February 2012

Report REGULATION AND GENERATION OF CELL THERAPY MEDICINAL PRODUCTS

Project Translational Research Dutch National Cancer Control Programme 2005-2010 dr. J. Oostendorp dr. P. Meij dr. L.A. Veltrop-Duits

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Table of Contents

TABLE OF CONTENTS .................................................................................................... 2 ABBREVIATION ............................................................................................................... 3 1.

INTRODUCTION ..................................................................................................... 4

2.

REGULATION CONCERNING (CELL THERAPY) MEDICINAL PRODUCTS IN THE NETHERLANDS ........................................................................................ 6

3.

CTMP DEVELOPMENT ........................................................................................ 10

3.1. Quality Control (QC) and Qualified Person (QP) ................................................... 10 3.2. Reagents and Starting material ................................................................................ 10 3.3. Release criteria for a CTMP .................................................................................... 13 4.

CLINICAL STUDY ................................................................................................ 16

4.1. Routing for application CTMP ................................................................................ 16 5.

DISCUSSION REGULATION AND GENERATION OF CTMP ......................... 18

5.1. Researchers and pharmacists lack specific knowledge ............................................ 18 5.2. Qualification of reagents and materials ................................................................... 18 5.3. Validation of analytical procedures ......................................................................... 19 5.4. Preclinical toxicity tests ........................................................................................... 19 5.5. GMP-license ‘fabricantenvergunning’ .................................................................... 19 WEBSITES ....................................................................................................................... 21 REFERENCES .................................................................................................................. 22

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Abbreviation ATMP BGGO BROK CAT CBG CCMO CHMP COGEM CTMP EMA EU GMP GTMP IGZ IMPD MEB MREC PSF QC QP RIVM SCT SOP VROM WMO WVKL

Advanced Therapy Medicinal Products Bureau Genetisch Gemodoficeerde Organismen Basiscursus Regelgeving en Organisatie voor Klinisch Onderzoekers Committee for Advanced Therapies College ter Beoordeling van Geneesmiddelen Centrale Commissie Mensgebonden Onderzoek Committee for Medicinal Products for Human Use Commission Genetische Modificatie Cell Therapy Medicinal Products European Medicines Agency European Union Good Manufacturing Practice Gene Therapy Medicinal Products Inspectie voor de Gezondheidszorg Investigational Medicinal Product Dossier Medicines Evaluation Board Medical Research Ethics Committees Product Specification File Quality Control Qualified Person Rijksinstituut voor Volksgezondheid en Milieu Stem Cell Transplantation Standard Operational Procedure Ministerie van Volkshuisvesting, Ruimtelijke Ordening en Milieu Medisch-Wetenschappelijk Onderzoek met Mensen Wet Veiligheid en Kwaliteit Lichaamsmateriaal

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1. Introduction 1.1. Development of an advanced cell therapy medicinal product Potential advanced cell therapy medicinal products (CTMP) are rapidly expanding in the research laboratory, spanning many diseases and medical practices. As the understanding of cell development and cell interactions has progressed, manipulation of cells for intervention is possible. CTMP are already being tested in clinical trials. In general, the development of most non-cellular medicinal product is a long process. On paper the development is a straight forward process starting with the fundamental research, followed by preclinical studies and later on phase I/II studies, after which the medicinal product can enter a phase III study in order to get registered in the European Union (EU) (figure 1A). It takes many years, sometimes up to 15-20, before a product is finally entering the registration procedure, In contrast to the non-cellular medicinal products, most CTMP are patient specific / tailormade and therefore not suited for broad application. As a consequence, most of these products are not manufactured at a large scale and therefore products are of limited commercial interest. In addition, most studies will continuously move back and forth from phase I/II to preclinical research for improvement of the product and will stay in the translational phase of research (figure 1B). A significant part of the CTMP is developed by academic translational researchers. Two obstacles can be indicated in the development of the CTMP 1) the lack of knowledge on pharmaceutical development by researchers 2) the lack of knowledge on cell products by the pharmacists. In addition to the difficult regulatory issues involved in the generation of a noncellular medical product for clinical studies, the viable material forming the CTMP makes them hard to fit in the “standard” regulatory procedures (1,2). Cell products are in fact unique and subjected to variation. As all donors of the cell products differ, so will all cell products by themselves differ from each other. They do not expand, stimulate or activate exactly the same as previous cultures. This makes CTMP difficult to fit in the “standard” regulation.

1.2. Development of a CTMP in combination with gene therapy Gene therapy includes a broad range of therapies. Novel and/or repair DNA and/or genes are introduced in cells of a patient in order to cure life threatening diseases. In case expression vectors are part (half products) of the final CTMP, the CTMP is considered as a gene therapy medicinal product (GTMP). Information about GTMP can be found at the website of the CCMO or “Loket Gentherapie” of the RIVM.

1.3. Outline of this report This report describes three steps in the production of a CTMP; a) the regulations involved, b) the production process of CTMP, and c) the application route involved in a clinical study with CTMP.

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A. Medicinal Product

February 2012

B. CTMP

fundamental research discovery

fundamental research discovery Release criteria

Pre-clinical studies

Pre-clinical studies Selecting materials

Phase I

Phase I / phase II

Approval METC

Phase II

Phase III

Medicine registration: CBG / EMEA

Regulatory review approval

Phase IV

Figure 1. Steps in development of medicinal products

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Approval CCMO

Report Regulation and Generation of Cell Therapy Medicinal Products

2. Regulation concerning Netherlands

(Cell

Therapy)

February 2012

Medicinal

Products

in

the

This chapter describes the Dutch laws „wetten‟ and European Regulation involved in clinical studies with (cell therapy) medicinal products. The relevant European directives are here depicted as well. An overview is shown in table 2.

2.1. Regulations concerning clinical trails All clinical trails with or without medicinal products have to follow the „Wet MedischWetenschappelijk Onderzoek met Mensen (WMO)‟ published in 1998 (3). This WMO describes the protection of participants, healthy individuals as well as patients, in a clinical trial.

2.2. Regulation of Investigational Medicinal products (IMP) Article 13 of the WMO describes the use of investigational medicinal products (IMP) in a clinical trial (3). In 2006 the European directive 2001/20/EC (4) was implemented in the WMO (4,5,6) indicating that clinical trails with IMPs for human use should follow Good Clinical Practice (GCP) (4). This implies amongst other things that the IMPs should be manufactured according to Good Manufacturing Practice (GMP) as has been described in the „geneesmiddelenwet 2007‟ (7). Production of a medicinal product according to this „wet‟ indicates that it is mandatory to have a „fabrikantenvergunning‟, or so called GMP-licence for the production of investigational medicinal products (article 18).

2.3. Regulations concerning human cells and tissues for human use. Cell products have traditionally been used in the field of stem cell transplantation (SCT). For this application the stem cell graft is harvested after which an isolation procedure can be performed before infusion. To ensure the quality and safety of the stem cell product the Dutch government published in 2003 the „Wet Veiligheid en Kwaliteit Lichaamsmateriaal (WVKL)‟ (8) followed by the „Eisenbesluit Lichaamsmateriaal‟ in 2006 (9), describing the rules to ensure quality and safety of the donation, procurement, testing, preservation, storage and distribution of tissue and cells, including requirements for donor and product traceability. From these regulations it is mandatory for the processing stem cell laboratories to be licensed as a „weefselinstelling‟ (Tissue Establishment). In order to release products the laboratories should be licensed as „orgaanbank‟ (organ bank).

2.4. Regulations concerning Cell Therapy Medicinal Products for human use. Advanced cell therapy medicinal products (CTMP) have evolved out of research laboratories that have extended their reach beyond basic investigation to cell manufacturing for human administration spanning many diseases and medical practices (1). They include amongst other things somatic cell therapy products, manufactured from viable autologous, allogeneic or xenogeneic cells (2).

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With the adoption of EU Regulation 1394/2007 Advanced Therapy Medicinal Products (ATMP) in 2009 somatic CTMP have been combined in one regulation together with tissue engineered products and gene therapy medicinal products (GTMP) (10). The main reason to adopt this regulation was to brigde the gap between the European Directives on medical products and (implantable) medical devices. This means that CTMP, tissue engineered products and GTMP are all combined in one regulation and considered all as ATMP. A cell product is considered as ATMP when it is „substantially manipulated‟. In the ATMP regulation the term „substantially manipulated‟ is specified; a) All manipulation not listed Annex 1 of this ATMP Regulation should be considered as substantial manipulated (Table 1) (10), for example expansion of cells. b) All products that are not intended to be used for the same essential function in the recipient as in the donor, for example haematological stem cells for cardiac repair, are considered as substantially manipulated, irrespective of the type of manipulation of table 1. In both situations a cell product is regarded as medicinal product (reviewed in (11)). Since CTMP are considered as medicinal products, they CTMP in clinical studies have to follow the „geneesmiddelenwet 2007‟, indicating that CTMP used in a clinical trial should be generated under GMP-license „fabrikantenvergunning‟ (article 18)(7). On the contrary, cell products which are not substantially manipulated, e.g. cell products used in the field of SCT, isolated cell populations (using Streptamer procedure, islets of Langerhans), are not considered as medicinal products and therefore isolation of these cell products do not have to follow the „geneesmiddelenwet 2007‟. However, the WVKL is still in force for these products. As in most cases the starting material of these CTMP is of cellular origin (e.g. blood product, bone marrow), the donation, collection and release of this material has to follow the earlier mentioned „WVKL‟ and „Eisenbesluit lichaamsmateriaal 2006‟ (8,9). This also implicates that the laboratory collecting and releasing the starting material has to be licensed as an „orgaanbank‟ (organ bank). Table 1: Non-substantial manupulations listed in Annex I of the ATMP Regulation Cutting Cell separation, concentration or purification Grinding Filtering Shaping Lyophilisation Centrifugation Freezing Soaking in Antibiotic or antimicrobial solution Cryopreservation Sterilization Vitrification Irradiation

From april 2010 the EU directive 2009/120/EC should have been adopted in the member states, replacing part IV of Annex I to Directive 2001/83/EC (European directive for medicinal products) (12). In this EU directive 2009/120 specific requirements, such as material, characteristics and manufacturing, for all ATMP (and thus also CTMP) are stated. Furthermore, this directive states that with a risk-based approach the extent of quality, nonclinical and clinical data of the ATMP (including CTMP) should be determined. Risk factors to be considered are for example origin of cells, ability to proliferate and/or differentiate, initiating an immunerespons and level of cell manipulation.

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2.5. Generation of CTMP under “Hospital Exemption” For CTMP, that are not studied in a clinical trial, registration via the Hospital Exemption might be an option without intention for marketing authorization. Article 28 of the ATMP Regulation 1394/2007 states that the (EUD 2001/83/EC on Medicinal Products) „geneesmiddelenwet 2007‟ for Human Use shall not apply to „ATMP which are prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medicinal practitioner, in order to comply with an individual medicinal prescription for a custom-made products for an individual patient‟ (10). This rule might be an option for medicinal products, which will never be registrated, but already have been tested for safety in a phase I/II study. For the generation of an ATMP under Hospital Exemption approval is necessary from the „Inspectie voor de Gezondheidszorg‟ (IGZ). For the production of the CTMP under Hospital Exemption a GMP-licence is not necessary. However, the production should be manufactured in the pharmacy under GMP-conditions, paying extra attention to pharmacovigilance, tracing of products and responsibility of the QP for release of the end product. Important, manufacturing CTMP as an investigational medicinal product to be used in a clinical trial, falls outside the scope of the Hospital Exemption.

2.6. Marketing authorization concerning medicinal products for human use Most European and Dutch regulations involved in the study and development of medicinal products are focused on marketing authorization. It is assumed that the product will be registered for the European market after a clinical trail. A company/institute (in the EU) that wishes to bring a medicine to the market may submit a single application to the European Medicines Agency (EMA) for a 'marketing authorization' (license) that is valid simultaneously in all EU Member States, plus Iceland, Liechtenstein and Norway. The EMA, a decentralized body of the EU, is responsible for the protection and promotion of public and animal health through the evaluation and supervision of medicines for human and veterinary use (13). The „College ter Beoordeling van Geneesmiddelen (CBG)‟ / Dutch Medicines Evaluation Board (MEB) assesses and monitors the efficacy, risks and quality of human and veterinary medicinal products in the Netherlands. Therefore, the MEB judges every medicinal product before it is released for the Dutch market. Furthermore, the MEB is the primary source of information on new medicinal products, new applications and current risk information and works actively to communicate this information. The Committee for Advanced Therapies (CAT) was established by the EMA in accordance to Regulation (EC) No 1394/2007 on ATMP. It is a multidisciplinary committee to assess the quality, safety and efficacy of ATMP, and to follow scientific developments in the field. The main responsibility of the CAT is to prepare a draft opinion on each ATMP application submitted to the European Medicines Agency, before the Committee for Medicinal Products for Human Use (CHMP) adopts a final opinion on the granting, variation, suspension or revocation of a marketing authorization for the medicine concerned (14,15).

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Table 2: Overview Law and Regulations involved in Clinical trials with CTMP Law/Regulation Important for CTMP WvKL +  Quality and safety of the donation, procurement, Eisenbesluit Lichaamsmateriaal 2006 testing, preservation, storage and distribution of tissue and cells.  Tissue Establishment „weefselinstelling‟  Organ bank „Orgaanbankvergunnning‟ EU regulation 1394/2007

 Mentioning ATMP/CTMP  Definition substantially manipulated  Substantially manipulated: medicinal product

Geneesmiddelenwet 2007

 Regulation considering production and marketing of medicinal products

WMO

 Protection of participants in a clinical trial  Production medicinal product for clinical trial under GMP-license „fabrikantenvergunning‟

GMP

 Manufacturing of CTMP

EU Directive 2009/120/ec

 Specific requirements for all ATMP are described

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3. CTMP Development In the development of a CTMP the fundamental research product (lead product) has to be translated to a product ready for clinical use (Figure 2). The production process and its ingredients have to be adjusted to clinical grade standards and the criteria to release the product for administration have to be determined (Figure 2). Finally the quality, manufacturing and control of the CTMP have to be documented in an Investigational Medicinal Product Dossier (IMPD) (see chapter 4 Clinical Study, IMPD). Production of a CTMP for a clinical trial has to occur in the presence of a GMP-license.

3.1. Quality Control (QC) and Qualified Person (QP) The responsibilities for the manufacturing and release of a CTMP should be well documented. The person responsible for Quality Control (QC) is an independent person not involved in the production process (GMP annex 13 (16)). Quality control should be performed in accordance with the Product Specification File (PSF) (GMP annex 13(16)). A PSF contains all the information for processing, packaging, quality control testing, batch release and shipping of an investigational medicinal product (GMP annex 13 (16)). The Qualified Person (QP) is essential to the safety control of medicines. It is the responsibility of the QP to certify finished batches of medicinal products before being released (GMP annex 13 and 16 (16)). Assessment of each batch for certification prior to release may include as appropriate: - batch records, including control reports, in-process test reports and release reports demonstrating compliance with the product specification file - production conditions - validation status of facilities, processes and methods - examination of finished packs Important is that the person for QC and the QP are two different persons.

3.2. Reagents and Starting material 3.2.1. Starting material In case of generating a CTMP the starting material will be of cellular origin and forms the basis of the final CTMP. This starting material should be collected, tested and released by an Organ bank. The donor of the cellular material has to be checked for his physical condition and relevant laboratory measurements. Furthermore, microbiological screening of the donor, as described in EU Directive 2006/17, has to be performed and includes at least HIV 1 and 2 (anti-HIV-1, 2), Hepatitis B (HBsAg, anti-HBc), Hepatitus C (anti-HCV) and syphilis (17). Additional microbiological screening might be necessary. In case of an autologous donor positive test results do not necessarily have to form a barrier to use the starting material in the generation of the CTMP if appropriate isolated storage facilities are available to ensure no risk of cross-contamination with other grafts and/or no risk of contamination with adventitious agents and/or mix-ups (17).

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3.2.2. Ancillary materials, half products and excipients for administration Ancillary materials are reagents and materials required for the manufacturing of CTMP. These materials and reagents are used in the manufacturing process of the therapeutic substance, such as media, cytokines, growth factors, purification materials, etc. Important, ancillary materials are not intended to be present in the final product. Half products, on the other hand, are (intermediate) products and reagents which will be part of the cellular end product. Excipients for administration are reagents added to the CTMP for stabilization, antiadherence etc, and will be infused into the patients with the CTMP (e.g. albumin). Although no official regulations stating criteria for ancillary materials in the production process of CTMP are described and no test are stated in the European Pharmacopoeia, guidelines by the EMA on human cell-based medicinal products (EMA/CHMP/410869/2006) advice that each substance used in the procedure should be clearly specified and evaluated as to its suitability for the intended use (18). The quality of ancillary materials as well as of half products or excipients for administration can affect the stability, safety, potency and purity of a CTMP. They may form a safety risk for the CTMP by containing infectious agents or toxic properties that can not be adequately removed in subsequent processing steps and can be present in the CTMP. For that reason, no discrimination should be made in the criteria for selecting ancillary materials, half products or excipients for administration for the generation or administration of a CTMP.

3.2.3. Risk evaluation for ancillary materials and half products Qualification of an ancillary material or half product is the process of acquiring and evaluating data to establish the production process, source, identity, purity, biological safety and suitability of a specific ancillary material or half product. It is advised to evaluate the safety risk of the materials and reagents for the CTMP. Guidelines, described by US Pharmocopeia (31-NF26S2, Ancillary materials for cell, gene and tissue-engineered products), may be useful in the choice of ancillary materials and half products (19). In this guideline reagents are classified as low, moderate or high risk materials. Low risk materials include registered medicinal products for in vivo human use, or reagents intended to use for the generation of CTMP. Materials with a moderate risk are produced for in vitro diagnostic testing and not intended for use in the production of CTMP. Materials with the highest risk include toxic substances with known biological mechanism and animal-derived fluid materials. These guidelines also suggest qualifications or risk reduction activities for the three groups of materials as depicted in Table 4.

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Table 4. Qualification or Risk Reduction Activities (19) Low risk

Moderate risk

High risk

-

Drug Master File cross reference (when possible and practical)

-

Drug Master File cross reference (when possible and practical)

-

Drug Master File cross reference (when possible and practical)

-

Certificate of analysis

-

Certificate of analysis

-

Certificate of analysis

-

Assess lot-to-lot effect on performances

-

Assess lot-to-lot effect on performances

-

Assess lot-to-lot effect on performances

-

Assess removal from final product

-

Assess removal from final product

-

Assess removal from final product

-

Stability assessment on materials as stored for use in manufacturing

-

Stability assessment on materials as stored for use in manufacturing

-

Stability assessment on materials as stored for use in manufacturing

-

When relevant confirm certificate of analysis test results critical to product (could include functional assay)

-

When relevant confirm certificate of analysis test results critical to product (could include functional assay)

-

Vendor audit

-

Vendor audit

-

Upgrade manufacturing process for material to GMP

-

Develop stringent specifications

-

Determine if lot-to-lot biocompatibility, cytotoxicity, or adventious agent testing are needed

internal

Important, the responsibility for the use of an ancillary material, half product or excipient for administration resides with the developer or manufacturer of the CTMP and/or the qualified person (QP) involved in the production process. When an ancillary material, half product or excipient for administration is selected and documentation is provided by the manufacturer of the reagent, it is advised to include all available information of the product in a „QP release‟ statement. This statement will include (when available) a GMP certificate, an outline of the production process, a risk evaluation on compounds of biological origin and stability approach. Extra information can be added, such as purification or inactivation steps or in house testing of the product. This statement gives a clear overview on the selection of the ancillary material or half product in the production process of the particular CTMP.

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3.3. Release criteria for a CTMP 3.3.1. Quality control A CTMP will be released when the results of the Quality Control testing (QC) of the CTMP are in accordance with the chosen specification, described in the PSF. These tests can be performed on the end-product, but these can also include in-process (IP) controls or intermediates. The criteria will be set by the principal investigator. The release specifications of the CTMP should be selected on the basis of parameters defined during the preclinical characteristic studies. It should be clear from this preclinical work how and why the criteria are set. Despite the fact that in most fundamental research the application of a CTMP is far away, it is advised to think about the release specifications as early as possible in the development of a CTMP. Furthermore, by validating the procedure with test-procedures, it should be clear that the test-CTMP generated meet the set IP testing criteria and release criteria (see below). Selection of tests is product-specific and has to be defined by the manufacturer. Whenever possible, specifications for release testing should include identity, purity, potency, impurities (see below), sterility, cell viability and total cell numbers, unless otherwise justified (18). The CTMP has to be released by a QP. If certain release tests cannot be performed on the CTMP, but only on key intermediates and/or as in-process tests, this needs to be justified (18). In these cases an adequate quality control has to rise from the manufacturing process, supported by the results of the (pre-) clinical studies. These exceptions may include the following: - Some release testing might not be feasible on the combined components of the active substances/finished product for technical reasons. The product will be released on in process (IP)-testing - Complete release testing can not eb performed due to limitations on available product. The release of the product should be justified by the validation of the cell manipulation process and in-process controls. - A complete release testing can not be finalized before the product is administered to the recipient due to time restrictions. However, a critical set of essential tests that can be performed in the limited time prior to clinical use must be defined and justified.

3.3.2. Retrospective testing Although prospective testing of the quality control of a CTMP is preferred, sometimes it is not possible to finalize all tests before the product is administered to the patient. In these cases, the release criteria tests should be performed retrospectively. Together with a table describing tests performed retrospectively, risk analysis should be included in the IMPD, indicating the safety risk of obtaining results of the CTMP after infusion into the patient (Table 5). It should describe the harm that can be caused by the product, when results of the retrospective testing are different than expected. Furthermore, it should also be clearly stated, which procedures will be performed in case the results are out of specification.

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Table 5. Risk analysis: Testing microbiological contamination Risk Effect Chance on Effect LOW, when monitoring of the aseptical process is extensively performed and includes:  Generation of the product in a qualified Laminar Microbiological AirFlow (LAF) Cabinet in a classified cleanroom contamination of Infection of patient  Microbiological monitoring by settle and contact plates cell product  Training of personnel  Validation aseptical proceedings  Test of the product 24 hours before infusion is negative

3.3.3. Impurity 3.3.3.1. Cellular impurities Contaminating cells The cellular population of interest could contain other cells due to procedure, for example as established by FACS analysis. Where a specific cell type is required, the unwanted or nonspecific cells should be defined in the end-product and their amount should be controlled. The release criteria should clearly state the maximum percentage of contaminating cells allowed. Furthermore, the presence of these cells should be justified. It should be clear from testing or from literature, that this percentage of contaminating cells will probably cause no/low effect on the specific cell type or no/low side-effects in the patient when receiving the CTMP (18). Cellular mixture In case the desired biological activity and efficacy of the product requires a complex mixture of cells, the cell mixture needs to be characterized and its composition controlled by appropriate in-process and release testing. The composition of the cell mixture should be clearly stated (18). Non-viable cells Irrespective of the cell type, the CTMP can be contaminated with non-viable cells. Since cell viability may be an important parameter for product integrity and directly correlated to the biologic activity, the ratio between non-viable and viable cells should be determined in most cases and specifications should be set.

3.3.3.2. Impurities of ancillary materials and/or half products The presence of ancillary materials or half products in the CTMP, which are not intended to be part of the end product, will be named as impurities. During the manufacturing process of a CTMP, variable amounts of impurities (product- and process-related) may be introduced into the final product. Any reagents known to be harmful in humans should be analyzed in the final product (18). Overall, the presence of the impurity can be 1) based on calculating the concentration of the impurity in the final product after dilution, 2) determined by measuring the impurity during process validation, 3) directly measured in the final cellular product. The possible presence of impurities of ancillary materials or half products in the CTMP should be justified.

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3.3.4. Validation 3.3.4.1. Qualification/Validation of analytical tests QC testing of the CTMP should be qualified/validated to ensure that analytical test data and results are consistent, accurate and precise. Dependent on the measurement of the analytical test (e.g. yes/no discrimination to exact concentration), the qualification/validation procedure may vary and include different qualifications, such as: specificity, linearity, range, detection limit or quantitation limit. 3.3.4.2. Process validation Process validation is the test to control the robustness of the whole manufacturing process of the CTMP. In most process validation procedures minimal three CTMP batches will be generated exactly according to the procedure described in the Standard Operating Procedures (SOPs). All materials and reagents, including starting material, ancillary materials and half products, have to be the same or comparable to the reagents and materials, which will be used in the real manufacturing process of the CTMP. Results of the Quality Control testing (QC) of the CTMP should be in accordance with the chosen specification. Furthermore, extra information on the CTMP can be obtained during process validation, for example concentrations of impurities (see before).

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4. Clinical study With the generation of a CTMP under GMP a clinical study can be started. The study design should be set up in corporation with the responsible clinicians and has to be approved.

4.1. Routing for application CTMP Research with CTMP involving human subjects that falls within the scope of the WMO must be assessed in advance by the Central Committee on research Involving Human Subjects (CCMO). The CCMO is an independent governmental body with a legal status that reaches a legally binding decision on research protocols. An instruction manual on research with medicinal products has been produced with guidelines for investigators and sponsors. The instruction manual can be found on the CCMO website, as well as all required documents or document templates. 4.1.1. Investigational Medicinal Product Dossier (IMPD) One of the documents that needs to be submitted as part of a clinical trial dossier is the Investigational Medicinal Product Dossier (IMPD), describing the production process of the investigational medicinal product (or CTMP), its qualifications and controls. The production process will be clearly stated in this document as well as the QC tests itself and the criteria to which the CTMP product should fulfil. The original IMPD discriminates between „drug substance‟ and „medicinal product‟. For most CTMP this discrimination is not possible as in the generation of the CTMP no clear formulation step is present. A manual for an IMPD for CTMP might be helpful in the generation of the IMPD for CTMP. This template is in development and includes the specific characteristics of CTMP. This manual is added as appendix 4.

4.1.2. Investigators Brochure (IB) An Investigator Brochure (IB) is a summary of the clinical and preclinical results of the investigational medicinal product to be used in a clinical trial. An IB should contain physical, chemical, and pharmaceutical properties and formulation, nonclinical studies (nonclinical pharmacology, pharmacokinetics and product metabolism in animals, toxicology) and effects in humans (pharmacokinetics and product metabolism in humans, safety and efficacy, marketing experience). When both IB and IMPD should be submitted tot the CCMO, in case clinical data are present, the CCMO advises „to have as little overlap between the two documents as possible‟. This can be achieved by cross referencing between the two documents. The most efficient approach may be to supply the relevant production data in the IMPD. The relevant preclinical and clinical data and a short summary on the product information can then be included in the IB.‟ 4.1.3. Approval After approval of the CCMO the board of the institute where the clinical trial will take place should judge the local feasibility of the clinical trial, before the trial can start.

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Fundamental research product

Development of CTMP product

Yes

Reagents and Material

Tests preclinical work

Impurities

Clinical grade (table 4)

IP testing / QC testing

determination

No

Validation analytical tests

Risk analysis

Qualified by QP

Process Validation

Manufacturing of CTMP

Quality Control

Release by QP

Clinical grade CTMP for clinical study

Figure 2. Development of CTMP

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5.

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Discussion Regulation and Generation of CTMP

5.1. Researchers and pharmacists lack specific knowledge Most CTMP are developed in academic centers. Specific knowledge and experience regarding the production process of a CTMP or study with a CTMP is often absent with clinical researchers. The constantly renewing regulation is difficult to understand and for most researchers the understanding of these regulations does not have priority. As a consequence most researchers do not realize the consequences of starting a clinical study with a medicinal cell product. Furthermore, most pharmacists lack the experience of working with a cell product as medicinal therapeutic product. The generation of a CTMP is different compared to the traditional medicinal products, due to the fragile character of the cell products; cell products are often generated for a particular patient in stead of bulk production. The reproducibility of the cellular production process is largely dependent on the heterogeneity of the cellular starting material, having consequences for setting specifications for in process controls and release criteria of the final product. In order to improve the knowledge on the production of CTMP of the researchers as well as of the pharmacists extra courses are required regarding the regulations or generation of CTMP, respectively. General information (not specific for CTMP) is part of the „BROK cursus‟. Furthermore, the specific knowledge that already is present in most laboratories for stem cell therapy might be useful. Interaction with these laboratories might benefit the CTMP translational research. Also the interaction between different (academic) centers via a forum (on internet) in order the exchange expertise or knowledge on CTMP development and translational research might help researchers and pharmacists.

5.2. Qualification of reagents and materials During translation most researchers search for a clinical grade version of reagents that are used at the research laboratory. However, not all reagents exist in a clinical-grade version. When non-clinical grade reagents are used a risk analysis should be performed, as described before, to determine the safety risk for the patient. Obviously, the viral and microbiological safety of these components needs to be ensured and the risk for transmittable spongiform encephalitis should be minimized. For a part of the reagents used in the generation of a CTMP it is not possible to obtain a complete qualification. Materials like culture media or components of biological origin can not be qualified (completely) on identity, purity and/or content. In case a complete qualification is not possible a risk analysis for the specific reagent/material should evaluate the risk for the patient. According to the analyzed risk it will be decided to either use the reagent in the production process of the CTMP or not. Considerations and risk analysis can be included in a QP release statement. By means of QP-release the institute should take the responsibility for the release of the reagents or materials that are not completely defined and characterized.

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5.3. Validation of analytical procedures The assays for the in-process testing and quality control have to be validated. This can be complicated for relevant assays running in research laboratory for years. Most of these assays have never been validated according to GMP standards. In the validation procedure it should be clear what is measured in the assay and what the results imply. Furthermore, reference samples and standards may be used and/or introduced during measurements and machines should be checked and calibrated regularly. However, little information can be found on validation, especially on validation test for CTMP. Since different tests require different forms of validation, the information for validation should be easily accessible in order to help in the validation process.

5.4. Preclinical toxicity tests Toxicity studies for medicinal products should only be performed in relevant animal models. For the development of anticancer drugs the EMA published a note, describing the minimal considerations for initial clinical trials in patients with advanced cancer whose disease is refractory or resistant to available therapy, or where current therapy is not considered to be providing benefit (20). This note was published for small molecules and biotechnologyderived pharmaceuticals and describing that prior to phase I studies the a minimum of safety (effect on vital organ function), pharmacokinetics and general toxicology is recommended to test in an appropriate animal model with the same tumor types intended for clinical evaluation. The toxicity studies and in vivo potency testing of a CTMP form a problem. The choice and availability of an appropriate animal model is difficult, due to the inherent immunological differences between man and animal. For most CTMP preclinical toxicity studies in animal models is useless. The main problem is that in most animal models the cells will be rejected. If the cells are not immediately rejected, it is suggested to combine the studies with safety, pharmacology, local tolerance or proof of concept and efficacy studies (18). No regulations on the toxicity testing have been described for CTMP, so far. Toxicity studies in animals should only be performed when relevant information will be expected. When no relevant animal model is present, no relevant answer will be found. As an alternative, in vitro (potency) testing can be suggested to verify biological activity. Furthermore, a risk analysis can be performed when no animal model is present. Discuss which aspects can not be tested, what is relevant to know and what will be the consequence or risk for the patient. As a guideline for a risk based approach an article of Kenter and Cohen can be informative (21).

5.5. GMP-license ‘fabrikantenvergunning’ As already indicated the performance of clinical trials has to apply to the WMO and therefore the production of investigational medicinal products should be performed under GMPconditions as part of an EU manufacturing license. Currently, most - if not all - CTMP are prepared in hospitals for a single patient or at a small scale (i.e. 1 batch for a maximum of 5 patients) as part of CCMO-approved clinical trials. In 2010, the IGZ introduced a procedure for production and clinical application of CTMP as part of the earlier mentioned Hospital Exemption. Since the Hospital Exemption procedure does not apply for CTMP that are being used in clinical trials, the WMO is leading. Consequently, all CTMP need to be prepared as part of a GMP manufacturing license.

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Obviously, CTMP cannot be sterilized in their final container. Therefore, CTMP will need to be prepared under aseptical conditions. Since the GMP guidelines are not developed for individual preparations, it is expected that the requirement of a GMP-license for aseptical production as described in GMP Annex 1 (16) will form a challenge for many translational research laboratories. Hopefully, the IGZ will keep in mind the individual character of the CTMP when inspecting translational laboratories for their GMP-license for CTMP.

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Websites CBG-MED

http://www.cbg-meb.nl/cbg/nl

CCMO

http://www.ccmo-online.nl

Forms

http://www.ccmo-online.nl/main.asp?pid=10&sid=13

IMPD and IB

http://www.ccmo-online.nl/hipe/uploads/downloads/Toelichting-IMPD.doc

http://www.ccmoInstruction manual online.nl/hipe/uploads/downloads_cati/Instruction%20manual%20versie%202.p df

EMA

http://www.ema.europa.eu

CAT

http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general _content_000126.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac058 00292a5

CHMP

http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general _content_000094.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac058 0028c79

GMP

http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

Eudralex GMP

http://ec.europa.eu/health/documents/eudralex/index_en.htm http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

Eur-lex

http://eur-lex.europa.eu/en/index.htm

GGO loket

http://bggo.rivm.nl/paginas/loket.htm

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References 1.

Gastineau, D. A. Will regulation be the death of cell therapy in the United States? 2004 Bone Marrow Transplant. 33:777-780.

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Salmikangas, P., Flory, E., Reinhardt, J., Hinz, T., and Maciulaitis, R. Regulatory requirements for clinical trial and marketing authorisation application for cell-based medicinal products. 2010 Bundesgesundheitsblatt.Gesundheitsforschung.Gesundheitsschutz. 53:24-29.

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Wet van 26 februari 1998, houdende regelen inzake medisch-wetenschappelijk onderzoek met mensen (Wet medisch-wetenschappelijk onderzoek met mensen). 1998 Staatsblad 161:1-11.

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Commission Directive 2001/20/EC of the European Parliament and of the Councilof 4 April 2001 on on the 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 medicinal products for human use. 1-5-2005 OJ L 121:34-44.

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Wet van 24 november 2005 tot wijziging van de Wet medisch-wetenschappelijk onderzoek met mensen en de Wet op de Geneesmiddelenvoorziening ter implementatie van richtlijn nr. 2001/20/EG inzake de toepassing van de goede klinische praktijken bij de uitvoering van klinische proeven met geneesmiddelen voor menselijk gebruik (Wetenschappelijk onderzoek met geneesmiddelen). 2006 Staatsblad 3:1-13.

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Wet van 24 november 2005, houdende wijziging van de wet tot wijziging van de Wet medischwetenschappelijk onderzoek met mensen ter implementatie van richtlijn nr. 2001/20/EG inzake de toepassing van de goede klinische praktijken bij de uitvoering van klinische proeven met geneesmiddelen voor menselijk gebruik (Wetenschappelijk onderzoek met geneesmiddelen). 2006 Staatsblad 4:1-3.

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Wet van 8 februari 2007 tot vaststelling van een nieuwe Geneesmiddelenwet. 2007 Staatsblad 93:1-53.

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Wet van 6 februari 2003, houdende regels inzake de veiligheid en kwaliteit van lichaamsmateriaal dat kan worden gebruikt bij een geneeskundige behandeling (Wet veiligheid en kwaliteit lichaamsmateriaal). 2003 Staatsblad 90:1-7.

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Besluit van 17 januari 2007, houdende nieuwe eisen inzake de veiligheid en kwaliteit van lichaamsmateriaal (Eisenbesluit lichaamsmateriaal 2006). 17-1-2007

10. Regulation (EC) No. 1394/2007 of the European Parliament and of the Council of 13 Novemeber 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Reg (EC) No 726/2004. 1012-2007 OJ L 324:121-137. 11. Oostendorp, J., de Goede, A., and Slaper-Cortenbach, I. Advanced therapy medicinal products – entering the hospital pharmacy arena. 2010 European Journal of Hospital Pharmacy Practice 16:53-55.

12. 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. 15-9-2009 OJ L 242:3-12.

13. EMEA website: http://www.ema.europa.eu. 2010

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14. EMEA website: http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_ 000126.jsp&murl=menus/about_us/about_us.jsp&mid=WC0b01ac05800292a5. 2010

15. Celis, P. CAT--the new committee for advanced therapies at the European Medicines Agency. 2010 Bundesgesundheitsblatt.Gesundheitsforschung.Gesundheitsschutz. 53:9-13.

16. Good manufacturing practice (GMP) Guidelines. EudraLex - Volume 4 of "The rules governing medicinal products in the European Union". 2011

17. 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 tissues and cells. 9-2-2006 OJ L 38:40-52.

18. EMEA: Committee for Medicinal Product For Human Use (CHMP). Guideline on Human Cell-Based Medicinal Products. 1-9-2010 EMEA/CHMP/410869/2006

19. USPharmocopeia (31-NF26S2, . Ancillary materials for cell, gene and tissue-engineered products.

20. EMEA: CHMP/ICH. Note for Guidance on Nonclinical Evaluation for Anticancer Pharmaceuticals (ICH Topic S9) . 2008 EMEA/CHMP/ICH/646107/2008

21. Kenter, M. J. and Cohen, A. F. Establishing risk of human experimentation with drugs: lessons from TGN1412. 14-10-2006 Lancet 368:1387-1391.

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