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`AstraZeneca Exhibit 2086 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00900
`Fresenius—Kabi USA LLC V. AstraZeneca AB IPR2017-01913
`
`

`

`PARENTERAL
`
`TECHNOLOGY
`
`MANUAL
`
`AN INTRODUCTION TO
`
`FORMULATION, PRODUCTION AND QUALITY
`
`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 Teehrieiegy Manual _, Firsr Edition, 1985
`
`Reprinted, 1986
`
`Second Edition, 1988
`Second Edition iSBN; Q~935§84-10-4
`
`@Copyrigm, January 1989 by Inierpharm Frees Inez,
`13.0. Be}: 530,
`
`Prairie View, {L 60069, USA
`
`Aii rights regerved. This home: is eroieered by cepyrighr. Ne parr of it: may be
`reproriuceci, stored in a rerrierai system, or rransmirred in any farm or by any means,
`
`eieerrenie, rrreeiranieai, photocopying, recording, or mherwise, Withflm written
`permiseieri frem rhe prihiisher, Made in the United States, ef Ameriee.
`
`”Where a preduct rmdemark, registration mark or other protected mark is made
`
`in the text, the ownership er“ the mark remains with the lawful owner of the mark.
`
`Ne claim 0f ownership, intentional or otherwise, is made by reference re any such
`marks in this beek.
`
`While every efferr has“ been made by interpherm Press km. to ensure the accuracy
`of the int‘mmatien eenraineri in rhis beak, this erganizatien accepts rm responsi«
`bility fer ermre 0r emissieee.
`
`AstraZeneca Exhibit 2086 p. 3
`
`

`

`PARENTERAL TECHNOLOGY MANUAL
`
`SECOND EDITION
`
`
`
`Chapter 3
`Overview .............................................
`
`1
`
`Charmer 2
`Psrspsctives on the Use and Essential
`Requirements of Parenteral Products ..................... 3
`
`Chapter 3
`Warm ............................................... 1’?
`
`Chapter 4
`Electmlyms and Adjuvams ............................. 3‘?
`
`Chaprer 5
`Non-Aqueous Systems, Dispersions and Emuisioms ........ 49
`
`Charmer 6
`Hyperalimentstisn Soluticms and Admixturss ............. {:33
`
`Chrzprer 7
`Dry Powders ......................................... 73
`
`Chapter 8‘
`Fiitration ........................................... 83
`
`Charmer §
`Containers and Their Seals ................ ,.............. 99
`
`Charmer It}
`Sterilizstmn and Depymgsrlatien ........................ 119
`
`Chapter II
`Sterility Testing, Pyrogsns and Pymgsn Tasting ........... 145
`
`Charmer £2
`Particulate Contaminatisn and Testing ................... 1§9
`
`Chapter 33
`The Production Environment; ........................... 183
`
`Chapter 14
`The Qualiry sf Injectsbls Precincts ...................... 195
`
`Chapter I5
`Regulation Issues Affecting the Parenteral industry ........ 209
`
`Index ................................................... 225
`
`vii
`
`AstraZeneca Exhibit 2086 p. 4
`
`

`

`FIGURES
`
`
`
`Chapter 2
`
`1. Injection routes into and through the skin ............. ’7
`2. Intrarhecal injection routes into the separachnoio space
`surrounding the spinal cord ......................... 8
`3. Intracisternal route for withdrawing eerebrospinal fluid . 9
`4. The effect of route of injection on the intensity of
`action of a hypothetical drug as measured by the
`blood level-«time curse .............................. ll)
`
`Chapter 3
`5. Preparation of Water for injection (WFI) ............. 19
`6. A simple water still ................................. 20
`’l. Temperaturex’energy diagram for water ................ 21
`8. Multiple effect stills with boilers and condensers
`connected in series ................................. 21
`
`9. Vapor compression still ............................. 23
`10* Relationship between remperatnre and pressure of
`
`water vapor ....................................... 24
`11. Principle of Reverse Osmosis (R0) ................... 25
`12. Water storage system ............................... 29
`13. Pure steam generator................................ 31
`Chapter 5
`14. Preparation of a sterile suspension ................... 52
`15. Production flow diagram for a hypothetical
`intravenous emulsion ............................... 5’?
`
`Chemise ?‘
`16. Preparation of a crystalline powder fill ................ 7’4
`1?, Freeze drying as applied with a powder fill or an
`in site lyophilizarion ................................ 75
`18. Water vapor pressure vs temperature curve for water .
`.
`. .7?
`19. Phase equilibrium diagram for a typical salt
`water system ....................................... ’38
`20. Preparation of a sterile spray dried powder ............ 80
`Chapter 8
`21. Mechanisms for particles to impinge on a capturing
`surface. ........................................... 87
`
`is
`
`AstraZeneca Exhibit 2086 p. 5
`
`

`

`22. Straioing mechanism for bacteria and debris passing
`through a diagrammatic membrane filter .............. 39
`23. Diffusive flow measurements for filter integrity testing . .92
`24. Types of membrane filtration units nsecl in the large
`scale production of sterile fluids ..................... 94
`Chapter 10
`25. Logarithmic death curves for a hypothetical bacteria
`population exposed to a constant heat stress .......... £24
`26. Death-time curve for a hypothetical bacterial spore
`suspension exposed to increasing thermal stress ....... 326
`2?. Autoclave cycle, temperaturotime curves ............. BO
`28. Schematic diagram of a simple steam autoclave ....... 134
`29. A pharmaceutical autoclave ........................ 136
`Chapter It
`30. Generalized structure of endotoxins .................. 152
`
`31. Cascade effect for producing fever in man ............ i513
`Chapter 32
`32. Particle size distributions of six samples of sodium
`chloride injection solution selected from three batches . 165
`33. Low pressure pulmonary circuit and high pressure
`systemic circuit ................................... 166
`34. Decrease in size of blood vessels .................... 168
`
`35. Major sites for phagocytosis ........................ l69
`36. Principle of the HIAC counter ...................... 172
`3?. Sizes of particles as seen by the HIAC ............... 173
`38. Principle of the Coulter Counter .................... 175
`39. Relationship between cumulative limiting number (per ml)
`and diameter are for official limit tests .............. 377
`40. Integral between limits to produce an area under the curve
`used to limit particulate in injection solutions ......... 178
`Chapter 13
`41. Flow sheet for a large VQleB parenteral filled in
`a plastic container. ................................ 184
`42. Different flow regimes are met an open neck of a
`bottle ............................................ 189
`
`
`
`AstraZeneca Exhibit 2086 p. 6
`
`

`

`TABLES
`
`
`
`Ceapter 4
`1. Approximate body compartment electrolyte
`composition (mEq) ................................. 39
`2. Buffer systems used to maintain the pH of iajeetaole
`solutions .......................................... 40
`
`3 Antioxidants used in parenteral products ............. 41
`4. Antibacterial compounds used as preservatives in
`parenteral aqueous solutions ......................... 42
`Cheeses 5
`5. Distribution of fatty acids from the triglycerides of
`Intralipio and Liposye intravenous emulsions .......... 55
`6. Components of natural lecithin ...................... 56
`’7. Quality control procedures carried out on iajeetable
`lipid emulsions .................................... 59
`Chapter 6
`St The calorie eontent of common intravenous fluids ...... 64
`
`Ckspter 9
`9. Basic types of containers used for parenterals ......... 100
`10. Additives commonly used in plastics ................. 110
`11. Additives used to improve the properties of natural
`and synthetic rubbers .............................. ll:
`12- Synthetic rubbers used for pharmaceutical closures .
`.
`. .113
`13. Performance of elastomers used for sealing parenteral
`produets..H............i..i...i ................. 113
`Chapter 30
`14. Sterilization methods .............................. 12l
`
`Chapter 12
`15. Approximate sizes of some contaminants reported in
`intravenous solutions .............................. 162
`
`iii
`
`AstraZeneca Exhibit 2086 p. 7
`
`

`

`CHAPTER
`
`PERSPECTIVES ON THE USE
`
`AND ESSENTIAL REQUIREMENTS
`
`OF PARENTERAL PRODUCTS
`
`
`
`LEARNING ORIECTIVES
`
`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 thrQa' (besides, other than) and suragov (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
`
`CHAPTERE
`
`Freedom from viable microorganisms may he achieved by heating
`
`the product 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 microorganisms is achieved without damaging the product. Since
`
`the contents of the container can now he described as “sterile”. there
`
`is no need to risk violating the integrity of the product until immedi
`
`state before administration to the patient.
`
`Some drag products may be damaged he sterilisation processes. in
`
`this situation? a product mayr he assembled from sterile components
`under carefully controlled conditions to minimise contamination with
`microorganisms; the final assembled product inside the sealed container
`is not exposed to a terminal sterilization process. This type of product
`
`is described as “aseptic”, examples being fractionated blood products
`
`and drug admixtures.
`
`Solutions that contain gram—negative bacteria are capable of pro
`
`dncing febrile reactions on injection, even if the solution is sterile. These
`
`febrile or pyrogenie reactions are due to the presence of bacterial celt
`
`wall fragments caiicd “endotoxins” that are capable of triggering a
`
`response by the body’s thermal control mechanism. Humans are prob»
`
`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;
`
`dttction there has been bacterial contamination of the product. The
`sensitive methods for quantification of endotoains now available pros
`ride a measurement that serves as an indication of the hygienic condi;
`
`tions under which the product has been prepared.
`The same comment may be made about extraneous particulate cons
`tamination. A product may be sterile hut minute particles of extraneous
`insoluble matter are almost impossihie 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 particulate contamination have
`
`been defined in some cases by regulatory agencies.
`
`HISTORICAL BACKflROUND
`
`The intravenous route of drug administration and the other parena
`teral routes can be dated back to 1656 when Dr. Christopher “insert2
`
`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 opium dissolved in wine
`into a dog using a syringe and a narrow pipe No one scorned too con»
`cerned about the fact that the same syringe couid have been used previ~
`
`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 3658. Here the “soinnteer”, 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
`nest 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 recognized
`
`quite early, the requirement for sterility was not documented officially
`
`until the midulQZOs,
`
`During World War it, dried blood plasma and penicillin injections
`
`were occasionally reconstituted tinder battle conditions with available
`
`water, frequently from stagnant paddled it was essential to get these
`
`materiais 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 amoont of insult.
`
`However, a patient is not healthy. For many years injections were
`
`administered that may not always have been sterile, were occasionally
`
`pyrogenic, and frequently contained a large quantity and variety of nan
`
`ticulate 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
`
`

`

`ti
`
`CHAPTER?
`
`FORM AN!) FUNCTIGN OF INJECTABLES
`
`Drugs prepared for injection are usually in the form of a simple
`
`aqueous solution. However, some drugs may not he stable in the pres
`
`ence of water or may be required to be released into the body more
`
`slowly. Nonnaqueous systems such as oil dispersions of powdered solids
`or oils emulsified in water may be employed. Alternatively, a product
`
`may he lyophilised or dried. to he reconstituted with water prior to use.
`
`Parenteral administration of a drug usually has a number of advan-
`
`tages over the oral route.
`
`1. Drug action is usually more rapid.
`
`2. The whole dose of the drug is administered.
`
`3. Some drugs, such as insulin or heparin, are completely inacti-
`
`vated when given (snailsr and have to be administered parenterally.
`
`4. Some drugs are irritants when given orally out can be tolerated
`
`when given intravenously, for example, strong solutions of dextrose.
`
`5. If a patient is dehydrated or in shock, the administration of
`
`intravenous fluids will often save his or her life.
`
`ROUTES OF ADMINISTRATION
`
`Using a hollow needle of the appropriate diameter, parenteral injeo
`
`tions can he introduced into the body by a number of different routes
`
`as illustrated in Figures 1—3.
`
`I. thcnteneous (so) injections are introduced into the soft tissues
`
`just underneath the skin surface. Since the available space in these tissues
`
`is limited, the volurne of these injections does not eaceed lrnL. Care
`
`is required to males certain that the formulation conforms closely to
`
`physiological conditions in terms of pH and tonicity.
`
`2. Intramuscular (inn) injections are introduced directly into the
`
`muscle, usually of the arm or the gluteal 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 volume of the injection must
`
`he kept small, generally not more than EmL. The blood supply to
`
`muscles is usually sufficient to ensure that the entire drug close is not
`
`immediately available. For this reason, muscle “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 hotly.
`
`3. intravenous (in) injections are introduced directly into the blood
`
`stream. it is possible, with care, to give small volumes of concentrated
`
`AstraZeneca Exhibit 2086 p. 11
`
`

`

`Parenteral Precincts
`
`‘3'
`
`seluiinns that weuid normally irriiaie tissues. These are administered
`
`slowly so that the solutinns are diluted by the blend flowing past the
`
`needle point as they are given. The intravennna mute is also used tn
`
`give larger volumes of replacement and hyperalimentation solutions.
`
`Fallewing majer trauma, a patient may receive as much as lQO iiters
`
`of fluid over a period of weeks.
`
`4, Innnenfanenas (in) injection is inn‘educed directly into the
`
`epiuermis just below the stratum eerneum. This route is used in give
`
`smali volumes (OJ-“0.5mm of diagnostic maierials er vaccines.
`
`5. Inirurheen! snlniione are need fer inducing spinal or lumbar
`
`anesthesia by injecting solutions
`
`inn)
`
`the subaraehnnicl Space.
`
`Cerebrnepinal fluid is usually withdrawn first to avoid increasing the
`
`fluid unlnme and inducing pressure on the spinal nerve mete. Velunies
`
`0f lemL are usually administereni The density of the selniinn may
`
`
`
`
`Figure 1. Injection routes into and ihreugh the skin.
`
`lniraeumneuue (iniradermal) (used l‘m‘ diagnosiie snlutions)
`1C
`snbeuianenus
`SC?
`iM intramuscular
`W intravenous
`
`lC.
`
`
`
`
`Epidermls
`Dermis
`
`E2
`
`“Subcutaneous
`
`
`
`
`
`AstraZeneca Exhibit 2086 p. 12
`
`

`

`8
`
`CHAPTERZ
`
`be adjusted to make the anesthetic move up or down the Spinal canal
`
`according to the posture of the patient.
`
`6. Infra-articular injections are used to introduce materials such as
`
`anti—inflammatory drugs directly into damaged or irritated joints.
`7. Intrucardial, 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—
`
`
`Intrathecal injection routes into the subarachnoid space surrounding
`Figure 2.
`the spinal cord.
`
`PD peridural
`IT
`intrathecal
`
`Po
`
`Pemdural space
`Fllum terminate
`
`3rd Lumbar
`
`Duro mater
`
`Arochnoid
`
`Nerve
`
`PlCl mater
`
`
` 4th Lumbar
`
`l.T
`
`Subormchnond
`
`Space
`
`5th Lumbar
`
`
`
`AstraZeneca Exhibit 2086 p. 13
`
`

`

`Parenteral Products
`
`9
`
`
`
`Intracistemei mute fer withdrawing eerebrospinat fluid and eeeesimr
`Figure 3.
`all}; fer administering antibioties in eases 0f meningitie. The procedure is diffi-
`cult, requiring eeneidetable care in the injection technique and the pteperatien 0f
`the injection semtion (complete aseeeie, pH, density and freedom from partieies).
`
`Ctetemt}
`
`Magma
`
`
`
`
`Sub—ureetmmé
`
`Space
`
`
`
`.....Spme1t card
`
`
`
`wefling catheter. Catheterizatien inmlvee 21 Surgical procedure and is
`generally only encountered in specialist units found in the larger
`
`beepitale.
`
`8. Intt‘aperiteneel 6.13.) is a route used for applieatiens such as the
`rabies vaccine. It may also be used for kidney diatysis solutions.
`9. Intraeistemel and peridm'e! routes are injections into the
`
`AstraZeneca Exhibit 2086 p. 14
`
`

`

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`AstraZeneca Exhibit 2086 p. 15
`
`
`

`

`Parenteral Products
`
`11
`
`intracraniai cistern and dura mater of the spinai cord. Both are diffi~
`
`cult procedures, with criticai requirements for the injections.
`
`The effect (in, rate and intensity of action) produced by a drug
`
`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 shortelived. A subcutaneous
`
`injection, on the other hand, forms a depot from which the drug is
`
`slowly released. The onset of action is therefore slower, the intensity
`
`is reduced, and the duration of action is longer as seen in Figure 4.
`
`injections do have drawbacks.
`
`I. Some srnaii element 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 doctor 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 overdose is
`
`administered, the effects are difficult to reverse.
`
`4. Administration of any material through the skin requires con—
`
`siderable care since air or microorganisms macsr ire introduced 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 rnust 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
`rials under conditions that minimize the chances of contamination with
`
`microorganisms (aseptic processing)
`
`2. Substantially free from bacterial endotoains and other pyrogenic
`materials.
`
`3. Suhstantiaiiy free from extraneous insoluble materiais.
`
`REFERENCES
`
`Avis, K.E., Lachman, L. and Lieberman, H.A., Pharmaceutical
`
`Dosage Forms: Parenterai Medications, Vols. 1 and 2, Marcel Beaker,
`
`New York (1984,
`
`i986}.
`
`AstraZeneca Exhibit 2086 p. 16
`
`

`

`I2
`
`SHAPTERE
`
`Duma, RJ. and Akers, M.3., Chapter 2 in Pharmaceutical Dosage
`
`Farms: Parenteral medieatiens (Editors: Avis, ICE, Laehman, L. and
`
`Lieberman, HA.) Marcel Dekker? New Yark, I, 33 (1984).
`
`Graves, M.J., Parenteral Products: The Preparation and Quality
`Control 01" Products far Injection: Heinemann Medical, London (19273).
`
`013011, W.P.: and Groves, MJ. (Editors), Aeepiie Pharmaceutical
`
`Manufacturing: Technology far the 19903, Interpharm Press, Prairie
`
`View, IL (i987).
`
`Triaael, L.A., Handbaak on Injeetable Drugs, American Society 0f
`
`Hospital Pharmacists, Washingtan, DC (1986).
`
`AstraZeneca Exhibit 2086 p. 17
`
`