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`bockpoge
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`sainsdeo*9sialqet'fiu!usaIqndoso‘rufiwidoo
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`"I.
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`time. The simplicity of liquid formula-
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`tions means they can enter first—in—man
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`studies more quickly than solids-based
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`capsule formulations. In addition,
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`today’s pilot-scale liquid—dosing
`machines minimize the amount of API
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`required to manufacture Phase I sup-
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`plies. There are also fewer problems
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`with scaling up liquid capsule formula-
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`tions, thus reducing the time needed
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`in late-phase development compared
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`with solids-based formulations.
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`Other advantages of liquid drug de-
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`livery Systems, some of which l only
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`touched on, include better stability,-
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`greater protection against oxidation;
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`enhanced bioavailability; reduced
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`manufacturing and plant infrastructure
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`costs; fewer excipients, better accom-
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`modation of low-melting-point APls,-
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`more flexibility in thedosage form,-
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`and greater ease in developing forrnu—
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`lations that employ controlled release
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`and multiple-product compounding.
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`Ts-C
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`-Jfilledcamlcs
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`cytotoxic capsule formulation, we used
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`Filling liquids into hard gelatin cap-
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`a pharmaceutical isolator to suspend
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`sules began in France in the l83Ds.
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`the drug in a semi-solid matrix that
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`With the development and commer-
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`provided adequate containment. We
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`cial availability of two—piece hard
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`also monitored the downstream
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`gelatin capsules in the USA around
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`processes—including bead-milling of
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`1895, the focus shifted to encapsulat-
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`the suspension, liquid filling, and seal-
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`' ing powders, granules, pellets, and
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`ing—without creating operator expo-
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`combinations of dry fills, including
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`sure issues. Had we been handling a
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`tablets. Most aqueous and oil-based
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`solids—based cytotoxic formulation, we
`formulations--particularly vitamins
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`would have needed elaborate air han-
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`and other nutritional supplements—~
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`dling systems, isolation rooms, and
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`were encapsulated in softgels. But in
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`extensive control systems to ensure
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`the 19805 liquid-filled capsules began
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`to draw renewed interest for several
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`operator safety and environmental
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`reasons.
`compliance.
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`Content uniformity, especially
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`when handling high-potency/low-
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`dose compounds, is another factor.
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`Formulations that include such com-
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`pounds require not just containment,
`but excellent content uniformity in the
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`final product to ensure accuracy at the
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`low-milligram or nanogram level.
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`That's much simpler to do with a liq-
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`uid than it is with a solid. Another fac-
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`tor favoring liquids: Capsule filling
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`mechanisms that close liquids use
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`high-precision piston pumps that pro-
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`vide more accuracy than capsule filling
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`mechanisms that close powders, gran-
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`ules, or pellets.
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`The FDA's mandate in the mid-
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`l980s that all OTC products must be
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`sealed using tamperevident technology
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`also advanced the adoption of liquid-
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`filled capsules. That's because the
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`order led to the development of cap-
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`sule sealing machines, which provided
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`not only tamper evidence, but pre-
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`vented the encapsulated liquids from
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`leaking. Product leakage is one of the
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`main concerns when encapsulating
`liquids in two-piece capsules.
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`The high cost of drug development
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`and the competitive nature of the
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`pharmaceutical industry also play a
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`role, because they have sharpened the
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`focus on reducing drug development
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`The first reason is solubility. Today,
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`much dnig development begins with
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`combinatorial chemistry and receptor-
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`based screenings. These methods
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`often lead to discovery of either I}
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`large organic and polar molecules with
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`poor solubility and membrane trans-
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`port properties or 2) lipophilic mole-
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`cules with poor aqueous solubility. In
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`fact,
`I have seen estimates that 40 to
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`50 percent of all new chemical entities
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`(NCEsl are considered Biophar—
`rnaceutics Classification System Class
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`ll low—solubility and high—permeability
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`drug candidates. Using conventional
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`solid dose formulation methods {e.g.,
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`particle size reduction) to enhance
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`bioavailability cannot effectively deal
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`with these characteristics. A better
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`approach is to formulate these difficult
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`NCES into drugs that use a lipophilic
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`solution or a micro-emulsion as the
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`drug delivery system. They can then
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`be filled into two—piece capsules.
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`The need to contain potent AP|s is
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`also driving the revival of liquid fills.
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`For example, many companies are
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`developing oncology drugs, and
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`many of the NCE5 are cytotoxic,
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`which means they require contain-
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`ment to minimize operator exposure
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`during manufacturing. When I was
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`involved in manufacturing an oral
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`Donald K. ljgbfloot
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`an independent consul-H
`tant, 2826 W Placita
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`Patients, Tucson, AZ
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`35742. Tel. 520 229
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`3506. E-inuil: donaltl.
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`liglJIjfooi@corncast.net.
`'
`He netiralfrmn Glaxo—
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`Snn'tlJKlI'nr after -16 years tlsm. As
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`director of manufacturing and Rel), fJ'f
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`gained extensive production experience in
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`capsule anal other processes, including
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`granulation, lalrlet compression, tablet coat-
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`ing, pellet coating, and suppository manu-
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`facturing. His rxiierlisr spans manufactur-
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`ing oflrotlr clinical and commercial supplies.
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`.-
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`Page 1 of 1
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`Capsugel Exhibit 1034
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`Page 1 of 1
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`Capsugel Exhibit 1034