«Flexible manufacturing – utilizing disposable-based technology for Mab manufacturing in a multi-product facility Jonas Öjerstam Molecular ...»
UPTEC X08 041
Examensarbete 30 hp
Flexible manufacturing – utilizing
disposable-based technology for
Mab manufacturing in a multi-product
Molecular Biotechnology Programme
Uppsala University School of Engineering
Date of issue 2008-10
UPTEC X 08 041
Flexible manufacturing – utilizing disposable-based technology
for Mab manufacturing in a multi-product facility
A fictive future monoclonal antibody production facility was modelled for manufacturing of several products. This was done to evaluate potential flexibility benefits and the economic feasibility of novel disposable-based manufacturing technology. A range of scenarios were identified were disposable-based technology was economic favourable compared to traditional stainless steel technology.
Keywords Disposables, single-use technology, monoclonal antibodies, biopharmaceutical manufacturing, production simulation, scheduling, multi-product manufacturing Supervisors Karol Lacki GE Healthcare Scientific reviewer Günther Jagschies GE Healthcare Project name Sponsors Language Security English Classification ISSN 1401-2138 Supplementary bibliographical information Pages Biology Education Centre Biomedical Center Husargatan 3 Uppsala Box 592 S-75124 Uppsala Tel +46 (0)18 4710000 Fax +46 (0)18 555217 Flexible manufacturing – utilizing disposable-based technology for Mab manufacturing in a multi-product facility Jonas Öjerstam Populärvetenskaplig sammanfattning Användningen av engångsutrustning ökar inom produktionen av bioteknologiska molekyler, som antikroppar och proteinläkemedel. Idag finns engångsutrustning som alternativ för alla procedurer i produktionsprocessen; allt ifrån bioreaktorer upp till hundratals liter till engångskolonner upp till 20 L. Grundtanken är att allt material som kommer i kontakt med processvätskan ska bytas ut kontinuerligt. Istället för att använda dyr stålutrustning används istället material av plast. Implementering av den nya teknologin medför ökade kostnader för förbrukningsvaror, men teknologin har även en rad fördelar, däribland minskad risk för kontamination, ökad flexibilitet, minskade kapitalinvesteringar ochledtider, och färre rengöringsprocedurer.
I detta projekt utvärderades några utav flexibilitetsfördelarna med engångsutrustning vid produktion av monoklonala antikroppar i en fiktiv fabrik designad för produktion av flera produkter. Den nya engångsteknologin jämfördes också med traditionell stationär stålutrustning när det gäller produktionskostnaden per gram antikropp. Modeller för produktionsprocessen, schemaläggning och kostnadsberäkning utvecklades för en fabrik som antingen baserades på engångsutrustning eller traditionell teknologi.
Fabriken designades med en total reaktorvolym på 10 000 L och tillverkning för 10 produkter planerades. Fabriken som baserades på engångsutrustning fick en produktionskapacitet som var 34 procent högre än för den traditionella fabriken. Ett resultat som berodde på snabbare omställning mellan produkter och körningar inom samma produktkampanj. Engångsteknologin möjliggör en annan design av fabriken, vilket ledde till minskat behov av arbetskraft och bättre utnyttjning av utrustning. Trots fördelarna var, i basfallet, tillverkningskostnaden per gram antikropp högre i den nya fabriken, vilket framförallt berodde på höga kostnader för ett väldigt dyrt material (Protein
A) som kan återanvändas många gånger i den traditionella processen. Om materialet kunde återanvändas 3 gånger i den nya processen var produktionskostnaderna lika. Vidare visade resultaten att engångsutrustning var att föredra vid låg kapacitetsutnyttjning och mindre skala. Resultaten visade en rad scenarios när fabriken baserad engångsutrustning gav en lägre tillverkningskostnad.
Examensarbete 30 poäng Civilingenjörsprogrammet Molekylär Bioteknik Uppsala Universitet oktober 2008 Table of contents 1 Introduction
1.2 Scope of the study
2.1.2 Market environment
2.2 Monoclonal antibody production
2.3 Disposable versus Stainless steel technology
2.4 Bioprocess simulation modeling
2.4.1 Capabilities of today’s simulators
2.4.2 The role of process simulation
4 Base case setup
4.1 Process description
4.1.1 Stainless steel process
4.1.2 Disposable based fed-batch process
4.1.3 Disposable-based perfusion process
4.2 Facility design
4.4 Cost assumptions
4.4.1 Capital investment
4.4.2 Cost of goods
5 Results and discussion
5.1 Changeover and capacity analysis
5.2 Equipment requirements and utilization
5.3 Different production scales
5.5 Capital investment comparison
5.6 Cost of goods comparison
5.7 Sensitivity analysis
5.8 Scenario analysis
7 Future research
A1. Changeover delay
A2. Annual number of batches
Abbreviations BNE Bottleneck Equipment COG Cost of Goods Conventional conv CIP Cleaning in Place DSP Downstream processing DISP Disposable-based MAb monoclonal Antibody RtP Ready-to-process SIP Steam in Place SP Schedule Pro SPD Super Pro Designer SS Stainless Steel 1 Introduction
1.1 Problem The number of biologics, like antibodies and vaccines, in the pipelines of biopharmaceutical companies is increasing . Among several factors related profitability for biologics, time-to-market, manufacturing flexibility and cost-effectiveness has been identified to be among the key ones . A fast market penetration can mean the difference between a block-buster drug and a drug that is just covering research and development expenditures . To cope with the need for a quick introduction of a new drug to the market after drug approval, the manufacturing facilities must be more flexible in terms of fast changeover between products and fast startup times. Furthermore, to maximize profitability and productivity, biopharmaceutical companies try to reduce process maintenance costs and minimizing system downtime, two of the most price-sensitive aspects of manufacturing . All of these improvements must be done without sacrificing product quality, safety and compliance with regulations.
Issues liked those described above have led to the development of flexible manufacturing concepts that enable design and operation of multiproduct facilities. The concept of flexible manufacturing is often closely related to disposable technologies and/or single use technologies. Contract manufacturing organizations (CMOs) have taken the lead in implementing the new disposable technology because of the intrinsic multi-product character of their production . For pharmaceutical companies to adopt the technology, quantitative measures of the advantages of disposables are welcomed. To achieve this, computer simulation tools can be used to model different production scenarios and compare different production technologies.
1.2 Scope of the study The aim of the study is to examine aspects on the use of disposable technologies in manufacturing of monoclonal antibodies. The aspects in focus are the potential flexibility that can come with an implementation of disposables when producing several products and the economic viability of disposables at a larger scale.
To achieve this objective, a comparison of two future multi-product manufacturing facilities producing monoclonal antibodies using either new disposable technologies or conventional stainless steel equipment will be done using process and scheduling simulations.
2.1 Biopharmaceuticals 2.1.1 Definition Biopharmaceuticals can be defined as “medical drugs that are produced using biotechnology. Biopharmaceuticals are proteins (including antibodies), nuclide acids (DNA, RNA and antisense oligonucleotides) used for therapeutic or in vivo diagnostics purposes, and are produced by means other than direct extraction from a native (non-engineered) biological source.” .
2.1.2 Market environment The biopharmaceutical market is growing faster than the traditional small molecules market and biopharmaceuticals has become a multi-billion dollar industry [1, 7].
The biopharmaceutical market has been dominated by recombinant protein products.
Many of these product segments have become mature and instead technology advances have open for rapid growth of monoclonal antibodies products.
The main therapeutic areas for new biopharmaceuticals in the next few years are oncology, central nervous system diseases, cardiovascular, autoimmune diseases, inflammatory diseases, diabetes, hormone/enzyme replacement, respiratory and infectious diseases .
Oncology is considered to be the major driving force for market growth in the coming years.
Advances in diagnostics and biotechnology in general could lead to realization of the personalized medicine concept, in which an increase in the number of products in the market, but with lower demand, is anticipated. The usually high doses in therapeutics with biopharmaceuticals have the opposite effect giving high production demand. Today, biopharmaceutical products are very expensive due to high development and production costs. Drug expenditures of governments and other healthcare providers are rapidly increasing, making the providers implement a cost-to-benefit view when choosing drug treatment subsidizes. The cost containment policies practiced in most developed countries are a major barrier to market growth for biopharmaceuticals. To get a wide use of biopharmaceuticals, manufacturing companies must be able to produce many products with varying demand to an acceptable cost per dose. This has led to an increased attention on effective production and new production technologies.
Biogenerics, generic biopharmaceuticals launched by a competitor after patent expiration, poses a threat to the biopharmaceutical market. For every month of delayed production, companies lose time on their patent life-time. In addition, a later market entry significantly increases the risk of competitors being first in the market introducing a substitute drug.
Thus, fast time-to-market is crucial for the success of biopharmaceuticals.
2.2 Monoclonal antibody production In this report the production of the monoclonal antibodies (MAbs) will be studied. MAbs are used in diagnostic tests as well as in therapeutic treatments. The market for MAbs is growing in relative importance. Platform procedures both upstream and downstream have been developed. Therefore, a facility producing MAbs is suitable for examining advantages of new production technologies like disposable systems. The production is demanding both in terms of capacity requirements and technology. Therapeutic MAbs require doses of several milligrams up to grams for the whole course of therapy . This kind of product can have a world demand of hundreds of kilograms per year.
The most commonly used expression system of recombinant antibodies is mammalian cells like Chinese hamster ovary (CHO) and murine lymphoid cell lines . Major improvements in the productivity of these mammalian cell cultures have been made in the last decades. Today, new antibody products can have titers (product concentration in harvest) of 5 g/L , as compared to under 1 g/L ten years ago . This improvement of in the upstream processes has led to a pressure to increase performance of the downstream purification.
2.3 Disposable versus Stainless steel technology The value of disposable technologies is getting more and more accepted within the industry. Even though disposable alternatives exist for every procedure in the production process, fully disposable systems have not yet been widely implemented, but incremental increases in integration of disposables in manufacturing processes have been seen .
The conventional stainless steel technology is associated with a fixed design. Stainless steel tubing and other components for mixing and storage require much space whether they are in use or not. Single-use containers can use space more efficiently as they can be moved around the facility on portable holders. Only equipment that are to be used take up space in the expensive production area, other equipment can be stored in cheap storage areas.
The support holders are often collapsible when not in use. The single-use components are not stored after use, instead they are discarded.
The number of stainless steel equipment is fixed and requires large capital investment.
Disposable bags are just-in-time consumables shifting the cost later in time, from capital investment to operating costs. As operating cost they become variable and only appear when the facility needs them. The steel vessels, which once installed will remain in place, experience more idle time.
The extensive costs and time consumption for the cleaning required in with stainless steel technology have been one of the main arguments for developing disposable systems .
Components in contact with processing fluids must be cleaned and sterilized before use.
Operations called SIP (steam-in-place) and CIP (clean-in-place) must be used between every batch in reused equipment which has been in contact with process fluids to minimize risk of contamination. Portable SIP stations and CIP skids are often used but the operation can also be integrated as a part of the equipment to be cleaned. Apart from just increasing the procedure turnaround time (with 1.5-3 hours), cleaning requires large amounts of WFI (water for injection), chemicals, steam and labor which all cost money . In addition the waste must be treated. It is commonplace that disposable components are presterilized by the supplier and are “ready-to-use”. As a consequence, the number of cleaning utility systems can be reduced which have impact on the capital investment when constructing a new facility and reduces the commissioning and validation of their operations.