NOBBIO Consulting LLC

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

Late Clinical Phase (until production of registration and process validation batches after Ph 3 batches production)

• 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 (for preparation of PAI)
    • 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 (for preparation of PAI)
    • 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

Commercial Manufacturing Stage

Periodical audit by Marketing License Holder and/or Contract giver

Management and monitoring 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)

Other GMP/GDP issues

Second site management and technology transfer issue

Research for Pharmaceutical Affairs and GXP law/regulations in USA and EU

The activities listed above are just example of our consultation services, and we are always open to discuss with you for a possible service, even though no information is available in the activities above. If you have any uncertainty or questions of our service, please let us know by using a “CONTACT” tag of the front page. We will be pleased to advise you of the detailed information of our proposal for consultation, and if you agree to our proposed service, we will start consultation after execution of the service agreement. The consultation fee will be usually claimed, depending on how much time/hours are spent (hands-on basis), but we can accept monthly or quoter based payment, if you need our engagement to your project in a middle or long term period.

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 or too low, in contrast to traditional approach for typical medicinal products. 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. For example, in case of human cells or tissues, because of its un-homogeneous nature, it will be difficult to assure the product quality by complete meeting with a strictly defined specification thereof, and rather, prefer to assure the product qualify by controlling manufacturing process. Thus, it is important to establish the control strategy for manufacturing robustness based on better understanding of the mutual interaction between critical quality attributes (CQA) and process parameters (critical and/or key process parameters, CPP or KPP) and checking of the quality with in-process testing. In addition, GMP compliance in manufacturing and quality control for regenerative medicinal products is the same conditions as required for bioproducts, that is, under aseptic condition and/or viral controlled environment at GMP certified facility and therefore will be required to be managed adequately by a competent group of s with high specialty for GMP for aseptic products. In fact, Swiss authority has published the interpretation of revised Annex 1, 2022 that all of the requirements would principle apply to ATMPs and management of CCS would be one of the major targets during inspection. Further, the authorities like FDA and EMA evaluate during inspection the compliance status in manufacturing and quality control of regenerative products with guidance for sterile products (EU GMP Annex 1 and FDA Guidance for Industry of Sterile Drug Product) and there are several Warning Letters or Non-Compliance Reports available reporting compliance deficiency in such guidance.

Meanwhile, the accelerated review and support by Japanese authority for filing and approval for commercial license can be applied if an authority admits the potential merit for medical treatment by administration 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 even under early development stage for regenerative products, in particular, planning to establish scientific proof for efficacy, safety and robustness of product quality for accelerated approval purpose.

Even if the conditional and time-limited manufacturing and marketing license is approved in Japan, you will be required to verify the stable manufacturing status has been kept and verified continuously for up to 7 years until resubmission for commercial license application is made, because the authority recognize it will be impractical that complete process validation data could 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 of data into resubmission documents to receive a formal license for preapproved regenerative products. Consequently, you need to establish an effective quality management system, including implementation of an adequate quality risk management system in place and also documentation system to record the details for production and quality controls, particularly system for collection and/or analysis of data generated in the field of aseptic control, material control and qualification and preventive maintenance of equipment. Further, it is a responsibility of the manufacturer or QP of regenerative products site under EU regulation, to provide instructions and trainings of reconstitution of the regenerative product at the hospital, if necessary.

Further, if your regenerative products are manufactured from recombinantly manipulated cells, you must file an application and receive approval for the facilities, either Type 1 or Type 2 use, depending on risk significance, that must be in compliance with Convention on Biological Diversity treaty (Cartagena Act),. For preparation of such an application, a special technical and regulatory knowledge is required, particularly knowledge for impact evaluation for biological diversity and so on.

In summary, when compared to bio (medical) products, there are so many issues to be resolved during development and for approval of the regenerative products, so that proactive management strategy will be required to obtain scientific sound constructive data for many aspects of efficacy and safety issues and thus it is globally well-recognized among the CDMO companies that a closed cooperation with authorities, throughout a frequent discussion and consultation, would be the fastest way to receive an approval for marketing application. PMDA is very open minded and welcome to provide such a consultation even in an early development stage, but you will be obligated to show a scientific sound evidence for efficacy and safety in an application for clinical trial or IND, and thus it is critical for the company to decide the strategy for what data shall be disclosed and how to plan and obtain such data, through advanced investigational research or preclinical study.

Nobbio Consulting will provide excellent service to help you in evaluation of an effectiveness of the control strategy for robust quality assurance as applied for the appropriate development stage, depending on 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
• Research for relative laws and regulations in USA and/or EU or inspection trend by the competent authorities (FDA, EMA)

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 you with conducting investigations for safety, efficacy, stable supply of the raw materials, such as vectors and cell substrates that will be required for high degree of safety under regulation, particularly in the gene therapy field.