Drug substance manufacturing process (The CMC Development Plan is initiated during discovery and preclinical development, and is expected to be in place by the PCD stage gate) Jul 26, 2011 · This case study outlines an application of quality by design principles to a drug substance manufacturing process. Critical steps and intermediate products should be indicated as well as relevant process parameters, in-process controls (IPCs) and acceptance criteria. We will start by looking at the Drug Substance. active pharmaceutical ingredient production, bulk production or primary manufacturing) and drug product manufacturing (a. 1 The goal was to encourage a transition to manufacturing processes and approaches that could produce high-quality drugs reliably without extensive Dec 21, 2010 · Process validation includes laboratory optimization, pilot-plant introduction, and process implementation on manufacturing scale, as well as monitoring batches after implementation and continuously improving the manufacturing processes. Oligonucleotide manufacturing is our core competency. Jan 1, 2020 · As the industry moves toward specialized low volume products, the production process needs to shift from large-scale traditional batch processing to continuous integrated manufacturing (e. We supply ADCs to more than 60 countries. fill-to-finish or secondary manufacturing): The mRNA drug substance is synthesized in the production bioreactor using the in vitro Feb 2, 2012 · The Q11 document includes several illustrative examples for application of Q11 principles to the drug-substance manufacturing process, including how to: link material attributes and process parameters to drug-substance CQAs, select appropriate starting materials, use quality risk management to support life-cycle management of process parameters Jan 1, 2018 · A typical ADC product supply chain in which the antibody and small molecule drug are produced and released as intermediates, which are then conjugated in the ADC drug substance manufacturing process. We were the first CMO to serve the oligonucleotide therapeutic market. Lyophilized, liquid, frozen and co-formulations for drug product. Opt to partner with a manufacturer that provides all three and seamlessly pivot as demand evolves throughout different clinical phases, affording a dynamic, cost Jun 1, 2006 · modification occurs near the end of a drug substance manufacturing process rather than the beginning. 2. Each molecule has unique requirements and challenges, and a variety of solutions for drug substance synthesis and manufacturing are available, so it is important to have a keen understanding of the strategies that can help streamline these processes Manufacturing process optimization completed a) Design-of-experiments and quality-by-design (QbD) methodology with consideration given with ICH Q8, Q9 and Q10 guidance b) Drug substance manufacturing process optimization, scale-up, and pilot studies (e. For the protein-based biopharmaceuticals (recombinant proteins and monoclonal antibodies) and the viral vectors, many times the drug substance is formulated during the last purification step (UF/DF allows exchange of buffer solution including introduction of During early product and process development • Risk assessment can help identify the material attributes and process parameters with the potential for impacting drug substance CQAs. 22, 28, 45, 57, 64 The final formulated product is typically labeled as the drug substance (DS) or bulk drug substance (BDS). Drug Substances Manufacturing . 14 • Data to support the proposed structure (e. Aug 30, 2023 · Pharmaceutical formulation is the multistep process where the active drug is mixed with all other components by considering the factors of particle size, polymorphism, pH, and solubility and becomes the final beneficial medicinal product. DESCRIPTION OF MANUFACTURING PROCESS AND PROCESS CONTROLS [{DRUG SUBSTANCE NAME}, {MANUFACTURER}] The description of the drug substance manufacturing process represents the applicant’s regulatory commitment for the manufacture of the drug substance. 3 depicts the typical steps of the DP manufacturing processes, i. , the post-TFF steps in the AAV manufacturing workflow. 3. Pre-formulation research to formulation development for drug substance. Beside the more 3 days ago · The adoption of continuous manufacturing (CM) in the pharmaceutical industry is increasing because of the advantages and opportunities it offers, including the ability to handle hazardous reactions, a higher degree of process integration, and improved sustainability. Our GMP production center follows the internationally leading design concept and is a true "zero-crossover, unidirectional flow" plant, which meets global regulatory requirements. Both branded drug manufacturers filing new drug applications and generic drug companies seeking approval for off-patent products must complete process validation to clearly show that their processes are reproducible and produce batch-to We offer a tailored approach from drug intermediate manufacturing through to drug substance manufacturing. The manufacturing process should be validated using the new route of synthesis. Nov 1, 2019 · Drug substance (DS) appearance is an important quality attribute that is tested before product release. We have the flexibility to produce your first 50 mg of preclinical material, or hundreds of kilograms in support of your As defined in ICH Q8, Q10, and Q11, every drug substance manufacturing process must have an associated control strategy. 10 Process Temperature Control Systems; 7. Oct 6, 2020 · To develop a comprehensive understanding of pharmaceutical drug substance manufacturing (DSM) processes, we conducted a data mining study to examine 50 new drug applications (NDAs) approved in 2010-2016. There are many opportunities to change and optimize operations. The organic impurities to be controlled in the drug substance are the process impurities and degradation products. Feb 24, 2021 · As noted in Chapter 2, production of the nation's drug supply involves manufacture of the drug substances—the active pharmaceutical ingredients (APIs)—and ultimately of the drug products that are delivered to patients. We analyzed the prevalence of several frequently deployed in-process control (IPC) techniques an … Overall, an end-to-end manufacturing process consists of 3 main steps: Drug Substance, Drug Product, and Finished Good. With innovative products working seamlessly together at every scale, as well as over 35 years of applications knowledge and support, our products help you address the complex challenges you face in bringing your purified drug to market. Benefits and constraints of the active pharmaceutical ingredients (APIs), valuable excipients, associated interactions, and manufacturing procedure are the . 6 (ICH M4Q). Apr 11, 2023 · Definition of drug substance. Before we start doing experiments, we focus first on things like which reagents to use and how to make the process as efficient as possible. These impurities are most commonly introduced due to their specific synthetic utility; however, the formation of a PMI can also occur indirectly from a manufacturing process and/or when performed for early steps. 15 Vacuum Systems; 7. The API industry utilizes optical process analytical technologies (PAT) like FTIR, NMR and Raman at various stages of operations. , a viral vector is a starting material for an ex vivo gene therapy, but a drug substance for an in vivo gene therapy) 6. , active ingredient production, bulk production, primary manufacturing) and drug product manufacturing (i. Impurity carryover studies and spike/purge studies should be conducted as appropriate. 3, 4 A functional mRNA structure comprises the 5′ cap, 5′ untranslated region As India’s largest and most trusted Contract Drug Substance manufacturer, Kemwell provides world-class GMP for the production of mammalian cell culture-based biologics. The drug substance can be derived from various sources, including natural sources, chemical synthesis, or biotechnology. Aug 6, 2010 · This guidance addresses the information to be submitted for drug substances to ensure continued drug substance and drug product quality (i. Cell line development (CLD) is a critical activity in biologic manufacturing processes (exception: in autologous cell therapy, where the starting material comes from the patient’s own cells). 12. To accomplish its mission, CDER has a critical role in fostering manufacturing innovations that can improve product quality and prevent drug shortages that have become all too frequent. Antibody-Drug Conjugates (ADC) are one of the more common bioconjugates and are synthesized by biochemically modifying an antibody and covalently linking it to another active pharmaceutical ingredient (API). , equipment or site changes) are viewed as Dec 2, 2008 · From the standpoint of risk control, the manufacturing process stated in the application should include processes that are essential for ensuring drug-substance quality. Rosado ([email protected]) is a process development data scientist, Badua Merheb ([email protected]) is a data sciences senior manager, and Alejandro Toro ([email protected]) is currently the executive director of drug substance process development, all at Amgen Manufacturing Limited in Juncos, Puerto Rico, supporting commercial The process flow diagram for RNA vaccine production is shown in Figure S1 of the SI document both for drug substance production (i. The platform nature of oligonucleotide drug substance manufacturing provides opportunities to optimize process development, streamline process validation, and expedite Feb 24, 2021 · Production of the nation's drug supply involves manufacture of drug substances—the active pharmaceutical ingredients (APIs)—and ultimately the drug products that are delivered to patients. Working with our clients, we have been involved in the development and GMP manufacture of many of the world’s most notable vaccines developed over the last two decades. Some manufacturing processes don't include a separate BDS step and go directly into the bulk regulatory starting material in the drug substance manufacturing process. The background information in this contribution describes current guidance and terminology for Feb 24, 2021 · Ensuring patient access to safe and efficacious drugs is a primary public-health mission of the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER). The controls can include parameters and attributes related to active pharmaceutical ingredients (APIs) and finished drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and The final mRNA manufacturing process was split into 6 primary unit operations based from the above-described process development: a DNA Linearization step, an IVT reaction step, an Ultrafiltration Diafiltration (UFDF1) step, a Chromatography step, a second Ultrafiltration Diafiltration (UFDF2), and finally Bulk Drug Substance filtration and fill. The discussion is organized into three major sections. Drug Substance: Manufacturing Process. The coronavirus pandemic has 2. Typically, the first step of the drug product manufacturing process is the thaw of the drug substance. A workflow for exploring and Jun 12, 2023 · Approval of Prior-Approval Supplement will help to ensure the future, long-term supply and clinical activities for Ferring’s novel intravesical gene therapy for non-muscle invasive bladder cancer (NMIBC) Two new manufacturing sites, including one of the world’s largest viral vector facilities, currently under construction in Finland and the U. 12 Process Bio-Waste Handling; 7. Jun 21, 2018 · As drug substance is typically stored frozen, adequate storage capacity is required at the drug product manufacturing site to warehouse the drug substance within the storage temperature specifications prior to manufacturing. Clients have access to an end-to-end bioconjugate supply chain, all under one quality system supported by global regulatory services. 2 – 3. In the beginning, we don’t pay too much attention to yields as long as the conversion is relatively decent. 1). +91-8026982400 [email protected] Adoption of Process Technologies from Other Industries. May 11, 2024 · Combining process chemistry expertise with analytical solutions for your program. These strategies can be employed to overcome the manufacturing process challenges and streamline process development efforts for high-concentration drug substance manufacturing. e. Eurofins CDMO (Contract Development & Manufacturing Organization) network of companies provides active pharmaceutical ingredient (API) and drug substance development services with pharmaceutical and biotechnology applications for complex, niche, small molecule programs from preclinical to Phase III and commercial Additional considerations for high-concentration drug substance manufacturing, such as appearance attributes, stability, and freezing and handling are also discussed. In addition, tight control of the upstream production process the drug substance manufacturing process beginning with the first use of a “starting material”. The synthetic portion of the manufacturing process for semisynthetic drug substances manufactured by the chemical modification of an intermediate produced by conventional fermentation. 29 Feb 1, 2024 · These activities include development of a manufacturing process for the drug substance, development of a formulation and design of the drug product, analytical development, pre-clinical toxicology and safety studies in animals, cGMP manufacturing of the DS and DP, writing of the common technical document and submission of the IND application to Nov 30, 2023 · Synthetic therapeutic oligonucleotide drug substances are commonly manufactured using the same basic unit operations, i. Manufacturing process development Pharmaron’s small molecule drug substance services provide innovative and cost-effective solutions for drug development. Understanding the difference between these two concepts is crucial for anyone involved in pharmaceuticals, whether they are in research, manufacturing Aug 13, 2023 · 6. Jun 22, 2022 · Continuous manufacturing (CM) is gaining traction in pharmaceutical manufacturing. , pegylation). • A manufacturing approach in which drug substance and drug product unit operations are integrated across the boundary between drug substance and drug product to form a single CM process (i. of onsite cGMP warehouse space; CRL RightSource SM QC testing labs located within the Wheeler premises . First, the quality attributes of the product were evaluated for their potential impact on safety and efficacy using risk management tools. Feb 9, 2023 · Pablo J. Dec 20, 2024 · This process, which is crucial to drug development, entails multiple key steps, from pharmaceutical ingredient synthesis and API manufacturing techniques to bulk drug substance process. A control strategy can include, but is not limited to: controls on material attributes (raw materials, starting materials, intermediates, reagents, primary packaging materials for the drug substance, etc. The goal of manufacturing process development for the drug substance is to establish a commercial manufacturing process capable of consistently producing drug substance of the intended The goal of manufacturing process development for the drug substance is to establish a commercial manufacturing process capable of consistently producing drug substance of the intended quality. For the genetically modied patient cells, the process is continuous from the drug substance to the drug product stage; but arbitrarily, after the nal Feb 1, 2021 · The manufacturing process can be summarized into five steps: (1) development of a stable and productive cell line expressing the gene of interest, (2) production of the desired antibody in host cells in high titres, (3) drug substance purification, (4) formulation steps and appropriate dosage forms (Fill & Finish), and (5) analytical testing Jun 16, 2023 · A flow chart of all successive steps of the drug substance manufacturing process should be provided starting from biological fluid/tissue/organ or from cell banks/viral seeds. Applicant’s commitment for the manufacture of the drug substance. This paper gives an overview of the mRNA/lipid nanoparticles manufacturing unit operations for drug substance/drug product. 11 Cryogenics and Process Cooling; 7. Materials and methods Plasmids and DNA template generation Mar 15, 2022 · Developing robust processes from the outset by building broad and fundamental process knowledge minimizes future validation and revalidation work for drug substance manufacturing. Manufacturing process and process controls. Beside the more efficient, safer, and greener synthesis route, a new process design paradigm and equipment selection and design is required. However, if API manufacturer Jun 29, 2023 · Although product manufacture and process validation of biotherapeutics are performed routinely in the industry, the process for mRNA manufacture is less well established and there are several variations between manufacturers. Technical Report No. Lifecycle Approach Annex 2: Biopharmaceutical . 3, 4 A functional mRNA structure comprises the 5′ cap, 5′ untranslated region An effective control strategy for the drug substance that links changes in drug substance attributes to finished product safety and efficacy ensures that the API manufacturing process consistently produces a product that meets those QTPP and CQAs throughout its life cycle, as shown in Fig. 1, 2 To support these efforts, the manufacturing of high-quality mRNA as drug substance is of utmost importance. Using this case study, unique aspects of the quench-crystallization operation are highlighted and contrasted with the development of more commonly discussed cooling/antisolvent crystallization operations. 1. After receipt of regulatory approval, drug substance manufacturing gets begins. Implementation of the guidance provided in Q11 requires knowledge of applicable ICH guidelines referenced specifically in of Guidance for Industry: Q11 Development and Manufacture of Drug Substances. 2. The RNA drug substance production was modelled based on Catalent Biologics’ drug substance development and manufacturing services leverage advanced technology and proven expertise to help clients meet their biologics drug substance needs. Color variation in DS batches or color change during storage can be indicative of the presence of contaminants, impurities or degradation products and may be linked to the manufacturing process, DS formulation or the stability of the therapeutic proteins. k. Specifically, the committee discusses innovations in unit operations, process intensification, and process drug substance and dosage form and changes in the dosage form itself are likely as the investigation progresses. 3. Our development teams collaborate closely with our bioanalytical testing and manufacturing teams to ensure that processes and products are scalable to clinical Mar 3, 2022 · This intensification will further increase the demand for manufacturing the RNA drug substance (DS) and LNP formulated drug product (DP), which has already been strained by global demand for vaccines against SARS-CoV-2. ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products Apr 1, 2022 · The final mRNA manufacturing process was split into 6 primary unit operations based from the above-described process development: a DNA Linearization step, an IVT reaction step, an Ultrafiltration Diafiltration (UFDF1) step, a Chromatography step, a second Ultrafiltration Diafiltration (UFDF2), and finally Bulk Drug Substance filtration and fill. The assurance should Process flow diagram for mRNA drug substance production (a. , modification of synthetic Jun 16, 2023 · The process stages from the bulk drug substance to the final drug product varies across the different types of biopharmaceuticals. Learn more. 1. ) 4 days ago · The drug substance manufacturing process for biologics consists of several interconnected phases, each requiring specialized expertise and equipment to ensure product quality and efficacy. Information should be provided to adequately describe the manufacturing process and process Drug Substance and drug product formulation development. Is the pre-recovered stream likely to contain any vulnerable amines, nitrosating agents or nitrosamines. Jun 11, 2020 · The book contains information that broadens understanding of various continuous unit operations involved in drug substance and product manufacturing. We describe the development of a triphasic quench-crystallization operation to isolate an intermediate in the manufacture of the sotorasib drug substance. Therapeutic biology encompasses different modalities, and their manufacturing processes may be vastly different. , ADC), and then formulated prior to being held as the bulk drug substance. Therefore, the . The Nanjing pilot manufacturing campus can support preclinical non-GMP toxicology batch manufacturing and clinical phase 1/2 GMP drug substance manufacturing. , solid phase oligonucleotide synthesis, cleavage and deprotection, purification, and isolation. 44 • A manufacturing approachin which drug substance and drug product unit operations are 45 integrated across the boundary between drug substance and drug product to form a single 46 CM process (i. Similarly, process par … Jan 3, 2025 · The drug substance manufacturing process for biologics involves multiple stages, each requiring meticulous attention to detail to ensure the final Drug Product's efficacy and safety. During upstream development, an optimum process is developed to maximize product titer with the correct Quality Target Product Profile (QTPP). Alternatively, it would be possible to combine the antibody intermediate and conjugation processes within a single end-to-end production facility. Amgen’s drug substance manufacturing plant will be located in the Friendship Innovation Park, north-west of Holly Springs and south of US Highway One, in the Raleigh-Durham metro area of Wake County. Mechanistic modeling and simulation tools are being used for equipment The International Society for Pharmaceutical Engineering (ISPE) has organised conferences on CM and has published a number of useful articles, including on sampling considerations in continuous manufacturing and on process validation of small molecule drug substance and drug product CM [134,135]. drug substance manufacturing process. Also, certain kinds of modifications (e. +91-8026982400 [email protected] We strive to produce economical processes for high-purity drug substances that can be rapidly scaled from grams to multi-kilograms and offer innovative solutions when it comes to synthesizing and manufacturing challenging APIs. S. 11 The article describes how Quality by Design principles can be applied to the drug substance manufacturing process of an Fc fusion protein. INTRODUCTION The two main components that make up the pharma-ceutical manufacturing process are those of drug substance and drug product manufacturing. The purpose of this post is to highlight some of the differences between small molecule Drug Substance (DS) and Drug Product (DP) continuous manufacturing (CM), which may be helpful in considering the development and execution of CM for pharmaceutical manufacturing. A hybrid process chemistry model consisting of mechanistic and empirical components was developed to guide the selection and verification of a design space. The current trend is towards increased process integration as opposed to isolated continuous unit operations in an overall batch process and more advanced control strategy approaches including PAT Sep 7, 2021 · Location of the Amgen manufacturing plant in Wake County. In Drug Substance Manufacturing, we provide master / working cell banks, master / working virus seeds, manufacture of bulk drug substance, and multiple manufacturing platforms. , the drug substance is continuously d and processed through forme 47 integrated unit operations to result in the final drug product) 48 While the obtaining/manufacturing of starting materials discussed in Chap. Therefore, commercially available chemical as SM is not required to be performed under cGMP. The first describes innovations in the As a result, pharmaceutical companies increasingly prefer to partner with contract development and manufacturing organizations (CDMOs) that have end-to-end capabilities, where knowledge sharing between process research and development (PR&D), analytical, and formulation teams leads to rapid parallel development and optimization of both drug This commentary brings together expertise and knowledge from biopharmaceutical scientists and discusses the various manufacturing process steps that could adversely impact the quality of drug substance (DS). • The ability of the drug substance manufacturing process to remove that impurity or its derivatives should be considered in the assessment Aug 23, 2023 · Our Mammalian Drug Substance Manufacturing Capabilities There are three major biologic manufacturing strategies, each with specific advantages: scale up, scale out, and continuous. Mar 15, 2022 · Process validation is a requirement of regulatory authorities that involves demonstration of process control. Process Validation: A . The partner of choice, from preclinical to commercial supply. ICHQ13: Continuous Manufacturing of Drug Substances and Drug Products Dec 11, 2023 · In the evolving landscape of pharmaceutical manufacturing, a comprehensive continuous production process is being crafted for the small-scale production of active pharmaceutical ingredients. Is the recovery process likely to introduce and / or purge any of the above. In this chapter, the committee focuses on the manufacture of drug products. Aug 5, 2024 · In the pharmaceutical industry, the terms “drug substance” and “drug product” are frequently used, yet they refer to distinct entities in the drug development and manufacturing process. , perfusion based cell culture, continuous purification steps, and modular filling of drug products) that requires strong fundamental understanding of Advantages of Catalent Biologics’ Drug Substance Manufacturing Services: The development and biomanufacturing teams work closely together to ensure scalability to full CGMP production. 1 Introduction; 8. 13 Drains and Waste Collection; 7. Due to the complex nature of biological products, the drug substance manufacturing process itself significantly impacts product quality, safety, and efficacy. Jun 16, 2023 · A starting material for one gene therapy manufacturing process, can be a drug substance for another gene therapy manufacturing process (e. Drug substance is an active ingredient that is intended to furnish pharmacolog- It is critical to precisely determine the molecular structure of the drug substance throughout the development process. The degree of regulatory flexibility is generally predicated on the level of relevant scientific knowledge provided in the application for marketing authorisation . This manufacturing method has its own challenges. Some manufacturing processes don't include a separate BDS step and go directly into the bulk Jun 29, 2023 · Although product manufacture and process validation of biotherapeutics are performed routinely in the industry, the process for mRNA manufacture is less well established and there are several variations between manufacturers. ICH Q7 states that appropriate GMP (as defined in that guideline) should be applied to the manufacturing steps immediately after “API starting materials” are entered into the process (see ICH Q7 Q&A 1. We hope the valuable insights gained from this study can benefit the process development of mRNA drug substances in the pharmaceutical industry to ensure the consistent and reliable quality of mRNA-based vaccines and therapeutics. Sep 25, 2023 · The goals of this Perspective are threefold: (1) to inform a broad audience, including machine learning (ML) and artificial intelligence (AI) academics and professionals, about synthetic drug substance process development, (2) to break down the general synthetic drug substance process development task into more tractable subtasks, and (3) to highlight areas in which machine learning and Sep 3, 2024 · The drug substance is responsible for the drug’s pharmacological activity, making it the most critical component in the manufacturing process. in drug substances or drug products generated during the manufacturing process and/ USP42 or storage. A multistaged experimental plan was employed to address specific goals at each stage of model development and design space biopharmaceuticals, the puried drug substance is conjugated with either PEGylation or a chemical drug (i. ICH Q11 Development and Manufacture of Drug Substance 6 Control Strategy General Principles Control Strategy is a planned set of controls, derived from current product and process understanding, that assures process performance and product quality Every drug substance manufacturing process whether developed through traditional or hd( biti fbth)h The goal of manufacturing process development for the drug substance is to establish a commercial manufacturing process capable of consistently producing drug substance of the intended quality. This article discusses the considerations and approaches adopted by Pfizer, Eli Lilly, GSK, and Amgen in designing and May 2, 2013 · Several countries have adopted ICH guidelines as law; however, FDA only considers the guidelines as guidance. This study focuses on continuous crystallization with separate nucleation and crystal growth units, as well as continuous downstream processing, encompassing filtration, washing, and drying until the The process development team at Catalent is equipped to work with GPEx® or external cell lines, to develop a process leveraging fed-batch or process intensification technologies (such as N-1 perfusion). 2 Process Oct 6, 2020 · To develop a comprehensive understanding of pharmaceutical drug substance manufacturing (DSM) processes, we conducted a data mining study to examine 50 new drug applications (NDAs) approved in Continuous manufacturing of drug substance and small molecules: process and equipment view The continuous manufacturing of pharmaceutical compounds and fine chemicals is in high interest for the industry due to significant technical, quality, and economical advantages. The similarities between the properties of process streams in biologic-drug production and product streams in other industries—such as the food and beverage, industrial enzyme, plasma fractionation, and wastewater-processing industries—provide opportunities for the adoption of alternative unit operations. Food And Drug Administration (FDA): “Active pharmaceutical ingredient means any substance that is intended for incorporation into a finished drug product and is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of 2. The following are the key differences from our •Annex III: CM of Therapeutic Protein Drug Substances • Augments the main Guideline by providing additional considerations for therapeutic protein drug substances and drug substances used as intermediates for subsequent conjugation (e. 1 Drug Substance Quality Link to Drug Product The intended quality of the drug substance should be determined through consideration Oct 3, 2019 · The challenges in drug substance manufacturing and validation are unique as the process incorporates multiple process loops and the reaction process itself might be a many day process. The organic impurities to be controlled in the drug product are only the degradation products of the drug Jun 26, 2022 · Moving off the critical path: Streamlining strategies for drug substance synthesis and manufacturing. Thanks to advances in cell line engineering and medium development, as well as other intensification strategies such as bioreactor pooling or fed-batch production, today’s antibody manufacturers can take advantage of process intensification techniques to campaign more •Annex III: CM of Drug Substances (Therapeutic Proteins) • Augments the Part I by providing additional considerations for therapeutic protein drug substances and recombinant proteins used as intermediates for subsequent conjugation (e. 9 Process and Utility Gases; 7. NMR, IR, UV) • Structural data may be limited at early stages of development 20 manufacturing process during the drug product 2application’s postapproval period. Details of the Amgen drug substance manufacturing plant Our microbial drug substance manufacturing assets in Visp, Switzerland ranges from 70 L -15,000 L, supporting clinical and commercial manufacture. An applicant can choose either a traditional approach or an enhanced approach to drug substance development, or a combination of both. Control GOALS/DEFINITIONS: A detailed plan to complete initial drug substance (DS) and drug product (DP) characterization, and define the initial cGMP manufacturing process. manufacturing process where the mAb reagent is used to purify the drug substance. 60-3. Thus, understanding and controlling the manufacturing process is essential in ensuring that the biological product consistently meets its intended quality attributes. 6 required adherence either to the principles of GMP or cGMPs, the upstream produc - tion for manufacturing of the biopharmaceutical drug substance requires strict adherence to cGMPs. , the identity, strength, quality, purity, and drug substance manufacturing process beginning with the first use of a “starting material. Drug substance is an active ingredient that is intended to furnish pharmacological activity, directly impact the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the human body, but does not KEY WORDS: drug substance; manufacturing; in-process control; workup procedure. It also provides guidance on what information should be provided in sections 3. drug substance. The process involves multiple intricate steps, including: A Synthesis: The drug's API is synthesized in controlled laboratory environment / conditions. Apr 23, 2021 · The continuous manufacturing of pharmaceutical compounds and fine chemicals is in high interest for the industry due to significant technical, quality, and economical advantages. Adoption of Process Technologies from Other Industries. Open communication between development and production teams also minimizes loss of process knowledge, streamlining process validation and reducing time to market. Drug substances are defined differently by regulatory bodies: U. Jan 1, 2022 · A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. Similarities include the need for Quality Target Product Profile (QTTP), analytical development, formulation development, container Jun 6, 2023 · Synthetic routes to drug products typically introduce several potentially mutagenic impurities (PMIs) which require controlling to a safe level in the final drug substance, generally directed by the control options within the ICH M7 guideline. Wheeler’s drug substance manufacturing services provide our clients with: Up to 500L of drug substance material; BSE/TSE statement; Drug May 25, 2022 · Here we share the results of a streamlined life cycle assessment on a biological bulk drug substance (BDS) manufacturing process utilizing single use technology (SUT) with the goal of highlighting where pharmaceutical companies, biologics producers in particular, can reduce the environmental impact of their drug substance manufacturing. This is often referred to as the API of a product and is always the first step in a pharmaceutical manufacturing process. manufacturing process such that it will consistently produce APIs and drug products meeting those attributes relating to identity, strength, quality, purity, and potency. ISBN: 978-1-945584-24-4 Jul 1, 2024 · Fig. The major process steps discussed here are commonly used in mAb production using mammalian cells. , fill-to-finish or secondary manufacturing). 1 Development Genetics professionals, about synthetic drug substance process develop-ment, (2) to break down the general synthetic drug substance process development task into more tractable subtasks, and (3) to highlight areas in which ML and AI might be beneficially applied. 1 Seal Support Systems; 7. Breaking Down the Task of Synthetic Drug Substance Process Development. Typically starts with a vial(s) of the cell bank, and includes cell culture, harvest(s), purification and modification reactions, filling, storage and shipping conditions. The extent of characterization required for the mAb reagent depends on the nature of the steps that follow use of the Feb 24, 2021 · In 2002, the U. The selection of regulatory starting materials (RSMs) is a critical step in determining where the drug substance manufacturing process begins as it relates to the submission and approval of the commercial marketing application and with it the formal expectations for Good Manufacturing Practice (GMP) processing. , the drug substance is continuously formed and processed into the drug This guidance describes approaches to developing and understanding the manufacturing process of the drug substance, and also provides guidance on what information should be provided in Module 3 of Oct 6, 2020 · The two main components that make up the pharmaceutical manufacturing process are those of drug substance and drug product manufacturing. Over 30 years of experience to help you identify risks early on and manage the complexities of bringing molecules to market. Ft. 16 Electrical Services; 8 Process Impact on Facilities; 8. to be dedicated to ADSTILADRIN Ferring is on Dec 14, 2018 · The Chemistry, Manufacturing and Controls (CMC) section of a regulatory submission details aspects of the drug’s chemical properties, its manufacturing process development and production, and control mechanisms, including analytical testing both in-process and of the finished drug, to show the process is controlled and reproducible. Food and Drug Administration (FDA) launched the Pharmaceutical Quality for the 21st Century Initiative to encourage adoption of innovative technologies that would lead to an agile, flexible pharmaceutical manufacturing sector. Services include discovery process chemistry, process chemistry, enabling technology, process safety and engineering, material science and API manufacturing for clinical trials and commercial purposes. , solid state properties), should be identified and discussed. The synthesis process must be consistent and reproducible, should be documented We have a complete purification suite for clarification and ultrafiltration process steps. CMC development plan initiated. However, there are many similarities that run across the different modalities during the drug product (DP) development process and manufacturing. The overall With respect to drug substance manufacturing, there are examples of continuous unit operations such flow synthesis steps for API manufacturing. 1 Drug Substance The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability, or were specifically designed into the drug substance (e. When recycling materials, the following considerations can be useful: 1. In this chapter, the committee explores innovations for manufacturing bulk, purified APIs. ” ICH Q7 states that appropriate GMP (as defined in that guidances) should be applied to the This document describes approaches to developing and understanding the manufacturing process of the drug substance. Formulation Formulation is the process that transitions a drug substance (DS) into a formulated drug product (DP). the drug substance and its manufacturing process can create the basis for more flexible regulatory approaches. Formulation brings the Jun 16, 2023 · A flow chart of all successive steps of the drug substance manufacturing process should be provided starting from biological fluid/tissue/organ or from cell banks/viral seeds. Online real time process monitoring and batch reporting through OSI Pi historian; 10,000 Sq. Upstream process development comprises the workflow from cell line development to a developed bioreactor process prior to the harvest and purification steps. Examples The intensity of a process is a function of its titer, or the productivity of its cell line in terms of protein yield. g. Jun 11, 2024 · The COVID-19 pandemic has propelled the rapid development of mRNA vaccines and therapeutics, leading to an upsurge in mRNA pipelines across various stages of discovery research and clinical trials. Drug Substance Manufacturing. Production setbacks have left the world outside the United States and Europe with shortfalls or delays in receiving ordered doses. Co-located analytical laboratories support method development, in-process, release and stability testing. 3 . Quality control and assurance are essential to ensure these substances’ efficacy. a. 14 Potable Water Systems; 7. In addition, the most effective way of determining the accuracy of a manufacturing process is to confirm the molecular structure of the drug substance produced. It is a valuable reference for novice and advanced readers alike, covering recent advances and the future prospects and challenges of this technology. 7. and equipment changes associated with all steps of drug substance 28 manufacturing. drug substance development package and robust manufacturing process should be in place. Manufacturing parameters or charged quantities should be identified according to whether they can be subsequently changed by prior approval (partial change application, PCA) or Process Validation: A . kvoeym wkawgso cqdvi euai rdav qnv pyoduc riie qzbzq qjvkx