2 1S T E D I T I O N
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`Remington
`
`The Science and Practice
`of Pharmacy
`
`LIPPINCOTT WILLIAMS & WILKINS
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`Copyright 1889, 1894,
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`
`theory
`the
`4 treatise on
`of
`Pharmacy
`Practice
`Remington: The Science and
`and practice of the pharmaceutical sciences, with essential
`a
`information about pharmaceutical and medicinal agents;
`the professional responsibilities of the pharmacist as the
`guide to
`drug information specialist of the health team ... A textbook and
`reference work for pharmacists, physicians, and other practitioners of
`the pharmaceutical and medical sciences.
`
`also,
`
`EDITORIAL BOARD
`
`Paul Beringer
`Ara DerMarderosian
`Linda Felton
`Steven Gelone
`Alfonso R, Gennaro
`
`Pardeep K. Gupta
`John E. Hoover
`Nicholas G. Popovich
`William J. Reilly, Jr
`Randy Hendrickson, Chair
`
`AUTHORS
`
`Remington were written
`of
`edition
`this
`of
`The 133 chapters
`by the au­
`and
`the editors, by members of the Editorial Board,
`xi to xv.
`pages
`thors listed on
`
`by
`
`Director
`
`Philip P Gerbino 1995-2005
`
`Twenty-first Edition—2005
`
`Published in the 185th year of the
`PHILADELPHIA COLLEGE OF
`
`PHARMACY AND SCIENCE
`
`I
`
`0003
`
`

`
`860
`
`PART 5: PHARMACEUTICAL
`
`MANUFACTURING
`
`preapproval
`to
`subject
`is
`The manufacturer
`
`
`by inspections FDA, FDA also con­
`periodic GMP postapproval
`ducts inspections of the suppliers of active ingredients, both for­
`
`certain inactive ingredients
`
`and pack­
`eign and domestic, and
`aging operations. The manufacture is subject to recalls of
`batches of product that do not meet quality requirements.
`In
`some cases a recall may result not from actual failed test re­
`sults but from a lack of assurance that the product will continue
`to meet quality
`requirements
`through
`its
`
`agents
`
`surface
`touch
`
`-'•>
`
`or
`
`dropper
`
`antimicrobial,
`
`serious infections of the cornea. It can cause complete
`and
`inspections
`1
`oil
`
`sight in 24 to 48 hr. In concentrations
`tolerated
`tis
`by
`sues of
`eye, it seems that
`all
`the
`antimicrobial
`ussed in
`following sections may be ineffective against some strai
`this organism.
`A sterile ophthalmic solution in a multiple-dose coni r
`can be contaminated in a number of ways unless precam
`Hon,
`are
`
`
`taken. For example, if a dropper bottle is used, the tip •
`tin
`
`
`of dropper while out the bottle can
`touch
`the
`•
`shelf
`life.
`or shelf if laid
`down, or
`it
`can or eyelash of "*
`
`Ih,
`p a t i e n t d u r i n g a d m i n i s t r a t i o n . I f t h e D r o p - T a i n e r ( A / c o i i 1 1
`Pharmacy Compounding
`
`
`of bottle is used, the dropper tip can touch an eyelash or the
`Oil,
`to permit
`while removed
`
`administration, may u
`-k
`Compounding of individual patient prescriptions by pharma­
`a table or finger, and that
`edge can
`touch
`
`
`the tip ,?
`cists has been and continues in some areas
`to be an integral part
`cap is replaced.
`of pharmacy practice. The need to routinely compound sterile
`effective but the
`
`an
`contain
`The solution may
`ophthalmic products
`
`is longer required with no
`
`
`the broad range
`next use of the
`
`contaminated solution may occur before enouofc
`of commercially manufactured
`products available today. Most of
`time has elapsed for all of the organisms
`to
`
`be and li'. m killed,
`
`the new and generic prescription ophthalmic products marketed
`organisms can
`
`find their way through an abrasion into the
`today have been subjected
`to FDA's rigorous requirements
`for
`
`corneal stroma. Once in the corneal stroma,
`
`any residual tnce;
`proof of safety and efficacy or bioequivalence as well as the
`of antimicrobial agents are neutralized by tissue coniponcnts
`above-described manufacturing
`
`
`quality and requirements.
`and the organisms
`
`find an excellent culture
`
`medium for rapiij
`If the pharmacist is requested to compound a prescription
`growth and dissemination
`through
`the
`for a noncommercial product such as a preservative-free
`ver­
`segment of the
`eye.
`sion or pediatric strength, he or she should be well versed in the
`OTHER ORGANISMS—Bacillus subtilis may produce a
`preparation
`of sterile
`products,
`have proper equipment the
`
`
`and
`serious abscess when it infects the vitreous humor Ttu
`facilities and
`be knowledgeable
`about
`the
`special
`requirements
`pathogenic fungus
`
`considered of particular importance in eyt
`for ophthalmic
`formulations and packaging. Reference infor­
`is Aspergillus
`fumigatus.
`
`Other fungi or molds may be
`solutions
`mation on the standards and technology for pharmacy com­
`harmful by accelerating
`deterioration
`of
`the
`prod­
`pounding with
`special
`emphasis
`on
`preparation
`of
`sterile
`
`42 as cases of epidemic ker­
`With regard
`to viruses, as many
`
`ucts should be consulted.53,54 The pharmacist must
`also consult
`
`atoconjunctivitis were caused by one bottle of virus- coataoi-
`the rules and
`regulations
`of the
`
`applicable phar­
`state
`board
`of
`nated tetracaine
`
`solution. Virus contamination
`is
`particulatlv
`macy concerning
`sterile
`pharmacy
`
`compounding well as any
`as
`preservatives
`difficult to control
`because
`none
`of the
`federal regulatory requirements promulgated by the FDA.
`able is virucidal. Moreover, viruses
`
`are
`
`removable not by filtra­
`Congress included
`in
`the
`1997
`FDA
`Modernization
`Act
`certain
`tion. However,
`they are destroyed by autoclaving. The pharma­
`legal conditions for which compounding as
`
`defined in the Act
`cist and physician
`
`not have been made adequately
`
`
`aware of the
`would be exempt from FDA regulation. The pharmacy com­
`dangers of transmitting viral infection via contaminated solu­
`pounding section of the Act was subsequently
`litigated and
`tions. This
`is
`
`particularly pertinent
`to
`the
`adenoviruses
`overturned
`in
`its entirety because it contained unconstitutional
`
`III and VIII), now believed to be the causative agents ofvini)
`restrictions on commercial speech. FDA may
`
`seek new legisla­
`conjunctivitis
`such
`as
`epidemic
`keratoconjunctivitis.
`tion to address
`
`their concerns regarding manufacturing
`in
`the
`The danger of non-sterile preparations is exponentially in­
`
`guise of compounding. In the meantime, FDA has issued a guid­
`creased for products
`intended
`to
`be
`injected
`ance document on how the Agency intends to regulate phar­
`Endophthalmitis and loss of vision can occur within a short
`macy compounding of human drugs considered
`to be outside the
`time of onset
`of a bacterial
`infection.
`in
`violation
`of
`the
`bounds of traditional
`pharmacy
`practice
`and
`Food, Drug and Cosmetic
`Act
`(www.fda.gov/cder/pharmcomp).
`Methods
`STERILIZATION
`STEAM UNDER PRESSURE—Terminal
`sterilization
`by
`autoclaving
`is
`
`an acceptable, effective method of sterilization
`Common methods of sterilization include moist heat under
`however, the solution or suspension components must be suf­
`pressure
`(autoclave),
`dry
`
`heat, gas sterilization, filtration,
`
`and
`ficiently heat-resistant to survive the procedure. If sterih.11-
`ionizing radiation.
`
`Please refer to Chapter
`
`40 where these ster­
`tion is carried out in the final container, the container alsfl
`detail.
`ilization procedures
`are
`described
`in
`must be able to survive heat and pressure. A recent addition
`DANGERS OF NONSTERILE MEDICATIONS—The
`to this technique is the so-called air-over-steam autoclave.
`possibility of serious ocular infection resulting
`
`from the use of
`This combination allows pressure adjustments to be ma i
`contaminated ophthalmic solutions has been documented
`amply
`during the
`autoclave
`cycle. Pressure
`manipulations
`in the
`literature. Such solutions have
`
`
`the been cause repeatedly
`autoclave sterilization of materials that while heat-resistarj'.
`solu­
`of corneal ulcers and
`even
`
`
`of loss eyesight. Contaminated
`tend to deform
`(ie, polypropylene
`containers).
`tions have been found in use in physicians' offices, eye clinics,
`cycle for a product should be carefully validated and assiin1
`and industrial infirmaries, and dispensed on prescription in
`that sterilization temperature
`and time are monitored at du
`community and hospital pharmacies. The microbe most fre­
`coldest spot of the autoclave load to assure sterility of t'1*
`quently found as a contaminant is the Staphylococcus group,
`product.
`Pseudomonas aeruginosa is a less frequent contaminant,
`and
`that
`states
`FILTRATION—The USP
`the solution most often found contaminated is sodium
`membrane
`tration under aseptic conditions is the preferred method 1
`fluorescein,
`sterilization. Membrane
`
`filtration offers the
`substantial
`pyocyaneus; Pseudomonas pyocyanea; blue
`
`(B.
`P. aeruginosa
`tage of room temperature operation with none of the deleteri­
`pus bacillus) is a very dangerous and opportunistic organism
`ous effects of exposure
`to
`heat
`or
`gas.
`sterilizing
`that grows well on most culture media and produces both tox­
`by filtration does involve the transfer of the fin­
`Sterilization
`ins and antibacterial products. The
`latter
`
`tend to kill off other
`ished sterile product into previously sterilized
`
`containers, us'!^
`
`allow the P. aeruginosa
`contaminants
`and
`
`in grow pure cul­
`to
`
`aseptic techniques. The membrane
`filtration equipment
`its1'1
`ture. This gram-negative bacillus also grows readily in oph­
`usually is sterilized as
`an
`assembly
`by autoclaving.
`thalmic solutions, which may become the source of extremely
`
`cornea
`
`(tfypes
`
`The
`
`'•
`
`advan­
`
`0004