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  1 OVERVIEW OF PHARMACEUTICALPRODUCT DEVELOPMENT AND ITSASSOCIATED QUALITY SYSTEM C HUNG  C HOW  C HAN , P H .D.  Eli Lilly Canada, Inc. E RIC  J ENSEN , P H .D.  Eli Lilly & Company, Indianapolis 1.1 INTRODUCTION Pharmaceutical product development consists of a series of logical and system-atic processes. When successful, the final outcome is a commercially availabledosage form. However, this process can become a long and complicated pro-cess if any of the steps lose their focus. The industry has undergone manychanges over the years to increase focus on efficiency and efficacy of the devel-opment process. The overall cycle of pharmaceutical product development issummarized in Figure 1.1. The clinical study of drug development is the mostobvious and best known to laypersons and scientists. However, many associatedbehind-the-scene activities are also actively pursued in a parallel and timely man-ner to ensure the success of pharmaceutical product development. Clinical andcommercial success cannot be achieved without successful completion of theseother activities. It is important to note that the clinical phase boxes in Figure 1.1may not be aligned exactly chronologically with other development activities.  Analytical Method Validation and Instrument Performance Verification , Edited by Chung ChowChan, Herman Lam, Y. C. Lee, and Xue-Ming ZhangISBN 0-471-25953-5 Copyright  ©  2004 John Wiley & Sons, Inc. 1  2  PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM Productdecision Phase I Phase II Phase IIIDefineformulation/ syntheticrouteDefinitivestabilitymanufac-ture ManufactureprocessvalidationDevelop earlyanalyticalmethod Support earlydevelopment formulation/ synthesisDevelopfinalmethodFinalanalyticalmethod Optimizeformula-tion/ synthesisQualitycontrollabManufac-turingMarketDiscoveryresearch Figure 1.1.  Overview of the drug development process. Historically, the time period for pharmaceutical drug product development isusually on the order of 10 to 15 years. However, with the ever-increasing com-petition between pharmaceutical companies, it is of utmost important to reducethe time utilized to complete the development process. 1.1.1 Discovery Research In the discovery research phase of drug development, new compounds are createdto meet targeted medical needs, hypotheses for model compounds are proposed,and various scientific leads are utilized to create and design new molecules.Thousands of molecules of similar structure are synthesized to develop a struc-ture–activity relationship (SAR) for the model. To reach this stage, large phar-maceutical companies rely on new technologies, such as combinatorial chemistryand high-throughput screening, which are cornerstones in drug discovery. Thenew technologies increase the choice of compounds that can be synthesized andscreened. Various in vivo and in vitro models are used to determine the value of these new candidate compounds.The sequencing of the complete human genome was completed in 2000 throughtheHumanGenomeProject,whichwasbegunin1995.Knowledgeofthecompletehuman genome will provide the basis for many possible targets for drug discoverythrough genomics, proteonomics, and bioinformatics. 1.1.2 Preclinical Phase The most promising drugcandidateswould be worthlessif they couldnot be devel-oped, marketed, or manufactured. New therapeutic drugs from drug discovery will  INTRODUCTION  3 undergoextensivetestingtoobtaininitialsafetyandefficacydatainanimalmodels.Upon completion of successful animal safety and efficacy evaluation, submissionto appropriate regulatory bodies is made to gain approval to administer the firsthuman dose in the clinical phase I trial. 1.1.3 Clinical Phases The clinical phase I trial is used to assess the safety and, occasionally, the efficacyof a compound in a few healthy human volunteers. These studies are designedto determine the metabolism and pharmacological action of the drug in humans,the side effects associated with increasing doses, and if possible, to gain veryearly information on the drug’s effectiveness. Safety data from these trials willhelp determine the dosage required for the next phase of drug development. Thetotal number of subjects in phase I studies is generally in the range 20 to 80.Clinical phase II trials are conducted to evaluate the effectiveness of a drug fora particular indication or indications in patients with the targeted disease. Thesestudies also help to determine the common short-term side effects and risksassociated with the drug. Phase II studies are typically well controlled, closelymonitored, and conducted in a relatively small number of patients, usually nomore than several hundred.  Active Pharmaceutical Ingredient (API).  In this early stage of drug devel-opment, only a small quantity of drug substance is needed. As developmentprogresses into later stages, greater quantities of drug substance are needed andwill trigger efforts to optimize the synthetic route.  Formulation Development.  The formulation of the new drug product will bedesigned in conjunction with medical and marketing input. Excipients to be usedwill be tested for chemical and physical compatibility with the drug substance.The preliminary formulation design will be optimized at this stage.  Analytical Development of API and Drug Products.  Early methods to sup-port synthetic and formulation developments are often developed in the form of potency assay, impurities/related substance assay, dissolution, Karl Fischer, iden-tity, chiral method, and content uniformity. These analytical methods are devel-oped and validated in a fast and timely manner to support all phase II studies. Common Studies Performed on the API and Drug Product.  At this stage of thedevelopment, it is important to gain preliminary information of the stability of theAPI and drug product. Therefore, open dish (i.e., nonprotected) stability studiesare carried out to understand the chemical and physical stability of both theAPI and the drug product. Preliminary packaging stability studies are conductedto obtain a preliminary assessment of packaging materials that can be used,and photostability and thermal studies are conducted to determine the light andthermal stability of the API and drug product.  4  PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM Successful efficacy and safety data will guide the decision to proceed to clinicalphase III in product development. In this stage, the new drug is administered toa larger population of patients using blinded clinical studies. These studies maydemonstrate the potential advantages of the new compound compared with similarcompounds already marketed. The data collected from this stage are intendedto evaluate the overall benefit–risk relationship of the drug and to provide anadequate basis for labeling. Phase III studies usually include from several hundredto several thousand subjects and often include single- or double-blind studiesdesigned to eliminate possible bias on the part of both physicians and patients.Positive data from this stage will trigger implementation of a global registrationand commercialization of the drug product.  Impurities Level in New Drug Product.  As the new drug product formulationprogresses to this late stage of development, impurity profiles may differ fromthose of earlier formulations. The rationale for reporting and control of impuritiesin the new drug product is often decided at this stage as are recommended storageconditions for the product. Degradation products and those arising from excipientinteraction and/or container closure systems will be isolated and identified. Theimpurity profile of the representative commercial process will be compared withthe drug product used in development, and an investigation will be triggered if any difference is observed. Identification of degradation products is required forthose that are unusually potent and produce toxic effects at low levels.Primary and developmental stability studies help development scientists under-stand the degradation pathways. These studies are developed to get informationon the stability of the drug product, expected expiry date, and recommendedstorage conditions. All specified degradation products, unspecified degradationproducts, and total degradation products are monitored in these studies.  Impurities in API.  Treatment of the impurities in the API is similar to that forthe new drug product. Impurities in the API include organic impurities (processand drug related), inorganic impurities, and residual solvents. Quality controlanalytical procedures are developed and validated to ensure appropriate detectionand quantitation of the impurities. Specification limits for impurities are set basedon data from stability studies and chemical development studies. A rationale forthe inclusion or exclusion of impurities is set at this stage. The limits set shouldnot be above the safety level or below the limit of the manufacturing processand analytical capability.  API Development.  The synthetic route will be finalized and a formal primarystability study will be undertaken to assess the stability of the API.  Formulation Development.  The formulation is finalized based on the experiencegained in the manufacture of clinical phase I and II trial materials. Scale-up of themanufacturing process will be completed to qualify the manufacturing capabilityof the facility. The primary stability study is initiated to assess the stability of the drug product.
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