The Keys to RTU Parenterals - Sterile Parenteral Drug Contract ...

Volume 11 Number 5SEPTEMBER 2009PLUSDEGRADATION TEST-INGGLOBAL CONTRACTMANUFACTURINGSCALE UPNEW SERIESBringingMassSpecto the MassesFrom niche tool to necessity: the history of MSin the pharmaceutical industrywww.pharmaquality.com

FormulationRTU DRUG PRODUCTSThe Keys to RTU ParenteralsThere are a number of challenges when it comes toready-to-use products | BY PAULA YOUNGBERG WEBB, MS, ANDRAO CHILAMKURTI, PHDEditor’s Note: This is the first in a three-part series on ready-to-use parenteral products. Part two willappear in our October/November issue.Many parenteral drug products are administered as intravenous (IV) infusionsin multiple-patient care settings, from hospitals to alternate carefacilities. The drug product, typically packaged in a vial or ampoule, isadded to an IV solution such as normal saline or 5% dextrose prior to intravenousinfusion. 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 drugproducts 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, manufacturingprocess development and tech transfer, and stability testing programs for registrationbatches.All About RTUsLike most IV infusion solutions, RTU drug products for IV infusion are packaged inflexible plastic containers; however, some drugs that adsorb to plastic materials, suchas nitroglycerin, may be packaged in glass containers. Flexible plastic containers offerseveral advantages over glass infusion bottles with respect to safety, handling, storage,and so on. Solution volumes of RTU drug products for IV infusion typically rangefrom 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 distributedand stored in a frozen state and thawed prior to use. They are given a long-termFigure 1. Categories of Parenteral RTU Drug Solutions For IV Infusionshelf life in a frozen state and a thawedshelf life at room or refrigerated temperature.Figure 1 (see below) depicts varioustypes of parenteral RTU products basedon type of container and manufacturingprocess.Parenteral RTU products for IV infusionoffer many benefits compared toadmixed IV drugs. One of the primarybenefits is elimination of complex proceduresrequired for traditional IV admixtureand compounding, saving both timeand labor. The use of RTU drug productsin hospitals allows the pharmacist to allocatemore time to clinical and other activities.These products also help to improvecompliance with patient safety guidelinesand reduce the risk of medicationerrors, medication contamination, andneedle stick infections. Additionally, theyhelp pharmacists to comply with stringentJoint Commission on the Accreditationof Healthcare Organizations and U.S.Pharmacopeia 797 guidelines.The formulations of liquid RTU productsare optimized for stability in the chosenIV diluent, which results in a longershelf life than the “beyond use date” forcompounded solutions. The formulationof frozen RTU products is also optimizedfor long-term stability during frozen storageand short-term stability after thawing.Due to formulation optimization, thethawed shelf lives of frozen RTU productsare often longer than the “beyond usedate” of compounded solutions. Thelonger thawed shelf lives allow the pharmacistto recycle the unused product(products not administered to any patient)for use at a later time. The RTU drugproducts are generally iso-osmotic due tothe ability of the manufacturer to adjustthe concentration of the tonicity agent,such as dextrose.Formulation and ContainerSelectionSeveral factors, including clinical, formulation,container, and marketing, play akey role in selecting a parenteral drug toP FQwww.pharmaquality.com

e developed as an RTU product. Becausethe RTU products typically deliver a unitdose, the dosing regimen for candidatedrugs involves a fixed standard dose; thedrugs are administered with an IV diluentsuch as sodium chloride injection, dextroseinjection, or lactated ringers injection.The type of diluent selected oftendepends upon clinical considerationssuch as sodium or electrolyte levels andlimitations on carbohydrate intake (suchas dextrose for the diabetic patient population).The solution volume of the productselected also depends upon the recommendedrate of infusion for a specificdrug. Injection site interactions such aspain or erythema, along with limitationson fluid intake, are also considerations inselecting the solution volume. In additionto these clinical considerations, the benefitsof RTU drug products for infusion overthe traditionally compounded drug admixturesplay a major role in the decisionto develop and market an IV drug for infusionas a RTU product.Key considerations in selecting a containersystem for an intravenous RTU productinclude drug-container compatibility,protection of drug from external elements,safety profile, and functional performance.Adsorption of drug to plastic film orabsorption, particularly during autoclavesterilization, must be considered as a partof compatibility. A pH change in solutiondue to leaching of plastic excipients isanother important factor; pH change mayresult in increased drug degradation ordrug precipitation. Leached extractablesmay also precipitate in solution in thepresence of certain drugs or may causethe drug to precipitate.The chosen container system shouldprotect the drug from light and oxygen, ifnecessary, and should have low water vaportransmission to ensure minimumwater loss. Water loss from flexible plasticcontainers may affect delivered volumeand may also result in increased concentrationof drug in the solution over time.The selected container system must alsoact as a barrier to microbial ingress. Itmust pass biological testing and toxicologicalevaluation. Finally, the containersystem must exhibit relevant functionalperformance with respect to integrity, deliveryof dose, and rate of delivery.Figure 2. Effect of Formulation Factors on Drug StabilityFormulation DevelopmentThe primary purpose of formulation developmentis to achieve the desired stabilityand shelf life of the final productthrough optimization of various factors affectingthe stability of the drug in aqueoussolutions. These factors, as depicted inFigure 2 (see above), include solution pH,buffer type and concentration if required,drug concentration, diluent type and concentration,oxygen, and light. For mostdrugs, stability in aqueous solutions is affectedby pH. Therefore, a thorough understandingof the pH-rate profile is essential.If the solution pH cannot be maintainedwithin the optimal range, a bufferthat is suitable for IV administration canbe added. However, the type of buffer selecteddepends upon the formulation pHand the dissociation constants of thebuffer to achieve the desired level ofbuffering capacity. The amount of bufferadded must be optimized to ensure maintenanceof pH and to minimize buffercatalysis. In addition, the amount/concentrationof buffer must be acceptablefrom a toxicological perspective. In someinstances, different concentrations of adrug may show different rates of degradationdue to self-association.The type of diluent that is added tothe formulation—sodium chloride or dextrose,for example—may also play a rolein the degradation of a drug. Addition ofsodium chloride may result in increasedionic strength, which may alter the degradationrate or cause potential precipitationof drug. Stability of certain drugs canalso be affected by the presence of carbohydrateslike dextrose. Finally, oxygen andlight may play a significant role in drug stability.These factors can be controlled bythe use of an appropriate container systemand/or the addition of antioxidants.In general, due to phase changes thatoccur upon freezing of a drug solution,formulation development and optimizationfor drug stability for frozen products ismore complicated than for those liquidformulations stored at room temperature.When a drug solution is frozen, water crystallizesas ice, and the remaining solutionbecomes concentrated. At the intendedlong-term storage temperature, for example–20° C, the drug (and some excipients)may precipitate from the solution or remainin a concentrated state. Dependingon the temperature, it may also exist as aglassy state.(Continued on p. 42)Table 1. Examples of Commercially Available RTU Parenteral Products for IV InfusionSeptember 2009

FORMULATIONRTU Drug ProductsTable 2. Example: Formulation Optimization - VariablesTable 3. Example: Formulation Optimization – Test IntervalsIf precipitation of drug occurs, the long-term stability of thedrug in the frozen state is much more enhanced than in the liquidstate. If the drug remains a concentrate, the degradation rate orkinetics could change relative to liquid state. Although the presenceof drug in glassy state may enhance the stability in comparisonto 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 extremelyimportant to understand the effect of each formulationfactor as well as combination effects. A multi-factorial design canbe utilized to understand these effects. Such studies will help tomeet regulatory requirements. 1Tables 2 and 3 (see left) illustrate an example of formulationoptimization design and relevant storage conditions to evaluatethese factors. During the formulation studies, monitoring andevaluation of impurities/degradation products is critical, becauseone or more impurities/degradation products may become thelimiting factors for meeting overall specifications and achievingthe desired shelf life. These studies will form the basis for qualificationof impurities as required by the ICH Q3B guideline. 2 In addition,pH, visual inspection, particulate matter, and color areessential parameters to be monitored. nYoungberg Webb is senior director of stability operations and Dr. Chilamkurti is seniordirector of pharmaceutical technology at Baxter Pharmaceuticals & Technologies. ReachDr. Chilamkurti at rao_chilamkurti@baxter.com.(Continued from p. 41)REFERENCES1. International Conference on Harmonisation of Technical Requirements forRegistration of Pharmaceuticals for Human Use (ICH). ICH Guideline Q 8(R1): Pharmaceutical development. Geneva, Switzerland; 2008.2. International Conference on Harmonisation of Technical Requirements forRegistration 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.