Unlocking the secrets of analytical services: An insider interview with colman byrne

Could you introduce yourself and your background in analytical services?

My name is Colman Byrne, and I am the head of Analytical Services at DSI. With nearly 17 years at DSI and over 40 years of industry experience in the analytical field, I bring a wealth of knowledge and expertise to the organization.

My career began as a bench chemist, followed by managing a contract testing lab specializing in biological and protein-peptide samples. I later joined several small virtual pharma and biotech companies, where I coordinated their analytical services and bioanalytical testing and oversaw the activities of contract test organizations.

Since joining DSI when it was founded, I have contributed to various areas, including early-stage analytical method development, method validation, specification, and shelf-life justifications, regulatory filings, post-filing support for Complete Response Letters, post-approval release testing of commercial products, and analytical investigations.

How do analytical services significantly improve pharmaceutical products' safety, effectiveness, and quality?

Analytical services are at the crux of all pharmaceutical development activities because they are required for the active material to establish its purity/quality from the beginning of development.

They are also necessary for establishing the efficacy and safety of the drug product at the time of release. Testing ensures that the product, if adequately stable, establishes its shelf life.

Purity is initially ensured by employing the best manufacturing practices during the synthesis of the API and drug product, and keeping the product under control and under cGMP. Appropriate, specific, and adequately sensitive analytical tests are then used to verify this purity.

Could you elaborate on DSI's analytical services, particularly its development, application, and research of analytical methods?

Design Space InPharmatics (DSI) does not perform testing. Instead, it provides hands-on experience, working with clients to provide the most appropriate advice and oversight for their contract laboratories.

Occasionally, DSI helps select these contract labs. Usually, however, they work with existing contractors to ensure the client's interests are preferentially taken care of during the development process.

Due to the industry's nature, contract organizations commonly focus on high or rapid sample throughput to maximize revenues. Even with the best-quality scientists involved, contractors can rush the evaluation of data, neglecting information important to a client's specific needs or that may require further investigation in favor of confirming whether a product meets the early-stage, loosely defined acceptance criterion.

DSI helps clients ensure the highest standards are met during testing while providing additional oversight and phase-appropriate evaluation of the results. They also help identify and solve problems that arise during the analytical testing and ensure sufficiently thorough incident investigations.

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

If a contractor fails to provide an appropriate evaluation, DSI would advise the client to insist on a thorough investigation. Contractors have their own internal drivers and business pressures. Due to a lack of analyst experience, contractors may not recognize the true cause of a testing issue.

DSI's SMEs have extensive experience with troubleshooting and can also assist in designing sufficiently detailed test methods to reduce the possibility of errors.

DSI also evaluates the raw data and the final reported results, particularly for clients with products in early-stage development, to look for patterns with historical test data, ensuring methods continue to behave as designed and that products are not showing.

Often, contract organizations generate data without providing a detailed evaluation. DSI aids clients in evaluating a contractor's performance and determining instances where less oversight is required.

Clients benefit from these services as DSI ensures that contract work is performed up to standard and that any product knowledge gained is available to clients and transferrable 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 drugs to larger-molecule fermentation products based on natural products.

They have worked with biological products, both synthetic peptides and proteins, and have also recently started working with RNA and DNA analog products.

DSI has experience with everything from simple solutions and suspensions in early-stage development to solid oral dosage forms, capsules, over-encapsulated tablets, immediate and extended-release tablets, sterile injectables, inhalers, and antibody-drug conjugates.

In terms of veterinary products, DSI has experience with drugs dosed in animal feed, soft chews, and solutions dosed orally via syringe. They are also willing to tackle new product types and delivery mechanisms and learn about novel dose form specialist CMOs.

Many of the same basic analytical principles can be applied across dose forms, and insights from CMOs help DSI and its clients better understand the challenges of newer dose forms.

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, and developing an appropriate test procedure involves ensuring accurate measurements. Some biological products have very specific impurities that behave in different ways, and it may be required to establish their activity in a cellular system analogous to a human system.

Technology is always advancing in this field, and keeping up with advancements can be challenging. However, DSI works with many organizations at the cutting edge of such research, providing valuable insights into emerging approaches.

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

It is vital to consider the analytical group when ensuring that a client's data is as accurate and reliable as possible. Understanding if specific elements of a method are not working properly means that they can be corrected, ensuring that the client can fully trust the results and make appropriate development decisions.

This could mean having a suitable test design with clear parameters to include the most applicable measurement technique and challenging the methods as early as possible in the development process.

Techniques must be properly qualified or validated before initial human use and in GMP environments and challenged under well-established consistent conditions.

Alterations may be required based on specific client needs. For example, if extremely low levels of impurity detection are required, a sufficiently sensitive method is necessary. DSI can assist the client in interpreting the data correctly for the relevant development phase.

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

General recommendations issued by the International Council on Harmonization (ICH) and its veterinary equivalent (VICH) define the general categories used for challenging methods.

These guidelines help stakeholders ensure that methods are appropriate and define the type of information required when filing an NDA/BLA with the regulatory authorities.

Nevertheless, these recommendations are designed to be very general. They permit different options for producing the relevant data and may require specific interpretation for an individual client’s needs.

The guidelines serve as a basis for designing a thorough validation study without detailing explicitly what must be executed.

DSI's expertise is valued in justifying to the CMOs why a specific and less frequently used approach may be needed to validate a method at a particular stage of development.

Regulators also have varying requirements on how thorough a validation needs to be at primary versus subsequent stages of development. In the early stages, a client may be confident that the method gives accurate results through limited qualification. Later in the process, more thorough, regulation-guided validation activities will occur. 

In the early development of a product, a contract laboratory may inappropriately use a higher level of rigor (required for late-stage and commercial products) because they are used to dealing with the latter. However, a client's requirements may not require such precision to necessitate them moving forward in development.

DSI can identify the required validations in the early stages, allowing clients to supplement the required information with the remainder of the information necessary for full validation.

Based on ongoing test data, clients can also define areas where further method optimization may be indicated, helping them conserve resources early in development while maintaining adequate confidence in the results.

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

DSI SMEs can swiftly notice when an explanation is likely inappropriate or not adequately presented. They can then direct the investigating lab to explore or re-evaluate earlier data to add depth to their response or point out more logical and data-supported causes for the issues observed.

For most investigations, the focus should be on improving the process for the future. Understanding why a result was different from what was expected means that necessary preventive and corrective actions can be implemented.

Explicit mechanisms and methodologies are generally followed in a well-designed investigation. First, a paper investigative exercise would be performed to look for anomalous or incorrect method performance.

This would be followed by investigative testing of existing samples from the initial analysis to discern if initial hypotheses generated about the cause of the incident from patterns in the original data can be confirmed. Finally, additional samples can be attained if the original results are invalid.

The linear progression through an investigation is established in the industry and should be thoroughly documented in an investigation report as appropriate.

Rarely, and due to inexperience or expediency, some CMOs may choose to stop at the paper investigation or initial hypothesis stage rather than adequately evaluating the original data.

Here, DSI (working as the client’s representative and having detailed knowledge of the client's product and methods) can typically aid the client by evaluating the anomalous data based on historical norms and working with the lab to suggest alternative experiment design.

DSI is also able to point out illogical results or indicate when initially selected explanations are not sufficiently supported by the facts, helping create a mechanism for figuring out what went wrong and leading to more trustworthy results.

Subsequent corrective and preventive actions then guarantee compatible, trustworthy results in the future, eliminating the recurrence of the same problem.

Image Credit: DS InPharmatics

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

Different types of results can be discerned using established ranges for drugs and other products. The acceptable ranges for the product's parameters should be elected within a product specification listing all the tests and acceptance criteria that must be met. 

Within these ranges is the historical expectation for how the product and test procedure should perform. Results outside the range should be investigated because they likely indicate areas for improvement—either with the product itself or the methods used to test it.

Much of the above is guided by industry standards, but a product's intended use defines some ranges. Specifications should be clearly defined and stated in regulatory filings and manufacturing documents.

Out-of-specification investigations are crucial because their occurrence means there could be something wrong with the product.

However, out-of-expectation or out-of-trend investigations can occur during development when detailed knowledge about the product is lacking, but sufficient data is still available to establish an expected range of results.

For example, if a substance is monitored in a stability study, a certain amount or degradation rate may be expected. If this changes suddenly or drastically, this could be based on something that occurred with a specific batch of material, or it could be something that might occur at a reasonable frequency but there have not been enough batches to note it before.

It may also occur toward the end of shelf life due to multiple factors or indicate an issue with the method.

Out-of-trend investigations establish whether there is a method or product problem causing issues. Out-of-specification investigations are more typically investigated as a product-related problem, looking to establish whether there is a real concern or whether a problem is a result of a lab accident or another isolated parameter.

For the latter, it is possible that something can be learned about test procedure improvements. It is common for out-of-specification investigations to find analytical problems rather than actual product inaccuracies.

Several different phrases and mantras 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...." You will frequently find something that does not work as expected in a test method, but you use the information from your investigations to learn, fix it, and do better the next time.

How does DSI offer support for analytical regulatory affairs?

DSI offers support by assisting with drafting Investigational New Drug applications (INDs) within the US, the corresponding IMPD within the EU, and various other international documents. Such documents are a collection of information supplied by the clients to regulatory authorities, demonstrating all aspects of clinical, manufacturing and testing features.

The DSI analytical group works within the chemistry, manufacturing, and controls (and occasionally the pharmacokinetic) sections to ensure that the appropriate level of testing is being carried out for each phase of development.

The IND stage occurs near the beginning of the process. Testing at this stage is less demanding than the middle and final stages of development.

DSI ensures clients have the appropriate quantity and quality of methods for their current development phase. It also aids regulatory affairs groups to ensure that the documents are thorough and complete.

NDA or BLA filings are needed to obtain approval of the product for commercial use. This phase is similar to the early phase but involves more thorough testing and data evaluation and is more detailed.

There may be situations where a client does not have a typical set of data by the time that they wish to make their regulatory filing. Even if the data is trending as predicted and demonstrates efficacy, purity, stability and safety, it must also be presented in a way that agency reviewers can readily understand.

The data quality must demonstrate that the product is acceptable and appropriate for approval. DSI's role is to evaluate this data, identify shortfalls, recommend mitigation strategies, and assist clients in presenting their data clearly and appropriately.

DSI also offers support following agency review and feedback on INDs and NDAs generated by a client’s internal regulatory teams, advising on how the client should respond to questions of whether the provided information is adequate.

This occasionally requires a more appropriate explanation of why supplied data is appropriate. Additional studies may be applicable or sometimes a successful response identifies why a requirement expected by the agency is inappropriate for the specific drug in question due to the inherent nature of the product. 

In this case, DSI's experience of agencies' expectations and knowledge of successful or alternative strategies and their potential risks and benefits mean DSI can tailor responses very specifically to a client's specific situation.

By addressing the agency's concerns, DSI can further aid a client's journey from the NDA/BLA filing to approval. This may only involve re-presenting disparate information previously made available, which the agency reviewers may not have connected.

DSI can also help present the information differently, addressing the agency's concerns and allowing them to see how the data is connected. Sometimes, the response may require additional testing or the generation of additional data, which DSI can also aid with.

Occasionally, the agency may have a standardized expectation that would usually need to be addressed, but due to the nature of the particular product, this is impractical or unrealistic. DSI will help the client reach 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 reports?

DSI strives to work collaboratively with CMOs with respect to available resources and time. There can sometimes be difficulties at the start of such a relationship because DSI is frequently more involved with a client than CMOs are used to. 

Some laboratories are more focused on sample throughput and avoiding problems; this can result in less 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 generated to understand the product better.

When CMOs and DSI work collaboratively, there will be a benefit to the client involved. DSI is able to understand the limitations under which labs operate and the SMEs can recommend efficiencies or testing strategies that fit with the constraints of a laboratory, while providing a client with the quality of data they need to understand their product and get it to the market.

Not all laboratories accept collaboration; some may focus on what works best for them rather than the client. In such a situation, a client may then be advised to move on or ask the laboratory to do better while considering the business risks to the product or program.

Such actions are ultimately the client’s decision, but DSI's goal is to always give clients the best and most appropriately tailored advice that will aid them in achieving their product goals.

How does DSI maintain long-term relationships with clients, providing support throughout the entire drug development life cycle?

The majority of clients will understand that there are times when tasks must be completed quickly; such clients appreciate the willingness of DSIs SME's to review the data, draft and write the regulatory document, and learn about the product to best represent the client's interests to CMOs.

It is important for DSI to exceed a client’s expectations by identifying potential problems with methods or products and notifying clients as early as possible. DSI should then persuade occasionally recalcitrant CMOs to address them to achieve sufficiently high-quality methods and data.

By helping a client identify issues early, assessing the risks to development, and suggesting appropriate potential solutions and a suitable time frame for execution, solutions can be implemented well before any issues become critical.

DSI can also identify immediate issues in other areas and offer advice on when they need to be addressed, informing clients of the practical risks if they are not addressed appropriately.

With smaller analytical clients in particular, DSI’s experience in analytical activities (as well as historical collaborations with regulatory, drug product, manufacturing, quality, and supply chain groups within DSI) gives them the ability to aid a nominally analytical client in identifying a commonly faced issue which has not been previously encountered.

Such knowledge can help clients avoid problems in non-analytical areas before they become critical.

DSI is well-placed to assist clients because its team consists of individuals who have worked in labs and manufacturing plants in the pharmaceutical, biological, and veterinary industries for many years.

DSI’s SMEs also have access to a network of experts in many other fields within DSI and across the entire PLG family. This means they can assist with any gaps in development programs and collaborate to provide the best quality service for clients. Such a level of expertise, combined with DSI's hands-on nature, means it has fostered long and positive relationships with its clients.

DSI’s services focus on decreasing risks and concerns regarding the development programs of clients, hands-on knowledge, good communication, and collaboration.