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Drug Regulatory Affairs

Discover the complex world of drug product regulatory affairs.
In the global environment marketing authorization procedures represent an enormous challenge. We provide advice in all areas of a marketing authorization throughout the lifecycle of a product and assist in the development of product-specific regulatory strategies in the field of small molecule and biotechnological products within the EU. Strategies for market applications in other regions in the world, namely the United States of America (USA), Canada and Japan will be prepared by Phact in cooperation with its regional partners.

Licensing procedures for pharmaceuticals have become more and more complex. Regionally differing and rapidly changing regulatory requirements and timelines make the regulatory market application in countries around the world a highly complex project involving experts from various departments and locations wide apart.

Against this backdrop the selection of an optimal product-specific submission strategy turns into a challenge. In particular for application procedures involving the European Union (EU) where centralized and decentralized (national) procedures with and without mutual recognition between the member states are possible and the right licensing strategy can save many resources.

Phact supports its clients in developing product-specific regulatory strategies for full or abbreviated application projects in the field of small molecule and biotech pharmaceutical products within the EU and assesses the most suitable route for submissions. Strategies for market applications in other regions in the world, namely the United States of America (USA), Canada and Japan will be prepared by Phact in cooperation with its regional partners.

Quality by Design (QbD) is “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management” (ICH Q8 (R2)).

QbD is the concept to built-in (to “design”) quality into a medicinal drug product or drug substance. It has replaced the traditional empirical “quality-by-testing” philosophy and requires a science and risk based pharmaceutical development. QbD includes a comprehensive understanding of the relationship between formulation and process-related attributes and their variables to the medicinal drug product performance and it helps to establish appropriate ranges of a multivariate design space for a drug substance or drug (medicinal) product. The resulting control strategies are based on a profound understanding of the product and the process.

This systematic approach utilises tools like prior knowledge, quality risk management (QRM), Design of Experiments (DoE) and Process Analytical Technology (PAT).

Phact’s expertise in this area helps to smoothly implement and file the QbD concepts during the period before the submission or at a later stage (post-approval change).

In general, any post-approval changes (PACs) to the once approved technical (CTD) dossier must be reported or approved by the licensing authority/ies. Post-approval changes are usually classified as minor, moderate and major – depending on the level of risk to public health and their possible impact on quality, safety, or efficacy of the product in question.

Regionally differing procedures and requirements must be considered before a proposed change request will be accepted by the licensing authority/ies and hence before the change can be implemented. Managing the post-approval regulatory change process for medicinal drug products at global level is complex and time consuming.

Other substantial differences that need to be managed are the varying timelines for the implementation of the proposed change and the administrative documentation as well as the varying requests for supporting data. These factors can result in a major hurdle for a marketing authorization holder.

Phact has accompanied many post-approval changes and develops product-specific strategies for filing post-approval changes within the EU. In addition Phact assesses the most suitable route for submission of a post-approval change. Strategies for market applications in other regions in the world, namely the United States of America (USA), Canada and Japan are prepared by Phact in cooperation with its regional partners.

Some years ago the transfer of regulatory submissions from applicant to regulators changed from the paper-based Common Technical Document (CTD) to the electronic transmission of the data in the ICH specified format of an electronic Common Technical Document (eCTD). All major authorities are following this approach by now and some of them have built up gateways that enable an electronic transfer of the eCTD from applicant to authority via the internet.

The eCTD is based on “Extensible Mark-up Language” (XML) technology. The data and document files that form part of a submission are mostly provided in a Portable Document Format (PDF) and are embedded into the XML backbone of the eCTD. The ICH eCTD specification defines the criteria that make an e-submission technically valid.

The challenge of eCTD submissions are regionally differing specification criteria for eCTD Module 1, additional requirements (such as Study Tagging Files for US-eCTDs) and different eCTD validation criteria. All these aspects need to be considered before an eCTD can be sent out.

An eCTD submission is a complex project requiring a suitable ICT infrastructure, related eCTD “e-skills” as well as project management knowledge and (document) workflow processes capabilities.

Phact is specialized in eCTD publishing and provides all necessary prerequisites to enable a smooth and successful eCTD submission. It creates and submits eCTDs in compliance with regionally differing requirements worldwide and supports its clients with optimizing their e-submission projects.

A technology transfer needs to be treated with great sensitivity, whether it is a pre- or post-approval, whether it is within a company or between independent enterprises. It needs to be carefully planned and managed. Authorities are alerted about failed technology transfers and request meticulous information from the applicant.

In addition to the technical details of a manufacturing process and/or analytical procedure(s) that are going to be transferred, the regulatory responsibilities of both parties involved (sending and receiving unit) need to be clearly defined and followed.

This includes the identification of the expected regulatory submission documents and which party will be responsible for preparation and submission of those documents. For a successful and efficient technology transfer, planning – including any regulatory activities – should begin at a very early stage.

Phact has supported several technology transfers with its regulatory advice, has accompanied related scientific advice meetings with the authorities and has compiled the submission-ready technical documentation of a technology transfer as well as leading the entire technology transfer process.

High-quality documentation is a key factor for a successful submission project. Well-structured and comprehensible technical information that is presented in scientific style and format are prerequisites to enable a smooth assessment by the authorities.

Furthermore, and as required by the relevant national eCTD validation criteria, the resulting Portable Document Format (PDF) files must be navigable and provide specific PDF-specific settings and properties when incorporated into an eCTD.

Phact has great competence in the creation of high quality technical documentation as regards to format and content.

The Drug Master File (DMF) system allows for the submission of confidential quality-related information directly from the drug substance (1) manufacturer to the licensing authority/ies. DMF systems exist in at least all major industrial nations, although regional differences concerning applicability and procedural aspects exist.

The EU Active Substance Master File (ASMF) procedure as laid down in EU Directive 2001/83/EC (2) is limited to so-called “well-defined” active substances and follows an “open-and-closed part” concept. Specific confidential information (e.g. detailed description of the manufacturing and control process) is provided in the ‘closed’ (restricted) part of an ASMF that is submitted to the competent authority/authorities directly by the API manufacturer. Less sensitive data are sent to the marketing authorization holder (MAH), i.e. the applicant, who incorporates the ASMF open part (applicant’s part, AP) into the related 3.2.S quality sections of the submission dossier. An ASMF, however, can only be submitted to the licensing authorities in support of a marketing authorization application.

The eCTD format is mandatory for human ASMFs submitted in a centralised procedure since July 1, 2016. For ASMF submission in national procedures with mutual recognition (decentralised procedure, DCP, and mutual recognition procedure, MRP) and for purely national procedures the related national requirements must be followed.

Phact creates and submits or assists in creating and submitting ASMFs in either eCTD or NeeS (3) format according to the relevant requirements.

  1. (1) Synonyms are active substance, active pharmaceutical ingredient (API)
  2. (2) 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 (OJ L 311, 28.11.2001, p.67); consolidated version
  3. (3) Non-eCTD electronic Submission (NeeS)

Authority meetings – either pre- or post-approval – are an important element of a successful submission project.

Whether the preparation of briefing meetings for innovative (borderline) products, scientific advice or protocol assistance of pre-submission meetings, Phact assists in

  • Planning and organizing the authority meetings
  • Filing / reviewing the ‘briefing packages’
  • Accompanying the authority meetings
  • Evaluating the outcome of the meeting and proposing measures to be taken