{Y' L E..VE._ )Pwl 5N“
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`Volume 11 Numbers
`SEPTEMBER 2009
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`PLUS
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`D EG RADATI O N TEST-
`ING
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`
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`G LO BAL CONTRACT
`MANUFACTURING
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`SCALE UP
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC — Exhibit 1028 — Page 1
`
`

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`Formulation
`The Keys to RTU Parenterals
`
`RTU DRUG PRODUCTS
`
`There are a number of challenges when it comes to
`ready-to-use products | BY PAU L A YO U N G B E R G W E B B , MS , A N D
`R AO C H I L A M K U RT I , P H D
`
`Editor’s Note:This is the first in a three-part series on ready-to-use parenteral products. Part two will
`
`appear in our October/November issue.Many parenteral drug products are administered as intravenous (IV) infu-
`
`sions in multiple-patient care settings, from hospitals to alternate care
`facilities. The drug product, typically packaged in a vial or ampoule, is
`added to an IV solution such as normal saline or 5% dextrose prior to in-
`travenous infusion. Several drugs for IV infusion, premixed in an intravenous diluent,
`are also commercially available. These products are referred to as ready-to-use (RTU)
`products or “premix” drug solutions. Examples of commercially available RTU drug
`products are listed in Table 1 (see p. 41).
`There are a number of key factors in the development of RTU parenteral products.
`In addition to container selection and optimization of formulation for drug stability,
`other key considerations include analytical method development, manufacturing
`process development and tech transfer, and stability testing programs for registration
`batches.
`
`All About RTUs
`Like most IV infusion solutions, RTU drug products for IV infusion are packaged in
`flexible plastic containers; however, some drugs that adsorb to plastic materials, such
`as nitroglycerin, may be packaged in glass containers. Flexible plastic containers offer
`several advantages over glass infusion bottles with respect to safety, handling, stor-
`age, and so on. Solution volumes of RTU drug products for IV infusion typically range
`from 50 mL to 1 L.
`Depending on the stability of a drug, these products may be terminally sterilized,
`aseptically filled, or aseptically filled and frozen. These frozen products are distrib-
`uted and stored in a frozen state and thawed prior to use. They are given a long-term
`
`Figure 1. Categories of Parenteral RTU Drug Solutions For IV Infusion
`
`shelf life in a frozen state and a thawed
`shelf life at room or refrigerated tempera-
`ture. Figure 1 (see below) depicts various
`types of parenteral RTU products based
`on type of container and manufacturing
`process.
`Parenteral RTU products for IV infu-
`sion offer many benefits compared to
`admixed IV drugs. One of the primary
`benefits is elimination of complex proce-
`dures required for traditional IV admix-
`ture and compounding, saving both time
`and labor. The use of RTU drug products
`in hospitals allows the pharmacist to allo-
`cate more time to clinical and other activi-
`ties. These products also help to improve
`compliance with patient safety guide-
`lines and reduce the risk of medication
`errors, medication contamination, and
`needle stick infections. Additionally, they
`help pharmacists to comply with strin-
`gent Joint Commission on the Accredita-
`tion of Healthcare Organizations and U.S.
`Pharmacopeia 797 guidelines.
`The formulations of liquid RTU prod-
`ucts are optimized for stability in the cho-
`sen IV diluent, which results in a longer
`shelf life than the “beyond use date” for
`compounded solutions. The formulation
`of frozen RTU products is also optimized
`for long-term stability during frozen stor-
`age and short-term stability after thaw-
`ing. Due to formulation optimization, the
`thawed shelf lives of frozen RTU products
`are often longer than the “beyond use
`date” of compounded solutions. The
`longer thawed shelf lives allow the phar-
`macist to recycle the unused product
`(products not administered to any pa-
`tient) for use at a later time. The RTU drug
`products are generally iso-osmotic due to
`the ability of the manufacturer to adjust
`the concentration of the tonicity agent,
`such as dextrose.
`
`Formulation and Container
`Selection
`Several factors, including clinical, formu-
`lation, container, and marketing, play a
`key role in selecting a parenteral drug to
`
`P F Q
`
`www.pharmaquality.com
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1028 – Page 1
`
`

`

`be developed as an RTU product. Because
`the RTU products typically deliver a unit
`dose, the dosing regimen for candidate
`drugs involves a fixed standard dose; the
`drugs are administered with an IV diluent
`such as sodium chloride injection, dex-
`trose injection, or lactated ringers injec-
`tion. The type of diluent selected often
`depends upon clinical considerations
`such as sodium or electrolyte levels and
`limitations on carbohydrate intake (such
`as dextrose for the diabetic patient popu-
`lation).
`The solution volume of the product
`selected also depends upon the recom-
`mended rate of infusion for a specific
`drug. Injection site interactions such as
`pain or erythema, along with limitations
`on fluid intake, are also considerations in
`selecting the solution volume. In addition
`to these clinical considerations, the bene-
`fits of RTU drug products for infusion over
`the traditionally compounded drug ad-
`mixtures play a major role in the decision
`to develop and market an IV drug for in-
`fusion as a RTU product.
`Key considerations in selecting a con-
`tainer system for an intravenous RTU prod-
`uct include drug-container compatibility,
`protection of drug from external elements,
`safety profile, and functional perform-
`ance. Adsorption of drug to plastic film or
`absorption, particularly during autoclave
`sterilization, must be considered as a part
`of compatibility. A pH change in solution
`due to leaching of plastic excipients is
`another important factor; pH change may
`result in increased drug degradation or
`drug precipitation. Leached extractables
`may also precipitate in solution in the
`presence of certain drugs or may cause
`the drug to precipitate.
`The chosen container system should
`protect the drug from light and oxygen, if
`necessary, and should have low water va-
`por transmission to ensure minimum
`water loss. Water loss from flexible plastic
`containers may affect delivered volume
`and may also result in increased concen-
`tration of drug in the solution over time.
`The selected container system must also
`act as a barrier to microbial ingress. It
`must pass biological testing and toxico-
`logical evaluation. Finally, the container
`system must exhibit relevant functional
`performance with respect to integrity, de-
`livery of dose, and rate of delivery.
`
`Figure 2. Effect of Formulation Factors on Drug Stability
`
`Formulation Development
`The primary purpose of formulation de-
`velopment is to achieve the desired sta-
`bility and shelf life of the final product
`through optimization of various factors af-
`fecting the stability of the drug in aqueous
`solutions. These factors, as depicted in
`Figure 2 (see above), include solution pH,
`buffer type and concentration if required,
`drug concentration, diluent type and con-
`centration, oxygen, and light. For most
`drugs, stability in aqueous solutions is af-
`fected by pH. Therefore, a thorough under-
`standing of the pH-rate profile is essential.
`If the solution pH cannot be main-
`tained within the optimal range, a buffer
`that is suitable for IV administration can
`be added. However, the type of buffer se-
`lected depends upon the formulation pH
`and the dissociation constants of the
`buffer to achieve the desired level of
`buffering capacity. The amount of buffer
`added must be optimized to ensure main-
`tenance of pH and to minimize buffer
`catalysis. In addition, the amount/con-
`centration of buffer must be acceptable
`from a toxicological perspective. In some
`instances, different concentrations of a
`drug may show different rates of degrada-
`tion due to self-association.
`
`The type of diluent that is added to
`the formulation—sodium chloride or dex-
`trose, for example—may also play a role
`in the degradation of a drug. Addition of
`sodium chloride may result in increased
`ionic strength, which may alter the degra-
`dation rate or cause potential precipita-
`tion of drug. Stability of certain drugs can
`also be affected by the presence of carbo-
`hydrates like dextrose. Finally, oxygen and
`light may play a significant role in drug sta-
`bility. These factors can be controlled by
`the use of an appropriate container system
`and/or the addition of antioxidants.
`In general, due to phase changes that
`occur upon freezing of a drug solution,
`formulation development and optimiza-
`tion for drug stability for frozen products is
`more complicated than for those liquid
`formulations stored at room temperature.
`When a drug solution is frozen, water crys-
`tallizes as ice, and the remaining solution
`becomes concentrated. At the intended
`long-term storage temperature, for exam-
`ple –20° C, the drug (and some excipients)
`may precipitate from the solution or re-
`main in a concentrated state. Depending
`on the temperature, it may also exist as a
`glassy state.
`
`(Continued on p. 42)
`
`Table 1. Examples of Commercially Available RTU Parenteral Products for IV Infusion
`
`September 2009
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1028 – Page 1
`
`

`

`FORMULATION RTU Drug Products
`
`Table 2. Example: Formulation Optimization - Variables
`
`Table 3. Example: Formulation Optimization – Test Intervals
`
`ence of drug in glassy state may enhance the stability in compari-
`son to a concentrate, the existence of drugs in a glassy state above
`–20°C is not common.
`In optimizing the drug formulations for stability, it is ex-
`tremely important to understand the effect of each formulation
`factor as well as combination effects. A multi-factorial design can
`be utilized to understand these effects. Such studies will help to
`meet regulatory requirements.1
`Tables 2 and 3 (see left) illustrate an example of formulation
`optimization design and relevant storage conditions to evaluate
`these factors. During the formulation studies, monitoring and
`evaluation of impurities/degradation products is critical, because
`one or more impurities/degradation products may become the
`limiting factors for meeting overall specifications and achieving
`the desired shelf life. These studies will form the basis for qualifi-
`cation of impurities as required by the ICH Q3B guideline.2 In ad-
`dition, pH, visual inspection, particulate matter, and color are
`essential parameters to be monitored. (cid:1)
`Youngberg Webb is senior director of stability operations and Dr. Chilamkurti is senior
`director of pharmaceutical technology at Baxter Pharmaceuticals & Technologies. Reach
`Dr. Chilamkurti at rao_chilamkurti@baxter.com.
`
`(Continued from p. 41)
`If precipitation of drug occurs, the long-term stability of the
`drug in the frozen state is much more enhanced than in the liquid
`state. If the drug remains a concentrate, the degradation rate or
`kinetics could change relative to liquid state. Although the pres-
`
`REFERENCES
`1. International Conference on Harmonisation of Technical Requirements for
`Registration of Pharmaceuticals for Human Use (ICH). ICH Guideline Q 8
`(R1): Pharmaceutical development. Geneva, Switzerland; 2008.
`2. International Conference on Harmonisation of Technical Requirements for
`Registration of Pharmaceuticals for Human Use (ICH). ICH Guideline Q 3 B
`(R2): Impurities in new drug products. Geneva, Switzerland; 2006.
`
`Reprinted with permission from PFQ Magazine September 2009.
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1028 – Page 1
`
`