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A one-size-fits-all strategy is not the best approach for the development of a chemistry, manufacturing, and controls program.
The landscape of drug development has continued to shift over time. Just a few decades ago, most drugs were developed from beginning to end by large pharmaceutical companies with well-defined systems of control. Today, this has significantly changed; much early development (Pre-investigational new drug [IND], Phase I, Phase II) work is performed by small- to medium-size companies, many of which are virtual companies.
The goals, drivers, and challenges encountered by these smaller companies are significantly different than their larger counterparts. Instead of an end goal of commercializing a new drug, the goal may be to generate the appropriate interest to sell the intellectual property or company. Instead of a large team of experts who are responsible for the various analytical requirements, the responsibility falls to a few individuals, and in many cases, just a single person. As a result, smaller companies commonly rely on the expertise of contract laboratories to perform analytical work, act as partners in the development process, and help design the appropriate chemistry, manufacturing, and controls (CMC) analytical activities that will meet their company’s specific goals.
The challenge for designing these CMC programs is that each becomes a custom program; there is no one-size-fits-all model to be applied. A unique combination of drivers must be considered when designing an appropriate program.
For many small or virtual companies, funding is a primary driver for decision making. This can often lead to conflicts between what testing “should” be done versus what “has” to be completed. It is not uncommon for small pharma companies to encounter one of the following funding challenges.
Milestone funding. Under milestone funding, the infusion of additional development funds is tied to reaching a certain milestone, which releases funds to continue development. With this approach, companies may focus efforts on attaining the funding milestones rather than regulatory or development drivers. In these scenarios, studies that may be required for regulatory approval or studies that would aid in the longer-term development goals are postponed for a later point in favor of studies that will achieve the next funding milestone.
Limited funding. In a limited funding scenario, which can impact both small and large companies, the analytical development functions are given a finite amount of funding that cannot be exceeded. With limited funding, companies may design programs that focus on obtaining the bare minimum requirements, while delaying or foregoing work that may be beneficial in the longer term. This process can be summarized as the conflict between the “nice to have” studies versus the “have to have” studies.
Regulatory guidance for early-phase analytical CMC support is limited. FDA and the International Conference for Harmonization (ICH) have several guidances that can be used to design the program to meet expectations, including FDA’s Current Good Manufacturing Practice for Phase 1 Investigational Drugs Guidance for Industry (1), Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drug, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products (2), and INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information (3); and ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (4).
These guidances encourage the use of a phase-appropriate approach and provide a basic foundation for expectations of what is appropriate for different clinical phases of CMC analytical programs. It is not uncommon, however, to find pharmaceutical companies and contract research organizations (CROs) that are not taking advantage of the phase-appropriate approach and simply reference the typical ICH guidances for analytical items, such as method validation (5) or stability (6), when the guidances are not meant to be applied to early-phase support.
There are two reasons why companies take these steps. First, while the FDA guidances encourage the use of a phase-appropriate approach, they lack specific details of the actual requirements. As a result, companies may prefer to reference the quantitative requirements held within the ICH guidances as a conservative approach. A second reason may revolve around the possible difficulty in implementing a CGMP quality system that allows for differing levels of CGMP compliance throughout the various clinical phases of development.
The development goals of many smaller or virtual companies stop short of commercialization. Many companies know they will not have sufficient funding to support commercialization of their product. They adopt a development strategy to bring the drug to a certain point within the development cycle (i.e., Phase 2A), then enter into a co-development agreement with a larger pharmaceutical company or sell the company (or the drug) to another company to continue the development. In these scenarios, the focus may not be on the regulatory requirements or long-term developmental needs, but rather the studies and data required to entice a partner or buyer.
These various drivers for the smaller pharma companies are not only complex but, in some cases, may conflict with another driver. This strategy often complicates the design of an appropriate program. To design the program, it is important to understand the typical analytical CMC activities and their limitations and challenges.
Analytical methods to test pharmaceuticals must be “fit for their intended purpose” (7). Method developers evaluate the intent of the method’s purpose prior to starting any development work by asking if the method is for assay or impurities, if the method needs to be stability indicating, and if the testing is for an API or drug product.
Additional questions that are important for the early-phase work include the phase of product development and if the synthesis or manufacturing routes are finalized.
The development of stability-indicating methods can be expensive and lengthy, leading to the question of whether such testing needs to be performed for early-phase clinical materials.
Consider the example of a Phase I API in development. The current synthetic scheme is used to produce 1 kg of material. While this amount is sufficient for Phase I, the scheme will have to be scaled up and optimized for Phases II and III, which will likely result in a new impurity profile versus the Phase I material. For the Phase I material, only two batches are expected to be produced.
Do pharma companies need to spend the time and effort to develop-and validate-a stability-indicating method knowing that it may likely need to be redeveloped after being applied to only two batches of API? Unfortunately, many pharma companies that have taken a conservative approach and answered “yes,” wasting time and money when they had to redevelop the method to address changes.
For the phase-appropriate approach, method development should start as early in the process as possible; however, developers should understand the intent of the method is to be applied to early-phase material in addition to the normal “intent of the method” questions. Using this principle will allow for efficient method development with reduced costs and time.
In many cases, applying a generic high-performance liquid chromatography (HPLC) method may suffice during Phase I and early Phase II until more is known about the compound, and the synthetic and manufacturing routes are final.
Once developed, the method must be validated to demonstrate that it is fit for the intended purpose. ICH Q2(R1) (5) and United States Pharmacopeia <1225> (8) provide specific expectations on what elements are required for Phase III and commercial materials; however, this level of validation would be wasteful and detrimental to an early-phase development program. The analytical characteristics often included in the registration validation include the following:
As with method development, it is important to evaluate the development drivers in regard to the program. What attributes would be needed to ensure that the method is fit for purpose as applied to an early-phase program? The answer will vary depending on the specifics on the product and application of the method.
FDA’s Phase I guidance states that the analytical methods “should be scientifically sound (e.g., specific, sensitive, and accurate), suitable, and reliable for the specified purpose (2). The Phase II guidance does not list specific criteria but only states that “appropriate validation data should be available” (3). While some of the attributes would be applicable to early-phase programs, others would not need to be applied until later in the developmental cycle. Therefore, a pharma company can develop a phase-appropriate validation that not only serves regulatory expectations, but also allows for conservation of resources to be applied to other activities or held until later in the developmental cycle.
A phase-appropriate validation for a Phase I material could then be designed around the following elements:
Stability studies are perhaps the most expensive and time-intensive portions of analytical support during drug development. The studies can cost more than $100,000 and take years to complete. While the regulatory requirements for stability for commercialization are well defined by the ICH Q1 guidances, they are not practical given the drivers for early-phase programs. Again, FDA gives limited guidance on the expectations.
For Phase I materials, the guidance states that a stability study should be performed “to monitor the stability and quality of the Phase I investigational drug during the clinical trial” (2). The minimum requirements would then translate to performing a stability study to cover the length of dosing the drug that will be used in the clinical study (i.e., If the clinical study is one month long, the stability study would only need to cover that length of time). In many instances, stability studies are performed in conjunction with the clinical trials, with the initial time point being conducted prior to starting the clinical study and the final time point being conducted after the date of final dosing. This approach does minimize the total cost expenditure for the stability study and may be beneficial for those companies with funding constraints. It may be beneficial to continue the stability studies beyond the dosing timing to gather additional development data useful in the longer-term developmental goals of the product.
For Phase II material, the guidance does not provide additional guidance beyond that offered for Phase I, stating that a description of the stability performance to support clinical studies should be submitted. The only difference here is that when moving into Phase II, it is expected a company would have already generated stability data to support its clinical dosing timelines prior to initiating the studies.
Designing a phase-appropriate CMC analytical development strategy can be crucial to the success of a small or virtual pharma company. The successful program will balance various drivers to provide a program that meets the overall development goals without sacrificing the requirements of the program. A successful strategy cannot be accomplished with a one-size-fits-all model, but rather requires evaluation of the company’s individual drivers and goals along with the specific requirements of the compound being developed.
Given that these companies typically rely on CROs to help guide this decision-making process, it is crucial for the pharma-CRO relationship to be a true partnership in the developmental process. This level of relationship requires that the CRO be more than a simple testing laboratory and be a partner/consultant with the pharma company to design the programs.
1. FDA, Current Good Manufacturing Practice for Phase 1 Investigational Drugs, Guidance for Industry, (Rockville, MD, July 2008).
2. FDA, Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drug, Including Well-Characterized, Therapeutic, Biotechnology-derived Products, Guidance for Industry, (November 1995).
3. FDA, INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information, Guidance for Industry, (Rockville, MD, May 2003).
4. ICH, Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (November 2000).
5. ICH, Q2 (R1) Validation of Analytical Procedures: Test and Methodology (November 2005).
6. ICH, Q1, Stability Testing of New Drug Substances and Products (February 2003).
7. FDA, Analytical Procedures and Methods Validation for Drugs and Biologics, Guidance for Industry (Silver Spring, MD, July 2015).
8. USP, General Chapter <1225>, “Validation of Compendial Procedures,” USP 42–NF 37.
Wayland Rushing, PhD, is director, scientific affairs for Eurofins, BioPharma Product Testing.
Supplement: Outsourcing Resources
When referring to this article, please cite it as W. Rushing, “Best Practices for Vacuum Conveying of Pharmaceutical Powders," Pharmaceutical Technology Outsourcing Resources Supplement (August 2019).