Pharmaceutical Product Development BI a Ts oO PRODUCT DEVELOPMENT OVERVIEW: The Pharmaceutical Development describes the knowledge that establishes that the type of dosage form selected and the formulation proposed are suitable for the intended use. The aim of pharmaceutical development is to design a quality product and its he intended performance of the product. nufacturing process to consistently deliver # the pr ie os Jes can be helpful in prioritizing the Appropriate use of quality risk management princip! ; additional pharmaceutical development studies to collect such knowledge. The -— and conduct of pharmaceutical development studies should be consistent with their intended scientific purpose. This chapter includes sufficient information in each part to provide an ‘understanding of the development of the drug product and its manufacturing Process: Content: 1.1.1 Introduction 1.1.2 Stages of Product Development Definitions: Drug Development: It is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. Process Analytical Technology (PAT): It has been defined as a mechanism to design, analyze, and control pharmaceutical manufacturing processes through the measurement of Critical Process Parameters (CPP) which affect Critical Quality Attributes (CQA). Preclinical Studies: It is a stage of research that begins before clinical trials (testing in humans) can begin, and during which important feasibility, iterative testing and drug safety data are collected. Quality Risk Management: It is a systematic process for the identification, assessment and control of risks to the quality of pharmaceutical products across the product lifecycle. New Drug Application (NDA): It is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. ee ee eee es ore 5 = e physical, chemical and mechanical properties of a s , lop stable, safe and effective dosage form. Pharmacokinetics: It is the study of drug absorption, distribution, metabolism, and excretion. , Pharmacodynamics: It is the study of the biochemical and physiological effects of drugs. & scanned with OKEN Scannerinformation and knowledge manufacturing experience prov: the design space, specific gained from pharmaceutical development studies and ide scientific understanding to support the establishment of ‘ations, and manufacturing controls. Information from Pharmaceutical development studies can be a basis for quality risk management. It is important to recognize that quality cannot be tested into products; ie, quality should be built in by design. Changes in formulation and manufacturing processes during development and lifecycle management should be looked upon as opportunities to gain additional knowledge and further support establishment of the design space. Similarly, inclusion of relevant knowledge gained from experiments giving unexpected results can also be useful. Design space is proposed by the applicant and is subject to regulatory assessment and approval. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product. In addition, the applicant can choose to conduct pharmaceutical development studies that can lead to an enhanced knowledge of product performance over a wider range of material attributes, processing options and process parameters. Inclusion of this additional information in this chapter provides an opportunity to demonstrate a higher degree of understanding of material attributes, manufacturing processes and their controls. This scientific understanding facilitates establishment of an expanded design space. nel Mel 1c Sg Cs a LCL ne Figure 1.1.1: Process of Product Development @ scanned with OKEN ScannerPharmaceutical Product Development 5 3 exist to develop more flexible regulatory In these situations, opportu approaches, for example, to facilitate: * Risk-based regulatory decisions (reviews and inspections); * Manufacturing process improvem in the approved design space described in the dossier, without further regulatory revi * Reduction of post-approval submissions; + Real-time quality control, leading to a reduction of end-product release testing. To realize this flexibility, the applicant should demonstrate an enhanced knowledge of product performance over a range of material attributes, manufacturing process options and process parameters. This understanding can be gained by application of, for example, formal experimental designs, process analytical technology (PAT), and/or prior knowledge. Appropriate use of quality risk management principles can be helpful in prioritising the additional pharmaceutical development studies to collect such knowledge. The design and conduct of pharmaceutical development studies should be consistent with their intended scientific purpose. It should be recognized that the level of knowledge gained, and not the volume of data, provides the basis for science-based submissions and their regulatory evaluation. 1.1.2 STAGES OF PRODUCT DEVELOPMENT Any drug development process must proceed through several stages in order to Produce a product that is safe, efficacious, and has passed all regulatory requirements. Below are the in-depth overview of many stages in the drug development process and necessary studies: a) Drug Discovery b) Preclinical Study ©) Investigational New Drug Approval (INDA) 4) Clinical Trials ©) New Drug Application (NDA) ) Post-Marketing @ scanned with OKEN ScannerBV A Text Book of Pharmaceutical Product Development eat vc ec Figure 1.1.2: Pharmaceutical Product Development Process A. Drug Discovery New drugs may be discovered from variety of natural resources or synthesized in the laboratory. They may be discovered by accident or as the result of many years of tireless quest. According to the FDA, a new is not recognized drug is any that being safe and effective in the conditions recommended for its use among qualified by scientific training experts who are and experience. Discovery often begins with target identification - choosing a biochemical mechanism involved in a disease condition. Once scientists confirm interaction with the drug target, they typically validate that target by checking for activity versus the disease condition for which the drug is being developed. After careful review, one or more lead compounds are chosen. A drug need not be a new chemical entity to be considered new. A change in a previously approved drug product's formulation or method of manufacture constitutes newness under the law, since such changes can alter the therapeutic efficacy and safety of a product. ‘The Food and Drug Administration (FDA or USEDA) is a United States government ageiicy that protects and promotes public health, by regulating food safe pti ver-the-counter fcogarga cine wid sae -y regulating fety, tobacco, prescription drugs, 0 @ scanned with OKEN ScannerPharmaceutical Product Development 7 aE eee ‘A combination of two or more old drugs or a change in the usual proportions of drugs in an established combination product is considered new if the change introduces a question of safety or efficacy. Following are the steps for new drug discovery: © Target identification and validation * Assay development * Lead identification + Lead optimization + Pre-development Researchers discover new drugs through: + New insights into a disease process that allow researchers to design a product to stop or reverse the effects of the disease. © Many tests of molecular compounds to find possible beneficial effects against any of a large number of diseases. «Existing treatments that have unanticipated effects. + Natural Sources through plant material have contributed and is served as a reservoir of potential new drugs. ‘* New technologies, such as those that provide new ways to target medical products to specific sites within the body or to manipulate genetic material. * Molecular Modification which is a chemical alteration of a known and previously characterized organic compounds for the purpose of enhancing its usefulness as a drug. * Enhancing drug specificity for a particular body target site, increasing potency, improving its rate and extent of absorption, reducing its toxicity or changing its physical or chemical properties to provide desired features. ‘© Mechanism Based Drug Design in which molecular modification to design a drug that interferes specially with the known or suspected biochemical pathway or mechanism of a disease process. ‘Alead compound in drug discovery is achemical compound that has pharmacological or bi activity likely to be therapeutically useful, but may nevertheless have suboptimal structure that requires modification to fit better to the target; 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Therefore, it is customary to compose a simple formulation to be presented as the drug product in the IND and used in phasel studies to deliver the drug to human subjects. For example, an oral FIH trial design may utilize drug supplied as a powder; an appropriate quantity is weighed out by the pharmacist and placed in a gelatin capsule prior to administration. For both oral and intravenous FIH trial designs, a specific amount of drug may be supplied in a clinical vial (also known as powder in bottle, or PIB) to which the appropriate volume of vehicle (specific liquid component) is added prior to administration. These approaches are most useful for early phase 1 trials involving relatively few human subjects. As the clinical trials become more complex and involve more subjects, oral formulations may be prepared in tablets or capsules containing scaled quantities, or ‘strengths,’ of the drug (for example, 50 mg, 100 mg, and 200 mg) so that each Patient can take a combination of quantities to target individual body weight. Once the unit dose is established (usually after phase 2 and before phase 3 clinical trials), a formulation 8 selected as the final drug product for later stage clinical trials and product release. As described above for APIs, all formulations intended f are prepared under rigorous specifications as outlined in the GMP puidelj — guidelines. i F P » Analytical and Bioanalytical Methods @ scanned with OKEN Scannerdrape 2773 ti analyte, plasma proteins twat ‘ Tugs that might interfere in the analysis. All these lanning an analysis. * Pharmacokinetic and Drug Disposition Study Pha cokinet, ¥ studies Sonne and ADME (Absorption /Distribution/ Metabolism /Excretion) ca AUG Geen rnetT wane for formulation scientists. PK studies yield parameters such Tmax (ime at whine ©), Cmax (maximum concentration of the drug, B blood and ere eres reached). Later on, this data from animal PK studies is ee rom early stage clinical trials to check the predictive power of animal . ledge of the fate of a drug, its disposition (absorption, distribution, metabolism, and excretion, known as ADME) and pharmacokinetics plays a central role throughout pharmaceutical research and development. Pharmacokinetic studies based on a traditional intensive design model are usually conducted using carefully selected volunteer subjects, a controlled experimental design, and collection of multiple blood samples. After measurement of drug and metabolite concentrations in all samples, pharmacokinetic models are applied to determine parameters such as elimination half-life, volume of distribution, and clearance. During the new drug development process, a series of pharmacokinetic studies are conducted to determine the influence of major disease states or experimental conditions hypothesized to affect drug disposition. Such factors might include age, gender, body weight, ethnicity, hepatic and renal disease, co-administration of food, and various drug interactions. Classical pharmacokinetic studies can determine quantitative effects of anticipated influences on drug disposition under controlled circumstances, but cannot identify the unexpected factors affecting pharmacokinetics. Pharmacokinetics is the discipline that applies mathematical models to describe and predict the time course of drug concentrations in body fluids, whereas pharmacodynamics refers to the time course and intensity of drug effects on the organism, whether human or experimental animal. Both have evolved as the techniques for measuring drug concentrations, and drug effects have, become more accurate and sensitive. Evolving in parallel is kinetic-dynamic modeling, in which the variable of time is incorporated into the relationship of effect to concentration. A concentration-effect relationship is, in principle, the most clinically relevant, because it potentially validates the clinical rationale for measuring & scanned with OKEN Scannerpharmaceutical Product Development 23 drug concentrations in serum or plasma. A kinetic-dynamic study in clinical psjchopharmacsogy ‘ypically involves medication administration (usually under placebo- controlled, double-blind laboratory conditions) followed by quantitation of both drug concentration and clinical effect at multiple times after dosing, Measures of effect necessarily depend on the type of drug under study, > Preclinical Toxicology Testing The nonclinical safety assessment for marketing approval of a pharmaceutical usually includes pharmacology studies, general toxicity studies, toxicokinetic and nonclinical pharmacokinetic studies, reproduction toxicity studies, genotoxicity studies and, for drugs that have special cause for concern or are intended for a long duration of use, an assessment of carcinogenic potential. Other nonclinical studies to assess phototoxicity, immunotoxicity, juvenile animal toxicity and abuse liability should be conducted on a case-by-case basis. The need for nonclinical safety studies and their relation to the conduct of human clinical trials is delineated in this guidance. Preclinical testing analyzes the bioactivity, safety, and efficacy of the formulated drug product. This testing is critical to a drug’s eventual success and, as such, is scrutinized by many regulatory entities. During the preclinical stage of the development process, plans for clinical trials and an Investigative New Drug (IND) application are prepared. Studies taking place during the preclinical stage should be designed to support the clinical studies that will follow. The main stages of preclinical toxicology testing are: i. Acute Toxicity Studies Acute toxicity information has been obtained from single-dose toxicity studies in two mammalian species using both the clinical and a parenteral route of administration. However, such information can be obtained from appropriately conducted dose-escalation studies or short-duration dose-ranging studies that define an MTD in the general toxicity test species. Acute toxicity studies look at the effects of one or more doses administered over a period of up to 24 hours. The goal is to determine toxic dose levels and observe clinical indications of toxicity. Data from acute toxicity studies helps determine doses for repeated dose studies in animals and Phase I studies in humans. When this acute toxicity information is available from any study, separate single-dose studies are not recommended. Studies Providing acute toxicity information can be limited to the clinical route only and such data can be obtained from non-GLP studies if clinical adrninistration is supported by appropriate GLP repeated-dose toxicity studies. 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They aim to learn how a drug is processed in the body and how it affects the body. In these trials, a very small dose of a drug is given to about 10 to 15 people. A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates in order to decide which has the best pharmacokinetic parameters in humans to take forward into further development. ii, Phase I (Human Pharmacology): Thirty days after a biopharmaceutical company has filed its IND, it may begin a small-scale Phase I clinical trial unless the FDA places a hold on the study. Phase I studies are used to evaluate pharmacokinetic parameters and tolerance, generally in healthy volunteers. These studies include initial single-dose studies, dose escalation and short-term repeated-dose studies. The drug will be tested in a small group of 20 to 100 patients. Doctors start by giving very low doses of the drug to a few patients. Higher doses are given to other patients until side effects become too severe or the desired effect is seen. The drug may help patients, but Phase I trials are to test a drug's safety. Ifa drug is found to be safe enough, it can be tested in a phase Il clinical trial. iii, Phase II (Therapeutic Exploratory): Phase II clinical studies are small-scale trials to evaluate a drugs preliminary efficacy and side-effect profile in 100 to 300 patients. Additional safety and clinical pharmacology studies are also included in this category. The drug is often tested among patients with a specific type of cancer. Phase II trials are done in larger groups of patients compared to Phase I trials. Often, new combinations of drugs are tested. Patients are closely watched to see if the drug works. However, the new drug is rarely compared to the current (standard- of-care) drug that is used. If a drug is found to work, it can be tested in a phase II clinical trial. Phase II studies are sometimes divided into Phase IIA and Phase IIB. There is no formal definition for these 2 sub-categories, but generally: * Phase IIA studies are usually pilot studies designed to demonstrate clinical efficacy or biological activity (‘proof of concept studies); * Phase IIB studies look to find the optimum dose at which the drug shows biological activity with minimal side-effects (‘definite dose-finding’ studies). Sir Ronald A. 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