Seeing the forest for the trees: CMC and Regulatory Affairs

To say that someone ‘cannot see the forest for the trees’ means that a person or organization is unable to see the big picture as the focus is too much on the details. It would be like someone needing to paint an entire house in a day but spending half of the day on picking out the right color.

Image Credit: DS InPharmatics 

The forest

Broadly written guidelines raise so many half-truths and misconceptions and are subject to interpretation, so at any given phase of clinical development it is hard to know with any certainty what constitutes a recommendation and what is an actual requirement.

Sometimes it is difficult to see situations as they really are while in the midst of them. In short, when someone is too heavily invested in a particular situation, approach, organization, etc. they can lose their perspective.

FDA regulations in 21 CFR Section 312.23(a)(7)(i) states, “that an IND for each phase of investigation include sufficient CMC information to ensure the proper identity, strength or potency, quality, and purity of the drug substance and drug product” and continues, “The type of information submitted will depend on the phase of the investigation, the extent of the human study, the duration of the investigation, the nature and source of the drug substance, and the drug product dosage form.”

The problem is that drug development management must translate guidance into clear program objectives, identifying the information and data that must be provided, and prioritize expenditures and resources.

The trees

Analytical techniques and product characterization

Analytical techniques are the foundation for gathering product knowledge. It is vital to develop and qualify a series of techniques that are useful for characterizing product attributes like purity, structure, biological activity and chemical modifications.

It is unlikely that a recognized reference standard already exists early in development, so an in-house primary reference must be created and fully characterized via the development of analytical techniques and tools.

During early product development and throughout the product life cycle, a reference standard is an indispensable resource. A reference standard has many uses. It is crucial in the development of analytical techniques and to monitor their performance over time. It will act as a valuable benchmark during process development to bridge lot-to-lot comparability and consistency.

In some instances, it may be utilized as a working assay standard as a control to set assay acceptance criteria or to produce standard curves. It also will be utilized to track trends in product attributes, assess stability, and to ensure against product drift or overtime.

Analytical method development and stability

Both small molecule drugs and biologics are susceptible to a variety of environmental influences including oxidation, temperature, pH, ionic strength, light, drying and chemical modification.

It is crucial to have an understanding of how different degradation or denaturation pathways influence the product. Accelerated stability and forced degradation studies can be helpful tools to gather insight on product stability.

Early efforts toward developing reliable and meaningful analytical techniques which characterize pathways of chemical and physical instability are particularly useful in conjunction with forced degradation studies.

There are benefits to developing physicochemical techniques as stability indicators because they can supply great precision and are usually simpler. These assays can sometimes reveal trends that are early predictors of stability issues and can be utilized to predict stability for later batches where real-time data may be limited.

Stability programs should be designed to focus on product attributes that are vital to activity and safety and stability-indicating assays should be developed and qualified early on.

Stability-related alterations can lead to safety issues like immunogenicity and unwanted side effects or toxicity from degradation products. Correlating forced degradation studies with genotoxicity and/or immunogenicity experiments supply supporting data for recognizing product attributes that are associated with safety and assessing the risk of degradants.

It is crucial to focus on those attributes that address product properties as they relate to its function and safety, when choosing release tests. To ensure quality and consistency these must be incorporated into a quality system for product release.

FDA Guidance states that the confidence in and reliability of analytical results come “from thorough assay optimization, qualification, validation, and tracking of performance over time.”

Process characterization and in-process testing

Timing is crucial. It becomes increasingly difficult and perceivably risky to make critical changes once human trials progress into Phase III. Process characterization and the identification of critical product attributes should happen earlier during Phase I and II stages of development rather than later as a result of this.

Now, the emphasis is on proactively designing product quality and process control through better understanding of the manufacturing design space and underlying science.

Carefully planned designed experiments and process optimization will help to pinpoint variability and generate key information and data which is useful for defining the ‘edge of failure.’ This information supplies a scientific basis for setting acceptable limits around key process variables and in process controls.

Usually, specifications are set with broad limits early in development then as processes and the level of product understanding are refined they are narrowed. Appropriate specifications should be determined which balance manufacturing capabilities, product needs, and industry standards.

Once again, such efforts are highly reliant on the development of suitable analytical techniques utilized to set acceptable limits around key process variables. Analytical techniques capable of characterizing pathways of physical and chemical instability can be incorporated into process optimization studies to optimize process robustness and extend product shelf life.

Understanding and controlling vital process parameters is crucial for monitoring product consistency and quality. Early investment in process characterization can reduce batch failure and supply supporting data and information to assess the impact of deviations and process alterations as they arise without causing program delays. There is no substitute for product knowledge.

Process modifications and lot-to-lot consistency

During the course of clinical development manufacturing process changes are inevitable, whether for scale-up or refinements to improve manufacturability for commercialization. Following any significant process change it is vital to show comparable strength, stability, and especially safety (e.g., impurities and contaminants).

Again, to demonstrate lot-to-lot comparability following a process change analytical techniques which fully characterize the product and its vital quality attributes must be in place. This is particularly important for biologics, where the process largely defines the product.

Development programs which also show a scientific understanding of process and product characterization can greatly decrease the perceived risk-associated changes by regulatory authorities.


Early investments in optimizing the formulation and the resulting PK/PD profile of the API can mean the difference between clinical success and failure. Many drug candidates possess strong scientific foundations but therapeutic relevance is dependent upon whether a drug ever reaches its target, in a consistent, active form and at the right dose, so that it has a chance to complete its intended task.

Variations in dose because of delivery or stability issues can confound the interpretation of clinical data severely and make the difference between meeting or failing to achieve statistical significance of clinical endpoints.

Analytical method development should ideally be integrated along with a formulation development program to identify the appropriate product attributes as early as possible, along with traditional elements like optimal storage conditions.

Later formulation modifications which are largely driven by stability concerns carry the risk of unanticipated influences on the clinical outcome. Often, regulatory authorities need extensive retesting of ADME and clinical safety studies.

Reference standards

Establishment of a reference standard does not have to wait for a finalized process or extensive knowledge of product stability. It is vital to store a batch in aliquots for utilization as reference and it should be fully evaluated by all available analytical tools as soon as, or even before, a process begins to resemble what will be used to generate clinical trial material.

Avoid the validation bog

The word ‘validation’ has become a miniature industry in and of itself. Validation proves that the user is measuring what they intend to measure, but it will not tell them what they are missing.

Too frequently, small biotech/pharma companies spend precious time and resources validating analytical methods before or during Phase I. It is not uncommon for techniques to be tweaked (e.g., solvent changes) to better resolve peaks or even to see them replaced entirely with a technology more appropriate for larger scale processes.

Then, sponsors must spend time and money re-validating methods but that money is better spent on advancing process knowledge. Validating analytical methods may not be necessary until later stages, but they should be suitably qualified to give a high level of confidence that the results are dependable.

Using unreliable data to make vital decisions can have catastrophic consequences. It is better to invest resources in the development and qualification of analytical techniques which balance product function and safety with manufacturing capabilities than validating early methodology.

Expanded change protocols

Carefully written information packages (Comparability Protocols) which supply a scientifically cohesive logic trail and resolution and a summary of the major technical issues give the necessary support for interactions with regulatory authorities.

Expanded Change Control procedures are consistent with current regulatory practice and supply a mechanism for requesting pre-approval of comparability protocols.

Know your product

There is simply no substitute for having a sound scientific understanding of your product and the processes which are employed to create it. The correct application of the regulations — requirements versus recommendations — during preclinical and early-stage clinical development is crucial.

The FDA initiative of quality by design (QbD) was intended to promote the idea of controlling the quality of final products through process and product understanding and building in better process control via knowledge of key variables and in-process analytics.

You will never know everything there is to know about your product. Still, you will be able to make informed decisions and deal effectively with unanticipated problems that inevitably will arise the more effort you put into understanding your product and process throughout development.


Produced from materials originally authored by Edward A. Narke from Design Space Inpharmatics.

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.

Sponsored Content Policy: publishes articles and related content that may be derived from sources where we have existing commercial relationships, provided such content adds value to the core editorial ethos of News-Medical.Net which is to educate and inform site visitors interested in medical research, science, medical devices and treatments.

Last updated: Mar 14, 2024 at 10:24 AM


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