日本語 / English

NOBBIO Consulting LLC

Tel
:
043-286-1557
Mail
:
tateishinbo@nobbio.net

Consultation to support Product Development and Commercial Manufacturing

The following is an example of our consultation service to GXP activities in product development and commercial manufacturing of medical supplies such as small molecule drug products, biopharmaceuticals and/or regenerative medical products. The services described here can be extended, in principle, also to medical device and cosmetics.

Consulting Overview

Non (pre) clinical stage (drug research phase)

  • Planning of R&D strategy (road mapping)
  • Planning of development strategy (scenario and progress check)
  • Planning of development strategy of product candidate (establishment of proof of concept)
  • GMP management for investigational medicinal product (clinical trial material) including oversight l of the contract manufactures and/or test facilities
  • Regulatory compliance and Quality Assurance of investigational medicinal product, including timely updates of the clinical trial applications (IND and IMPD)
    • Planning of an initial specification for raw materials/excipients, intermediates and final product
    • Establishment of a master record and maintenance management of a manufacturing and testing records (log book)
    • Planning of GMP record and document system for manufacturing process, analytical methods and specifications, and others with assurance of its integrity
    • Analytical method validation (to the extent required under IND and IMPD)
    • Stability testing (to the extent required under IND and IMPD)

Clinical stage (Chemistry, Manufacturing and Control (CMC) and clinical trial application)

Early Clinical Phase
  • Quality Assurance of Investigational Medical Product (compliant to GMP and regulatory dossier)
    • Documentation of manufacturing and testing procedures (Product Specification File and SOP)
    • Qualification of facilities and equipment
    • Registration of specifications for raw materials (including packaging material) and final product
    • Procedure for product release approval (cooperation with QP in Europe)
    • Validation of manufacturing process (to the extent required under IND and IMPD)
    • Aseptic process assurance (validation)
    • Cleaning validation/verification (to the extent required under IND and IMPD)
    • Deviation management and change control
    • Label management (to the extent required under IND and IMPD)
  • Updates of clinical trial applications/stage shift (IND, IMPD and investigator’s brochure)
  • Qualification and contracts with suppliers for raw materials, container/closure etc., contract manufactures, and product storage and distribution agents
  • Consultation meeting with authorities (development and/or approval strategy, documentation and quality issues)
Late Clinical Phase
  • Establishment of manufacturing and quality control strategy for commercial products (NDA/BLA preparations)
    • Establishment of a commercial manufacturing process
    • Qualification of facilities and equipment used for commercial manufacturing
    • Process validation and analytical method validation for commercial manufacturing
    • Completion of cleaning validations and environmental monitoring for commercial manufacturing
    • Maintenance and control of manufacturing and testing records (with data integrity)
    • Other GMP/GDP relating matters
      • Risk management
      • Employee trainings and GMP education
      • Qualification and contracting with domestic or overseas contract manufacturers and/or testing organizations (CDMO)
      • Qualification and business contracting with venders or suppliers of raw material, labelling materials, container/closure etc., and product storage and transportation agents
      • CSV compliance (including data integrity)
      • Supply chain management including validated transportation for clinical and/or commercial products (GDP compliance)
  • Consultation meeting with the regulatory authority (approval strategy, documentation and quality issues)

Filing of commercial license and Pre-approval inspection

Handing of Q&A from a regulatory authority pertinent to commercial license application
Preparation of Marketing and Manufacturing license Application (NDA/BLA, CTD and DMF)
Consultation meeting with regulatory authority (approval strategy, documentation and quality issues)
Filing of Marketing and/or Manufacturing license registration application
Foreign Manufacturer Accreditation application and appointment of domestic agent
Readiness for Inspection (Pre-Approval Inspection) by a domestic and overseas authority
Mock Inspection and Inspection readiness management

Commercial Manufacturing Stage

Periodical audit
Management and oversight of domestic and overseas raw material suppliers (audit)
Management and supervise of domestic and overseas contract manufacturers and/or testing organizations (audit)
Readiness for audit by a marketing license holder (mock inspection and/or GMP education and training)
Inspection by authority
Hosting and management for Inspection by domestic and/or overseas authorities (mock inspection and GMP training and education)

Regenerative medicinal product, nucleic acid medical supplies and gene therapy

It is globally well understood that development of regenerative medicinal products, such as human cells and/or tissue products, nucleic acid medical supplies and a gene therapy, will require early establishment of manufacturing and quality controls securing the safety and efficacy. This is because the regenerative medicinal products are targeted for unmet diseases area where no medical and medicinal treatments are available and thus the numbers of the potential patients targeted would be very limited to low. This fact will lead to the clinical difficulty to provide scientifically acceptable evidence about efficacy and safety of the products when compared to a typical chemical or biological medicinal candidate where many patients can be administered during the clinical trial to provide satisfactory numbers with statistical significance. Further, in case of human cells or tissues, it will be difficult to prove the efficacy of the product with scientific sound, because of its un-homogeneous nature. Consequently, the accelerated review and support by Japanese authority for filing and approval for commercial license can be applied if an authority admits the potential for medical merit of the product (“Joken oyobi Kigen tuki syonin”: Conditional and Time limited Approval). The same concept of accelerated review and expedited approval process is also available in EU (PRIME) and USA (Breakthrough therapy). Therefore, unlike the development of other medicinal products, the special strategy is required in early development stage for regenerative products, in particular, planning to establish scientific proof for efficacy, safety and further robustness of product quality for accelerated approval purpose.

For human cells and tissue products with its characteristic of un-homogeneity, it is important to manage product quality by effective control of each manufacturing step, rather than strict management for compliance with product specification, so that good understanding of inter-relation of critical quality attribute (CQA) of the product and critical process parameter (CPP) for process performance and further monitoring by in-process analysis, is a key of control strategy to stably produce the targeted products with expected quality.

Even if the conditional and time-limited manufacturing and marketing license is received, you will be required to verify the stable manufacturing status continuously for 7 years until resubmission for commercial license application is made, because complete process validation data would not be available at the time for first filing to prove that sufficient and effective manufacturing and quality controls have been established. You must include such proof into resubmission documents. Consequently, you need an adequate quality risk management system in place and also to establish effective documentation system for production and control records, particularly management system to collect and/or analyze data generated in the field of aseptic control, material control and qualification and preventive maintenance of equipment.

Further, you must file an application for approval of Type 1 or Type 2 use depending on risk significance to be in compliance with Convention on Biological Diversity treaty (Cartagena Act), if your regenerative products are manufactured from recombinantly produced cells. For preparation of the application, a special technical knowledge is required for, including but not limited to, evaluation for biological diversity.

In summary, development and approval of the regenerative products will require proactive management and measurements for many aspects of efficacy and safety issues when compared to bio (medical) products and thus it is globally recognized that a closed cooperation with authorities, through a frequent consultation, would be the fastest way to receive an approval for marketing. PMDA is very positive and welcome to take such a consultation even in an early development stage, but you will be obligated to show a scientific evidence for efficacy and safety in an application for clinical trial and thus it is critical to establish the strategy for what and how to create and collect data, through investigation research or preclinical study.

We will provide our service to help you in evaluation of an effectiveness of the control strategy for robust quality assurance as applied for the appropriate development stage and in accordance with the product characteristics. We will also provide our support to identification and resolution of any issues at the manufacturing, testing and distribution site for the purpose of GMP, GCTP and/or GDP compliance. The following is a list of our service.

  • Establishment of effective Quality (Risk) Management System for GCTP facilities
  • Establishment of aseptic assurance and validation (sterilization assurance of facilities and equipment)
  • Establishment of donor screening and appropriate decision method for eligibility
  • Compliant to “Biological Raw Material Standard” regulation (ICH compliance), including microbial and viral testing
  • Optimization and validation/verification of manufacturing process
  • Establishment of manufacturing and control records master
  • Validation of analytical method for in-process control, characterization analysis and a release testing (ICH compliance)
  • Establishment of vender/supplier control
  • Establishment of control strategy, including identification of quality attributes and critical/key performance parameter
  • Valid documentation (system) of various reports and SOPs, etc. (data integrity)
  • Establishment of validated (stable and safety) transportation within or between the facilities
  • Consultation meeting with regulatory authorities (approval strategy, documentation and quality issues)
  • Communication (Q&A) with authorities in regard to Marketing and Manufacturing License application



You must bear in mind that more compliant documents are required under GMP/GCTP for regenerative medicinal products, when compared to those for bio (medical) products, and thus integrity of data shall be assured through validated document control system, particularly for good maintenance of the documents.
In addition, the services are also available to support the investigations for safety and efficacy of the production raw materials that will be required under regulation in the gene therapy field, such as regulatory acceptable vectors and raw materials with (higher) safety.