MANAGEMENT

TECHNICAL FIELD

The present invention relates in general to banking of tissues and cells, in particular to ATMP (Advanced Therapy Medicinal Product) manufacturing process management and handling corresponding documentation.

BACKGROUND

Advanced Therapy Medicinal Products (ATMPs) are advanced therapeutic drugs that are based on cell therapy or gene therapy.

Regenerative medicine combines fields of medicine, science and economy, and is focused on developing new technologies that will improve quality of life of patients and enables disease treatment using more efficient and safer methods. One of the major themes of regenerative medicine is stem cell-based cell replacement therapy for different diseases.

In spite of tremendous advancements in the medical field, the group of ‘no-option’ patients is becoming larger and larger, and those patients are unable to take a full advantage of the recently implemented treatment modalities.

Importantly, readily achievable (off-the-shelf) and highly effective allogeneic cell type for cell replacement therapy is yet to be determined. For instance, the pluripotent stem cells and adult stem cells, including mesenchymal stem cells, are considerable usable cells for regenerative medicine.

The major challenge in using stem cells is optimized, repeatable manufacturing, optimal matching of ATMP product and patients and constant development of ATMP product based on clinical data.

SUMMARY

The invention relates to manufacturing systems and methods for producing and selecting an allogeneic stem cells for patient treatment based on simultaneous HLA-typing, anti-HLA antibodies monitoring and clinical observations.

The object of the invention is a computer-implemented system for managing a manufacturing process of an advanced therapy medicinal product (ATMP), the system comprising: a banking module that provides a functionality of a data warehouse on the ATMP and storing data corresponding to sample identifiers, number and location of samples in the warehouse, activities performed on the sample, records of product distribution medicinal products to patients, prompts to prepare further samples of the medicinal product for the patient, record of medicinal product returns; a materials module configured to store data on apparatus and materials used during the manufacture of the ATMP, comprising apparatus list, apparatus parameters, apparatus inspection prompts and data related to management of disposable materials; a personal data module comprising a database of system users and a database of patients; a patients performance module configured to monitor the efficacy and safety of the ATMP in patients; and a statistical analysis module configured to extraction specified ranges of data collected in the other modules and to exporting said extracted data.

The object of the invention is also a method for managing a manufacturing process of an advanced therapy medicinal product (ATMP) by means of the computer-implemented system presented herein, the method comprising: in response to receiving an order for the ATMP, storing the order details in the banking module and creating a record for the ATMP and the corresponding patient in the patients performance module; selecting an active substance for the ATMP based on data stored in the patients performance module and storing the selected active substance information in the banking module; preparing the ATMP and storing data on each stage of the preparation process in the banking module; controlling the procedure and product release and storing the acceptance of the production process in the banking module; and applying the ATMP to the patient and storing information on ATMP efficiency and any side effects in the patients performance module.

The system according to the invention is designed for data and process management in tissue and cell banks, as well as cell culture-oriented factories. The advantage of the presented system is the ability to manage and constantly control the production processes and quality control tests by integrating the control and measuring equipment with devices used in the process, such as cell culture systems. The system allows monitoring the path of the source material from the moment of its acceptance to the application of the manufactured product to the patient. In addition, thanks to the possibility of integration with diagnostic and clinical systems, it is possible to monitor the safety and effectiveness of its processing and application to the patient. The warehouse and equipment module allows controlling expiry dates, reagent consumption or equipment inspection dates, which is required by GMP (Good Manufacturing Practice) standards, and is also important for the possible control of production line costs or the operation of banks or factories. In accordance with GMP requirements, all changes in the database can be monitored in system log files, both from the level of the application and from the level of other external tools. The system comprises an audit trial mechanism for collecting change logs in all or selected database tables, which ensures control of all documented processes.

These and other features, aspects and advantages of the invention will become better understood with reference to the following drawings, descriptions and claims.

BRIEF DESCRIPTION OF FIGURES

The present invention is shown by means of example embodiment on a drawing, wherein:

Fig. 1 shows a schematic modular structure of an embodiment of the system according to the present invention.

Fig. 2 shows an example of a procedure for manufacturing an ATMP.

Fig. 3 shows a computer system for implementing the functionality presented on Fig. 1.

DETAILED DESCRIPTION OF AN EMBODIMENT

The following detailed description is of the best currently contemplated modes of carrying out the invention. The description is not to be taken in a limiting sense, but is made merely for the purpose of illustrating the general principles of the invention.

Fig. 1 shows a schematic modular structure of an embodiment of the system according to the present invention.

A banking module 101 is a data warehouse on the medicinal product. It stores data corresponding to sample identifiers, number and location of samples in the warehouse, activities performed on the sample, records of product distribution medicinal products to patients, prompts to prepare further samples of the medicinal product for the patient, record of medicinal product returns. It may be configured to control product distribution to patients. The banking module 101 is configured to allow searching for samples according to specified criteria, results of commissioned or external tests on the sample. The banking module 101 is communicatively connected with an IT infrastructure of a laboratory where the tests are performed. The banking module 101 is used for controlling the process of manufacturing a medicinal product according to adopted manufacturing procedures and schemes, in particular for recording individual activities performed on the sample. For example, a user of the system may scan barcodes and supplement data, or the laboratory equipment may automatically generate and transmit corresponding data. The banking module 101 is used to monitor critical points of individual stages of medicinal product production and create reports or protocols on activities performed at various stages of production medicinal product.

An equipment and materials module 102 is configured to store data on apparatus and materials used during the manufacture of a medicinal product, such as apparatus list, apparatus parameters, apparatus inspection prompts and data related to management of disposable materials, such as material inventory, material disposal based on registered activities performed in the production process and/or inventory reports

A personal data module 103 is comprises database of system users (defining the roles and authorizations of users) and database of patients. The module may also define which users may access data of particular patients.

A patients performance module 104 is configured to monitor the efficacy and safety of the medicinal product in patients. It comprises a database of patients who received the medicinal product (such as identification of the study or research project, identification of the patient, identification of the administered medicinal product, medical history, observation results, laboratory tests and imaging results such as X-ray or MRI). It further comprises data on safety assessment of the medicinal product and is configured to report adverse events (AE) or serious adverse events (SAE).

A statistical analysis module 105 is used for extraction of specified ranges of data collected in databases of the system and exporting data to files in standardized formats (such as. csv or.xls) for the purposes of subsequent statistical analysis.

Arrows on Fig. 1 represent the following information exchanged between the modules:

1 a list of apparatus, reagents and materials necessary to perform a particular activity, corresponding parameters and expiration dates

2 log files of apparatus operation, use of reagents, materials while performing a particular activity

3 access rights

4 access rights

5 access rights

6 access rights

7 definition of prepared product, information on clinical trial, order to prepare a product for a patient

8 definition of prepared product, product selection

9 clinical data

10 results of statistical analysis

11 production data, status of product repository 12 results of statistical analysis that can affect product selection

13 analysis and optimization of use of reagents and materials used

Example of application use of the system

Fig. 2 shows an example of a procedure for manufacturing an ATMP. Data collected and generated in steps 202-204 are stored in the banking module 101 of the system and data generated in step 201 and acquired in step 205 are stored in the patients performance module 104.

In step 201 an order for the Advanced Therapy Medicinal Product (ATMP) (also called Investigational Medicinal Product (IMP)) is received. The order details are stored in the patients performance module 104.

Next, in step 202, an active substance is selected for the process. In that step, corresponding data on the order and the active substance are stored in the banking module 101. HLA typing and anti-HLA antibodies assessment is performed , and based on these data the best product is selected for the particular patient depending on the samples stored in the repository.

Next, in step 203, the ATMP is prepared. In that step, tasks related to planned procedures related to cell culture are stored in the banking module 101. Data related to each stage of observation, control, passage of the culture and finally the preparation of the product are stored. Data on each stage comprises information about the amount of used materials and reagents. The data on used materials and reagents are also used to update the repository of materials stored in the equipment and materials module 102 to keep track of the current status of resources. Moreover, information on use of equipment is entered to the module 102, thereby allowing to keep track of daily operation of equipment corresponding to particular production process.

Step 204 comprises control of the product by a Quality Person and release of the ATMP. In that step, the QP verifies all stages of the production, quality control results, equipment status check and any deviations that occurred during the procedure, by inspecting data stored for each production stage. Finally, the QP enters the acceptance of the production process, as required by the GMP legal regulations.

Finally, the ATMP is applied in step 205 in clinical site. In that step, the release of the ATMP from the production site is noted in the banking module 101. A transmission protocol is generated and a scan of the protocol is stored in the module 101. Next, patient data are collected from other electronic patient records. During use of the product by the patient, information on product efficiency and any side effects are stored in the patients performance module. Patients personal data may be anonymized.

Based on previous reports for mesenchymal stem cells (MSC) about their low immunogenic potential the transplanted Wharton’s Jelly mesenchymal stem cells (WJMSC) are anticipated to survive for period of time sufficient to initiate and support the regenerative processes. However, in animal model the Major Histocompatibility Complex (MHC) matching was found very important for obtaining the strongest immunomodulatory efficacy (Zinockeretal et al. Basic Immunology 2012) and MHC histocompatibility may be important for regeneration efficacy. Thus, HLA typing and subsequent matching was proposed for obtaining the best patients-ATMP product compatibility.

WJMSC will be HLA-typed in loci A, B, C (class I) and loci DRB1, DQB1 (class II) at low molecular resolution. In particular cases (e.g. two potential matched products) the HLA typing will be done at high molecular resolution in class I loci. Patients will be HLA typed in loci A, B, C (class I), and DRB1, DQB1 (class II) at low molecular resolution. Matching between patient and the ATMP will be done based on HLA analysis, however most import will be matching at HLA class I of MSC. Before administration of the ATMP looking at the presence of anti-ATMP antibodies in patient serum will check the level of immunization. In case of immunized patient, the specificity of alloantibodies will be evaluated. This algorithm will allow avoidance of non-accepted differences between the ATMP and the patient and will allow best matching.

HLA typing is performed for all mesenchymal cells and recipients/patients for loci A, B, C and DRB1. Typing is done by the SSOP molecular method at the low-resolution level on the Luminex platform (Immucor). Results are accepted only if there are no ambiguities (unequivocal results) for each tested locus at the low-level resolution (two-digit result). Difficulties (e.g. homozygosity, poorly documented alleles) are resolved by retyping the sample using the SSP method.

HLA typing performed by the SSOP method is validated by the SSP method. Typing three different DNA samples by both, the SSOP and SSP method, provides HLA validation. No differences in HLA typing results are accepted. If any discrepancies occur, the procedure is revaluated and the typing is repeated. Quality of the working areas is determined by DNA wipe tests.

The sensitization level of recipients/patients is screened in sera by the solid phase method (Luminex). In the case of sensitized recipients/patients, the specificity of anti- HLA antibodies (against class I and II) are determined. Knowledge about the DSA (donor specific antibodies level) is crucial to avoid unacceptable mismatches. Patients with DSA the “raw value” above 3000 are declined. The DSA level in patient’s sera are also analyzed two months after administration of the ATMP.

For the procedure to be validated, three different serum samples are tested for anti-HLA antibodies. All samples are tested in duplicates. Qualitative differences between repeats are not acceptable (raw value above 2000). Quantitative differences between repeats are acceptable, however, the difference should not exceed 15% of the “raw value”.

Computer-implemented system The functionality of the system presented in Fig. 1 can be implemented in a computer system 300, such as shown in Fig. 3. The system 300 may be realized by means of one or more physical computers or virtual machines configured to operate in a cloud. The computer includes at least one nontransitory processor-readable storage medium 310 that stores at least one of processor-executable instructions 315 or data 316; and at least one processor 320 communicably coupled to the at least one nontransitory processor-readable storage medium 310. The at least one processor 320 may be configured to (by executing the instructions 315) perform the procedure of Fig. 1. The data 316 corresponding to databases of particular modules 101-105 may be stored on the same storage medium or separate storage media for each database, in the same physical facility or distributed over a network.

While the invention has been described with respect to a limited number of embodiments, it will be appreciated that many variations, modifications and other applications of the invention may be made. Therefore, the claimed invention as recited in the claims that follow is not limited to the embodiments described herein.