Manufacturing development and comparability assessments of Cell and Gene Therapy products for marketing in Europe

Transcription

1 Manufacturing development and comparability assessments of Cell and Gene Therapy products for marketing in Europe Margarida Menezes Ferreira Senior Assessor at INFARMED PT expert at BWP/CHMP - EMA member of the CAT - EMA (margarida.menezes@infarmed.pt) I attend this conference as an individual expert and do not represent the CAT. The views expressed here are my personal views, and may not be understood or quoted as being made on behalf of the CAT or reflecting the position of the CAT

2 ADVANCED THERAPY MEDICINAL PRODUCTS - ATMP Gene Therapy Medicinal Products Somatic Cell Therapy Medicinal Products Tissue Engineering Products Genetically modified cells medical device + ATMP combined ATMP

3 MAAs / CAT APPROVED AND LATER WITHDRAWN: ChondroCelect for cartilage repair, 2009 *(withdrawn 06/2016) MACI for cartilage repair, 2012 *(closure of EU manufacturing site 09/2014) Provenge for treatment of advanced prostate cancer, 2013 *(withdrawn 05/2015)) APPROVED : Glybera for treatment of LPL deficiency, to be withdrawn 10/2017 Holoclar for treatment of limbal stem cell deficiency, 2015 Imlygic for treatment of advanced melanoma, 2015 Strimvelis for treament of ADA-SCID, 2016 Zalmoxis for treatment of high-risk haematological malignancies (adjunctive to HSCT), ATMPs under evaluation, several new ones expected

4 ADVANCED THERAPY MEDICINAL PRODUCTS ARE BIOLOGICAL MEDICINAL PRODUCTS BIOLOGICAL SUBSTANCE : + produced by or extracted from a biological source + characterisation and quality control based on physicochemical-biological testing together with the production process and control. Diective 2001/83/EC annex 1

5 ICHQ8 Q9 Q10 Q11 now Q12 applies to chemical and biotechnological products ICH Q8 formulation development of final product focused on chemicals defines QbD ICH Q9 Introduces the risk analysis approach required to understand process validation under QbD Document seen only in inspection ICH Q10 Sets the pharmaceutical quality system : process performance - state of control ensured - continual improvement verified in inspection ICH Q11 Process development and manufacture of active substances based on ICHQ9 Chem + Biotech for MA assessment ICH Q12 ongoing Process life cycle management - Defines established conditions and post-approval changes connection to variations regulation Chem + Biotech bio - MA assessment 5

6 Mab.. plasmid viral vector. cell Known complexity Platform knowledge Cell bank for entire life cycle Purified Variants and impurities controlled Microbiological/viral safety built in purification Complexity multifactorial / dynamic Single process / activation, modification Cell autologous / cell stock Separation not purification Poor definition of impurities Safety only through materials procurement and aseptic process

7 Cell Therapy is QbD Possible?

8 Dominici et al. Cytotherapy (2006) Vol. 8, No. 4, Rama et al. N Engl J Med 2010;363:147-55

9 ICH Q11 development and manufacturing of active substances For BIO/BIOTECH not directly usable to ATMP but relevant for general principles on process development and control strategy Process key elements CQA, CPP, control strategy applicable : - history small scale model changes require comparability - target product profile complex and often poorly defined - comparability difficult for CBMP define final process as early as possible Not so applicable to control of impurities - definition of product related substances and impurities challenging Traditional or enhanced approach not mutually exclusive can be partial enhanced approach very difficult but partial eg. multivariate DoE to singled CQA possible? eg. biological reagent combination for optimum cell profile / differentiation in autologous setting if target profile allows! Limited to certain units of operation Difficult to foresee a design space

10 Active Substance consistency for MA From process characterisation to process validation Developed for biotech but

11 PROCESS CHARACTERISATION 1. process development setting the process: for each step - identification of : INPUTS material attributes (starting, raw,, process parameters - OUTPUTS quality attributes, process performance indicators Justified by risk based approach / scientific knowledge

12 PROCESS CHARACTERISATION 2. process evaluation studying the process: for each step : linking INPUT ranges with OUTPUT relevant quality criteria define process parameter acceptable ranges Platform knowledge eg. viral vector manufacturing Non standard conditions healthy donor vs patient materials Small scale models cell culture

13 PROCESS VERIFICATION Developed for biotech but final manufacturing process is able to produce an active substance or intermediate meeting its predetermined acceptance criteria, on an appropriate number of consecutive batches produced with the commercial process and scale. Small scale studies correlated with commercial scale Prospective process validation expected Continuous process verification requires extensive process performance knowledge Prospective validation preferred Concurrent validation : Ongoing process verification protocol recognised in ATMP-GMP 13

14 CHANGE MANAGEMENT Raw material - Supplier qualification linked to ongoing process verification protocol Start early from development to validation Small scale studies enable acceptance criteria Studies on critical raw materials might require comparability Managed through pharmaceutical quality system

15 COMPARABILITY Gene Therapy Medicinal Products Cell based Medicinal Products : somatic cell therapy tissue engineered Genetically modified cells (gene therapy) Margarida Menezes Ferreira

16 Gene Therapy Medicinal Products Margarida Menezes Ferreira

17 Appropriate comparability studies according to the principles outlined in ICH Q5E for biotechnological/biological products should be conducted in order to demonstrate comparability of the pre- and post-change product. The criteria for determining comparability of GTMP medicinal products after manufacturing changes should be justified.

18 genotypic and phenotypic identity, purity - ratio of infectious to non-infectious particles Empty particle number Particule size / aggregates biological potency/therapeutic sequence activity, infectivity/transduction efficiency replication capacity

19 Mostly Q few NC considerations NOT COMPARABILITY GUIDANCE Change in vector design Change in packaging cell line Retroviral transduced cell product Adenoviral vector humanised Plasmid selection marker change Encapsulated cells promotor change AAV serotype change RV to RV-SIN

20 Cell based Medicinal Products : somatic cell therapy tissue engineered Genetically modified cells (gene therapy) Margarida Menezes Ferreira

21 Sources of variability in cell therapy MATERIALS Donor Collection Cell starting material Biological raw materials MANUFACTURE Same process different cell dynamics different differentiation stages Complex process multiple stages holding steps Length of process CONTROL Bioanalytical methods No standardised reference materials ADMINISTRATION Complex system often surgical procedures Patient response

22 GUIDELINE ON HUMAN CELL-BASED MEDICINAL PRODUCTS small section on comparability Critical steps identified during development needed for comparability analytical tools for comparability should be established through product development. Develop comparability tools as early as possible During the pivotal clinical studies changes should not be introduced to the manufacturing process and the final product. guidance can be found in ICH Q5E Comparability 22

23 ICHQ5E quality considerations DIFFICULT TO APPLY CHARACTERISATION AND CONTROL - specs PROTEINS / PEPTIDES Directive 2003/63/EC Quality in ICH Q6B : physicochemical properties, biological activity, immunochemical properties (if any), purity, impurities, contaminants, and quantity. structure of the active substance(s) based on physico-chemical and/or immunochemical and/or biological methods + impurities + safety aspects MOLECULAR ENTITY CELLS Directive 2009/120/EC Quality = identity, purity, viability, potency, karyology, tumourigenicity, genetic stability. Identity / purity as heterogeneity profile Biological characterisation complex surrogate testing required to be valdated with functionality assay(s) non-clinical investigations often complement biological characterisation. extracellular matrix part of a tridemensional product COMPLEXITY + DYNAMIC 23

24 ICHQ5E scenarios - too strict for CBMP? HIGH SIMILARITY based on quality attributes almost impossible ANALYTICAL PROCEDURES used are not sufficient to discern relevant differences that can impact the safety and efficacy of the product. Potency often based on surrogate markers and combined testing approaches - difficult to interpret in terms of comparability. DIFFERENCES JUSTIFIED due to no adverse impact on safety or efficacy how to justify dynamic aspects that are difficult to address? PRODUCT RELATED IMPURITIES - cells of unwanted lineage, or undifferentiated, supportive cells how to qualify impurities as part of the comparability exercise. Should there be compliance to range or maximum limits? PRODUCTS NOT HIGHLY SIMILAR = NOT COMPARABLE cells will hardly be highly similar ALWAYS NECESSARY TO CONFIRM SAFETY AND EFFICACY? 24

25 ICHQ5E general principles apply ICH Q5E on comparability should be considered as broadly applicable to CBMP - link specific requirements to broader guidance and avoid overlapping. comparability exercise should start with quality data and then continue as appropriate with non-clinical and clinical studies. the product should be evaluated at the process step most appropriate to detect a change in the quality attributes. This may entail evaluating the product at multiple stages of manufacture. extent of studies will depend on: o the production step where the changes are introduced; o potential impact on the purity as well as on the physicochemical and biological properties of the product, particularly considering the complexity and degree of knowledge of the product (e.g., impurities, product related substances) o suitability of analytical techniques to detect potential product modifications and results o relationship between quality attributes and safety and efficacy, based on overall nonclinical and clinical experience. 25

26 ICHQ5E general methodology apply Comparability exercise include: Extended characterisation; assessing critical control points in the manufacturing process that affect product characteristics (e.g., intermediate, drug substance, and drug product); need for stability data, including from accelerated or stress conditions, to identify differences in the degradation pathways of the product and, hence, potential differences in product-related substances and product-related impurities; demonstration of manufacturing consistency; redefine in-process controls including critical control points to maintain the quality historical data to provide insight into potential drift of quality attributes with respect to safety and efficacy Consider nonclinical or clinical characteristics of the drug product and its therapeutic indications 26

27 What quality atributes for comparability? GUIDELINE ON HUMAN CELL-BASED MEDICINAL PRODUCTS EMEA/CHMP/410869/2006 Identity markers, morphology, cell interactions, metabolism, matrix, scafold Cell purity relevant cells, ratio of viable to non viable Impurities : product / process unwanted cells, degradation products, metabolites / adventitious agents, bioactive reagents Potency according to intended function required for comparability, consistency and stability Tumourigenicity, Karyology, Genetic Stability Release specifications for final products or intermediates : identity, purity, potency, impurities, sterility, cell viability and total cell number, structural component (Directive 2009/120/EC) SPECIFICTIONS + EXTENDED CHARACTERISATION 27

28 Product characterisation : PURITY CHARACTERISATION physico-chemical PURITY = phenotypic and genotypic profile = Phenotype + Quantify / viable total (flow cytometry) - Relevant cells - Deleterious cells - Apoptotic cells - Non viable cells - Cell debris - Exosomes = Genotype (sequencing PCR STR) - clonal cells - differentiation stage - non genetically modified genetic stability Margarida Menezes Ferreira

29 Product characterisation : POTENCY Release stability - consistency comparability Potency should reflect relevant biological properties mode of action Potency is quantitative specificity, sensitivity to deviant analyte and accuracy Standardisation necessary define reference preparations for cross referencing Multifactorial aspects might need to be considered multiple assays Functional assay often needed 29 Margarida Menezes Ferreira

30 Difficulties with potency of CBMP insufficent knowledge on the active component(s) limited sample size / shelf life (autologous, primary cells) unknown mode of action / lack of appropriate biological atribute Structural complexity / Multifactorial actions - poor specificity Interfering substances / poor parallelism - poor accuracy inappropriate tools acceptance criteria / specifications too wide non linearity characterisation under dynamic conditions 30

31 CBMP scenario: periodic introduction of new cell stock MCB often with limited time span not covering the entire life cycle of the product Validated process from various cell stocks Establish a predefined comparability program applied to various lots originated from several stocks Include accelerated/stressed stability data Validate the process with different stocks Comparability protocol acceptable DO AND RECORD procedure scenario already in GMP-ATMP 31

32 CBMP scenario: Technology transfer Multiple sites with same manufacturing process often required for autologous setting Enhanced focus on critical manufacturing steps IPC s, intermediates quality atributes and stability Manufacturing process validated for multiple sites with comparable outcome statistical considerations Side by side comparability exercise of statistically significant number of batches Comparability of analytical methods Split samples when possible 32

33 Genetically Modified Cells (GMCell) characterisation Revision just started! Requirements as in the Guideline on human cell-based medicinal products (EMEA/CHMP/410869/2006) + Absence of adventitious viruses, replication-competent vector, transposase sequences (when using transposon vectors) transduction efficiency, vector copy number, sequence of transgene (and of other regions as needed), level of transgene expression, quality of the expressed molecule(s),.

34 Comparability of GM-CELLS Viral vector changes Critical process steps CPP Consistency of the cell bank Infectious viral titre / total particules Infectivity Transgene sequence Transgene expression Stability Confirmation of transgene expression in permissive cell Transduced cells Critical process steps - CPP Immunophenotypic profile Transduction efficiency Vector copy number Transgene sequence Biological characterisation Potency Stability Confirmation with patient cells

35 Comparability - Change management Change in raw materials Change in starting materials - viral vector - cells Process improvement Tech transfer Multiple sites Consult authorities how to approach comparability requirements Changes during clinical trials require prior approval (substantial amendment) Consult Variation Regulation + GL on specificities Revised 2012 DIFFICULT BUT DOABLE START AS EARLY AS POSSIBLE 35

36 THANK YOU! 36