`

`PARENTERAL
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`TECHNOLOGY
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`MANUAL
`
`AN INTRODUCTION TO
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`FORMULATION, PRODUCTION AND QUALITY
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`ASPECTS OF PARENTERAL PRODUCTS
`
`SECOND EXPANDED EDITION
`
`Michael J. Groves
`
`College of Pharmacy
`University of Illinois at Chicago
`
`AstraZeneca Exhibit 2086 p. 2
`
`

`

`Printing History:
`
`
`Parenteral Teehnniegy Mennai H First Edition, 1985
`
`Reprinted, 1986
`
`Second Edition, 1988
`Second Edition iSBN; Q~935i84-10-4
`
`igCOpyrighii JanuaryF 1989 by Inierpiiarm Frees Inez,
`13.0. Be}: 530,
`
`Prairie View? {L 60069. USA
`
`Aii rights reeerved. This none. is emieered by enpyright. Ne pare of it: may he
`reprociueeci, stored in a retrievai system, or transmitted in any farm or by any meensi
`
`eieerrnnie, mechanical, photocopying, recording, or ntherwise, Withem written
`permiseien frern ihe priniisheri Made in tire Unireci States, ef America.
`
`Where a precinct ‘rreriernarias registration mark or other protected mark is made
`
`in the text, the ownership (if the mark remains with the lawnt owner of the mark.
`
`Ne claim 0f ownership, intentional or orherwise, is made by reference re any such
`marks in this beek.
`
`Wiiile every efferr nae been made by inierphnrm Press Ine. to ensure the accuracy
`of the ini‘nrmetien eenraineci in this bank, this nrganizatinn accepts ne resp0n3i«
`biliry inr errers 0r emissinns.
`
`AstraZeneca Exhibit 2086 p. 3
`
`

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`PARENTERAL TECHNOLOGY MANUAL
`
`SECOND EDITION
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`Chapter 3
`Overview .
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`Charmer 2
`Parspectiveg on the Use and Essential
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`Electralytes and Adjuvams .
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`Chapzfer 5
`Non-Aqueoug Systems, Dispersions and Emuisioms .
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`{:33
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`Charmer 6
`Hyperalimentatim Solutiom and Admixtures .
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`Chzzpfer 7
`Dry Powders .
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`Chapter 8‘
`Fiitration .
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`Chaprer §
`Containers and Their Seals .
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`Charmer It}
`Sterilizatian and Depymgenatinn .
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`Chapter II
`Steriiity Testing, Pyrogens and Pyrogen Testing .
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`Charmer £2
`Particulate Contaminatian and Testing .
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`Chapter 33
`The Production Environment; .
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`The Qualiiy Qf Injectable Precincts .
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`Chapter I5
`Regulation Issues Affecting the Parenteral industry .
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`Index .
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`. .225
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`vii
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`AstraZeneca Exhibit 2086 p. 4
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`

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`FIGURES
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`Charmer 2
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`injection routes into and through the skin .
`1.
`2. Intratheeai injection routes into the separachnoid space
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`3. Intracisternai route for withdrawing eerebrospinsi fluid . 9
`4. The effect of route of injection on the intensity of
`action of a hypotheticai drug as measured by the
`blood level-«time curse .
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`5. Preparation of Water for injection (WFI) .
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`11. Principle of Reverse Osmosis (R0) .
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`14. Preparation of e. steriie suspension .
`15. Production flow diagram for a hypothetical
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`16. Preparation of a crystalline powder fill .
`1?. Freeze drying as applied with a powder fill or an
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`19. Phase equilibrium diagram for a typical sen;
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`20. Preparation of e. sterile spray dried powder .
`Shooter 8
`21. Mechanisms for particles to impinge on a capturing
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`. .87
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`ix
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`AstraZeneca Exhibit 2086 p. 5
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`

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`22. Straining mechanism for bacteria and debris passing
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`23. Diffusive flow measurements for filter integrity testing . .92
`24. Types of membrane filtration units used in the large
`scaie production of sterile fluids .
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`25. Logarithmic death curves for a hypothetical bacteria
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`suspension exposed to increasing thermal stress .
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`30. Generalized structure of endotosins .
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`31. Cascade effect. for producing fever in man .
`Chapter 32
`32. Particle size distributions of six samples of sodium
`chloride injection solution selected from three batches . 165
`33. Low pressure pulmonary circuit anti high pressure
`systemic circuit
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`38. Principle of the Conlter Counter .
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`39. Relationship between cumulative limiting number (per m1)
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`40. Integral between limits to produce an area under the curve
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`Chapter 13
`41. Flow sheet for a large voirrne parenteral filled in.
`a plastic container.
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`AstraZeneca Exhibit 2086 p. 6
`
`

`

`TABLES
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`Cfraprer 4
`I. Appreximete bedy cempertment electrolyte
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`cempesitien (mEq) .
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`3t Antiexictams used in parenteral products .
`4. Antibacterial cempeunds used as preservatives in
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`Chapter 5
`5. Distributien of fatty acids from the triglycerides of
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`’7. Quality centrel precedures carried eut on injecteble
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`Chapter 6
`8s The calorie centth of cemmen intravenous fluids .
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`. .64
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`Ckrrpter 9
`.
`.
`.
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`9. Basic types cf centainers used for parenterels .
`.
`.
`.
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`10. Additives commenly used in plastics .
`.
`.
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`.
`.
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`11. Additives used tcs improve the properties of natural
`.
`.
`and synthetic rubbers .
`.
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`12. Synthetic rubbers used for pharmaceutical clesures .
`13. Performance et‘ elastemers used for sealing parenteral
`products .
`.
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`Chapter 30
`14. Sterilization methods .
`
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`_ .100
`. .110
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`. .1I2
`. .113
`
`.
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`. 113
`
`r
`
`. 12i
`
`Chapter 12
`15. Appmximete sizes of scme contaminants reported in
`intravenous solutions .
`.
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`t 162
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`xi
`
`AstraZeneca Exhibit 2086 p. 7
`
`

`

`CHAPTER
`
`PERSPECTIVES ON THE USE
`
`AND ESSENTIAL REQUIREMENTS
`
`OF PARENTERAL PRODUCTS
`
`
`
`LEARNING OBJECTIVES
`
`1. Understand why and how a parenteral product is different from
`
`other pharmaceutical products.
`
`2. Become familiar with routes of administration of injectable prod-
`
`ucts, advantages and disadvantages of each route and the effects pro-
`
`duced on drug action, metabolism and excretion.
`
`3. Be aware of the essential requirements for injectable products.
`
`INTRODUCTION
`
`A substance administered to the body by injection is said to be paren—
`
`teral from the Greek words flood (besides, other than) and svrsgov (the
`
`gut). Injections are fluid preparations of drugs introduced into the body,
`
`into or through the skin or through the mucous and the serous mem-
`
`branes. Volumes of up to 100 mL are termed Small Volume Parenterals
`(SVPs). Other injectable products given directly into the venous blood
`
`circulation are termed infusion fluids or, more usually, Large Volume
`
`Parenterals (LVPs).
`
`Because a parenteral product bypasses the usual body defense
`
`mechanisms associated with the oral route of administration, it is essen—
`
`tial that an injectable be free from viable microorganisms. A paren—
`
`teral must not cause reactions on administration due to poor
`
`formulation, the presence of particulate contamination or pyrogenic
`materials. Accordingly, parenteral products have essential requirements
`for their preparation, storage and administration that make them dif-
`
`ferent from other pharmaceutical products.
`
`AstraZeneca Exhibit 2086 p. 8
`
`

`

`4
`
`CHAPTER}.
`
`Freedom from viable microorganisms may be achieved by heating
`
`the precinct to a degree that wiil totaiiy destroy all living matter. This
`
`process is carried out on the final sealed container as a “terminal steriliw
`
`ration”, the conditions being carefully selected so that destruction of
`
`the mieroorganisnis is achieved without damaging the product. Since
`
`the contents of the container can now be described as “sterile”, there
`
`is no need to risk violating the integrity of the product until irnrrrecli~
`
`ateiy before administration to the patient.
`
`Some drag precincts may be damaged by sterilization processes. in
`
`this situation? a product may be assembled from sterile components
`under carefully controlled conditions to minimise contamination with
`microorganisms; the final assembled product inside the sealed eontainer
`is not exposed to a terminal sterilisation process. This type of precinct
`
`is cieserioetl as “aseptic”, examples being fractionated blood prodnets
`
`and drug admixtures.
`
`Solutions that contain gram—negative bacteria are capable of pro-
`
`ducing febrile reactions on injection, even if the solution is sterile. These
`
`febrile or pyrogenie reaetions are one to the presence of bacterial cell
`
`wall fragments caiied “endotoxins” that are capable of triggering a
`
`response by the body’s thermal control mechanism. Humans are pro?»
`
`ably one of the most sensitive animals to endotoains. The presence of
`
`small quantities of endotosin is an indication that at some stage in pro-
`
`tinetion there has been bacterial contamination of the product. The
`sensitive methods for quantification of endotosins now available pro~
`ride a measurement that serves as an indication of the hygienic cones
`
`tions under which the product has been prepared.
`
`The same comment may be made about extraneous particulate con—~
`tamination. A product may be sterile out minute particles of extraneous
`insoluble matter are aimest impossioie to remove completely. However,
`these particles also serve as an indication of the conditions under which
`
`a product is prepared and are readily measured using the appropriate
`instrumentation. Acceptable limits for partienlate contamination have
`
`been defined in some cases by regulatory agencies.
`
`HISTORICAL BACKGROUND
`
`The intravenous route of drug administration anti the other paren-
`teral routes can be dated back to 1656 when Dr. Christopher Wren,
`
`a mathematician but aiso a Professor of Surgery—later to be architect
`
`AstraZeneca Exhibit 2086 p. 9
`
`

`

`Parenteral Products
`
`5
`
`of St, Paul’s Cathedral in Londonwinjected ooiom dissolved in wine
`into a dog using a syringe and a narrow piper No one scorned too con»
`cerned about the fact that the same syringe could have been used prowl»
`
`ously for enemas and douches. There was even less comment about
`
`the use of a pig’s bladder and goose quill for subsequent experiments
`leading to the first human trial in tars. Here the “volunteer”, described
`as “a malefactor who was unruly and deserved to be hanged”, promptly
`
`fainted following injection of an antimony salt. He was then allowed
`to escape; unfortunately, history does not record how long the “patient”
`(or victim) survived. Occasional experiments were carried out over the
`neat two hundred years but the only injection therapy with any success
`was intravenous administration of saline solutions into cholera victims
`
`in the middle of the 19th century. injections of painkilling agents were
`
`used with increased frequency following the invention of the gradm
`ated glass syringe fitted with a hollow needle, “like the sting of a wasp”,
`by Aieaander Wood of Edinburgh in 1853,
`Bevelopment of the dosage form continued rapidly after the dis—
`covery of the antisyphilitic, Salrarsan, the first of the magic ballets.
`
`If Salvarsan had been active orally it is doubtful if the progress would
`
`have been so rapid. Although the need for “cleanliness” was recognised
`
`quite early, the requirement for sterility was not documented officially
`
`until the 111316149205,
`
`During World War ll, dried blood plasma and penicillin injections
`
`were occasionally reconstituted under battle conditions with available
`
`water, frequently from stagnant paddles, it was essential to get these
`
`materials into a traumatized patient who would otherwise have lost
`
`his life. it is probably true that some soldiers may have died of “war
`
`wounds” later but the majority survived with nothing worse than a few
`
`boils. This anecdote is related to make the point that the human body,
`
`when healthy, is capable of withstanding a certain amount of insult.
`
`However, a patient is not healthy. For many years injections were
`
`administered that may not always have been sterile, were oreasonnailsr
`
`pyrogenic, and frequently contained a large quantity and variety of one
`
`ticnlate contamination. Today standards have improved and we demand
`
`that our injections should be completely free of viable microorganisms,
`
`should not cause febrile reactions, and contain only limited numbers
`
`of particles,
`
`AstraZeneca Exhibit 2086 p. 10
`
`

`

`6
`
`CHAPTER?
`
`FORM AN!) FUNCTIGN OF INJECTABLES
`
`Drugs prepared for injeetion are usually in the form of a simple
`
`aqueous solution. However, some drugs they not he stehle in the pres
`
`once of water or may be required to be released into the body more
`
`siosdy. Nonnaqueoos systems sneh as oil dispersions of powdered solids
`or oils emulsified in water may be employed. Alternatively, a prodnet
`
`may he lyophilieed or drieds to he reconstituted with water prior to use.
`
`Parenteral administration of a drug usually has 2: number of advan-
`
`tages over the oral route.
`
`1. Drug aetion is usually more rapid.
`
`2. The whole dose of the drug is administered.
`
`3. Some drugs, such as insulin or heparin, are completely ineeti-
`
`voted when given oralligr and hose to be administered parentereliy.
`
`4. Some drugs are irritants when given orally but can be tolerated
`
`when given inirsvenously, for example, strong solutions of dextrose.
`
`5. If a patient is dehydrated or in shook, the administration of
`
`intravenous fluids will often save his or her life.
`
`ROUTES OF ADMINISTRATION
`
`Using 3. hollow needle of the appropriate diameter, parenteral injeo
`
`tions can he introdooed into the body by a number of different routes
`
`as illustrated in Figures 1—3.
`
`I. thenreneons (so) injections are introduced into the soft tissues
`
`just underneath the skin surfaee. Since the available space in these tissues
`
`is limited, the volume of these injections does not exceed lrnL. Care
`
`is required to make certain that the formulation conforms closely to
`
`physiological conditions in terms of pH and tonieity.
`
`2.. Intramusculer (inn) injections are introduced directiy into the
`
`muscle, usually of the arm or the glotesl region. This route is also used
`
`if the drug is irritant or is insoluble in water or oil so that it must he
`
`used in the form of a suspension. The solnme of the injeetion must
`
`he kept email, generally not more ihen ErnL. The hiood supply to
`
`muscles is usually sufficient io ensure that the entire drug dose is not
`
`immediately availshie. For this reason, musele “activity”, i.e., whether
`
`or not the patient is moving around or is lying supine, may influence
`
`the rate at which the drug is active in the body.
`
`3. Intravenous (in) injeetions are introduced directly into the blood
`
`stream. it is possible, with care, to give small volumes of concentrated
`
`AstraZeneca Exhibit 2086 p. 11
`
`

`

`Parenterei Precincts
`
`‘3'
`
`seluiions that weuid normally irritaie tissues. These are administered
`
`siewly so that the solutions are diiuteet by the bleed flowing past the
`
`needie point as they are given. The intraveneus mute is also need he
`
`give larger volumes of replacement and hyperalimentation solutions.
`
`Fellewing majer trauma, 9. patient may receive as much as 100 iiters
`
`of fluid ever a peried of weeks.
`
`4, Inzy‘eeufaneeus (Le) injection is intredueed directly into the
`
`epiciermis just below the stratum eemeum. This route is used te give
`
`small volumes (0.1-~0.5mL) of diagnostic maeerials er vaccines.
`
`5. Inzrarheca! seimione are used fer inducing spinal or lumbar
`
`anesthesia by injecting solutions mm the subamehneid Space.
`
`Cerebmspinal fluid is usually withdrawn first to avoid increasing the
`
`fluid velume and inducing pressure on the spinal nerve mete. Velumes
`
`ef 1-~2mL are 115113.113: administered* The density of the selmien may
`
`
`
`
`Fignre 1. Injection routes mm and ihreugh the skin.
`
`intraeutaneeus (intradermal) (used fer diagnostic salutions)
`1C
`subeuianeeus
`SC?
`EM intramuseuiar
`W intraveneus
`
`LC.
`
`Epidermts
`Dermis
`
`El,
`
`“Subcutaneous
`
`
`
`
`
`AstraZeneca Exhibit 2086 p. 12
`
`

`

`8
`
`CHAPTER}!
`
`be adjusted to make the anesthetic move up or down the spinal canal
`
`according to the posture of the patient.
`
`6. Infra-articularinjections are used to introduce materials such as
`
`anti—inflammatory drugs directly into damaged or irritated joints.
`7. Intracardiai, directly into the heart, is a route which may be used
`
`for injecting into the bloodstream large volumes of hypertonic or
`
`irritating solutions such as 70% dextrose. This requires a central ind—
`
`
`Intrathccal injection routes into the subarachnaid space surrounding
`Figure 2.
`the spinal cord.
`
`PD peridural
`intrathecal
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`
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`
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`
`5th Lumbar
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`
`
`AstraZeneca Exhibit 2086 p. 13
`
`
`
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`

`Parenteral Products
`
`9
`
`
`
`Intracistemai mum {at withdrawing cerebrospinai fluid and accasimr
`Figure 3.
`all}; far administering amibimics in cams 0f meningitis. The procedure is diffi-
`cult, requiring mnsidemble car: in the injection technique and the: preparatian 0f
`the injection smution (complate {33613313, pH, density and {madam from particies).
`
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`waning catheter. Catheterizatian inmIves, 21 Surgical procedure and is
`generally only encountered in specialist units found in the larger
`
`hmpitals.
`
`8. Intrczperizanem‘ 6.13.) is a route used for applicatimns such as the
`rabies vaccine. It may also be used for kidney diaiysis solutions.
`9.
`Intracisremczl and peridum! routes are injactions into the
`
`AstraZeneca Exhibit 2086 p. 14
`
`

`

`CHAPTER 2
`
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`AstraZeneca Exhibit 2086 p. 15
`
`
`

`

`Parenteral Pro ducts
`
`11
`
`intraeraniai cistern and dura mater of the spinai cord. Both are diffi~
`
`cult procedures, with criticai requirements for the injections.
`
`The effect (in, rate anti intensity of action) produced by a ring
`
`may vary according to the route of administration. intravenously, the
`
`drug is distributed rapidly throughout the body so the effect on the
`
`target organ is usually seen quickly. However, if the drug is excreted
`
`through the kidney, the action may also he shortdiced. A subcutaneous
`
`injection, on the other hand, forms a depot from which the drug is
`
`slowly released. The onset of action is therefore siower, the intensity
`
`is reduced, and the dnration of action is longer as seen in Figure 4.
`
`Injections do have drawbacks.
`
`I. Some srnaii eiernent of pain may be present that is often
`
`unpleasant for the patient, especiaiiy if there is difficulty in finding
`
`a suitable vein for intravenous administration.
`
`2. In most cases, a rioctor or nurse is required to administer a dose.
`
`3. Once administered, a drug is immediately available to its target
`
`organ. If the patient is hypersensitive to the drug, or an overciose is
`
`administered, the effects are difficult to reverse.
`
`4. Administration of any material through the skin requires con—
`
`sirterahie care since air or microorganisms triager be introriuced into the
`
`body. These side effects are usually manifested as reactions, such as
`
`nhlehitis, at the injection site.
`
`SUMMARY OF THE ESSENTIAL REQUIREMENTS FOR
`
`AN INJECTABLE PRODUCT
`
`Because of their critical nature, parenterais roost be prepared under
`carefully controlled environmental conditions and packed to ensure that,
`at the point of use, the product is:
`
`1. Free from microorganisms, sterile, or prepared from sterile mate
`riais under conditions that minimize the chances of contamination with
`
`microorganisms (aseptic processing)
`
`2. Substantially free from bacterial endotoains and other pyrogenic
`materials.
`
`3. Substantiaiiy free from extraneous insoluhie materiais.
`
`REFERENCES
`
`Avis, K.E., Lachntan, L. and Lieberman, H.A., Pharmaceutical
`
`Dosage Forms: Parenteral Medications, Vols. 1 and 2, Marcel Beaker,
`
`New York (1984,
`
`i986}.
`
`AstraZeneca Exhibit 2086 p. 16
`
`

`

`I2
`
`SHAPTERB
`
`Duma, RJ. and Akers, M.3., Chapter 2 in Pharmaceutical Dosage
`
`Forms: Parenteral medieatiens (Editors: Avis, 31.13., Laehman, L. and
`
`Lieberman, HA3 Marcel Dekker? New Yerk, I, 33 (1984).
`
`Groves, M.J., Parenteral Products: The Preparation and Quality
`Control 01" Products fer Injection: Heinemenn Medical, London (19173).
`
`Olsen, WP” and Groves, MJ. (Edimm), Aseptic Pharmaceutical
`
`Manufacturing: Technology fear the 19903, Interpharm Press, Prairie
`
`View, IL (i987).
`
`Trissel, L.A., Handboek on Injeetable Drugs, American Society of
`
`Hospital Pharmacists, Washingmn, DC (1986).
`
`AstraZeneca Exhibit 2086 p. 17
`
`