Protein Engineering, Drug Delivery and Regulatory Aspects
A.Y. 2024/2025
Learning objectives
The course aims to explore the development, formulation, manufacturing and marketing of Biotechnological and Advanced Therapy Medicinal Products. The course is divided in three modules covering: (i) the key-concepts and tools to understand the molecular strategies behind the rational design of proteins having new functions or activities, (ii) the biopharmaceutic aspects and the design of drug delivery systems intended for the main routes of administration, and (iii) the regulatory aspects related to their manufacturing and marketing.
Expected learning outcomes
At the end of the course, students will have acquired the knowledge and methods enabling them to study and think, critically and independently, about different issues of medicines for human use, with reference to biotechnological medicinal products. The students will learn how to rationally design, or modify, protein structures and activity. They will know the basis on how to approach this problem, and to propose solutions for implementing and improving protein functions according to a specifically requested need. They will know how to edit the genome of cells and even organisms with the aim of potentially crate new GMOs. Also, they will know how to set-up experiments for the high-scale production of proteins and characterize them post-production.
Based on the physico-chemical features of an active ingredient and the selected parenteral route of administration, the student will be able to choose the optimal technological approach to the design and manufacture pharmaceutical dose forms satisfying the criteria of quality, safety and efficacy.
Moreover, students will be able to recognise what is, and what is not, a medicinal product, and outline the steps required to place a medicinal product on the market, with particular reference to biotechnological and advanced therapy medicinal products. They are expected to be able to retrieve and understand the relevant parts of EU legislative acts.
Students will be also able to correctly understand the questions in the learning verification phase, to know how to elaborate and connect the knowledge acquired in all the didactics units of the course.
Based on the physico-chemical features of an active ingredient and the selected parenteral route of administration, the student will be able to choose the optimal technological approach to the design and manufacture pharmaceutical dose forms satisfying the criteria of quality, safety and efficacy.
Moreover, students will be able to recognise what is, and what is not, a medicinal product, and outline the steps required to place a medicinal product on the market, with particular reference to biotechnological and advanced therapy medicinal products. They are expected to be able to retrieve and understand the relevant parts of EU legislative acts.
Students will be also able to correctly understand the questions in the learning verification phase, to know how to elaborate and connect the knowledge acquired in all the didactics units of the course.
Lesson period: year
Assessment methods: Esame
Assessment result: voto verbalizzato in trentesimi
Single course
This course can be attended as a single course.
Course syllabus and organization
Single session
Responsible
Lesson period
year
Course syllabus
The teaching unit on "Biopharmaceutics and drug delivery" aims to examine the basic principles of the main routes of administration and to discuss their importance in designing a biotecnological medicinal product.
· In-depth analysis of pharmacokinetics and biopharmaceutical aspects of the main routes of administration.
· Parenteral dosage forms: formulative approaches
. Lyophilization and spray-drying
. Quality controls on parenteral dosage forms
· Stability of a medicinal product.
. Sterility and sterilization methods: heat sterilization, moist sterilization, irradiation and filtration
· Clean rooms and aseptic preparation.
. Water for pharmaceutical purposes: classification, requirements, production methods.
The lab activities will deal with the formulation and characterization of dispersed systems.
The teaching unit on "Regulatory aspects" (RA) focuses on the regulatory issues related to the manufacturing and marketing of medicinal products, with brief remarks on medical devices.
· EU law-making bodies and the European Medicines Agency (EMA)
· EU Pharmaceutical Law: aims and scope of Directive 2001/83/CE and Regulation (EU) No. 726/2004
· Definition of medicinal product: it's rationale and how it is meant to protect citizens' health (ref. Directive 2001/83/CE).
· The Manufacturing Authorisation of medicinal products: when it is necessary, how it is obtained (ref. Directive 2001/83/CE). Good Manufacturing Practice (GMP).
· The Marketing Authorisation (MA) of medicinal products. The 4 procedures for applying for a MA (ref. Directive 2001/83/CE and Regulation CE no. 726/2004).
· The dossier in a MA application and the Common Technical Document (CTD). Full, partial, simplified dossiers (ref. Directive 2001/83/CE). European Public Assessment Reports (EPARs). Variations to the terms of the Marketing Authorisation.
· Advanced Therapy Medicinal Products (ATMPs): regulatory aspects.
· Conditional MA and Authorisation in exceptional circumstances.
· Orphan medicinal products.
· The Paediatric Investigation Plan (PIP).
· Summary of Product's Characteristics, Labelling and Package Leaflet of medicinal products.
· Pharmacovigilance.
· Medical Devices: definition, classification, placing on the market.
· Intellectual Property Rights.
· Market access. Health economic Evaluation.
The teaching unit on Protein Engineering is characterized by 3 distinct sections. The first will revisit some basic concepts of biochemistry and molecular biology with a focus on the engineering aspect, and will include: protein nature and structure, transcription, protein production, protein maturation and modifications, plasmid production and expression, protein activity, restriction enzyme and cloning libraries. The second section will introduce some of the most used methodologies and techniques in protein engineering and will include: PCR, qPCR, direct evolution, random mutagenesis and error prone PCR, gene editing (CRISPR/Cas9 and TALEN technology), phage display for protein and ligand discovery, principles of optogenetics. The last section will list the most important protein characterization techniques like: 2D gel electrophoresis (also in DIGE modality), fluorescence microscopy (in confocal modality), Western Blot, immunoprecipitation techniques and immunofluorescence.
· In-depth analysis of pharmacokinetics and biopharmaceutical aspects of the main routes of administration.
· Parenteral dosage forms: formulative approaches
. Lyophilization and spray-drying
. Quality controls on parenteral dosage forms
· Stability of a medicinal product.
. Sterility and sterilization methods: heat sterilization, moist sterilization, irradiation and filtration
· Clean rooms and aseptic preparation.
. Water for pharmaceutical purposes: classification, requirements, production methods.
The lab activities will deal with the formulation and characterization of dispersed systems.
The teaching unit on "Regulatory aspects" (RA) focuses on the regulatory issues related to the manufacturing and marketing of medicinal products, with brief remarks on medical devices.
· EU law-making bodies and the European Medicines Agency (EMA)
· EU Pharmaceutical Law: aims and scope of Directive 2001/83/CE and Regulation (EU) No. 726/2004
· Definition of medicinal product: it's rationale and how it is meant to protect citizens' health (ref. Directive 2001/83/CE).
· The Manufacturing Authorisation of medicinal products: when it is necessary, how it is obtained (ref. Directive 2001/83/CE). Good Manufacturing Practice (GMP).
· The Marketing Authorisation (MA) of medicinal products. The 4 procedures for applying for a MA (ref. Directive 2001/83/CE and Regulation CE no. 726/2004).
· The dossier in a MA application and the Common Technical Document (CTD). Full, partial, simplified dossiers (ref. Directive 2001/83/CE). European Public Assessment Reports (EPARs). Variations to the terms of the Marketing Authorisation.
· Advanced Therapy Medicinal Products (ATMPs): regulatory aspects.
· Conditional MA and Authorisation in exceptional circumstances.
· Orphan medicinal products.
· The Paediatric Investigation Plan (PIP).
· Summary of Product's Characteristics, Labelling and Package Leaflet of medicinal products.
· Pharmacovigilance.
· Medical Devices: definition, classification, placing on the market.
· Intellectual Property Rights.
· Market access. Health economic Evaluation.
The teaching unit on Protein Engineering is characterized by 3 distinct sections. The first will revisit some basic concepts of biochemistry and molecular biology with a focus on the engineering aspect, and will include: protein nature and structure, transcription, protein production, protein maturation and modifications, plasmid production and expression, protein activity, restriction enzyme and cloning libraries. The second section will introduce some of the most used methodologies and techniques in protein engineering and will include: PCR, qPCR, direct evolution, random mutagenesis and error prone PCR, gene editing (CRISPR/Cas9 and TALEN technology), phage display for protein and ligand discovery, principles of optogenetics. The last section will list the most important protein characterization techniques like: 2D gel electrophoresis (also in DIGE modality), fluorescence microscopy (in confocal modality), Western Blot, immunoprecipitation techniques and immunofluorescence.
Prerequisites for admission
Prospective students are required to be familiar with the basic concepts of inorganic and organic chemistry, biochemistry and molecular biology as well as general knowledge on physiology. These topics are generally provided within courses at the Bachelor Degree.
Teaching methods
Lectures and practical classes in laboratory.
Attendance at lectures is recommended; attendance at practical classes and lab activities is compulsory.
During the "Biopharmaceutics and drug delivery" and "Regulatory aspects" (DD+RA) teaching units, different tasks (e.g. group projects and case studies) will be assigned to students or groups of students as an aid in understanding fundamental topics.
Attendance at lectures is recommended; attendance at practical classes and lab activities is compulsory.
During the "Biopharmaceutics and drug delivery" and "Regulatory aspects" (DD+RA) teaching units, different tasks (e.g. group projects and case studies) will be assigned to students or groups of students as an aid in understanding fundamental topics.
Teaching Resources
Lecture handouts will be available on the ARIEL website.
Aulton's Pharmaceutics, The Design and Manufacture of Medicines - Edited by Michael E. Aulton and Kevin M.G. Taylor
Pharmaceutical Biotechnology available at https://link.springer.com/book/10.1007/978-3-030-00710-2 (after loggin in at UNIMI online library)
Relevant guidelines for the Regulatory aspects are listed on the ARIEL website (in the 'Course information' section).
Shorthose S (Ed.). Guide to EU pharmaceutical regulatory law, seventh edition (2017). Kluwer Law International. Available for free on UNIMI's digital Library, direct link: https://unimi.primo.exlibrisgroup.com/discovery/fulldisplay?docid=alma991017345717906031&c ontext=L&vid=39UMI_INST:VU1&lang=it&search_scope=MyInst_and_CI&adaptor=Local%20Searc h%20Engine&tab=Everything&query=any,contains,pharmaceutical%20law
For the protein engineering, the students are encouraged to read Lewin's GENES XII 12th Edition by J.E. Krebs, E.S. Goldstein, S.T. Kilpatrick (Author) (earlier editions are also suitable) and Molecular Biotechnology: Principles and Applications of Recombinant DNA, Fifth Edition by B.R. Glick and J.J. Pasternak
Aulton's Pharmaceutics, The Design and Manufacture of Medicines - Edited by Michael E. Aulton and Kevin M.G. Taylor
Pharmaceutical Biotechnology available at https://link.springer.com/book/10.1007/978-3-030-00710-2 (after loggin in at UNIMI online library)
Relevant guidelines for the Regulatory aspects are listed on the ARIEL website (in the 'Course information' section).
Shorthose S (Ed.). Guide to EU pharmaceutical regulatory law, seventh edition (2017). Kluwer Law International. Available for free on UNIMI's digital Library, direct link: https://unimi.primo.exlibrisgroup.com/discovery/fulldisplay?docid=alma991017345717906031&c ontext=L&vid=39UMI_INST:VU1&lang=it&search_scope=MyInst_and_CI&adaptor=Local%20Searc h%20Engine&tab=Everything&query=any,contains,pharmaceutical%20law
For the protein engineering, the students are encouraged to read Lewin's GENES XII 12th Edition by J.E. Krebs, E.S. Goldstein, S.T. Kilpatrick (Author) (earlier editions are also suitable) and Molecular Biotechnology: Principles and Applications of Recombinant DNA, Fifth Edition by B.R. Glick and J.J. Pasternak
Assessment methods and Criteria
The evaluation is based on the ability to answer theoretical and practical questions on topics related to the lessons, to frame them in a wider scenario and to establish connections among them.
The final exam consists in oral exam for all moduli. Regarding the "Biopharmaceutics and drug delivery" (DD modulus) and "Regulatory aspects"(RA modulus), students should be able to clearly describe the design of drug delivery systems intended for parenteral administration: from the formulation design, process development and quality controls to the regulatory aspects of manufacturing, placing on the market and post-marketing surveillance. Students will be asked 3 questions on the basic concepts explained during the lectures and 1 question on lab activity.
The mark (66% final mark) can be increased by 10% when students successfully complete all the activities proposed in both DD and RA modulus. As an example, a 10-min presentation will be prepared by students clustered in small groups on given topics on "Biopharmaceutics and drug delivery" and "Regulatory aspects".
Regarding the Protein Engineering section (34% final mark), students will be asked 3 theoretical questions on the basic concepts explained during the lectures and 1 question will assess the logic and problem-solving skills of the candidates. The exam will last for about 30 minutes.
Assessment will be based on the degree of knowledge of the course topics, property of language, critical thinking skills and capability to organize the discourse in a logical manner.
The exam can be finalized only when all parts are passed.
The final exam consists in oral exam for all moduli. Regarding the "Biopharmaceutics and drug delivery" (DD modulus) and "Regulatory aspects"(RA modulus), students should be able to clearly describe the design of drug delivery systems intended for parenteral administration: from the formulation design, process development and quality controls to the regulatory aspects of manufacturing, placing on the market and post-marketing surveillance. Students will be asked 3 questions on the basic concepts explained during the lectures and 1 question on lab activity.
The mark (66% final mark) can be increased by 10% when students successfully complete all the activities proposed in both DD and RA modulus. As an example, a 10-min presentation will be prepared by students clustered in small groups on given topics on "Biopharmaceutics and drug delivery" and "Regulatory aspects".
Regarding the Protein Engineering section (34% final mark), students will be asked 3 theoretical questions on the basic concepts explained during the lectures and 1 question will assess the logic and problem-solving skills of the candidates. The exam will last for about 30 minutes.
Assessment will be based on the degree of knowledge of the course topics, property of language, critical thinking skills and capability to organize the discourse in a logical manner.
The exam can be finalized only when all parts are passed.
CHIM/08 - PHARMACEUTICAL CHEMISTRY - University credits: 4
CHIM/09 - PHARMACEUTICAL AND TECHNOLOGICAL APPLICATIONS OF CHEMISTRY - University credits: 7
CHIM/09 - PHARMACEUTICAL AND TECHNOLOGICAL APPLICATIONS OF CHEMISTRY - University credits: 7
Single bench laboratory practical: 16 hours
Lessons: 80 hours
Lessons: 80 hours
Educational website(s)
Professor(s)
Reception:
by appointment
Dept. Pharmaceutica Sciences - via G. Colombo, 71