Could you introduce yourself and your background in analytical services?

My name is Colman Byrne, and I am the head of analytical services for DSI. I have been with the organization for nearly 17 years and have over 40 years of industry experience working with a variety of companies in the analytical area. I started as a bench chemist and then ran a contract testing lab that focused on biological and protein peptide-related types of samples. I then joined a few small virtual pharma and biotech companies, coordinating their analytical services and bioanalytical testing and managing the activities of contract test organizations.

I joined DSI when it started and, since then, have worked in many areas, from early-stage analytical method development through method validation, specification and shelf life justifications and on regulatory filings and post-filing support for Complete Response Letters, out to post-approval release testing of commercial products and analytical investigations.

How do analytical services significantly contribute to ensuring the safety, effectiveness, and quality of pharmaceutical products?

Analytical services are at the crux of all pharmaceutical developments activities because they are required for the active material to establish it’s purity/quality from the beginning of development, and they are required to establish the efficacy and safety of the drug product at the time of release. Testing ensures adequate stability of the product and establishes the shelf life. Purity is ensured initially by having the API and drug product well manufactured, under control and under cGMP, but appropriate, specific and adequately sensitive analytical tests verify it.

Could you elaborate on the analytical services offered by DSI, especially in terms of developing, applying, and researching analytical methods?

DSI provides hands-on experience. We do not test materials ourselves but instead work for our clients to provide the most appropriate advice to, and oversight of, their contract laboratories. On occasion, we help select these contract labs, but more frequently, we work with a client’s existing contractors to ensure that the client’s interests are preferentially taken care of during the development process.

Because of the nature of the industry, it is common for contract organizations to focus on  high or rapid sample throughput to maximize their revenues. I’ve been on that side of the business and even with the best quality scientists involved, there is sometimes less time spent by the contractor than is appropriate for a product under development on data evaluation of what the information from a sample test means in relation to the client’s needs or what can be learned fro an investigation rather than whether a product meets an early stage, loosely defined, acceptance criterion.

DSI helps the client ensure that their testing is being done to the highest standards while providing additional oversight and phase-appropriate evaluation of the results and helping to identify and solve problems that arise during the analytical testing. We also help make sure that investigations of incidents are sufficiently thorough.

If the contracting team fails to conduct appropriate evaluations, would DSI intervene, or would they advise the client to take action?

We would tell the client to insist on a thorough investigation being done. Contractors have their own internal drivers and business pressures and sometimes, perhaps due to a lack of analyst experience with the specific product or of an understanding of what can go wrong during testing, may not recognize the true cause of an issue that arises during testing. DSI’s SMEs have extensive experience with hand on trouble-shooting and can also assist in the design of test methods that are sufficiently detailed to reduce the possibility of errors.

We also focus on evaluating the raw data, not just the final reported results, especially for our clients with products in earlier stages of development to look for patterns in data between tests done today and those done previously to ensure that methods are still behaving as designed and that products are not showing . Frequently, contract organizations do not provide that level of detailed evaluation as their role is cnsidered to be to simply generate the data and, if it’s acceptable, to move on. DSI can also help our clients to evaluate when a contractor is doing a more thorough job and when methods are rugged robust and well performing and, therefore, less oversight is required. The client benefits from our services because we ensure the work done on their behalf is done well and that product knowledge gained is available to client and transferrable by them to other organizations as development progresses.

What types of products and delivery mechanisms does DSI have experience with in their method development and optimization services?

DSI has worked with numerous drug products and substances, from small molecule synthetic drug substances, to larger molecule fermentation products that are based off of natural products.

We have worked with biological products, both synthetic peptides as well as proteins. We are also now working with RNA and DNA analog products.

We have worked with everything from simple solutions and suspensions in early-stage development to solid oral dosage forms, capsules, immediate and extended release tablets, over-encapsulated tablets, inhalers, sterile injectables and antibody drug conjugates. Within our veterinary experience, we’ve dealt with drugs dosed in animal feed, soft chews and solutions that are dosed orally via syringe. We also are willing to tackle new product types and new delivery mechanisms and we are very willing to learn about novel dose form specialist CMOs, as many of the same basic analytical principles can be applied across dose forms. They can teach us more about the challenges of newer dose forms, and we can take that experience, share it internally within the group and have it accessible to other clients.

What is the approach when something new comes along, but you also need to help with evolution? Do you learn from someone new and then transfer the knowledge?

Most new delivery systems are very similar to previous iterations. Developing an appropriate test procedure is about ensuring accurate measurements. Some biological products have very specific impurities that behave in different fashions, and you may need to establish their activity in a cellular system that is an analog of a human system.

The technology is developing further in this realm and keeping up with advancements can be a challenge. However, there are many organizations we work with that are on the cutting edge of such research and we can learn from them.

Why is it essential to understand the limitations of analytical methods in release and stability data, and how does DSI address this issue?

The analytical group is essential to making sure that a client’s data is as trustworthy and accurate as possible. It is necessary to understand if specific elements of a method are not working adequately so that they can be corrected to ensure that the client can place their trust in the testing results and make appropriate development decisions based on those rresults. This can mean having an appropriate test design with clear parameters to comprise the most appropriate measurement technique. It is also important to challenge the method(s) as early as possible during development. Before initial human use and in GMP environments, methods must be appropriately qualified or validated. This means challenging it under well-established standardized conditions. However, there may be requirements for modifications based on specific client needs. For example, if they desire extremely low levels of impurity detection, a sufficiently sensitive method is needed. DSI is able to help the client interpret method validation data appropriately for the relevant development phase.

Can you explain the process of method validation according to compendial ICH VICH requirements and its importance in pharmaceutical manufacturing?

Validation of test methods is how you ensure that they are producing reliable data. There are general guidelines issued by the International Council on Harmonization (ICH) and its veterinary equivalent, the VICH, that define the general categories used for challenging the methods to ensure that they are appropriate and aimed at defining the type of information that is required at the time of filing an NDA/BLA with the regulatory authorities.

However, these guidelines are designed to be very general and permit different options for generating the relevant data and can require specific interpretation for individual client’s needs. The guidelines are the basis for designing a thorough validation study but are not absolutely specific on what must be done, so DSI’s expertise can be valuable in justifying to the CMOs why a specific, less frequently used, but still acceptably accurate approach is required for the validation of a method at that stage of development.

Regulatory authorities also have different requirements of how thorough a validation needs to be at earlier stages versus later stages of development. In the early stage, you may be confident that the method is giving accurate results through a limited qualification. In later phases, there will be increasingly thorough and compendially guided validation activities.  For early stage development products, contract labs may focus inappropriately on the higher level of rigor required for late stage and commercial products simply because the latter are what they typically deal with, whereas a client’s requirements may not yet require such rigor to permit them to move forward in development

DSI is able to identify the required validations in the early stages, allowing clients to later supplement that information as needed with the remainder of the information needed for full validation as well as to define areas where further method optimization may be indicated based on ongoing test data. This helps to conserve resources early in development while maintaining adequate confidence in the results generated by the tests.

Could you provide examples of analytical investigations that DSI conducts, particularly in response to out-of-specification and out of trends results?

With our wealth of experience, DSI SMEs can generally see quite quicly when a provided explanation is likely not appropriate or adequately presented. We are then able to direct the investigating lab to delve more deeply into or reevaluate earlier data to add depth to their response or to point out more logical, data-supported, causes for issues observed than the improbable yet convenient explanation that is frequently selected when initial dataa evaluation doesn’t indicate a probable cause. With most investigations, the focus should be less on assigning blame for an incident, but rather on figuring out how to do better next time. It is important to understand why a result was different than expected so that necessary corrective and preventive actions can be im[lemented.

There are specific mechanisms and methodologies that are typically followed in a well-designed investigation. First a paper investigative exercise would be performed to look for anomalous  or incorrect performance of the method, followed as needed by investigative testing of existing samples from the initial analysis to see if initial hypotheses generated about the cause of the incident from patterns in the original data can be confirmed.   Finally, additional samples can be acquired if the original results were deemed invalid. The linear progression through an investigation is well-established in the industry and should be thoroughly documented in a laboratory incident, Out of Trend or Expectation, or Out of Specification investigation report as appropriate.

Occasionally, due to inexperience or expediency, some CMOs may choose to stop at the paper investigation or initial hypothesis stage of the investigation rather than evaluating the original data sufficiently. DSI, as the clients representative, with detailed knowledge of the client’s product and methods, can typically help here by evaluating the anomalous data based on historical norms and working with the lab to suggest a design of experiments. We can also point out illogical results, or when initially selected explanations are not sufficiently supported by the avaiable facts. This creates a mechanism for figuring out what went wrong and getting to trustworthy results. Subsequent corrective actions and preventive actions then ensure compatable trustworthy results in the future and eliminate recurrence of the same problem.

Image Credits: DS InPharmatics 

How can you differentiate out-of-specification and out-of-trend results?

Out of specification and out of trend results can be differentiated using established ranges for drugs and other products. The acceptable ranges for the product’s parameters should be designated within a product specification which lists all of the different tests, as well as acceptance criteria, that are required to be met.  Within those ranges, is the historical expectation for how the product and the test procedure should perform.  Results outside those expectations should be investigated, because they likely indicate areas for improvement, either with the product or the methods used to test it.

Much of this is guided by industry standards, but some are defined by the intended product use. The specifications should be very clearly defined and stated in regulatory filings and in manufacturing documents.

Out of specification investigations are critical because when they occur, it shows that there could possibly be something wrong with the product, so that needs to be checked urgently.

An out of expectation or out of trend investigation can sometimes occur during development when there is a lack of detailed knowledge about the product, but there is still sufficient to establish an expected range of results. For example, if a drug product or substance is being monitored in a stability study, a certain amount or rate of degradation may be expected. If that changes suddenly or drastically, it could be based on something that occurred with a specific batch of material, or perhaps it’s something that might occur at a reasonable frequency, but there were not enough batches to note it before. It may also be something that occurs toward the end of the shelf life as a result of multiple different factors or may indicate an issue with the method that could be.

Out of trend investigations are to establish if there is a method or product problem causing concern. Out of specification investigations are more typically initially investigated as a product-related problem which look to establish if there is a real concern or whether they’re a result of a lab accident or another isolated parameter. If it’s the latter, something can possibly be learned about test procedure improvements. It is frequently common for out of specification investigations to find analytical problems rather than actual product inaccuracies.

I have a number of different phrases and mantras that have served me well, including one from Nobel Prize-winning author, Samuel Beckett: “Ever tried. Ever failed. No matter. Try again. Fail again. Fail better….” There will frequently be something that you find does not work as expected in a test method , but you use the information from an investigations to learn and to fix it, and to do better the next time.

How does DSI offer support for analytical regulatory affairs?

DSI offers support initially through assisting with drafting Investigational New Drug applications (INDs) within the US, and the corresponding IMPD within the EU, or corresponding documents around the world. These documents are a collection of information supplied by the clients to the regulatory authorities, demonstrating all aspects of clinical and manufacturing and testing aspects.

DSI Analytical Group works within the Chemistry, Manufacturing, and Controls, or CMC sections and occasionally the pharmacokinetic, to make sure that the appropriate level of testing is being done for the particular phase of development.

The IND stage is very early on. Testing is less rigorous when compared to the middle stages of development and the final commercially marketed stage of the product. DSI makes sure that our clients have the appropriate quantity and quality of methods for their current development phase, and then helps their/our regulatory affairs group ensure that the documents are thorough and holistically complete. Later on, an NDA or BLA filing is required to obtain approval of the product for commercial, which is similar to the early phase but with greater detail and more thorough testing and data evaluation.

Different organizations accumulated different levels and quality of data regarding their product and there may be situations where the client does not have a typical set of data by the time that they wish to make their regulatory filing. All of the data may be trending and pointing in the correct and desired direction to demonstrate the correct efficacy, purity, safety and stability, but the available data has frequently to be presented in a way that agency reviewers can readily understand despite there possibly being some limitations in the quantity of data. The quality of the data must still show that the product is acceptable and that it is appropriate for the agencies to approve the product for marketing. DSI’s role is to evaluate the available data, identify inadequacies and recommend mitigation strategies and to assist our clients to present their data in a clear an appropriately favorable fashion.

There also have been many situations where we have provided additional support, following the agencies’ review and feedback on INDs and NDAs generated by the clients’ internal regulatory teams, on how the client should best respond when the agency questions if the provided information is adequate. Sometimes this may require a more appropriate explanation of why the supplied data is appropriate, sometimes additional studies are appropriate and sometimes a successful response simply identifies why a typically expected requirement by the agencies for drug products is not appropriate for the specific drug product in question because of the inherent nature of the drug product.  In this case, the data supported narrative as to why it’s appropriate to do something different to what may typically be expected is critical and this is where DSI’s SME’s experiences of agencies’ expectations and knowledge of successful or alternative strategies and their potential risks and benefits can permit us to tailor responses very specifically to a client’s specific situation

DSI can further help get a client from the NDA/BLA filing to an approval by addressing the concerns of the agency; this can be as simple as re-presenting disparate information that had previously made available, but which the agency reviewers may not have connected. We can help present the information in a different way, allowing the agency to see the ties and answer their concerns. There are times the response may require additional testing and additional data to be generated, and we are also able to assist the client with. Another situation that arises is when the agency has a standardized expectation that would typically needs to be addressed, but due to the nature of the particular product, it is unrealistic or impractical to achieve. The reviewer’s concern may need to be addressed another way. We try to get the client to the endpoint of a successful, accepted response, as quickly as possible, so they can get their product on the market expeditiously.

How does DSI collaborate with analytical and manufacturing labs to coordinate investigation strategies and generate data-supported investigation reports?

DSI collaborates as much as possible with our client’s CMOs, but our principal role is acting on behalf of the client as their oversight of the labs. We strive to work collaboratively with CMOs, many of whom are just trying to do things as best thety can within their internal limitations with respect to available resources and time. There can be sometimes be short-term pain at the start of a relationship because we are frequently more involved on behalf of our clients than they are used to.  Some labs are more heavily focussed on sample throughput and avoiding encountering problems which can result in looser control and less accurate data being generated.  Others try to apply a commercial quality control approach to GMP development projects and do not take the opportunity to learn from the data that is being generated to understand more about the product or how to generate more reliable methods to test it. 

There is a benefit to our clients when CMOs and DSI work collaboratively.  We get to understand the limitations under which the labs have to operate and, having all come from lab management evironments, our SMEs can recommmend efficiencies or testing strategies that fit with the labs’s constraints while providing our clients with the quality of data they ened to understand their product and get it to the next stage of development and ultimately approval. Not all labs accept the colaboration and focus on what works betst for them than for our clients so insuch situations we might then advise our clients whether to move on or how to demand better from labs, while considering the bisoness risks to the product or program. It is ultimately  the client’s decision, based on our advice and their interpretation, as to what actions they want to take, but our goal is always to give our clients the best and appropriately tailored advice that we can to help them achieve their goals for the product.

Can you share insights into how DSI maintains long-term relationship with clients, providing support throughout the entire drug development life cycle?

Currently, my most active client is one that I started working with backin 2008. I always look at the role of DSI and its consultants as a service provider to the client, doing what is needed, as appropriate for the development phase of the product.

Most clients will realize that there are times when tasks need to be completed quickly, and they appreciate DSIs SME’s willingness to get in the trenches, review the data, draft the document, write the regulatory document and learn about the product to best represent the client’s interests to CMOs. It is important for us to go the extra mile for our clients by identifying potential problems with methods or products, and notifying the clients as early as possible, then pushing occasionally recalcitrant CMOs to address them to get to sufficiently high quality methods and data. By helping our clients identify issues early, assessing the risk to the development progarm, and suggesting potential and aopropriate solutions and a suitable time frame within which sthey should be executed, the solutions can be implemented well before issues become critical.

Equally, we are able to identify immediate issues in other development areas and offer an appropriate sense of urgency for when they need to be addressed and the practical risks if they are not addressed at the appropriate time. Particularly with our smaller analytical clients, our experience in analytical activities, as well as our historical collaborations with our drug product, manufacturing, regulatory, quality, and supply chain groups within DSI, for example, can offer the ability to help a nominally analytical client to identify a commonly faced issue that they might not have previously considered because they had not previously encountered it. This cross-functional knowledge can help our client recognize and get ahead of problems in non-analytical areas before they become critical.

DSI is able to better assist our clients because our team is made up of those who have been in the pharmaceutical/biological/veterinary industry, in the labs and in the manufacturing plants for many years. Our SMEs have a wealth of individual experience, but also have access to a network of experts in many other fields within DSI and across the entire PLG family to assist with any gaps in a development program, and to collaborate to provide the best quality service for our clients.That level of expertise, as well as the hands-on nature of DSI, has served to keep our clients happy over the long-term.

DSI services are all about decreasing the risk and the worry about their develo pment programs for our clients. We do that through hands-on knowledge, good communication, and collaborative work.

About Colman Byrne

Colman Byrne received his education from Trinity College Dublin. Prior to joining DSI, Colman had worked at Charles River Labs, Eximias, Cardiokine in increasingly responsible analytical development, regulatory, quality and operations roles. At CRL, Colman was responsible for managing a cGMP laboratory performing chemistry, bioanalytical and analytical biochemistry testing on various chemical and biotech dose forms. At the subsequent organizations, he helped coordinate the activities of analytical and bioanalytical CMOs, and provided support with regulatory filings and API manufacture. With over 40 years of industry experience, Mr. Byrne is the most senior Analytical Services expert at DSI. Colman is technically proficient in all aspects of analytical services having spent years managing both contract laboratories and the AR&D groups at pharma and biopharma companies.

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.

---