Question 1
- Scale-up is a necessary process in product development that can provide a systematic guideline towards an increase in productivity. According to Altae-Tran et al. (2017), scale-up is a specific process in which a systematic increase can be done on production level by focusing on external demand and priority. By using the results obtained from the laboratory studies on a specific drug, the production process, and its scalability is to be measured and maintained. As this process includes a particular increase in production, it requires a measurable focus on the raw materials that are to be mixed properly for increasing the volume of drug production. In this perspective, whenever the process is based on small increments, it can provide a better guideline toward the ratio changes within the raw materials used. Apart from this, it also offers better financial control over the production process. This, in turn, makes the process a more specifically evaluated one. In this connection consideration of the opinion given by Blakemore et al. (2018) shows the importance of focusing on the basic production process to make the entirely produced drug a comprehensive one. Henceforth, for scaling up the drug production process, small increments are the influential ones that can put control over the manufacturing and the financial aspect. Such a similar small increment-based scaling up has also been done by Pacific Biotech in which gradual increase has been done from 1000 to 5000, 10000, and 20000 respectively.
- A significant example of international technology transfer can be found in case of Pacific Biotech, an ISO 9001 certified company of Thailand. This has included a continuous improvement process with the modernization of equipment and enhancement of storage places. According to Simó et al. (2019), international technology transfer is a consolidated approach to safeguard a better scaling up of a drug production process. In this regard, Pacific Biotech has institutionalized a strong material specification along with production, packaging, and QC methods with international entities. This, in turn, has not only helped the firm to increase its production capacity but also influenced its international business process.
Question 2
- PTG 100 is the selected drug that can be consumed orally for treating inflammatory bowel disease. As demonstrated in the second case study, this drug is an alpha four beta seven integrin one that has been made an effective one by following three distinct phases. These are discovery, translation and clinical trials. According to Altae-Tran et al. (2017), a drug can be considered as an efficient one only when it can pass out the clinical trials and the transitional period effectively. The discovery and development phase of this drug was associated with a multi-parameter optimization as demonstrated in the case study, followed by the designing, synthesis, and assay and analyzing process, the drug has been produced. However, the discovery process was featured with the scalability of its application through oral stability GI tissue examination and IBD disease model application. However, the translation process has been made by using healthy ice and cyno. In the end, the clinical process was done by giving the drug von some NHVs and the UC patients.
- Both preclinical and clinical trials have been made to assess the productivity and applicability of the drug to mitigate bowel issues. According to Borisa and Bhatt (2017), there is a basic difference between the clinical and preclinical trial and this difference is dependent on the factors on which the trials have been made. In this case, for preclinical trial, the PTG 100 drug was tested on mice and Cyno, and this is denoting that no human trial can be done in this phase. On the other hand, the clinical trial includes the involvement of humans. This has also been reflected in the clinical trial process of PTG 100. In this case, some NHVs and UC patients have been taken into consideration. Only after receiving expected positive results from the preclinical trial, the clinical trial has been made. On completion of the clinical trial successfully, the FDA certification has been obtained depending on its approval and review sharing process.
Question 3
Rational drug design is regarded as the process of the development of medications based on the study of the functions and target of target molecules (Lim et al. 2017). Apart from the development of effective drugs for therapy or treatment, it aims to wait for luck for designing an innovative and new drug or utilizing a shotgun approach for developing a cure.
The process of rational drug design is as follows:
- Identification of a specific target: Identifying a target is the first step in the process of rational drug design. The target molecule can be an enzyme or receptor which is identified based on a particular disease. The technique by which the specific target of biological macromolecules identified is with the help of proteomics (Rosell and Fernández-Recio, 2018). This can be defined as the quantitative and qualitative comparison of proteasomes under various conditions for unrevealing the biological process.
- Characterization of the target: The function and structure of the receptor or enzyme are characterized in the second step. X-ray crystallography is used for generating the design of the target molecule by the X-rays diffractions with the use of crystal. The analysis of the pattern of diffraction provides an electron density map from which the receptor or enzyme structure if a specific molecule is determined (Chegkazi et al. 2018). After the characterization, the design of particular target molecules is stored in a large database such as a databank of protein. Databank of protein contains structures of 52,000 molecules.
- Designing of a molecule for binding to the target: In the third step, a molecule of drug is created, which interacts with the enzyme or receptor beneficially. A lot of significant factors are taken into account while designing the molecule for binding to the target. The molecule of the drug must be selected for binding to the target biological molecule in the body. Useful information about the structure of a molecule and validated target are crucial for tee development if a new drug molecule. The charge and shape of the molecule is an essential factor that should be examined for determining its binding. Binding to any other molecule instead of a specific molecule will result in adverse effects. It has to be taken into consideration if it does not bind to the target, then it will be distributed, absorbed, metabolized and excreted by the body.
Question 4
A clinical trial is a form of research that studies a treatment or test that are given to the people. It shows that quizzes are helpful and safe for the diagnosis of the diseases. A clinical trial is a form of practice of drugs in humans as a form of controlled experiments in humans to determine the effectiveness of a putative treatment. The therapeutic index is defined as the ratio of the production of unwanted effects by the dose and production of desired results by the amount.
The key features of the four phases of clinical trials are:
- Phase I: Phase I help in finding the best dose of a new drug with very few side effects. The new drug is tested in a small group of patients (15-300). The drugs are administered to the patients in low doses to prevent any adverse effects. The safety of the drug is tested in Phase 1. With the prolonged use of the drug, the brain becomes adapted to the drug with the modification of neurotransmitters and reconfiguration of the regions of the brain (Travessa et al. 2017). After the drug is distributed in the body, it is metabolized and enters the bloodstream, which is then carried to the liver. Phase I takes months to years to complete.
- Phase II: Phase II is concerned with the assessment of the safety of the drugs if the drugs work in the patients. Trails of phase II are performed in a group of disease patients (50-500). In this phase, the beneficial effect of the drug is seen in patients, and it provides the first evidence of the efficacy of clinical trials with established doses (Angeletti et al. 2018). The time taken by phase II to complete is 1-2 years. In this phase, Placebo is made to resemble an active medication for functioning as a control in drug testing. This is done to prevent the patients from knowing whether the treatment is active or inactive. Pharmacodynamics and pharmacokinetics of the new drug molecule are tested in this phase.
- Phase III: The main aim of Phase III is the verification of the therapeutic action of new drugs administered in a large number of partners or determining the ratio of risk and benefit (Van Den Berg et al. 2019). Phase III trials begin by comparing a new drug with the standard drug. This kind of practice helps in easing the side effects of each of the medicines and working efficacy of the drug. Phase III trials are conducted in more than 100 to 1000 patients and take 3-5 years to complete the clinical trial. This is the extension of phase II, so a multisite trial is conducted at every hospital. The new drug provides benefits and does not offer harm than any existing treatment.
A crossover or double-blind trial takes place in this palace. A double-blind trial refers to the practice where neither the experimenter nor partners know who is receiving a particular treatment. Crossover trials refer to the longitudinal study where subjects recover sequential treatment. Responses of patients are assessed, and results of the test are analyzed. Inclusion criteria are considered, which refers to the disease stage of the participants or path physiological characteristics.
- Phase IV: The drug is tested in several thousand people allow them to perform research on long-lasting and short-lived side effects and its safety in real life (Sertkaya et al. 2016). If any adverse effects are found are reported and might promote authority for recalling the drugs. Some rare side effects are also found in large groups of people. Doctors can learn whether the drugs are working well and whether it is helpful when applied with other treatments. Informed consent is taken from the patients before participation, and transparency in conduct is maintained.
Question 5
- The selection and identification of targets is an essential aspect of the process of designing and delivery of the drugs. Genetics and cellular approaches are understood for identifying potential target molecules of drugs. The path for identification and validation of the candidate of drug molecules is specific to the strategy of narcotics. The macromolecules have particular sites that should match other molecules. The molecules should be extraneous or endogenous substances. The target should be selected for binding. Otherwise, the efficacy of the drugs will be lost. The structure of bimolecular changes when the molecules bind with the small molecules and changes in design is reversible. Changes in the system of bimolecular cause physiological responses to occur and induce cell regulation or regulation of body status, tissue or organ (Dzobo et al. 2018). The physiological reactions caused by the change in the structure of molecules play an essential role in complex regulation and pose an effect of therapeutics on pathological conditions.
Drug therapy is based on 500 molecules of the target of about 1000 possible targets. Among them, 45 % are G protein-coupled receptors, 115 are factors and hormones, and 28% are enzymes. Proper identification and selection of target and validation help to increase confidence in the association between disease and mark. This helps in exploring the modulation of the target. A proper target must be safe, efficacious, and met commercial and clinical needs should be druggable (Dzobo et al. 2018). A druggable target is always accessible to the putative molecule of the drug. A large or small molecule upon binding elicits a biological response which is measured in vivo and in vitro.
- Selection of essays in the development of drugs and testing of creativity helps in evaluating the impact of the chemical compounds on the molecular, biochemical’s and cellular processes of interest (Cozza, 2017). High-throughput screening of small molecules is used, and probes are generated with the help of such screens. These probes help in exploring protein and function of the cell, biological processes, and impact of chemicals of the environment which are relevant to the diseases and health of humans. These probes become the potential target in therapeutics in the pipeline of the development of drugs.
- Lead compounds are chemical compounds that show desired pharmacological or biological activity that initiates the development of innovative clinical and relevant compounds (Cozza, 2017). These are used as starting points in the designing of drugs for giving new entities of medicines. Strategies for designing drugs are used for improving the pharmacokinetic and pharmacodynamic properties. The resulting compounds from creating drug pass through a series of preclinical studies and become clinically proven if it does not show any adverse impact or toxicity in vivo and in vitro studies. After passing through the clinical trials, they are released into the market as new entities of drug. The sources of lead compounds are chemical libraries, natural products and computational chemistry of medicine. New entities of medications are monitored for safety and released into the market, which is referred to as post-marketing surveillance.
Question 6
- The two provided case studies have highlighted two different types of drugs that are to be used for separate issues. PTG 100 is a drug to control bowel problems, whereas the other one EMA401 is responsible for reducing pain. Clinical development is a systematic process, and Ramos et al. (2019) defined four specific stages of the first phase, Phase 0 is to be done among people in which a very small amount of a drug is to be delivered to a smaller volume of people. The second phase is to incorporate a comparatively higher amount of drugs within a higher volume of people. In phase II, that is in the third phase, both the volume of drug and patients are to be increased. The fourth that is Phase III is responsible for conducting the process by including the highest number of participants with the approach die of drugs that can help them to solve a problem.
- In the case of EMA401, three phases of a clinical trial have been performed, and the first case study is evidencing it. In the case of the other drug, similarly, these three phases have been eaten. As described in the second case study, phase 1 included about 20-80 NHVs, and phase II included about 10-300 patients than the third stage as conducted by giving them the drug in an adequate amount. For this, the total number of patients was 1000-3000 patients. In the case of EMA401, the trials have been done on the volunteers only whether the other one included not only NHVs but also the patients. As demonstrated by Thomford et al. (2018), in case of clinical trials, any drug manufacturing entity can conduct this phase over either some volunteers or some patients. However, the implication of a drug on the patients through this trial is the most significant aspect to assess the applicability of the product. Henceforth, the relevance of PTG 100 has been judged in a more obvious and justifiable way compared to the other one.
References
Angeletti, F., Chatzigiannakis, I. and Vitaletti, A., 2018. Towards an architecture to guarantee both data privacy and utility in the first phases of digital clinical trials. Sensors, 18(12), p.4175.
Borisa, A.C. and Bhatt, H.G., 2017. A comprehensive review on Aurora kinase: Small molecule inhibitors and clinical trial studies. European journal of medicinal chemistry, 140, pp.1-19.
Cozza, G., 2017. The development of CK2 inhibitors: From traditional pharmacology to in silico rational drug design. Pharmaceuticals, 10(1), p.26.
Lim, S., Othman, R., Yusof, R. and Heh, C., 2017. Rational drug discovery of HCV helicase inhibitor: improved docking accuracy with multiple seedings of Autodock Vina and in situ minimization. Curr Comput Aided Drug Des, 31, pp.160-9.
Rosell, M. and Fernández-Recio, J., 2018. Hot-spot analysis for drug discovery targeting protein-protein interactions. Expert Opinion on Drug Discovery, 13(4), pp.327-338.
Sertkaya, A., Wong, H.H., Jessup, A. and Beleche, T., 2016. Key cost drivers of pharmaceutical clinical trials in the United States. Clinical Trials, 13(2), pp.117-126.
Thomford, N.E., Senthebane, D.A., Rowe, A., Munro, D., Seele, P., Maori, A., and Dzobo, K., 2018. Natural products for drug discovery in the 21st century: innovations for novel drug discovery. International journal of molecular sciences, 19(6), p.1578.
Travessa, A.M., Rodrigues, F.B., Mestre, T.A. and Ferreira, J.J., 2017. Fifteen years of clinical trials in Huntington’s disease: a very low clinical drug development success rate. Journal of Huntington’s disease, 6(2), pp.157-163.
