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Adequate characterization of materials protects product quality.
Enhanced process and product understanding are the basic tenets of Quality by Design (QbD). Although significant advances have been made in this respect, appropriate characterization and management of raw materials remains a concern for the regulatory authorities. In view of the large number of raw materials that typically are used in biotech processes, a QbD-based approach for raw material management must be based on scientific knowledge and risk analysis. This will ensure that adequate characterization is performed on those raw materials that are expected to have the most effect on process consistency and product quality. Part 1 of this article will present an approach for raw material management following the QbD principles. Part 2 will discuss how to conduct risk assessments, and will give an example of the application of risk assessment tools for raw materials in biotech processes.
The contribution of raw materials to product quality, safety, and process performance is considerable. It is therefore important in designing processes and selecting raw materials that thought is given to understanding their purpose and suitability for intended use. Raw materials also are a major source of variability and steps must be taken to minimize any negative impact arising from materials and their sources. There are essentially two parts to this; prevention, through assessment, inspection, and control of incoming materials; and intervention, in which processing conditions are modified to account for the variability, sometimes through continued monitoring of materials and their impact on process performance.
Anurag S. Rathore, PhD
An initial assessment of materials must extend beyond the material specification and its direct effect on the process to include a host of additional issues such as the supplier's manufacturing processes, quality systems, and sourcing strategy. This is particularly true of biopharmaceuticals, where processes are highly complex and a wide range of different materials are used which can affect quality and process performance in both subtle and catastrophic ways, as with the recent experiences of heparin and melamine contamination. It is necessary to characterize and understand how these interactions can occur, and if they affect the process or product negatively, but it is unrealistic and impractical to explore every possible permutation of material variables and process parameters. Modern design approaches recommend taking a science- and risk-based approach to development1 and the following sections will focus on how risk management practices can be applied to prioritize the required studies.
Part 1 of this 20th article in the Elements of Biopharmaceutical Production series presents an approach for raw material management for biotech therapeutic products following the Quality by Design (QbD) principles. Part 2 will discuss how to conduct risk assessments, handle risk communication to stakeholders, and also will give an example of the application of risk assessment tools to raw materials for biotech processes.
ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (APIs) discusses the various sources of raw materials and makes recommendations on their handling.1 It defines an API starting material as "a raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API". This guideline provides recommendations on a variety of topics, such as quality management, personnel, buildings and facilities, process equipment, documentation and records, materials management, production and in-process controls, packaging and identification labeling, storage and distribution, laboratory controls, validation, change control, rejection and reuse of materials, complaints and recalls, and contract manufacturers. Furthermore, the guideline provides specific guidance for APIs manufactured by cell culture or fermentation and also on APIs used in clinical trials. The guidance presented in this document can serve as the foundation of the raw material management program for a company.
ICH Q8 Pharmaceutical Development introduces QbD as "a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management."2 The QbD approach involves identifying product attributes that are of significant importance to the product's safety and efficacy, design of the process to deliver these attributes, a robust control strategy to ensure consistent process performance, validation and filing of the process demonstrating the effectiveness of the control strategy, and finally ongoing monitoring to ensure robust process performance over the lifecycle of the product. Although the Q8 guidance is intended for drug product, some of the concepts are applicable for raw materials as well and should be taken into account when creating a raw material management program.
The ICH Q9 Quality Risk Management guideline provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality.3 These aspects include development, manufacturing, distribution, inspection, and submission or review processes throughout the lifecycle of drug substances, drug (medicinal) products, and biological and biotechnological products. As will become evident from this article, risk analysis and management pay a critical role in management of raw materials and as such, the ICH Q9 guideline serves as a useful reference when creating a raw material management program.
Besides the ICH guidelines mentioned above, specific guidance also has been provided by the US Food and Drug Administration,4 European Medicinal Agency (EMA),5 and the Japanese Ministry of Health, Labor, and Welfare (MHLW).6 Although they provide regulatory expectations from the different jurisdictions, they all share the foundation laid by the ICH guidelines.
Certain raw materials used in biotechnology processes are complex in nature as they often are not well-defined and known to exhibit lot-to-lot variability with respect to their impact on the process (for example, soy hydrolysate). There are a wide range of raw materials and components which have the potential to affect product quality or process performance. It includes process materials, process aids, materials contacting process fluids, excipients, devices, and primary and secondary packaging. A list of material categories is given in Table 1.
Table 1. Material categories used in bioprocessing. The list is not meant to be exhaustive but rather used for illustration.
Some of the several key challenges that the biotech industry faces with respect to raw material management are:7
1. With respect to complexity of raw materials, a particularly challenging problem is that of the various components that are mixed to form the media for microbial fermentation or mammalian cell culture steps. A large number of such components are used, often a mix of chemically defined raw materials and complex raw materials such as hydrolysates.8 The performance of the process step is known to be sensitive to small changes in some of these components and even to changes in the procedure used to produce the media from them.
2. A typical biopharmaceutical manufacturer may have anywhere from 20–50 vendors that are sourcing raw materials for a given process. Because the manufacturer is legally responsible for the quality of the raw materials that it procures and uses, raw material management is a complex task.
3. Biotechnology processes are known to use a large number of different raw materials (typically 50–100). It is not feasible to examine the effect of each raw material experimentally.
Variability in product quality caused by variability in the quality of raw materials has been highlighted as a concern by the regulatory authorities. It is widely accepted now that a robust raw material management system must be in place to facilitate implementation of QbD. This is greatest towards the end of the process, where the effect on the drug product quality is significant.
With the large number of raw materials that are used in typical biotech processes, characterization of raw materials requires use of advanced analytical tools in combination with chemometrics. In this section we review some of the approaches that have been proposed in the literature:
1. Proteomic analysis has been proposed as a tool for assessing complex raw materials such as the fetal bovine serum.9 Proteomic techniques were used to understand the lot-to-lot variability with respect to impact on growth properties of the cell culture process. A time course study was performed to monitor specific changes in the fermentation medium.
2. An approach for routine testing of packed raw materials used in pharmaceutical processes has been recently proposed.10 The chemometrics-based approach consists of three steps. First, the initial calibration objects are divided into two classes using a global principal components analysis (PCA) model. Next, two separate PCA models are constructed. Finally, soft independent modeling by class analogy (SIMCA) is applied for calculating acceptance area. The approach was successfully used to analyze fourier transform-near infrared (FT-NIR) spectra of taurine samples.
3. In a recent publication, a combined approach of near-infrared (NIR) spectroscopy and chemometrics for screening of lots of basal medium powders based on their impact on process performance and product attributes has been proposed.11 A combined NIR and chemometrics approach was able to finger print the raw materials to distinguish between good and poor performing media lots.
4. A recent book chapter described a number of upcoming analytical techniques, including high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), inductively coupled plasma- mass spectrometry (ICP-MS), and liquid chromatography–mass spectrometry (LC-MS) and described experience managing these methods and results as part of a retrospective investigation.12 A case study also was presented using NMR as an analytical tool and PCA for analyzing data for characterizing raw materials for a cell culture step.
With the above mentioned advances in characterization of raw materials, it is possible to fingerprint critical raw materials and ensure that only those lots that have acceptable quality are used.
Figure 1 presents an overview of one approach that could be implemented for managing raw materials in the QbD paradigm.13,14 As illustrated in the figure, raw materials are initially selected during early-stage or platform development, before detailed characterization during late-stage development, they are then subject to continual evaluation throughout the product lifecycle. The initial risk assessment is performed early in the development process to prioritize areas of concern and focus further research, and is repeated as greater knowledge is obtained. Typically, knowledge is limited in the early stages to general information about the material and its performance in similar processes. The process typically is not fully characterized until process characterization is initiated (typically after end-of-Phase 2 clinical studies are successful). Stage-appropriate risk assessment practices are followed at each point, with the level of detail increasing as more knowledge becomes available. Based on platform knowledge and product-specific knowledge, the raw materials can be categorized into three categories: (1) critical raw materials, (2) key raw materials, and (3) non-key raw materials. A combination of mechanistic modeling and multivariate analysis can be used to analyze the effect of the various raw materials on the different process and product quality attributes. The approach could be used to identify raw materials that have the most potential to impact and hence need the most characterization.10–12,15
Figure 1. Raw material management approach in the Quality by Design paradigm
Critical raw materials are known to significantly affect product quality and these raw materials are therefore thoroughly characterized and their mechanisms of process interactions well understood. A relationship is developed among the relevant raw material attributes and the quality attributes that are being affected. For these raw materials, acceptance criteria must be developed within which their attributes can vary without leading to unacceptable product quality. Furthermore, analytical tests are developed to monitor raw material attributes to ensure that each raw material lot meets the respective acceptance criteria before its use in the process.
Key raw materials do not significantly affect product quality but do impact process consistency. These raw materials can be characterized as thoroughly as critical raw materials, but this is a risk-based decision and will depend on the platform and the product. They might or might not require routine monitoring based on the significance of their impact. If a new key raw material is added to the platform, it should undergo the thorough characterization of a critical raw material before being used in the platform.
Non-key raw materials include the remaining (and majority of) raw materials. These materials are handled through the internal quality system of the biopharmaceutical manufacturer as in traditional pharmaceutical manufacturing.
For all raw materials, the biotech company should have an internal quality system that would ensure appropriate raw material management. Some key aspects of this system would be:7,16,17
1. Review of the certificate of analysis from vendor and confirmation that the raw material lot meets the internal specifications. Materials specifications are set based on materials meeting the performance requirements of the process in question. In the vast majority of cases, material specifications are predetermined by the supplier. It is still up to the manufacturer to determine if they are adequate for their intended use, and in some cases it may become apparent over time that alternative or additional specifications are required.
2. Analysis of raw materials as necessary. The testing plan should ensure that while critical quality aspects are examined, superfluous testing that is not providing useful information is not performed.
3. Review of any changes to the vendor's manufacturing process with respect to change in raw material quality and its impact on process consistency and product quality.
4. Vendor site audits at appropriate frequency to ensure vendor qualification as needed during product lifecycle. These may include technical audits by subject matter experts to assess supplier capabilities and competencies.
5. Appropriate supply chain management system in place to avoid failure of incoming raw material lots in meeting specifications.
6. Ensure traceability of raw materials.
7. Raw materials of animal origin should be checked with respect to requirements with animal feed, animal age, manufacturing practices of the vendor, and other relevant aspects.
8. Custom-synthesis based raw materials need to be thoroughly characterized to ensure the process that is used to make them is well controlled and the raw materials are comparable across lots and scales that were used over product lifecycle.
9. A robust change control program should be in place to assess potential changes of the raw material to evaluate the potential to impact product quality.
Raw material risk assessments are focused principally on the effect on the process in terms of quality and process performance, but additional risk factors should be considered in selecting and a material and its source, such as material risk (e.g., toxicity, immunogenicity, viral safety), and risks posed by the supplier (quality systems, business, and technical capabilities). This is presented in Table 2. Raw materials are required to meet industry standards where relevant, and should undergo testing to confirm compliance with user specifications. Materials should be fully traceable to the site of origin and handling procedures should be in place to prevent cross-contamination. Deliberate adulteration of raw materials for economic or other reasons is a particular concern. Its detection and prevention requires a combination of analytical controls and supplier relationship management.
Table 2. Raw material risk categories
Process Risk Related to Raw Materials
Process risks arise from the stage in the process where the material is used and the effect the material has on product quality or process performance at that point and at subsequent steps. The risk posed by the material, rather than by processing conditions, is assessed. As in all risk assessments, the evaluation should be performed by a multifunctional team consisting of the development team (experience of the specific molecule) together with subject matter experts with experience of similar molecules and unit operations, or packaging and delivery devices as appropriate. Process risks can affect product quality, and process performance (supply continuity, variability) and end-user satisfaction.
Risks Related to Material Properties
Certain risks arise from inherent properties of the materials used and from the processes by which they are made. It is therefore necessary to have an understanding of material properties such as toxicity and their potential to cause harm should they happen to be included in the final product, so that appropriate steps can be taken to protect the patient either by detection and removal methods. In some cases, e.g., animal-derived materials (a potential source of TSEs), safety may be secured by a number of methods such as sourcing from approved areas, by the processing of the material itself, or by demonstrating that the purification process is capable of removing infectious agents by spiking studies. There are a number of materials where specific guidelines or regulations cover their use and include, but are not limited to, residual solvents, residual metals, animal derived materials, materials at risk for melamine contamination, and filters.1–6,18–22 Some materials may be complex and consist of multiple components (e.g., predispensed media or media additives in single-use systems, prepacked columns) or themselves be components of drug product (e.g., prefilled syringes and delivery devices). In such cases, it may not be practical to take apart the material for testing, and the user is heavily reliant on the supplier's quality systems. Material risks are assessed by subject matter experts with the appropriate expertise, e.g., toxicology, immunology, materials science, mechanical engineering, and environmental health and safety (EH&S).
All suppliers of materials used in pharmaceutical manufacturing must be audited. The supplier audit should have an effective quality management system in place that is certified, where appropriate, to ISO9001:2008, ISO13485, or relevant industry standards e.g., ICH Q10 guidance.23 Manufacturers of API and excipients have to meet the highest standards. The supplier also should have suitable audit procedures in place for its sub-suppliers, with a strong preference for short, transparent supply chains, because of the increasingly concerning emergence of economic adulteration, as mentioned above. Sourcing should be done from trusted suppliers and sub-suppliers, and there should be evidence that the security of the supply chain in terms of safety has not been impaired. A more detailed set of requirements is given in reference 24. Additional supplier concerns are for business continuity.
Suppliers should have adequate capacity to meet increasing demands and should have recovery plans in place in the event of catastrophic events. Supply disruptions may not impact product quality, but they will impact patient wellbeing, which is also a health concern. Lastly, the supplier's technical capabilities in terms of product and process understanding should be assessed. Their understanding of the way their products are being used and commitment to service and support are fundamental to a good supplier relationship. This is especially true as manufacturers become increasingly dependent on complex single-use technologies, where the supplier becomes an integral part of the users manufacturing and quality systems. Some of the guidelines used for systems verification can be applied to these complex consumables.25
Part 1 of this article presents an approach for managing raw materials in the QbD paradigm. It should be understood that risk assessments are limited by what is known at a given point in time. Manufacturers should continue to monitor and correlate product quality and process performance with process parameters (inputs), including raw material attributes, and refine specifications and controls as appropriate, as part of continuous verification and improvement. Process analytical technology tools are highly appropriate for this purpose.26 The effect of a raw material may not be fully understood even at a relatively late stage in development.
Part 2 of this article will discuss how to conduct risk assessments, and will give an example of the application of risk assessment tools for raw materials in biotech processes.
The authors would like to thank Jennifer Mercer, Amgen Inc., Thousand Oaks, CA for her review of the manuscript and her helpful comments.
Anurag S. Rathore, PhD, is a biotech CMC consultant and a faculty member at the Indian Institute of Delhi, India, +91-9650770650, firstname.lastname@example.org Rathore also is a member of BioPharm International's editorial advisory board. Duncan Low is a scientific executive director in process development at Amgen Inc., Thousand Oaks, CA.
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