dosage forms through its Eudragit product line. In 2011, Evonik acquired the Resomer polymer business from Boehringer Ingelheim. These polymers are used for controlled release injectables, bioresorbable implants and medical devices.

In May 2011, Avantor Performance Chemicals opened a new pharmaceutical formulation application laboratory in Sinnar Nashik, Maharashtra, India, with its partner RanQ Remedies. The new laboratory is used to characterize excipients, perform functional testing, develop and characterize drug formulations, and support customer applications and product implementation. In terms of excipients, RanQ has a position in microcrystalline cellulose and sodium starch glycolate and also has expertise in developing premixed and other application-focused pharmaceutical excipients that result in a homogenous mix and coprocessed excipients.

In Ireland, FMC completed an expansion of its microcrystalline cellulose plant in Cork. Production from the final phase of the expansion began in March 2011 and increased FMC's global capacity by 25% for pharmaceutical- and food-grade microcrystalline cellulose. FMC operates another microcrystalline cellulose plant in Newark, Delaware. In March 2011, Grace Davison Discovery Sciences, part of W.R. Grace & Co., opened a new technical service knowledge center in Southern India for customers in the pharmaceutical and biotechnology industries.

Regulatory developments

Excipients also are an important area for regulation and related standards. Several recent developments include the launch of EXCiPACT, a draft FDA guidance to limit use of certain phthalate-based excipients, and proposed revisions to European excipients guidelines on labeling with respect to pediatric provisions.

EXCiPACT. In late January 2012, EXCiPACT, a new, voluntary international certification scheme, was launched. It was designed and developed to ensure that cGMP and current good distribution practices (cGDP) standards are being used in the manufacture and supply of pharmaceutical excipients. The scheme is a product of a mulitstakeholder effort, which included participation from the European Fine Chemicals Group (EFCG), the International Pharmaceuticals Excipients Council (IPEC) of the Americas, IPEC–Europe, the European Association of Chemicals Distributors, and the Pharmaceutical Quality Group.

The EXCiPACT scheme provides independent certification of manufacturers and suppliers of pharmaceutical excipients as a means of ensuring patient safety through supplier quality while minimizing overall supply-chain costs. The EXCiPACT standards act as annexes to ISO standards 9001, 19011, and 17021. Suppliers who do not hold ISO 9001 certification will be able to obtain an equivalent certificate through the forthcoming US national standard (ANSI–NSF 363), which also uses the EXCiPACT cGMP and cGDP standards, according to an EFCG analysis.

Phthalates-based excipients. In March 2012, FDA issued a draft guidance Limiting the Use of Certain Phthalates as Excipients in CDER-Regulated Products to provide the Center for Drug Evaluation and Research's thinking on the potential human health risks associated with exposure to dibutyl phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP) (1). In particular, the draft guidance recommends that the pharmaceutical industry avoid the use of these two specific phthalates as excipients in CDER-regulated drug and biologic products, including prescription and nonprescription products. The draft guidance does not address the use of DBP or DEHP in other types of FDA-regulated products or exposure to DBP or DEHP due to the presence of any of these compounds as an impurity, including as a result of leaching from packaging materials. The comment period for the draft guidance ends May 31, 2012.

Phthalates are found in certain pharmaceutical formulations, primarily as a plasticizer in enteric coatings of solid oral drug products to maintain flexibility (1). According to FDA's draft guidance, DBP and DEHP have been shown to be developmental and reproductive toxicants in laboratory animals. While the data in humans are less clear, epidemiological studies suggest that certain phthalates may affect reproductive and developmental outcomes. Although the human data are limited, FDA has determined that there is evidence that exposure to DBP and DEHP from pharmaceuticals presents a potential risk of developmental and reproductive toxicity and suggests that safer excipient alternatives to DBP and DEHP are available and should be used (1).

Pediatric considerations for excipients. In March 2012, EMA issued a concept paper to gain public input regarding revisions to its excipient guidelines on labeling and packaging to include safety concerns for pediatric populations and pregnant women (2). The current excipient guideline was last revised in July 2003 and does not address safety concerns regarding excipients as they relate to pediatric populations as had been addressed in other European regulations covering pediatric populations for pharmaceuticals (3, 4).

"It is important to note that the safety of excipients can affect children differently than adults due to the ongoing organ development and incomplete maturation depending on the age," stated EMA in its concept paper (2). EMA also noted in its concept paper that pregnant women are not covered in the excipient guidelines and that "safety labeling is needed for products intended for use in this population to ensure the safety of the unborn child(ren)" (2).

The public comment period ends at the end of May 2012. EMA also said in its concept paper that the labeling of several excipients are specified for a limited number of routes of administration and additional routes of administration need to be added. Also, the guidelines need to be expanded to include additional excipients (2). The draft revised guideline is expected to be released for a six-month month external consultation in the third quarter of 2013 to the first quarter of 2014. After the external consultation, the final guideline is expected to be available within 6–12 months.

Patricia Van Arnum is a executive editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com.

References

1. FDA, Draft Guidance for Industry: Limiting the Use of Certain Phthalates as Excipients in Center for Drug Evaluation and Research-Regulated Products; AvailabilityFed. Reg. 77 (42), 12852 (2012).

2. EMA, Concept Paper on the Need for Revision of the Guideline on Excipients in the Label and Package Leaflet of Medicinal Products for Human Use (CPMP/463/00) (Feb. 6, 2012).

3. EC, Guidelines: Medicinal Products for Human Use: Safety, Environment and Information: Excipients in the Label and Package Leaflet of Medicinal Products for Human Use (Brussels, July 2003).

4. EC Regulation No. 1901/2006, Pediatric Regulation (Brussels, Dec. 2006).