Given the need for accurate analyses to ensure the quality, safety and efficacy of drug products that reach the marketplace, analytical method development and validation compliance requirements are both extensive and stringent. They also continually evolve as new types of therapies and advances in analytical technologies are introduced. CDMOs that implement strategies for facilitating analytical method development and validation in anticipating evolving compliance requirements help their customers reach the market sooner while leveraging a more secure supply chain.
Evolving Regulatory Requirements
The pharmaceutical industry, while highly conservative, is far from static, as is emphasized in the concept of current good manufacturing practices (cGMP). Furthermore, in the effort to ensure continued safety and efficacy of APIs entering the consumer market, the regulating agencies are increasing their expectations of analytical testing. Advances in the accuracy and precision of existing instruments, as well as the portability and high-throughput capabilities of many analytical techniques, are providing greater quantities of valuable information.
Regulations exist to ensure that the analytical methods developed for raw material identification and purity/quality determination, in-process monitoring, drug substance quality and purity and final product release are appropriate and provide the appropriate information. As drug substance production supply chains become more globalized, and therefore increasingly complex, so have the processes needed to manufacture them and the analytical methods required for comprehensive characterization to ensure that they meet necessary quality standards. Regulatory agencies have, as a result, encouraged drug makers to design quality into their processes through the adoption of quality-by-design (QbD) and design of experiment (DoE) approaches. Companies are now being encouraged to also apply a QbD approach to analytical method development. This approach provides a greater level of understanding of the limits of the analytical methods, beyond standard method validation.
Control of final product drug substance quality is ensured through controlling impurities through the raw material supply. This requires more robust methods, and subsequently, regulators are also increasingly looking for validation of all analytical methods, not just methods for final product release, but those used in crucial process control points (i.e., for raw material identification and in-process monitoring). These expectations can be linked, in part, to the need for drug manufacturers to have greater visibility and control throughout the entire pharmaceutical supply chain over all ingredients and processes used to produce the medicines they deliver to patients.
Managing Differing Agency Requirements
Complicating the compliance challenge is the fact that regulations are generally not harmonized across countries and regions. Indeed, increasing expectations for the justification of analytical methods for critical raw materials and in-process monitoring are reaching the level of validation in the EU but have not gone that far in the United States.
Completing validation of these additional methods creates a greater workload, yet cannot impede or delay NDA filing for CDMO customers (sponsors). As such, the added validation work must be completed earlier in the program timeline, which requires appropriate scheduling. For raw material methods in particular, information must be available on the synthetic route and potential impurities in the raw materials before spike and purge studies can be designed to determine which impurities may impact the quality of the final drug substance and what methods will be required for those raw materials that are identified as critical.
It is also important to recognize that the allowed limits for unspecified impurities are different in the U.S. and EU. While the FDA has established a limit of 0.1%, the EMA has established a limit of 0.10%. A process with an impurity controlled to 0.08% would be suitable for the former, but may not be comfortable for the latter. The closer a specification level is to the allowed limit, the greater the information required, such as how the level was determined and how it is being controlled. In addition to the increased workflow, developing this information requires both chemists and instruments capable of performing these advanced analyses. Therefore, the analytical group must be of the right size and makeup to ensure that all activities can be completed without impacting a sponsor’s filing timelines.
Evolution of Analytical Expectations in Current Good Manufacturing Practice
Two recent areas of focus have been elemental and genotoxic impurities. The International Council for Harmonization of Technical Requirements for Pharmaceutical for Human Use (ICH) adopted the final version of its Guideline for Elemental Impurities Q3D (R1) on March 22, 2019. Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) reference ICH Q3D in their own guidance documents regarding elemental impurities. For compendial drug products, the FDA’s guidance also refers to the United States Pharmacopeia (USP, General Chapters <232> Elemental Impurities—Limits and <233> Elemental Impurities—Procedures).
As is evident from recent industry experience around product recalls for the presence of genotoxic impurities, control of these early on in process development is essential, and an increased regulatory interest may be expected. For genotoxic impurities, there are several different regulatory guidelines, including ICH M7 (Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic), which was adopted in 2014, an addendum to ICH M7 from 2015 and a draft guidance document entitled Application of the principles of the ICH M7 guideline to calculation of compound-specific acceptable intakes, also from 2015. The FDA, meanwhile, published the Guidance for Industry: Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches in 2008, and EMA’s guidances include the Guideline on the limits of genotoxic impurities from 2007 and Questions and answers on the Guideline on the limits of genotoxic impurities from 2010. These documents provide recommendations regarding the identification, categorization, qualification and control of genotoxic impurities.
Genotoxic compounds have the potential to be mutagenic and therefore cause damage to DNA, even at very low concentrations. Some genotoxic compounds are well characterized (sulfonated compounds, alkyl chlorides, aromatic nitrosamines), and certain chemistries (Fischer esterifications, HCl chemistry in alcoholic solvents, reactions with nitroaromatics) are recognized to have the potential to produce genotoxic impurities.
They have attracted significant attention in recent years following the identification of probable carcinogens N-nitrosodimethylamine and N-nitrosodiethylamine in APIs used for the production of a number of generic versions of angiotensin II receptor blocker medicines that complied with existing regulations.
In many instances, because of the structural elements of the molecule it may be nearly impossible to completely avoid the generation of genotoxic impurities, so they must be identified and controlled. Doing so is challenging, however, because there are no simple structural guidelines to indicate genotoxicity, and these genotoxic compounds can be highly reactive and damaging at levels much lower than those of most other impurities. It is thus necessary to identify all potential impurities that could form during the synthesis and upon storage of the drug substance and evaluate their genotoxicity using available literature data and appropriate modeling techniques.
CDMOs must have an effective strategy in place to manage the identification and control of genotoxic impurities. Transparent communication between the R&D chemists and analytical experts within the CDMO and with the relevant experts from their clients and raw material suppliers is essential. Completing this process as early in the project as possible is important to allow time for method development and validation, which is quite challenging and often requires the use of high-resolution mass spectrometry, head-space gas chromatography and other advanced methods performed by highly trained and experienced analytical chemists using state-of-the-art instruments. In order to prevent unexpected issues resulting from concerns around genotoxic impurities, it is essential that these tools and chemists be engaged at all steps of process development and validation.
Elemental Impurities
Elemental impurities can be introduced into drug substances or drug products through impurities in raw materials and other ingredients used in the process, such as homogeneous metal catalysts, the equipment used for processing and/or the general environment. For over 100 years, the compendial testing for final product heavy metals content has been a wet chemistry test known to have limitations in its effectiveness.
Advances in new analytical technologies have now allowed for limits of elemental impurities to be based on toxicological data, which is a substantial improvement from a patient’s perspective. The new guidelines for the control of elemental impurities, most notably heavy metals, replaces the traditional wet-chemical method using visual comparison with more reliable modern techniques, including inductively coupled plasma–atomic (optical) emission spectroscopy (ICP-AES) and inductively coupled plasma–mass spectrometry (ICP-MS).
In addition, a strategy must be in place for removal of any metals that might be present, with any condition that might impact their removal clearly understood. The process for removal and the means by which the process is controlled must also be clearly defined.
The Importance of Expertise and Technology
Indeed, the best CDMOs have analytical groups staffed by people with extensive experience and expertise and an understanding of the fundamental forces involved in advanced analytical techniques. They ideally also have previous exposure to the analytical needs of drug manufacturers.
In addition, the best CDMOs recognize the challenges faced by their analytical groups with respect to increasing workloads driven by growing regulatory requirements. As such, they have reasonable expectations regarding the time needed to complete specific tasks. They also continually invest in the advanced technologies and the instruments needed to perform increasingly difficult analyses. The groups are staffed with a combination of highly educated and experienced experts supported by colleagues new to the field that receive intensive training internally and externally.
Value of In-House Method Development and Validation
Clients of Albemarle Fine Chemistry Services (FCS) benefit from this type of advanced analytical group, both at our South Haven, Michigan API and Tyrone, Pennsylvania regulated raw material production sites. There is no need to outsource analytical method development and validation. Eliminating the need for transfer of externally developed or validated methods reduces delays due to unexpected validation challenges. It also accelerates development timelines, because projects can move directly from phase II to phase III with previously transferred and validated methods. Finally, the timelines of the analytical project are within the control of the CDMO.
Supporting Customer Supply Chain Security
Albemarle’s Tyrone facility produces some of the regulatory starting materials used at the South Haven site. Teams at the two sites work in close collaboration, expanding our process knowledge and understanding, enabling us to establish more extensive impurity profiles for our raw materials and allowing us to head off potential problems at the earliest stages.
Changes to processes at the Tyrone facility are readily managed through our joint management of change system. Because we understand our capabilities and chemistries at both facilities, we are able to reduce and control even the most challenging impurities, including elemental and genotoxic impurities.
Albemarle’s project sponsors benefit from this integration, particularly as it relates to identifying impurities, method development, process development, scale-up and regulatory compliance. The high level of transparency and communication, which is generally not possible with external suppliers, is significant given the increased emphasis on supply chain security and the need for greater knowledge of the processes (and their controls) used to produce regulatory starting materials.
In fact, at Albemarle we encourage our customers to participate in all phases of a project. We understand their need to have visibility into their supply chains, including recognition of the reasons behind the design of specific methods and the approaches used to validate them. Our analytical chemists are not only comfortable working with our clients; they welcome sponsor insights and ideas and seek opportunities to obtain customer input.