Keywords
Drug Substance, ICH Q7, ICH Q11, ICH Q9, Quality Risk Management (QRM)
Introduction
The ICH Q7 good manufacturing practice (GMP) guidance1 for active pharmaceutical ingredients (API) stipulates the basic GMP requirements involved in drug substance manufacturing from introduction of starting materials to processing and packaging. The guidance cover personnel, facility, equipment, material, manufacturing, laboratory, storage, laboratory, validation, change and quality management controls sections. ICH Q7 excludes vaccines, blood, plasma derivatives, radiopharmaceuticals and gene therapy pharmaceutical ingredients. API manufacturing utilizes designated starting materials (RSM), intermediates and raw materials at various steps, where some of the building block raw materials are commercially available. The API manufacturing segment differs from drug product GMP operations. API manufacturing has early stages of manufacturing building blocks for key steps and developing case by case rationale to determine the correct starting point of API manufacturing. ICH Q7 has attempted to clearly break down the requirements, for example, for a chemical synthesis. (Table 1)
The controls for API and intermediate manufacturing should be phase appropriate and in line with the stage of drug substance development. The guidance on development and manufacture of drug substance (ICH Q11) is relatively new, published in 2012.2 There are very few regulatory inspection compliance citations specific to the guidance at this time, in comparison to the well-established drug product Quality by Design (QbD) concepts (ICH Q8). The Q11 guidance and associated Q&A provide details on a QbD approach to drug substance process development, justification of starting materials, lifecycle process validation and Quality Risk Management (QRM). This article outlines the application of QRM throughout the stages of drug substance manufacturing and the methods to apply the ICH Q9 risk management principles.3
Drug Substance Manufacturing Process
Depending on the developed synthetic route (for example in case of small molecules), the number of intermediate manufacturing steps may vary (Figure 1). Intermediates and final API manufacturing operations have associated isolation and purification steps. Reprocessing by recrystallization, distillation, filtration, column chromatography, milling etc. are a general part of the manufacturing process. Mother liquor recovery of reactants, intermediates and API are performed as per the approved process and quality is confirmed prior to use. The reaction, crystallization and drying processes require management of bulk material quantities. Evaluation of safety and scale effects on the selected equipment train are therefore important for successful commercialization. Special considerations need to be in place for the use and traceability of the recovered material. Cross contamination controls are of particular importance when non-dedicated equipment such as reactors are utilized in the various steps. A robust cleaning validation and verification program with validated test methods is critical to ensure minimal carry over. Addressing these requirements is challenging for newly developed API synthetic routes, as the chemistry and process understanding is not well established. Validated/verified laboratory test methods are required for characterization at all development stages, raw material testing, registered starting material testing, intermediate material testing, final API testing, stability testing and in process testing. In-process control (IPC) testing of intermediate and API manufacturing encompasses assay, purity, water content etc. to determine adequacy of material quality at various stages. In some cases, the reaction continues while the IPC results are generated for further charging calculations.
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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 API industry utilizes optical process analytical technologies (PAT) like FTIR, NMR and Raman at various stages of operations. In addition, safety considerations are important as the reactions can be exothermic in nature. The process characterization studies including spike, fate, purge studies and design of experiment (DoE) based studies are performed during the process design stage. Design of Stage 2 Process Performance Qualification (PPQ) studies therefore warrants careful planning and risk assessment. The subsequent Stage 3 Continued Process Verification plan for drug substance needs to consider monitoring of processing loops and variables such as drying, reaction time etc. Drug substance intermediate and final API manufacturing steps need to consider the input variables. Some intermediate steps may be independent of the pervious steps. In most cases the quality attributes establish reaction end point and therefore minimal data may be available to determine within batch variability. Continued evaluation of evolving risks are hence important in drug substance manufacturing to enhance the control strategy. A preliminary risk categorization is the first step towards implementing QRM principles in drug substance manufacturing.
The drug substance manufacturing process for chemical entities involves synthetic route development and process development to enable successful chemical reaction conversion mechanisms. In some cases, it may involve numerous chemical conversions in multiple process steps to produce few grams of highly potent active pharmaceutical ingredient. The manufacturing process can extend to months. Process design becomes an important aspect of drug substance development and scale up for commercialization. Each drug substance manufacturing process is unique, depending upon complexities such as number of chiral centers and reaction mechanisms. Multistep synthesis strategies such as convergent or telescoping synthesis are commonly applied in isolating the API. Product yield, material cost, safety, environmental, quality and process efficiency are important in drug substance manufacturing and need to be considered as part of process development. Flow chemistry is an emerging segment of API process manufacturing with proven advantages for safety and efficiency. However, the possibility of different reaction pathways presents challenges in implementing standard processes. The industry thus has some unique needs and has advanced in certain areas of PAT in comparison to drug product manufacturing process, for example NIR. This scenario presents an opportunity to strengthen drug substance operations by identifying and using quality risk management tools at each stage.
Phase Appropriate Application of QRM
API development, manufacturing and testing can be divided into five categories and related to the lifecycle stages (Process Validation Stage 1, 2 and 3) as indicated in Table 2. The product and patient risk level increases as development moves from its early stages to commercial manufacturing (1-5). Category 1 primarily includes early development study batches including DoE’s to define critical process parameters and for process optimization. The analytical test methods at this stage are non-validated methods. Category 2 and 3 are primarily clinical, registration, stability, and demonstration batches some of which will be utilized for human clinical trials. The only diff erence between category 2 and 3 is the use of non-validated analytical test methods versus use of validated test methods. Analytical test methods including in process methods are typically in validation at this stage. Category 4 PPQ batches may be utilized for drug product-formulation development batches, PPQ batches, and commercial batches. The analytical test methods need to be fully validated at this stage. The drug substance PPQ studies involve increased level of sampling and testing plans. Category 5 includes commercial batches undergoing continued process verification. Throughout stages 1-5 the maturity of the risk management tools increases to accommodate the data and product/process knowledge captured throughout the lifecycle of the process.
Application of QRM Principles in Drug Substance QMS
The criticality of Stage 1 which includes QbD based development principles (ICH Q11) and the unique processing steps makes drug substance development and commercialization a distinctive segment. The reaction mechanism and processes, for example the ongoing charging, makes the in-process analysis critical in ensuring attainment of established quality attributes. The drug substance manufacturing operations involve multiple intermediate steps and variables, of which some are dependent and some are independent. Therefore, a tailored roadmap for QRM is recommended in drug substance development. Each of the categories defi ned requires varying levels of risk assessment and associated tools based on the development phase of the product. Table 3 provides a summary.
Throughout the product lifecycle, the data collected will be captured and risk assessments will be performed to enable knowledge of the process under assessment. Each stage of the process will utilize a combination of scientific data and risk management principles to ensure process robustness and ultimately ensure product quality. The list is not comprehensive and may act as a roadmap for selecting the most appropriate tool at each stage. A critical assumption in the execution of these risk assessments is cross-functional involvement, Research and Development is responsible for the synthetic route development and QbD process development; Analytical Support is responsible for AQbD based method development, validation and transfer; the Quality Unit is responsible for quality control laboratory operations, quality assurance, investigation, annual quality review and compliance; and Technology Operation is responsible for scale up, process transfer and PPQ. It is the cumulative involvement of all these players that enables a robust risk assessment.
Conclusions
Drug substance development and manufacturing operations are undergoing changes with the implementation of ICH Q7, Q11 and process validation lifecycle guidance requirements. The segment requires specialized quality risk management considerations due to the diverse nature of attributes that need to be considered at the various lifecycle phases. The article proposes a roadmap for implementing end to end quality risk management tools at drug substance development and manufacturing organizations. The guideline should aid in incorporating the quality risk management principles into the firm’s quality management system for routine use and risk mitigation activities. The use of statistical tools and visualization tools are important during QRM activities to decipher potential risks. Routine management risk review and communication are important elements of the QRM process to ensure that the residual risk is addressed in a timely fashion to reduce the impact on patients, and increase personnel safety and product quality.
Summary
A tailored approach is required for quality risk management (QRM) in drug substance development and manufacturing than drug product due to the difference in processes and control strategies. The purpose of a roadmap is to articulate the areas of QRM application and identify the tools that are “fit for” drug substance manufacturing which should help in standardization. Developing a QRM approach for a drug substance is of particular interest for the industry as there are more percentage of warning letters being issued to drug substance manufacturers. ICH Q7 allows for phase appropriate application of cGMP’s however provides no directive, further requiring extensive adoption of QRM approach in drug substance manufacturing.
References
- International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Q7- Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Nov 2000. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q7/Step4/Q7_Guideline.pdf
- International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Q11- Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities), May 2012. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf
- International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Q9- Quality Risk Management, Nov 2005. https://www.ich.org/fi leadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf
Note: This article was prepared by the authors in their personal capacity. The opinions expressed are the authors’ own and do not reflect the view of their employer, government, or any agency with which they are affiliated.