PROCESS DEVELOPMENT FOR THE PRODUCTION OF HUMAN CELL AND TISSUE IN ACCORDANCE TO GOOD MANUFACTURING PRACTICE: OUR EXPERIENCE IN UKM MEDICAL CENTRE

Tissue engineering is a relatively new field that uses living cells, biocompatible materials, and suitable biochemical (e.g., growth factors) and physical factors (e.g., cyclic mechanical loading), as well as combinations thereof, to create tissue-like structures. Most frequently, the ultimate goal is implantation of this tissue constructs into the body to repair an injury or replace the function of a failing organ. The critical functions may be structural (e.g., bone, cartilage), barrier and transportrelated (e.g., skin, blood vessels), or biochemical and secretory (e.g., liver and pancreas) [1]. In order to produce a high quality and safe product, the translation of cell manipulation from research laboratory to Good Manufacturing Practice (GMP) setting is required. Thereafter, standard operating procedures (SOP) are drawn up for each step of the production process (patient’s selection, cell collection, processing, characterization, evaluation and release of the final product), with particular attention given to traceability and quality control of the process and the product Tissue engineering, Stem cell, Good Manufacturing Practice, Processing, Production, Human Cell AR T I C L E IN F O AB S T R A C T KE Y W O R D S Submitted: Accepted: *Both authors contributed equally to this paper **Corresponding Author: Ruszymah Bt. Hj. Idrus Email: Public awareness on cell and tissue therapy treatment has inspired many research laboratories to produce cell and tissue based technology in treating patients. Translation from research base products to clinical application requires a set of internationally recognized guideline to be followed. Good Manufacturing Practise (GMP) is a guideline to ensure the quality and safety of products offered to the consumer meet the standards. Production aspects in a GMP compliant laboratory built for production of human cell and tissue will be discussed briefly in reference to the Pharmaceutical Inspection Convention/ Scheme (PIC/S) Guide and Good Distribution Practice (GDP) Guide. Critical materials that will be used in the production must be clearly defined. Production personnel dedicated to perform the manipulation must be trained to achieve the competency level required. Final product must be handled in a proper manner to maintain the quality and safety of the product. GMP is an internationally recognized guideline and has been followed by manufacturers worldwide. Therefore it is essential to set the production standard in accordance to this guideline so that the product can be distributed in the international market. In this article, we will describe our experience for the establishment and development of the processes involving cell culture and tissue reconstruction in accordance to PIC/S Guide to GMP for Medicinal Products; PE 009-9; 1September 2009 and GDP; Malaysia; First Edition January 2011. Regenerative Research Vol1 Issue 2 Dec 2012 57 [2]. Each step written in the SOP has to be validated to prove the effectiveness of the production steps and it can also be used for scientific evaluations. Therefore, the establishment of culture condition for cell and tissue intended for therapeutic or clinical application should follow the GMP guidelines. Good Manufacturing Practice can be defined as the quality assurance which ensured products such as foods, drugs, medical devices, cells and tissues are consistently produced and controlled in such a way to meet the quality and safety standards appropriate to their intended use as required by the regulatory authority. For clinical grade cells, European Medicines Agency and, the Food and Drug Administration required that the GMP guideline to be followed as it offers optimal defined quality and safety in cell transplantation. This guideline will apply on the development of the building or premises, hiring and training of personnel or staff, standard operating procedures, line of production and quality control, validation of equipments and materials, and packaging and releasing of the final products. It requires that all raw materials are traceable and that production follows validated SOP [3]. In Tissue Engineering Centre, Universiti Kebangsaan Malaysia Medical Centre, Cell Tissue Technology Laboratory, a GMP compliant laboratory with three clean rooms is set up to ensure quality and safety of the final products. The environmental conditions and equipment in this laboratory have been validated and have met specific standards. All critical materials selected for production were suitable for clinical use. The production process will need to be assessed with media fill validation before the actual process can be carried out on patient samples. Selection of Critical Material The substitution of research grade reagents with the appropriate clinical or “for further manufacturing” grade reagents were recommended in order to produce a final product which is suitable for clinical use. According to Pharmaceutical Inspection Convention/ Scheme (PIC/S) and World Health Organization (WHO), the source, origin and suitability of the critical material used in the GMP laboratory should be clearly defined [4]. All critical material must have their product certification such as certificate of analysis, certificate of quality or certificate of sterility. This certificate is important to show that the materials had undergone and passed certain level of quality testing to meet the purposes of the usage. The certificate should include, but not limited to, the product name, product code, batch/lot number, manufacturing date, expiry date and test results if applicable. In our production process, we prefer to use chemicallydefined reagents and human/microbial recombinant alternatives that are produced in a controlled production environment rather than animal-derived products. This is because the current good manufacturing practice (cGMP) applies strict qualification process for animal-derived products e.g. herd qualification, livestock processing establishment qualification, assessment of viral safety data or Transmissible Spongiform Encephalopathy (TSE) risk. GMP products guarantee an acceptable level of consistency, potency and purity for these key components of our processes [2]. For safety reasons, autologous human serum will be used in place of fetal bovine serum (FBS) as supplements to our culture medium since we have proven in earlier studies that human serum is equal i