Accurate analysis ensures the quality, safety, and efficacy of drug products that reach the marketplace. However, method development and validation regulations are extensive and stringent, and they are continually evolving as new therapies and analytical technology advancements are introduced. CDMOs can help their customers reach the market sooner if they anticipate evolving compliance requirements, and then implement corresponding method development and validation strategies. Those strategies should include a robust plan for supply chain security.
Evolving Regulatory Requirements
Current Good Manufacturing Practice (cGMP) shows us that the pharmaceutical industry, while highly conservative, is far from static. In their efforts to ensure continued safety and efficacy of APIs entering the consumer market, regulatory agencies are raising the standards for analytical testing. To meet these standards, - CDMOs are generating more high-value information through advances in the accuracy and precision of existing instruments, as well as the portability and high-throughput capabilities of many analytical techniques.
Certain regulations ensure that analytical methods – like those developed for raw material identification and purity and quality determination, in-process monitoring, drug substance quality and purity, and final product release – provide the appropriate information. As drug substance production supply chains become more globalized and increasingly complex, so have manufacturing processes and the analytical methods necessary for comprehensive quality characterization. As a result, regulatory agencies have encouraged drug makers to integrate more robust quality control into their analytical processes by adopting quality-by-design (QbD) and design-of-experiment (DoE) methods. A QbD approach to analytical method development provides greater understanding about the limits of the analytical methods, beyond standard method validation.
Regulators also encourage manufacturers to maintain greater visibility and control over the entire supply chain for all ingredients and processes used to produce their drugs. This calls for increased communication with regulators. For example, manufacturers increasingly manage final drug substance quality by controlling impurities in the raw material supply, which requires more robust methods. So,
regulators more commonly seek validation of all analytical methods – not just those for final product release, but also those used in crucial process control points, such as raw material identification and in-process monitoring.
Managing Differing Agency Requirements
Complicating the compliance challenge is the fact that regulations are generally not harmonized across countries and regions. In the EU, for example, expectations around justifying analytical methods for critical raw materials and in-process monitoring often reach the level of validation, while expectations have not gone that far in the United States.
Validation of these additional methods demands a greater workload, which CDMOs must manage without delaying clients’ timeline milestones, such as NDA filings. So, the added validation work must be completed earlier in the program. For example, in raw material methods, spike and purge studies determine which impurities may impact final drug substance quality and the methods required for analyzing critical raw materials. However, information about synthetic routes and potential impurities in the raw materials is required before those studies can be designed.
Limits for unspecified impurities also 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 acceptable 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 chemists and instruments capable of performing advanced analyses. Therefore, the analytical group must be of the right size and composition to ensure completion without impacting a sponsor’s filing timelines.
Evolution of Analytical Expectations in Current Good Manufacturing Practice
Agencies have begun to focus more intensely on 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).
Recent industry experience around product recalls for the presence of genotoxic impurities shows that controlling for these early in process development is essential, and manufacturers should expect increased regulatory interest.
Genotoxic compounds can be mutagenic and cause damage to DNA, even at very low concentrations. Some genotoxic compounds (sulfonated compounds, alkyl chlorides, aromatic nitrosamines) are well characterized, and certain chemistries (Fischer esterifications, HCl chemistry in alcoholic solvents, reactions with nitroaromatics) have the potential to produce genotoxic impurities.
These have attracted significant attention in recent years, following the identification of probable carcinogens (N-nitrosodimethylamine and N-nitrosodiethylamine) in APIs used for multiple generic versions of angiotensin II receptor blocker medicines that complied with existing regulations.
There are several different regulatory guidelines regarding the identification, categorization, qualification and control of genotoxic impurities. These include I CH M7 (Assessment and control of DNA reactive [mutagenic] impurities in pharmaceuticals to limit potential carcinogenic risk), adopted in 2018; and an EMA draft guidance document, entitled “A guideline to calculation of compound-specific acceptable intakes,” from 2015. Application of the principles of the ICH M7.
The FDA, meanwhile, published the Guidance for Industry: Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches in 2008. EMA’s guidance includes the guideline on the limits of genotoxic impurities from 2006 and questions and answers on the guideline on the limits of genotoxic impurities from 2010.
It is nearly impossible to completely avoid the generation of genotoxic impurities, and identifying and controlling them is challenging because there are no simple structural guidelines to indicate genotoxicity. So, it is necessary to identify all potential impurities that could form during the synthesis and upon storage of the drug substance, then evaluate their genotoxicity using available literature, data, and appropriate modeling techniques.
CDMOs must have an effective strategy in place to manage identification and control of genotoxic impurities. Transparent communication is essential between the R&D chemists and analytical experts within the CDMO and with the relevant experts from their clients and raw material suppliers.
Completing this process as early as possible allows time for method development and validation, which is quite challenging. It 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. These tools and chemists are vital to every step of process development and validation, if companies hope to prevent unexpected issues resulting from genotoxic impurities.
Elemental impurities can be introduced into drug substances or drug products through impurities in raw materials, or other ingredients like homogeneous metal catalysts, processing equipment, and the processing environment. For more than 100 years, the compendial testing for final product heavy metals content was a wet chemistry test of limited effectiveness.
However, advances in analytical technologies have produced new elemental impurities limits based on toxicological data – a substantial improvement from a patient perspective. The new method for controlling elemental impurities, especially heavy metals, combines 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).
Analytical teams still require a strategy, though, for removal of any metals. The process for removal and the means of process control must also be clearly defined, and the team must understand any conditions that might impact inhibit removal.
The Importance of Expertise and Technology
The best CDMOs have analytical teams staffed by highly educated, trained, and experienced experts who understand the fundamental factors involved in advanced analytical techniques. These companies also recognize the challenges their analytical groups face, such as increasing workloads driven by growing regulatory requirements. So, they have reasonable expectations about the time needed to complete specific tasks. They also continually invest in the advanced technologies and instruments necessary for performing these increasingly difficult analyses.
Clients of Grace Fine Chemical Manufacturing Services (FCMS) benefit from this type of advanced analytical group. At both 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 transfer of externally developed or validated methods reduces delays from unexpected validation challenges, thereby accelerating development timelines. Projects can move directly from phase II to phase III with previously transferred and validated methods, because the CDMO controls the analytical timelines of the project.
Supporting Customer Supply Chain Security
At Grace FCMS, we understand our clients’ need for process visibility. They want to understand, for example, the reasons behind the design of specific methods and the approaches used to validate them. We encourage our customers to participate in all phases of a project. Our analytical chemists welcome sponsor insights and ideas and seek customer input.
Grace FCMS clients also enjoy great benefits from our increased emphasis on supply chain security and our broad institutional knowledge of the processes (and their controls) for producing regulatory starting materials. Grace FCMS’s Tyrone facility produces some of the regulatory starting materials used at the South Haven site, and changes to processes at the Tyrone facility are readily managed through our joint management of change system. The teams at both sites collaborate to expand our process knowledge and understanding, which helps us establish more extensive impurity profiles for our raw materials and head off potential problems at the earliest stages.
Our clear understanding of capabilities and chemistries at both facilities allows us to design integrated solutions for securing the supply chain, identifying impurities, method development, process development, scale-up, and regulatory compliance. This level of integration, transparency, and communication is generally not possible with external suppliers. At Grace FCMS, though, it is how we reduce and control even the most challenging impurities, including elemental and genotoxic impurities.
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