In this interview, News-Med talks to Tammy Newbold about the Global Harmonization of Regulatory CMC within Veterinary Medicine.
Can you explain what global harmonization of regulatory CMC entails and why it is particularly significant in veterinary medicine?
Global harmonization is very important for veterinary medicine because the field is smaller and often has limited resources compared to human health. Startups in veterinary medicine usually do not receive as much funding as human pharmaceutical companies. Although this is changing, with some startups receiving substantial funding, efficient drug development is still vital. By adhering to harmonized CMC regulations, they can expedite market entry and approval, maximizing their limited resources.
Global harmonization ensures that when companies enter their first market, such as the US or Europe, they have already considered the regulatory requirements of the other market.
This means that entering the second market is easier because they have already completed most of the necessary studies, making the transition more efficient and cost-effective. The process works under a global harmonization development program, minimizing the time and money spent expanding into new markets.
How does the regulatory CMC framework influence the development and approval of new veterinary medicines?
The regulatory CMC framework sets the foundation for developing new veterinary medicines. Development of veterinary medicines moves much faster than human drug development because we go directly into our target species, bypassing the initial animal testing required for human drugs to check for the safety profile and other concerns. This direct approach allows for a faster development process.
Utilizing the CMC framework for veterinary medicine development allows for a structured approach to identifying the studies that need to be conducted for global approval. Utilizing these required studies a global timeline can be developed detailing when and where each study will occur.
The CMC framework serves as a roadmap for development. Following this roadmap helps us move into approval by limiting the additional studies that may need to be conducted. Some additional studies may still be required outside of the CMC framework as new information about the product’s behavior and effects emerges. However, the CMC framework lays out the complete roadmap for development.
This means that a CMC expert can be appointed project manager since they understand the roadmap and can ensure that the studies are conducted appropriately and within the necessary timeframes to advance toward approval.
What are some key challenges faced when aligning CMC regulatory practices internationally in the veterinary sector?
We do not have phases in veterinary medicine. We only talk about “phase three” for animal health because human drug developers understand this terminology, and most facilities the Veterinary Industry use to develop drugs are specific to human drugs. This direct jump to phase three is challenging for veterinary medicine because we lack the preliminary phases human medicine undergoes, resulting in limited knowledge about our drug. Sometimes, we understand the drug substance well, but we often lack detailed information about the product's manufacturing controls required to produce a robust and consistent product.
In human medicine, phases one and two provide extensive data and allow for process tweaking, including formulation and analytical methods. By the time human drugs reach phase three, significant knowledge about them exists not only from a manufacturing perspective but also from a clinical perspective.
We do not possess the knowledge gained from phases one and two in veterinary medicine. We move directly to phase three and then to approval, which means we have to learn as much as possible about our product before moving into approval. This truncated process and our limited knowledge present a significant challenge because we are not making multiple batches of the drug product.
Many companies in the veterinary medicine sector are starting to work on drug substances early, whether they are new chemical entities or even drug substances already used in human medicine. We focus on formulation development with a target product profile, such as a tablet dosed once a day.
We develop analytical methods and may run pilot studies, similar to phases one and two in human medicine, to test animal efficacy. While not submitted to the FDA as pivotal studies proving efficacy, these studies provide valuable learning about the drug's effects, potential adverse events, and trial glitches.
This approach provides valuable learning before we go into our pivotal trials, and it is becoming increasingly common in animal health. Previously, we used to produce a drug and go straight into pivotal trials without this intermediate step.
Another major challenge in veterinary medicine is global harmonization. Pursuing a global harmonization process is important, understanding market sizes and target regions such as the US, Europe, Japan, and South America. Estimating market sizes and production needs for the first three years is extremely important but difficult. In animal health, we are often developing the market itself. An example of this is using ivermectin to prevent heartworm in dogs. It is a very important product in veterinary medicine.
Heartworm, often fatal in dogs, had no preventative treatment in the 1980s. Merck was the first to develop a product that prevented heartworm, but the market size was unknown. Therefore, Merck had to estimate product demand despite being years away from marketing, in order to determine the scale of the development program.
If these estimates were wrong, it risked supply shortages or overproduction. Accurate estimates are vital to avoid additional development studies, scaling up batch sizes, and obtaining further FDA approvals, all of which can cause market delays and increased costs.
Misestimating market demand can cause significant issues: underestimation leads to supply shortages and scaling up production, while overestimation results in excess inventory and product write-offs due to expiration. Accurately estimating global product demand is very important at the beginning of the development process for veterinary medicine.
Image Credits: DS InPharmatics (DSI)
How do rigorous CMC regulations ensure the safety and efficacy of veterinary drugs on the market?
Like human health, veterinary drugs go through a rigorous regulation process. Data from all studies conducted are put together in a comprehensive CMC data package and then submitted to the FDA. It undergoes a rigorous review just like it does on the human side. The review process for veterinary drugs is as stringent as it is for human drugs, with reviewers applying the same standards and scrutiny.
In the United States, veterinary medicine products are manufactured according to GMP 210 and 211, similar to human drugs. GMP standards also apply in Europe and Japan for human and veterinary drugs. The rigorous approval process includes a thorough review of all studies by the FDA, which asks detailed questions to ensure compliance.
Once approved, the product undergoes the same regulatory oversight as human drugs. Annual reports detailing marketing, manufacturing volumes, and adverse events must be filed with regulatory agencies, and any significant manufacturing changes must be pre-approved by the agencies.
Veterinary drugs are also monitored through adverse event reporting databases, similar to those for human drugs. Veterinarians and pet owners can report adverse reactions, which are then reviewed by the FDA. If there are significant adverse events, the FDA may require the drug sponsor to address these issues through label changes, formulation adjustments, or other measures to enhance safety.
Could you discuss the major differences in CMC requirements between the FDA Center for Veterinary Medicine and the European Medicines Agency?
Similar to the human side, where the International Conference on Harmonization (ICH) harmonizes guidelines among major regions like Japan, Europe, and the United States, the Veterinary International Conference on Harmonization (VICH) serves the same purpose for veterinary medicines. This is done to provide a standard set of guidance documents for drug developers when they want to conduct a study.
Stability studies are a key example. Previously, to prove the stability of a drug, a sponsor had to run different stability studies to support Europe, the United States, Brazil, Japan, and other regions. Once the International Conference of Harmonization was established and harmonized these requirements, it streamlined the conduct of stability studies. A sponsor has a pretty good sense of what attributes need to be considered and can , hopefully, run one stability study that will meet a majority of the global markets.
In the veterinary world, the Veterinary International Conference on Harmonization (VICH) allowed us to standardize the product development process globally. This global harmonization means that if you consider the requirements of all regions from the start, there are a few differences worldwide.
A critical area is excipients. Some excipients in the United States may not be allowed in Europe, and vice versa. This includes color and sweeteners, which can vary between regions. When developing a formulation, you want to ensure that your excipients are accepted worldwide to maintain a single formulation.
For example, specific dyes and sweeteners may be permitted in one region but not another. Ensuring these components are globally acceptable is crucial for a single worldwide formulation. Before VICH, companies often developed different formulations for each region, complicating the supply chain with numerous SKUs.
Now, the focus is on ensuring your formulation can be developed globally. This is where the VICH guidance comes into play. After a drug is produced, VICH guidelines provide information on how to run the stability studies, design the analytical methods, and validate them. This framework streamlines drug development, reducing differences across regions and reducing development costs.
What role do analytical and quality assurance processes play in maintaining the integrity of veterinary drugs throughout the manufacturing cycle?
Analytical processes are crucial in maintaining the integrity of veterinary drugs throughout the manufacturing cycle. Early in development, analytical methods must first provide valid information, even if the accuracy is not what we want. These methods must be fit for purpose, giving us the necessary information to begin generating data.
As the development program progresses, the analytical method must become more stringent to ensure accuracy. We need to know that it can measure and provide valid data at the extremes of the product. All of our decisions are based on the data provided by the analytical methods. If the data is not valid, it can lead to incorrect decisions. In the animal drug development industry, since we jump directly into phase three as we develop a product, the analytical methods must be rigourously developed at a very early stage, it can drive analytical chemists up the wall.
We must continue to examine these analytical methods throughout the product's life cycle to ensure that they always provide valid data. Improvements in technology should be adopted to enhance data accuracy. Ensuring valid data from studies is one of the most critical aspects of veterinary drug development, as it directly influences decision-making.
Quality assurance processes are also very important for understanding what happens when something goes wrong in a manufacturing facility. They ensure that issues are appropriately investigated and addressed, leading to valid conclusions and preventive actions to avoid future occurrences.
Quality assurance (QA) is critical in the drug development program. Quality assurance also ensures that protocols and reports supporting the development of a drug substance or drug product are accurate and valid. Additionally, QA ensures that accurate data is entered into the dossiers of which the development protocols and reports are the foundation. Errors in data transcription can lead to significant scrutiny and delays. Quality assurance teams audit these documents to ensure data accuracy, preventing potential issues with regulatory agencies.
I have seen agencies often catch mistakes in dossiers, leading to significant number of follow up questions leading to delays in approval. Thus, analytical and quality assurance processes are very important in the development cycle of veterinary drugs.
Are there any recent innovations or technologies in CMC practices that have significantly improved the efficiency of veterinary drug development?
The Veterinary International Conference on Harmonization (VICH) has significantly improved the development of veterinary drugs. VICH guidelines have been extremely helpful, particularly in the area of stability.
Previously, stability programs were extensive, requiring products to be placed into a stability chamber and run for two years to meet the regulations of South America, the US, and Europe. Each region required separate studies, which were resource-intensive and time-consuming.
With harmonization the number of stability studies are limited and sponsors will often establish those studies during development streamlining efficiency and reducing costs, and expediting the time-to-market for veterinary drugs.
How important is continuous education and regulatory expertise in keeping up with global standards in veterinary medicine?
Continuous education and regulatory expertise are essential for keeping up with global standards in veterinary medicine. Develoopment projects for Veterinary Medicine benefits from a CMC regulatory person who knows animal health, and veterinary regulations on a global scale.
It is important because many of our developers and manufacturing facilities mainly focus on human health. They know human health inside and out, but studies required for human health on the CMC side are often not needed for animal health due to differences in lifespan and usage.
For example, humans have a long lifespan, necessitating long-term studies that are not required for animals like dogs, cats, and horses, which have shorter lifespans. Food-producing animals have implications on human health and have additional studies that are required to support the safety of humans.
However, small startups in veterinary medicine often work with CDMOs specializing in human health and may not be aware of these differences. These smaller startups may not have a CMC regulatory person, relying on the CDMO's regulatory person can lead to the conduct of unnecessary studies. This results in wasted resources and the obligation to submit all generated data to the FDA, even if it’s not required, incurring additional costs.
On the other hand, there are some studies we have to run in animal health that are not required in human health, particularly for food-producing animals. If the CDMO does not understand these requirements because of their background in human health, it can lead to significant delays when the FDA requests these studies at the approval stage. This underscores the importance of having someone with veterinary regulatory expertise to navigate these complexities and avoid costly delays.
In addition, regulatory expertise must be continually updated to keep pace with evolving global standards. Regulatory agencies worldwide are constantly developing new guidelines and regulations. Staying informed about these changes is critical for ensuring compliance and smooth approval processes. This transparency and proactive engagement with new guidance are essential for sponsors to consider emerging requirements and maintain adherence to global standards.
Given the smaller market size and fewer resources in veterinary medicine, how do companies optimize their CMC strategies to remain competitive?
Given the perceived smaller market size and fewer resources in veterinary medicine, companies need to optimize their CMC strategies effectively. However, it is important to note that the market size in veterinary medicine is not always small. For instance, the market for food-producing animals is massive compared to human health. Treating cattle is important for our food supply, making it a large market.
Drugs for food-producing animals have a different regulatory pathway compared to those for companion animals. While companion animals require prescription drugs from a vet, the large scale of food-producing animals means that drugs fall under the veterinary feed directive. This directive allows veterinarians to prescribe these drugs without overwhelming pharmacies, reflecting the vast market volume.
The veterinary feed directive, established to handle large food-producing animals, simplifies the distribution process. This distinction is key in optimizing strategies, as it allows for efficient handling of high volumes without the constraints of traditional prescription regulations.
For veterinary medicines, it is important to consider emerging fields like gene therapy. While gene therapy is a new human and veterinary medicine area, the potential markets differ significantly. In human health, it targets rare diseases with small patient populations, such as spinal muscular atrophy and Duchenne's muscular dystrophy. In contrast, veterinary applications for common conditions like feline leukemia target much larger populations. For instance, there are approximately 17 million cats in the United States alone, a substantial market compared to the smaller human markets for specific gene therapies.
The optimization of CMC strategies in veterinary medicine must start at the beginning of drug development. This can be done by defining the ultimate market goal of the product. Sponsors want to get the product out as quickly as possible. Therefore, the development process needs to be efficient. For instance, if developing a flavored tablet that most animals will readily consume is key, getting it to market quickly to gauge market response is essential.
Many sponsors streamline development by initially releasing a basic product version, such as a tablet taken once or twice a day, to understand market reception. We know that people do not want to give their cat or dog a tablet every single day, but that is what is available on the market. It fills a need.
However, improving patient compliance is vital. This can involve changing the drug’s formulation to reduce dosing frequency from daily to weekly or monthly. Enhancing the drug’s presentation to make administration easier for pet owners can significantly impact the product’s success.
Developing longer-acting formulations, such as monthly or tri-monthly injectables or even six-month implants, can significantly enhance patient compliance. Planning for this in the development phase ensures the end product aligns with market needs and improves compliance rates.
Market feedback is critical. We can predict what the market will do, but in the end, only the market can tell us the actual demand. This iterative process helps in optimizing the product based on real-world use. Laying out a comprehensive CMC development program from the start is essential. This involves understanding market expectations and the development timeline to avoid costly setbacks. Having CMC regulatory expertise for small sponsors ensures the product meets market needs without unnecessary delays.
For instance, if a company develops a daily injectable and later realizes a monthly formulation is needed, it can cause significant delays. Therefore, starting with a robust CMC framework and strategy ensures alignment with market demands from the outset, streamlining development and approval processes.
Looking ahead, what are the anticipated advancements or shifts in regulatory CMCs that could impact the global veterinary drug market?
CMC is a small portion of the regulatory landscape in the veterinary market. New FDA guidance could make our lives easier but can also complicate processes. For example, regulatory agencies might introduce new study requirements that were not needed before.
VICH was a significant advancement, but I cannot predict future changes. I try to stay on top of what regulatory agencies are discussing. We have seen small changes, like demands for objective methods for drug product appearance, which can be challenging to implement.
Significant changes in CMC specifically are uncertain. However, broader trends in veterinary medicine, like the increasing importance of pets as family members, are influencing the market. Pet owners are demanding better treatments for their animals, driving the development of new medicines.
On the food-production side, humane treatment practices are gaining attention. Even though animals are going to be slaughtered, it does not mean that they should suffer. It reflects on us as a human population to treat animals humanely. This shift is encouraging the development of products aimed at humane treatment.
Advancements like gene therapy, initially seen in human health, are emerging in veterinary medicine. While these therapies are expensive and take time to get approved, they represent a new frontier in animal health. Unlike human treatments, veterinary doses may be more affordable, addressing a larger patient population.
The growing focus on animal welfare is a significant driver in veterinary medicine. People demand better care for both pets and food-producing animals. This attention to animal rights is pushing the development of new treatments and ensuring better care practices.
About Tammy Newbold
Ms. Newbold is a biochemist by training, with 38 years in the pharmaceutical industry, three decades specifically dedicated to the field of animal health. Tammy’s career began with a strong foundation as a scientist in drug product formulation and process development, which included technology transfers, regulatory compliance, troubleshooting and lifecycle management.
Throughout her career, Tammy has contributed significantly to the development of, and gained FDA approval for, numerous pharmaceutical products tailored for food and companion animal products, including the ivermectin line of products, omeprazole for horses, Eprinomectin for dairy cattle, to more recently Entcye, Nocita and Galliprant. In addition to developing and gaining FDA approvals for drug products, she has been instrumental in developing and gaining FDA approval for several new chemical entities as well as companion animal products registered through the US Environmental Protection Agency.
She specializes in developing CMC regulatory strategy and development programs to obtain early regulatory approvals and streamlined reviews. She has experience in establishing harmonized approach for development programs that provide global registration. She has authored master files, CMC technical sections, as well as post approval submissions for drug products and drug substances.
About DS InPharmatics 
DS InPharmatics (DSI) provides regulatory, technical, and project management consulting services to healthcare product companies that manufacture and/or market pharmaceuticals, biopharmaceuticals, and cellular and gene therapy products.
Since 2007 we have provided our clients with innovative strategies and exceptional quality work products intended to enhance product development, approval, and marketing presence. Whether advocating CMC strategy, directing CMC operations or developing CMC submission content that represent the best interests of emerging biotech, we focus on the critical CMC issues and build programs that enhance development.
In April 2021 we were thrilled to announce that DSI has just become part of ProductLife Group.
French-headquartered ProductLife Group (PLG) is well-known in the Life Sciences market. It has a track record of successfully managing global outsourcing programs and insourcing services for its international client base. The company is on a mission to help transform human health outcomes by optimizing regulatory affairs, safety & vigilance, and quality compliance for life sciences organizations worldwide.
The fit between our two organizations could not be more perfect. We will complement PLG's growing biotech services portfolio. US biotech sponsors recognize DSI as a leader in consulting for go-to-market strategies and RA pre-market consulting. At the same time, PLG has a strong reputation for managing end-to-end outsourcing of regulatory affairs and pharmacovigilance activities worldwide.
Our merger with PLG will harness our combined strengths, offering our clients on both sides of the Atlantic support with their developed drugs approvals and post-approvals compliance, plus advisory services on the best market strategies to deliver a rapid ROI on their development. Together we will offer our clients increased pharmacovigilance capabilities - including a QPPV; pharmacovigilance consulting; and a fully validated safety database - as well as complementary toxicology-related services; RIM/electronic document management services; and support for medical device regulatory requirements.
We see enormous potential in this new chapter for DSI and you, our clients. As a PLG company, we have the opportunity to become part of a global force in life sciences regulatory and compliance solutions and services, and we're incredibly excited to add our momentum to that effort.
Lab to plant: Scaling up API processes with Dr. James Mencel's guidance