It is crucial to understand the drug development process and the many milestones and tasks that are essential to a comprehensive development plan to guarantee scientific and commercial success.
While the main purpose of a well-designed regulatory strategy is to ensure an efficient process for offering new, effective, and high-quality drugs for patients, maximizing the return on investment (ROI) is also important.
Every step along the path to commercialization is significant. Effective chemistry, manufacturing, and controls (CMC) strategies, as well as the successive communication plan, are integral components of overall product success.
Crucial ROI considerations on the path to product approval
A major milestone for drug sponsors is the shift from Phase 2 clinical studies (intended to evaluate drug effectiveness for a specific indication in patients) to Phase 3 expanded trial studies (designed to gather further information about the effectiveness and safety required to assess the risk/benefit relationship of the drug).
Intellectual property, safety, and efficacy are typically the value drivers. Often viewed as less important is the CMC profile, assuming there is no major weakness in the product's profile. CMC development principally allows for non-clinical and clinical development and is not a driver of asset value for many small molecules.
By the end of Phase 2, a sponsor company has invested significant time, expense, and expertise to comprehend the scientific mechanisms behind the drug’s functionality in humans and determine how to clinically administer the drug product to optimize its medical benefit and reduce its medical risks. The question arises, have similar investments been made to explore the science of how the drug product can be manufactured consistently to produce the desired quality?
A manufacturing process successful in preparing a clinical product for Phases 1 and 2 is no longer deemed good enough to progress to later-stage clinical trials commercial manufacturing.
The goal of pharmaceutical drug development is to create high-quality products and manufacturing processes that consistently deliver the expected product performance. The knowledge and information attained from development studies and manufacturing experience offer the scientific understanding to support the establishment of the product manufacturing process, specifications, and manufacturing controls.
Using enhanced product knowledge and product performance data across several material attributes, processing options, and parameters is increasingly becoming standard practice in scientific manufacturing decisions. This is a result of modern guidance and the evolving regulatory harmonization initiatives.
At this stage (transition from Phase 2), execution is essential for ensuring that all necessary activities for marketing approval are being planned for. Any identified CMC development impediment should be discussed with the regulatory agencies.
Design of experiments and statistical approaches for data analysis
Gaining in popularity as a tool for process development scientists is the concept of process design and control. Traditionally, a product control space is proposed by the sponsor and must go through regulatory assessment and approval.
However, as the product matures in its life cycle, factors like economics, scale-up, and others demand changes in the control scheme for the process. The scientific basis for expanding or moving the product control space is most often developed to compensate for process shortcomings long after the original process development work is completed.
Developing and subsequently filing a process that encompasses the product control space can offer further insights into the process. Movement out of this control space would then not be viewed as a significant change. However, deviations from a strictly defined process would be deemed significant and typically initiate a regulatory change control course of action.
Due to the publication of ICH Q8, Q10, Q11, and others, the chance now exists to develop an approvable process ahead of the commercial launch that can anticipate and accommodate continuous improvement. This enables manufacturers to make changes that improve the process, as necessary, without requiring major regulatory approval—assuming that the product control space remains inside approved processes and the agency agrees to what is filed upfront in principle.
Using statistical approaches to design experimental studies and conduct data analysis has resurfaced as a fundamental activity, particularly in cases where the number of clinical batches produced in clinical development at scale is low. Typically, many raw materials and process parameters affect any given unit operation in a process.
It is not always practical to understand the impact of each raw material and input parameter on each output parameter. A combination of design of experiments (DOE) and risk assessments has emerged as the method of choice to expedite this task and is present within the literature.
To understand the benefits of this method, the process development and manufacturing team must create and document the scientific foundation for the justification and approval in the Pharmaceutical Development areas of the CMC Module 3. This information comes from appropriately designed experiments that outline and assess the outer limits or edge of failure of the intended process. This assists in understanding the effects on the critical quality attributes (CQAs).
During process scale-up or tech transfer, information and data about the process control space, in addition to the critical process parameters (CPPs) within which the process control space operates, must be easily accessible prior to scaling or transferring the manufacturing operation.
To maximize the chance that Module 3 is received favorably, the most important approach is to avoid exaggerations, strive for clarity, and discuss (rather than hide) negative findings and deficiencies. Any claims that cannot be substantiated should be avoided, and it is good to remember the age-old advice that if something is not documented, it is a rumor.
As a part of the proposed manufacturing process, the process control space can be detailed in the section of the application that includes the manufacturing process description and process controls (3.2.S.2.2). Where appropriate, further information can be offered in the section of the application that addresses the controls of critical steps and intermediates (3.2.S.2.4).
The appropriate place to describe and summarize process development studies that provide the basis for the design space(s) is in the manufacturing process development section of the application (3.2.S.2.6). The relationship between the process control space and the general control strategy can be detailed in the section of the application that includes the justification of the drug substance specification (3.2.S.4.5).
Seek agency advice to avoid regulatory delays
As the agency has the ultimate power over a drug’s fate, it is advantageous for the sponsor to confirm that the reviewer understands the science behind the manufacturing process and product. This may sound simple, but some sponsors may find it daunting. What happens if the agency expects more to be done than what is currently planned? How would this affect the corporate-established marketing approval date?
Sponsors must acknowledge that it is not about assuming they understand the process and product better than the regulatory agency; rather, it is about involving the regulatory agency. Regulatory scrutiny is typically less stringent at the start of the process development and increases as clinical trials progress to later stages. They reach their highest level throughout commercial manufacturing operations.
The ideal opportunity to investigate the boundaries of the necessary process and product control envelope, as well as develop the scientific support and experience needed to fully realize the predictability and quality of the manufacturing process, is available during process development.
These opportunities are more limited once commercial operations begin. Sponsors require a reality check for their regulatory and compliance strategy at the transitory point between Phase 2 to Phase 3, and the agency can deliver it. Both FDA and EMA see the benefits of CMC-focused End-of-Phase 2 (EOP2)/Scientific Advice meetings with sponsors. They view these meetings as an essential interaction with particular importance.
Sponsors must advocate communication and teamwork with the regulatory authorities. Investing in process science can enhance manufacturing process control during later clinical stages and commercial production.
Meetings between the regulatory agency and the sponsor can assist in assuring sponsors that no major CMC strategic surprises will arise, which could substantially delay the marketing applications. Review and approval ensure that a given compound meets the requisite quality and technical elements to enable the successful commercialization of the drug and increase asset value.
Regulatory correspondence, specifically regulatory agency feedback, can guide the CMC to points of potential concern or places where mitigation strategies are underway or will require development. While reviewing, the sponsor must make linkages to other disciplines, such as safety and clinical, that may be impacted and therefore should be addressed in the broader team context.
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.
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