Abstract
The Food and Drug Administration's Pharmaceutical cGMPs for the 21st Century initiative emphasizes science and risk-based approaches in the manufacture of drugs. These approaches are reflected in the International Conference on Harmonization (ICH) guidances ICH Q8, Q9, and Q10 and encourage a comprehensive assessment of the manufacture of a biologic, including all aspects of manufacture that have the potential to affect the finished drug product. Appropriate assessment and management of raw materials are an important part of this initiative. Ideally, a raw materials program should strive to assess and minimize the risk to product quality. With this in mind, risk-assessment concepts and control strategies will be discussed and illustrated by examples, with an emphasis on the impact of raw materials on cell substrates. Finally, the life cycle of the raw material will be considered, including its potential to affect the drug product life cycle. In this framework, the supply chain and the vendor–manufacturer relationship will be explored as important parts of an adequate raw materials control strategy.
Introduction
Traditionally, the approach to the management of raw materials in the manufacture of a biotechnology product involves the management of the particular raw material as it affects its intended use. Generally, a closer look is given to complex raw materials such as culture media than to raw materials considered as well-defined. There is also a specific approach to those animal-derived raw materials that could pose a risk of contamination. A recent guidance on risk management provides a path to implementation of a raw materials management program that comprehensively evaluates all raw materials involved in the manufacture of a biotechnology product and provides a categorization on not only the immediate impact to the introduction of a raw material, but also how this raw material affects the finished product through its life cycle (1).
When considering the implementation of a raw materials management program, an understanding of what is a raw material is critical. Currently, there is no consistent definition of a raw material. Regulations refer to constituent materials, components, and in-process materials (2–4). ICH Q7 defines a raw material as a general term used to denote “starting materials, reagents and solvents intended for the use in the production of intermediates or APIs” (5). ICH Q6B refers to a monoclonal antibody used in affinity chromatography as a raw material (6). Each manufacturer will have to perform an assessment that will allow for proper evaluation of the raw materials involved in the manufacture of a particular biotechnology product. Generally, biologically derived raw materials are carefully evaluated and controlled for their potential ability to contaminate the final product with microorganisms that can adversely affect the final product, but caution should be exercised with those raw materials that, although not biologically derived, have been exposed to biological sources during their manufacture or throughout the supply chain.
A manufacturer of biotechnology products looking for guidance and regulations regarding raw materials is confronted with a lack thereof. Specific regulations for the control of raw materials are scattered and not detailed (7). Some ICH guidances address biologically derived raw materials (ICH Q5A (8) and ICH Q5D (9)) in detail, but a guidance that deals with raw materials in general is not available. Manufacturers have recently seen a need for implementation of raw materials management programs that are comprehensive and look at raw materials as part of the manufacture of a biotechnology product that should be integrated within the manufacturer's management systems. For example, several biotechnology and pharmaceutical companies are members of the Rx-360 Consortium (www.rx-360.org), which focuses on the management of the quality of supplies such as raw materials. ICH Q9 provides guidance on the application of quality risk management as part of materials management (1).
Raw Materials Can Affect Product Quality, Safety, and Efficacy
At any stage of the product life cycle, raw materials can affect product quality, sometimes to such an extent that safety and efficacy of the product are compromised. Changes in the quality of a raw material can affect a product's lot-to-lot manufacturing consistency, lead to product specification failure, and derail a product comparability program during manufacturing changes. In addition, the safety of a product can be directly affected by contamination of raw materials by adventitious virus, bacteria, or mycoplasma.
Although viral contamination has not been implicated in the transmission of infectious agents to a patient, cases of contamination arising during manufacture have been reported. Contamination during manufacture has implicated mostly bovine-derived raw materials as in the case of Cache Valley virus, epizootic haemorrhagic disease virus, and bovine viral diaorrhea virus (10, 11). Contamination by minute virus of mice has also been reported but the source has not been identified (12). More recently, Genzyme reported contamination of their production bioreactors (13). Investigation of cell culture crashes at the Allston, Massachusetts, and Belgium sites revealed a low-growth virus that provoked a sharp drop in cell viability after days in culture. Genzyme was forced to shut down production of Cerezyme and Fabryzyme for several weeks. The investigation found that the contamination was due to the presence of vesivirus 2117 in their cell cultures. Although the root cause of this contamination was not clearly established, it was attributed to culture media contamination. Control for animal-derived materials should not be limited to cell culture steps, but to all raw materials that can potentially bring in contamination due to microorganisms. This includes porcine trypsin, antibody affinity columns, and biological excipients.
Other case studies emphasize the need to have a comprehensive approach for the control of raw materials. One such example is the case of improper identification of a cell substrate that resulted in cross-contamination in a potency assay. Cell-based potency assays are at the core of the critical quality attributes required to demonstrate that a biological product such as a monoclonal antibody has the targeted activity and function. Generally, in cell-based potency assays a product sample is compared against its reference using qualified reporter cells. In this case, WISH cells that were used as readout for a potency assay were found to be contaminated with HeLa cells (14).
Raw Materials in the Use of Cell Substrates
Mammalian cell cultures are preferred cell substrates when it comes to the manufacture of monoclonal antibodies. Due to the potential ability of cell substrates to be infectious, there are well-established guidances and regulations requiring the implementation of tight controls on cell substrates (8, 9, 15).
In the case of cell substrates used as expression systems, the parental cell substrate of the established cell bank may be considered the raw material for that cell bank. Although cell banks are rigorously characterized, the parental cell substrate may not have undergone the same testing rigor. A careful assessment on the quality of the parental cell substrate should be made in order to determine the risk of using a particular cell substrate. Well-known cell substrates with a long history of safety may not require the scrutiny of poorly characterized cell substrates. Traceability is critical in controlling the quality of the cell substrate. Raw materials used during cell substrate and parental cell substrate culture should be carefully evaluated. For example, animal-derived components should be carefully traced for the potential to introduce adventitious virus. Bovine-derived materials require documentation to provide appropriate information on the tissue source and country of origin (16).
Raw Materials Need To Be Appropriately Controlled
The cases above illustrate the need for controlling the quality of raw materials appropriately. A starting point could be to define the expected profile of an “ideal” raw material. This may help to identify what controls should be in place in a good raw materials management program (Table I).
Defining the Expected Profile of an Ideal Raw Material
The safety of a raw material depends on how well its physico-chemical and/or biological activities are known, how these interact with the final product, and knowledge of its impurity profile. A well-characterized raw material enables the implementation of a better control strategy to qualify it and to maintain its quality throughout its life cycle. Characterization of a raw material should not be limited to the quality analysis of the supplier. There should be an assessment of the complexity of the raw material and the impact of introducing it in the manufacture of the biotechnology product in order to determine what additional tests should be performed for qualifying the raw material. In addition, known issues that pertain to a raw material (e.g., peroxides in Tween, formaldehyde in Tris) should be addressed. Proper characterization and control of raw materials are limited by the lack of a complete view of the raw material life cycle. As outsourcing, globalization, and testing capabilities increase, cases of raw material contamination or adulteration have recently been reported and have raised concern regarding the transparency of the supply chain (17). Therefore, a critical aspect of raw material control is the manufacturer–supplier relationship. Appropriate supplier qualification is key in assuring the quality of the raw material. This requires not only a thorough assessment of the supplier manufacturing, but the supplier's suppliers should also be considered. The quality of starting materials used in the manufacture of the raw material is not often adequately traced. This is a gap in the knowledge of the raw material quality that should be examined more closely. How far back the manufacturer should investigate the primary sourcing for raw material manufacturing will depend on the manufacturer's capabilities to pinpoint a change in raw material quality during qualification. This is not an easy task; complex raw materials such as cell culture media and chromatographic resins are multi-component materials that require analytical testing capable of detecting changes to the expected quality profile of the raw material. Some manufacturers have developed in-house, high-throughput methods such as nuclear magnetic resonance as a means to detect incoming raw material contamination or adulteration (7).
Raw material supply and availability is an additional aspect taken into account by raw materials management programs. The biotechnology industry has long recognized that some raw materials have a limited number of suppliers worldwide. Human serum albumin and protein A resin, for example, have specific applications and limited numbers of suppliers. In addition, vendors for these types of raw materials may discontinue manufacture, leaving the biotechnology manufacturer stranded. It is advisable, then, to qualify back-up suppliers that can take over the supply of a particular raw material without delaying the manufacturer biotechnology manufacturing program.
Risk-Based Raw Materials Management
Traditionally in the biotechnology industry, raw materials are managed and controlled by the manufacturing department and the quality control laboratories. Under this paradigm, incoming raw materials are quarantined and can be released for use or storage once they are qualified. Qualification includes testing that can range from identification only to a panel of analytical tests to ensure the raw material has the expected quality. Changes to raw materials during the life cycle of the biotechnology product manufacturing are expected, but many times the impact of these changes is not fully evaluated until a deviation occurs in the manufacturing of the biotechnology product. Deviations are handled by the manufacturer quality systems following a current good manufacturing practices (cGMP) process where a deviation is investigated in order to determine a root cause. Common root causes of deviations observed during the in-process, release, or stability testing of a biotechnology product relate to an unexpected change in the raw material. These deviations can be so critical to the drug product quality that the entire manufacturing program can come to a halt. Recently, manufacturers have started looking for alternative ways to manage their raw materials. The ICH published a guidance in 2006 for a risk-based approach to manage quality systems in the pharmaceutical and biotechnology industry (1). ICH Q9 lays out the basis for the implementation of a raw materials management program that enables the manufacturer to handle raw materials, for example, from the standpoint of the evaluation of the risk involved in introducing a given raw material to the manufacturing of a drug product. ICH Q9 is a four-tiered risk management program divided into risk assessment, risk control, risk communication, and risk review.
The primary goal of risk management of raw materials should be to appropriately control the risk that a raw material poses to the quality, safety, and effectiveness of the drug product. A risk management process should (1) have a comprehensive scope, (2) include risk assessment for prioritization, (3) use an appropriate risk assessment analysis tool, (4) have cross-functional input from appropriate personnel from all areas, and (5) include risk communication and risk review. During risk assessment, raw material definition is important in order to establish the list of raw materials that will be considered. This is not a straightforward process, as is illustrated by some of the case examples provided in this article. An evaluation of the criticality of a raw material is made during risk assessment. Some of the elements assessed during a risk assessment exercise are (1) type of raw material (e.g., biological, chemical, or physical), (2) amount and depth of knowledge of the raw material (current experience, historical or public knowledge), (3) where in the manufacturing process of the drug product the raw material is used, (4) its ability to introduce biological/chemical contamination, (5) the potential to affect safety and efficacy of the drug product, (6) the complexity of the raw material (e.g., sodium chloride vs culture media), (7) the intended use (as a buffer, reagent, etc.), (8) single or multiple use (chromatography resin vs chromatography buffer, or use in multiple drug products), (9) knowledge of the supplier (raw material manufacturing process, supply chain traceability), (10) stability of the raw material, and (11) whether the new raw material is comparable. These types of considerations should be carefully evaluated in order to classify the risk of a given raw material and to establish the proper controls.
Risk Identification, Risk Analysis, and Risk Evaluation
According to ICH Q9, once risk has been identified, analyzed, and evaluated, a risk control strategy should be implemented, the aim of which is to reduce risk to a manageable level. Unmanageable risks must be mitigated. For example, specific in-house testing of a critical raw material will help mitigate the risk of using that raw material. Lack of adequate traceability of a raw material could be the basis for failing qualification of a supplier. Once the risk is accepted, the manufacturer should make every effort to maintain acceptable risk at minimum levels. Certified animal-derived raw materials, extended raw material characterization testing, lot-to-lot consistency, specific sampling paradigms, comparability during raw material change, quality agreements, and supplier audits are some of the levels at which the manufacturer can establish controls to ensure a manageable risk of the raw material.
Conclusions
The management of raw materials in the manufacture of biotechnology products is a complex task not commonly handled as a comprehensive program, but rather managed by the manufacturer quality systems. Problems arising from raw materials failures require cGMP mechanisms of deviation reporting, investigation of root cause, and corrective and preventive actions. Problems with raw materials, where a raw material could critically affect the safety and effectiveness of the drug product, may slow or sometimes stall a manufacturing program. This article highlights the benefits of having a comprehensive raw materials management program implemented using a risk-based approach. ICH Q9 offers guidance on how to establish a risk-based raw materials management program. A robust raw materials management program that utilizes comprehensive risk assessment and mitigation strategies may minimize deviations attributed to raw materials and/or raw material changes so that it allows manufacturers to be preventive rather than curative when considering the impact that a raw material may have on the quality, safety, and efficacy of a biotechnology drug product.
Disclaimer
The views offered in this article represent the author's personal perspective on the issue and should not be construed as regulatory policy or guidance.
Acknowledgments
The author would like to thank the Office of Biotechnology Products at the Center for Drug Evaluation and Research, FDA, for the feedback and examples provided in this manuscript. Special thanks to Dr. Steve Kozlowski, Dr. Patrick Swann, Dr. Barry Cherney, and Dr. Emanuela Lacana for their valuable comments.
- © PDA, Inc. 2010
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- Abstract
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- Raw Materials in the Use of Cell Substrates
- Raw Materials Need To Be Appropriately Controlled
- Risk-Based Raw Materials Management
- Risk Identification, Risk Analysis, and Risk Evaluation
- Conclusions
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