The Lifecycle of Drugs from Development to Approval and Market Launch

Robert Dream - Managing Director, HDR Company LLC

The Future of Technology and Innovation in Manufacturing

Industry 4.0 technologies and new innovative materials will disrupt the entire manufacturing value chain by enabling digital factories and smart supply chains. The future of drug substances and drug products manufacturing lies with newer innovations including ATMPs, synthetic biology (SynBio) and other innovations that are in progress and promising treatments for individuals and group of patients. By 2030, SynBio has the possibility to be at the heart of bioeconomy and will have unlocked a range of new products and concepts through new biological systems or re-designing existing ones for useful purposes.

Gene Therapy Vectors for in- or ex-vivo Applications

These vectors are utilized across multiple in-vivo and ex-vivo applications. Viral vectors are an advanced tool of drug developers to deliver genetic information into a host cell paving the way for therapeutic potential previously unseen. Energized by the curative potential of these modalities and a tailwind of commercial success, there is a current intense focus in the market on gene therapy development and manufacturing. Organizations with gene therapy technology services are set up to service developers in a variety of production methodologies. To simplify tech transfer and minimize time-to-market for therapy, these organizations offer early-to-late-stage clinical- and commercial-manufacturing capability, providing seamless end-to-end project support and small- to large-scale gene therapy production. Gene therapy experience includes but is not limited to the following:

• Adenovirus (Ad)

• Adeno-Associated Virus (AAV)

• Herpes Simplex Virus (HSV)

• Plasmid transfection processes

• Helper virus infection/ transduction processes

• Producer cell line systems

• Platform manufacturing unit operations

• Platform analytical methods for quality control

European Medicine Agency Regulation for Advance Therapies

Advanced therapy medicinal products (ATMPs) are designed to ensure the free movement of these medicines within the European Union (EU), to facilitate their access to the EU market, and to foster the competitiveness of bio-pharmaceutical companies in the field that operate in the European Union market, while guaranteeing the highest level of health protection for patients, Figure 1.

Regulation (EC) No 1394/2007⁸ provides the overall framework on ATMPs. The regulation establishes the Committee for Advanced Therapies (CAT) as a multidisciplinary committee, whose primary responsibility is to assess the quality, safety and efficacy of ATMPs, and to follow scientific developments in the field. As of June 2009, the CAT issues scientific recommendations on ATMPs classification, Figure 2.

ATMP Classification

The CAT issues scientific recommendations on ATMPs classification in accordance with Articles 17 of the ATMP Regulation, Figure 3.

CAT recommendations are based on definitions laid down in EU legislative texts;

• Regulation (EC) No 1394/2007⁸ on ATMPs provides the definitions of ‘tissue-engineering product’ and combined ‘ATMP’.
• Part IV of Annex I to Directive 2001/83/ EC⁶ provides the definitions for ‘gene-therapy medicinal product’ and ‘somatic cell-therapy medicinal product.

Certification of quality and non-clinical data for micro-, small- and medium-sized enterprises (SMEs)

This procedure was introduced in accordance with Article 18 of the ATMP Regulation and in accordance with Commission Regulation (EC)

No 668/2009¹⁶ implementing Regulation (EC) No 1394/2007 with regard to the evaluation and certification of quality and non-clinical data relating to ATMPs developed by SMEs.

EU legislative framework applicable to ATMPs:

Regulation (EC) No 1394/2007, which provides the overall framework for ATMPs, amended the following legislation with regards to ATMPs:

• Directive 2001/83/EC (consolidated version 16/11/2012) of November 2001 relating to medicinal products for human use;
• Regulation (EC) No 726/2004¹² (consolidated version 5/6/2013) of March 2004 on procedures for the authorization and supervision of medicines for human and veterinary use and establishing the European Medicines Agency.

In addition, Commission Directive 2009/120/EC⁷ (amending Directive 2001/83/EC) updated the definitions and detailed scientific and technical requirements for gene-therapy medicinal products and somatic cell-therapy medicinal products. It also established detailed scientific and technical requirements for tissue-engineered products, as well as for ATMPs containing devices and combined ATMPs.

 Clinical Trials Directive and Clinical Trials Regulation

Companies developing ATMPs must ensure that the standards of good clinical practice (GCP) are applied when carrying out clinical trial studies:

• Directive 2001/20/EC of April 2001 lays down approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicines for human use.
• In April 2014 the new Regulation EU No 536/2014 on clinical trials on medicinal products for human use, repealing Directive 2001/20/EC, was adopted. The Regulation entered into force on 16 June 2014 was applied no earlier than 28 May 2016.

Good Clinical Practice and Good Manufacturing Practice

Companies developing ATMPs must be aware of legislation applicable to different stages of the process, including requirements on GCP and good manufacturing practice (GMP);

• Commission Directive 2005/28/EC of April 2005 laying down principles and detailed guidelines for GCP as regards to investigational medicines for human use, as well as the requirements for authorization of the manufacturing or importation of such products.
• Commission Directive 2003/94/EC of October 2003 laying down the principles and guidelines of GMP in respect of medicines for human use and investigational medicines for human use.

Pharmacovigilance Legislation

A package of legislation, first adopted in 2010 and further supplemented in 2012, lays down provisions to reinforce pharmacovigilance in the EU. This framework is applicable to all medicines, including ATMPs:

• Regulation (EU) No 1235/2010 and Regulation (EU) No. 1027/2012 amending, as regards pharmacovigilance, Regulation (EC) No 726/2004.
• Directive 2010/84/EU and Directive 2012/26/EU amending, as regards pharmacovigilance, Directive 2001/83/EC.
• Commission Implementing Regulation No 520/2012, which concerns operational aspects of implementing the new legislation.

Tissues and Cells Directive and Traceability

If tissues and cells are being used as starting materials in a medicinal product, applicants should consult:

• Directive 2004/23/EC, also known as the European Tissues and Cells Directive, covering standards for donation, procurement and testing, processing, preservation, storage and distribution of human tissues and cells, as well as its technical implementing directives, Figure 5.
• Directive 2006/17/EC, the First Technical Directive, covering certain technical requirements for the donation, procurement and testing of human tissues and cells.

» Directive 2006/86/EC, the Second Technical Directive, covering standards for traceability, notifi cation of serious adverse reactions and events, and requirements for coding processing, preservation, storage and distribution of human tissues and cells.

» Directive 2015/565, amending Directive 2006/86/EC, as regards certain technical requirements for the coding of human tissues and cells.

» Directive 2015/566, as regards the procedures for verifying the equivalent standards of quality and safety of imported tissues and cells.

Paediatric Regulation

Provisions of the Paediatric Regulation are applicable for ATMPs including the obligation to include the results of studies as described in an agreed Paediatric investigation plan, unless the medicine is exempt because of a deferral or waiver.

The Paediatric Regulation is comprised of:

• Regulation (EC) No 1901/2006 of December 2006 on medicinal products for Paediatric use.
• Regulation (EC) No 1902/2006, an amending regulation in which changes to the original text were introduced relating to decision procedures for the European Commission.

Variations Regulation

Commission Regulation (EC) No 1234/2008 of November 2008 (the Variations Regulation) lays down provisions concerning the examination of variations to the terms of all marketing authorizations for human and veterinary medicines.

Personal Data Protection

Directive 95/46/EC is the reference text, at European level, on the protection of personal data. It sets up a regulatory framework which seeks to strike a balance between a high level of protection for the privacy of individuals and the free movement of personal data within the EU.

Active Substance Master File

The Active Substance Master File (ASMF) procedure, formerly known as European Substance Master File (ESMF) procedure is used when Active Substance Manufacture (ASM) is not the applicant for a product marketing authorization.³ The main objective of the ASMF procedure is to protect the valuable knowledge on manufacturing the active substance, while at the same time allowing the applicant marketing authorization (MA) holder to take full responsibility for the medicinal product and the quality and quality control of the active substance. An ASMF is a way of providing detailed confidential information about manufacturing of active substance to national competent authority (NCA), EMA to demonstrate that the quality of the active substance is adequately controlled by the specification proposed by applicant. An ASMF is only used for the active substance to provide confidential information on manufacture of the active substance. The CMSs information on drug product and excipients can be provided in dossier application. NCA/EMA have full access to complete the information that is necessary for the evaluation of suitability of the use of the active substance in the medicinal product. An ASMF can only be submitted to NCA/EMA in support of a marketing authorization application (MAA) or marketing authorization variation.⁴ ASMF procedure is generally used when there is a matter of confidential between ASM an applicant/MA holder. It is not mandatory to present information on the active substance in the form of an ASMF. The information may form part of the application for authorization to place a medicinal product on the market.³ The applicant MAA has several options which with the ASMF procedure can be used while seeking approval to market a new product in Europe. There are four procedures as given below:

• Centralized procedure
• Decentralized procedure
• Mutual recognition procedure
• National authorization procedure

The ASMF procedure can be used for the following active substances, including herbal active substance preparation i.e.:

• New active substances
• Existing active substances not included in the European Pharmacopoeia or the pharmacopoeia of the EU member state
• Pharmacopoeia active substances not included in the European Pharmacopoeia or the pharmacopoeia of the EU member state

ATMP Manufacturing and Enabling Effective Regulatory Submissions

The development of a medicinal product involves a number of discrete stages designed to demonstrate the product’s quality, safety and efficacy. Typically, product development begins on completion of pre-clinical PoC (proof-of-concept) studies in in-vitro or in-vivo models of disease (the discovery phase). The developmental medicinal product would then be progressed into nonclinical studies to demonstrate safety and provide an initial indication of mode of action supportive of clinical trials in patients. If a clinical trial application (CTA) is approved based on the nonclinical data, the investigational medicinal product (IMP) would first be tested for general safety in Phase I (first-in-human) trials, next for common technical document (CTD), related safety and PoC of the therapeutic mechanism (initial efficacy) in Phase II trials, and then for confirmation of efficacy in Phase III (pivotal) trials. Data from Phase III clinical trials are used to support a BLA (US-FDA) and or MAA (EU-EMA) submittal to the regulatory authorities. If MA (marketing authorization) is granted, post-approval safety data are required to be obtained through Phase IV clinical trials to maintain the MA. Note, however, that it is not always possible to perform sequential Phase I, II, and III clinical trials for ATMPs, and sometimes the pre-pivotal trials follow a combined Phase I/II approach. In parallel with the nonclinical studies and clinical trials, manufacturing process development is undertaken to characterize the quality attributes of the IMP that correlate with safety and efficacy, Figure 6.

During early development, a number of characterization and analytical assays should be implemented to identify those assays relevant for a bases of the proposed commercial process on a BLA (US-FDA) or MAA (EU-EMA), and the selected assays should therefore be fully validated by the end of Phase III at the latest. Post-MA, any changes to the manufacturing process, which may have an impact on the quality of the medicinal product, will need to be submitted to the FDA and or EMA as variations to the MA for review and approval for the purposes of maintaining the MA. The effect of the changes on quality compared to the approved product will need to be demonstrated through comparability studies. Additional comparability studies at the level of safety and efficacy may also be necessary.

The development of a manufacturing process for a medicinal product (including ATMPs) can be considered to involve, first, manufacture of the drug substance from the starting materials and raw materials, and second, manufacture of the drug product from the drug substance and raw materials and/or excipients. The starting materials for ATMP manufacture include donated cells or tissues, banked cell lines and banked viral vectors expressing cloned genes (other types of vectors may also be used). Raw materials may include cell culture medium, serum and cell dissociation agents, while excipients (non-drug substance of the final product) may include stabilizers or cryopreservatives. The drug substance is the active substance (active pharmaceutical ingredient) responsible for a medicinal product’s therapeutic effect, and the drug product is the drug substance in its final formulation for administration to patients. The drug substance and drug product should be fully characterized during the development phase using appropriate analytical methods to identify the product-specific quality attributes. The critical quality attributes³ that correlate with safety and efficacy inpatients are typically used to define a release specification and stability profile for drug substance and/or drug product.² Some of the quality attributes included in the release specification and stability profile e.g., potency, product-related impurities) will be defined and justified as ranges based on data obtained during process and product characterization. The steps of the manufacturing process should be controlled through process parameters and in-process controls to ensure that the specifications can be achieved. Together, all activities involved in manufacturing process development: e.g.; inputs, process steps, analytical methods, characterization, outputs, and validation are referred to as CMC (chemistry, manufacturing and controls), Figure 7.

Proof of Concept (PoC) - proof of concept is an exercise in which work is focused on determining whether an idea can be turned into a reality. A proof of concept is meant to determine the feasibility of the idea or to verify that the idea will function as envisioned.

Project Management Office

The Project Management Office (PMO) is the backbone of an organization as they are the ones who manage all the processes smoothly, create plans, and ensure that they are followed and achieved on time.

PMO is a team that has the responsibility to maintain benchmarks for Project Management. They have to ensure that all the processes, operations, quality of deliverables are managed efficiently.

PMO is required where the organization has a number of projects that are running simultaneously. PMO helps to streamline the process, helps on project estimation and planning, defines goals and objectives, and improve the quality of the project. The lack of any of the stages can lead to failure of the project, that’s why PMO plays an important role in the project’s success.

The organization’s Management cannot track the day-to-day progress of the projects as they have other responsibilities to fulfill.

Project Managers handle the projects on the broader level. PMO ensures that all the projects are running on track and as planned. They ensure to deliver the projects on time and highlight the hurdles at the earliest to get them sorted on time. Most of the organizations opt for Project management tools such as Gantt Charts, Pert Chart, etc. which makes it easy to track the progress of the project. The planning outline is as follows:

• Team accountability meetings
• Establish schedule and cost
• Develop risk log
• Create vendor and service providers management plan
• Develop communication plan
• Guide and assist project lead(s) in assessment of stakeholder communication and training.

References

1. EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines; Part IV - GMP requirements for Advanced Therapy Medicinal Products, Date for coming into operation ATMP manufacturers should comply with these Guidelines no later than 22 May 2018. These Guidelines are specific to ATMPs. Other documents developing GMP requirements for medicinal products which are contained in Volume 4 are not applicable to ATMPs, unless specific reference thereto is made in these Guidelines.
2. CH Q11 Development and manufacture of drug substances (chemical entities and biotechnological/biological entities) - Scientific guideline, Step 5, Date for coming into effect November 2012.
3. ICH Q12 Technical and regulatory considerations for pharmaceutical product lifecycle management - Scientific guideline, Final adoption by CHMP, 30 January 2020.
4. Guidance Document, ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, Guidance for Industry, FDA, MAY 2021.
5. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices.
6. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use.
7. Commission Directive 2009/120/EC of 14 September 2009 amending Directive 2001/83/ EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products (Text with EEA relevance).
8. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (Text with EEA relevance).
9. Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells.
10. Commission Directive 2006/17/EC of 8 February 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells (Text with EEA relevance).
11. COMMISSION DIRECTIVE 2006/86/EC of 24 October 2006 implementing Directive 2004/23/ EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells.
12. Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (Text with EEA relevance).
13. Eudralex Volume 4 - EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use.
14. Regulation (EC) No 1394/2007 on ATMPs provides the definitions of ‘tissue-engineering product’ and combined ‘ATMP’.
15. Part IV of Annex I to Directive 2001/83/EC provides the definitions for ‘gene-therapy medicinal product’ and ‘somatic cell-therapy medicinal product’.
16. COMMISSION REGULATION (EC) No 668/2009 of 24 July 2009 implementing Regulation (EC) No 1394/2007 of the European Parliament and of the Council with regard to the evaluation and certification of quality and non-clinical data relating to advanced therapy medicinal products developed by micro, small and medium-sized enterprises.

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