Risk Mitigation in High-Potency Manufacturing

Cross-contamination is an ongoing concern in pharmaceutical manufacturing and is of particular importance in environments in which high-potency compounds are manufactured. The recently released Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP)Baseline Guide by the International Society for Pharmaceutical Engineering (ISPE) provides a scientific risk-based approach, predicated on the International Conference on Harmonization guideline (ICH) Q9 Quality Risk Management, to manage cross-contamination in order to achieve and maintain an appropriate balance between product quality and operator safety.

Patricia Van Arnum

History of Risk-MaPP

The process for Risk-MaPP began in 2004 when the basis of future dialogue between the US Food and Drug Administration and industry members emerged following an ISPE conference in which it was suggested that FDA may consider treating potent compounds similarly to the controls required for penicillin: that is facilities manufacturing potent compounds would need to be dedicated or segregated. That consideration led select industry members to present information at a subsequent ISPE conference in 2005 to show "how science could be used to control the risk of contamination," says Stephanie Wilkins, president of the consulting firm PharmaConsult Us (Bridgewater, NJ), cochair of the ISPE Risk-MaPP Baseline Guide Task Team, and former member of the ISPE International Board of Directors.

In 2006, industry members met with FDA to further discuss a science- and risk-based approach for controlling cross-contamination. "FDA was very receptive, and at the conclusion of this session, FDA agreed to work with ISPE to develop a document on the subject," says Wilkins.

In addition to advocating for a science- and risk-based approach with respect to controlling the risk of cross contamination, the ISPE Risk-MaPP Baseline Guide Task Team also recognized the importance of harmonizing global regulations with respect to dedicated facilities, compounds, and cross contamination. The task force offered input and its draft documents to the European Medicines Agency's (EMA) Dedicated Facilities Working Group as that group considered draft revisions to the European Union's guidelines on good manufacturing practices (GMPs). "We believe that our efforts helped EMA's Dedicated Facilities Working Group move their draft revisions to the EU GMPs more toward a risk-based approach rather than a laundry list of compounds or classes of compounds that would require dedicated facilities," says Wilkins.

The ISPE Risk-MaPP task force also sent draft copies of to the World Health Organization and the national regulatory agencies in Canada (i.e., Health Canada), Brazil (Agência Nacional de Vigilância Sanitária, or National Health Surveillance Agency), and Switzerland (Swiss Medic) and considered and incorporated any comments it received into the final version of Risk-MaPP.

Risk-MaPP

ISPE launched Risk-MaPP in Brussels on Sept. 20–21, 2010. The North American launch is planned for Oct. 4–5, 2010. A Japanese launch is planned on Oct. 21–22, and a Singapore launch on Oct. 25–26. ISPE is also offering a half-day session on Risk-MaPP at the ISPE Annual Meeting in Orlando, Florida on Nov. 10, 2010, and is planning two-day training courses for 2011.

The principles of Risk-MaPP can be applied to large and small molecules, preclinical and clinical materials, and commercially manufactured products in all operations. Wilkins says it is also important to note that the principles of Risk-MaPP are beneficial for all classes of compounds, not just high hazardous compounds. In considering Risk-MaPP, Wilkins says there are three important underlying elements: the relationship between risk, hazard, and exposure; the use of health-based limits; and how the modes of exposure are different for cross-contamination and operator safety.

The relationship between risk, hazard, and exposure. A key underpinnning of Risk-MaPP is the interconnection between risk, hazard, and exposure. "Risk is a function of the hazard and exposure to the hazard," says Wilkins. "The hazard is fixed with the compound, so to alter the level of risk, the exposure to hazard needs to be altered." She explains that the focus should be placed on high-risk situations not high-hazard compounds as high hazard does not always equal high risk.

Health-based limits. Wilkins explains that Risk-MaPP suggests the use of acceptable daily exposure (ADE), which is the daily dose of a substance below which no adverse effects are expected by a route, even if exposure occurs for a lifetime. The ADE is scientifically derived, based on health effects, and set by toxicologists from data from clinical studies, drug filings, package inserts, or other sources, which rely on the same data used to develop occupational exposure limits (OELs). "So the premise is that a safe level of a compound is below the ADE," says Wilkins. "Some of the more traditional limit-setting methods such as the use of 1/1000th of the low clinical dose or 10 ppm are not health-based and may be overprotective or underprotective of patient health." She points out that when a limit is underprotective, the implications are understood as to the related concerns, but there are also issues when the limit is overprotective. "When we look more closely using a limit that is lower than the safe limit (i.e., the ADE), the product is not any safer, but a manufacturer may spend more time in cleaning, or may dedicate equipment because the lower limits cannot be met, which all leads to an increase in the cost of manufacturing the product. To be clear, the cleaning processes should be controlled based on process capability and below the safe limit. The distance between the data and the safe limit is considered the margin of safety for the process.

Modes of exposure. Modes of operator exposure may be inhalation, dermal, ingestion, ocular, and mechanical. "Industrial hygienists have many tools and methods for both assessing and controlling occupational exposure," explains Wilkins. "Risk-MaPP borrowed these concepts from industrial hygiene and adapted them for cross-contamination issues." The exposure modes for contamination are mix-up, retention, mechanical, and airborne transfer. "Of these modes, mix-up and retention are the areas that could cause the highest risk while mechanical and airborne transfers tend to be lower risk issues," she says. Mechanical and airborne transfers require product on non-product contact surfaces to find a path into the process in amounts that would be above safe levels. "Many times this is not feasible as the quantities would not be large enough for the human eye to see," she adds.

Looking forward

As of press time, an ISPE meeting launching Risk-MaPP on a global basis was being held in Brussels. One item that will be watched is EMA's stance on the Risk-Mapp launch. EMA is currently revising the wording in its GMPs, which discuss the need to control issues of cross-contamination and dedicated facilities. In December 2009, EMA provided on update on its revision of Chapters 3 and 5 of its GMP Guide for dedicated facilities and outlined the agency's recent consideration of the matter. In February 2005, EMA published a concept paper that highlighted a lack of clarity in the existing GMP guide (Section 6, Chapter 3, Sections 18, 19, Chapter 5) with respect to when a medicinal product should be manufactured in dedicated, self-contained facilities. The concept paper proposed that any guidance in this field should take into consideration the principles and concepts of quality risk management as described in ICH Q9. EMA published its progress in January 2008. In its December 2009 communication, EMA said, "the drafting group has continued to look into the different aspects of this issue; it has been researching and evaluating all the scientific information related to this topic, including input from toxicological/pharmaceutical experts."

Although open to risk-based approaches for most compounds and classes of compounds, EMA stated in its December 2009 communication that dedicated facilities should normally be required when beta-lactam antibiotics are produced and live pathogenic organisms are handled. EMA further said in its December 2009 communication: "In the meantime for other products, manufacturers introducing a product into shared facilities should carry out an assessment of all relevant product and process characteristics to evaluate whether it is suitable for production in shared facilities. This assessment should include input from a toxicologist. Where the product has known sensitizing potential, or is highly potent or toxic, the Supervisory Authority should be consulted to discuss the manufacturer's risk-management measures." The ISPE conference in Brussels in late September will serve as an opportunity to gain an update on EMA's progress. Risk-based approaches will also be discussed at the ISPE conference in early October.

As for Risk-MaPP, Wilkins points out the value in incorporating a risk- and science-based approach to cross-contamination through quality risk-management plans. "Importantly, companies that have applied Risk-MaPP to their operations are better prepared for regulatory inspections and more knowledgeable about their products, processes, and facilities."

Investing in High-Potency Manufacturing

High-potency manufacturing and related services represent an area of ongoing investment by contract manufacturing organizations (CMOs) and service providers. For example, Ben Venue Laboratories (Bedford, OH) recently constructed a new 225,000-ft² manufacturing facility in Bedford, Ohio, for producing sterile finished dosage forms of cytotoxic and genotoxic products in clinical and commercial volumes. The facility is designed to provide containment for products with occupational exposure limits (OELs) as low as 0.1 µg/m³ with engineering controls and potentially lower OELs when combined with personal protective equipment and administrative controls.

Micronization of high-potency active pharmaceutical ingredients at Powdersize’s Quakertown, Pennyslyvania, facility. (Figure is courtesy of powdersize)

The facility was completed in 2010 and will be on line in the second quarter of 2011. The facility has three sterile filing lines and lyophilization capacity of nine lyophilizers. The facility is equipped and rated to handle flammable solvent and cosolvent formulations at both clinical and commercial scales. "This enables us to develop formulation approaches for molecules that may be difficult to solubilize in aqueous formulations," explains Darrell Jessee, vice-president of contract manufacturing services at Ben Venue. The facility also has a dedicated warehouse with temperature-controlled storage capabilities dedicated entirely to the cytotoxic/genotoxic products within the facility.

Boehringer Ingelheim Roxane (BIRI), which manufactures high-potency oral drugs as part of the contract manufacturing services offered at its facility in Columbus, Ohio, recently announced a $50-million investment to build a new 87,000-ft² high-containment facility on its existing campus. The new facility is scheduled to be operational in the summer of 2011 and will be capable of handling materials up to an OEL limit of 0.1 µg/m³ for oral forms of drug product with potent and cytotoxic active pharmaceutical ingredients (APIs), including steroids. This new facility will provide microdose formulation services for highly active APIs.

Powdersize (Quakertown, PA) recently expanded its milling and micronization services to include particle-size reduction of highly potent APIs and highly sensitizing compounds such as steroids and hormones. The company upgraded its facility in Quakertown, Pennsylvania, to include a new processing suite for processing highly potent compounds. A Universal Milling Containment isolator, designed by Powder Systems (Boise, ID), was completed and qualified in 2010. Placebo testing using lactose as a surrogate powder showed containment levels down to 10 ng/m³ . The facility has micronization capabilities, including 2-in., 4- in., jet mills, with scale-up potential to a 10-in. milling system within the isolator to accommodate research and development, clinical, and early commercialization volumes.

Carbogen Amcis (Bubendorf, Switzerland) opened a new high-potency API facility at the site of its parent company, Dishman Pharmaceuticals and Chemicals (Ahmedabad, Gujarat, India), in January 2010. The facility's large-scale capacity (currently up to 1600 L) will be capable of producing multimetric ton quantities of high-potency APIs (as low as < 1 µg/m³ ). The facility complements Carbogen Amcis's high-potency API facilities in Bubendorf.

Aesica (Newcastle upon Tyne, UK) will invest £3 million ($4.7 million) in a new high-containment manufacturing facility at its Queenborough, United Kingdom, site. The new unit will include suites for granulation, tableting, and blister packing. The company expects the facility to be completed by May 2011.

SAFC, part of the life-sciences chemical company Sigma-Aldrich (St. Louis), announced the opening of a $30-million expansion to its manufacturing facility in Verona, Wisconsin, earlier this year. The new facility complements SAFC's existing 63,000-ft² high-potency API site in Madison, Wisconsin, and houses commercial-scale reactors capable of producing batch sizes up to 4000 L. SAFC also completed an investment in Madison to increase current good manufacturing practice pilot-plant and large-scale kilogram laboratory high-potency API capacity. In St. Louis, Missouri, the company recently commissioned a suite for producing high-potency API conjugates. SAFC also invested $29 million to expand its large-scale production of bacterial and fungal fermentation-derived biologic high-potency APIs. The 50,000-ft² facility is designed to produce secondary metabolites, cytoxins, and large-molecule proteins.

The CMO AMRI (Albany, NY) received certification by SafeBridge Consultants (Mountain View, CA) of its high-potency research laboratories and good manufacturing practice facilities in Rensselaer, New York. The certification shows that the company is proficient in the safe handling of potent APIs.—PVA

Formulation development forum: liposomal-based nanotechnology

Researchers at the University of Rhode Island (URI) in Kingston recently reported on controlling drug delivery using nanoparticles embedded in a liposome triggered by noninvasive electromagnetic fields. Bilayer-decorated magnetoliposomes (dMLs) were prepared by embedding small hydrophobic superparamagnetic iron oxide nanoparticles at various lipid-molecule-to-nanoparticle ratios within dipalmitoylphosphatidylcholine bilayers. The dML structure was examined by cryogenic transmission electron microscopy and differential scanning calorimetry, and release was examined by carboxyfluorescein leakage (1). The superparamagnetic iron oxide nanoparticles embedded in the shell of the liposome released the drug by making the shell leaky when heat-activated in an alternating current electromagnetic field operating at radio frequencies.

Source

1. G.Bothun et al. ACS Nano 4 (6), 3215–3221 (2010).