Making changes to the processes used to manufacture biologics is common practice on the journey to market and beyond—from implementing new technologies to transferring processes to different facilities. However, it is important to fully understand the impact of these changes on the drug product, not only to ensure the “new” product is comparable in to the original, but to be compliant with current regulations.

This article highlights the need to apply a holistic approach to comparability testing. In doing so, they stress the importance of building a solid foundation of understanding before carrying out risk assessments and analytical studies.

Evolving processes in biologic manufacturing

In the early days of biologics production, it was generally believed that “the process is the product.” The limited techniques, approaches, and processes available when working with challenging biological systems meant that the product’s properties and characteristics were largely determined by the process and its limitations.
As the biologics space has matured, advances in technologies and our understanding of these systems have led to processing activities changing drastically, providing more control than ever before. Increasingly, we can directly influence and control the product’s characteristics by utilizing specific techniques and parameters. With greater bioprocessing control, we can now meet the desired product properties, meaning “the product is the process.”

Despite having significant control over the processes used to produce biologics, there are still some circumstances where these will need to be changed, including:

• Moving to a new manufacturing facility (e.g., when changing contract development and manufacturing organization (CDMO) partner);
• Restarting legacy programs that have previously been put on hold for an indeterminate period; and
• Changing or updating machinery (e.g., switching from stainless steel bioreactors to single-use alternatives or employing a new, improved chromatography resin).

However, if “the product is the process,” these changes will inherently have the possibility of impacting the product’s characteristics, potentially effecting its safety or efficacy. If the changes are significant, the resulting product might not be comparable to that produced using the previous methods, making the data collected up to this point in the biologics’ journey non-applicable.

The importance of comparability in bioprocessing

When altering bioprocesses, developers, manufacturers, and drug sponsors must demonstrate that the drug is comparable to that produced before the changes were made to safeguard efficacy and patient safety. This is achieved through a collaborative effort to conduct comparability studies, where the product produced using the “old” method and that produced using the “new” proposed method are compared.

Employing comparability studies allows developers to avoid repeating often costly and arduous clinical trials; instead, establishing the comparability will rely heavily on data generated through analytical studies. These studies will delve into the product’s biochemistry to provide an understanding of the product and the impact of process changes. 

These analytical techniques extend beyond release criteria considerations. Rather than just characterizing the major criticalities of the drug, comparability studies demonstrate that a comparable product can be made as well as provide evidence that there is control over the new process. By understanding the effects of alterations to the process, the possible subsequent impact on the drug properties can be better moderated.

Comparability studies will therefore not only ensure the biologic remains safe and efficacious but will help to reduce risk when bringing a biologic to market. Conducting these assessments prior to approval can help to avoid delays or withdrawal from the market if processes are likely to need changing in the future.

Meeting regulatory expectations

As well as avoiding the costs and time involved in re-conducting clinical trials, there is another reason developers and manufacturers should employ comparability studies: regulatory compliance.

It is commonplace in biologics development and manufacturing to change bioprocessing activities, either before the product is submitted and approved for market or after—although this is known to be more challenging. As a result, regulatory bodies have developed guidance for conducting comparability studies for products both before and after market approval.

The FDA and EMA have published guidance (Q5E and ICH Topic Q5E, respectively, and most recently FDA Comparability Protocols for Post-approval Changes to CMC Information in an NDA, ANDA, or BLA) to assist in the collection of relevant technical information which will serve as evidence demonstrating manufacturing process changes have not adversely impacted the drug’s quality, safety, and efficacy. Depending on the situation, this information could be gathered from studies including pharmacokinetic (PK), pharmacodynamic (PD), PK/PD, clinical efficacy, specific safety, immunogenicity, and pharmacovigilance.

In these documents, the FDA and EMA also highlight that these studies should be supported with the demonstration of control over the modified manufacturing process, which could include:

• Establishing possible modified specifications for materials (raw, source, and starting) and reagents;
• Carrying out bioburden and viral safety testing of post-change cell banks;
• Demonstrating removal of product- or process-related impurities; and
• Establishing maintenance of purity level.

It is therefore important that developers and manufacturers employ a robust strategy for comparability testing that provides a thorough understanding of the molecule itself as well as how exactly the changes proposed will impact its properties.

Assessing comparability: Not without challenges

The best way to determine whether changes in manufacturing processes have the potential to impact the characteristics of a drug is to directly compare drug substance and/or drug product samples produced before and after the process change. Ideally, the drug sponsors, developers, and manufacturers will have a close working relationship with transparent communication and a free exchange of data from the original process allowing for a simple, direct comparison.

However, this is not always possible, especially when considering the many different reasons why a bioprocessing change might be taking place. If the alteration is being made to a legacy project which has been put on hold for a long time, perhaps years, samples produced using the original process may no longer be stable or suitable for assessment. Additionally, with analytical methods becoming more sensitive, the methods originally used to assess the product prior to changes might no longer be suitable or regulatory compliant if the project has been halted for a long time.

If changing CDMO partner, the exchange of data from the original organization to the new one might not be smooth or swift, depending on the relationship with the drug sponsor. As the originator laboratory can’t always be relied upon to provide the information needed openly and expediently (or potentially at all), a thoughtful analytical team that can thoroughly analyze and understand the impact on the drug is essential. If information about the drug doesn’t exist or can’t be collected coming into the comparability study, it must be developed. This requires both extensive analytical experience and experience within process development.

A holistic approach is key to success

Comparability requires an understanding of whether the process will generate an equivalent product following a change as well as determining whether the process is robust enough to do this in a reproducible manner. The complexity surrounding processes for biologic manufacturing means demonstrating process robustness and assessing the risk a change could have to reproducibility is essential.

Ensuring an effective strategy for determining comparability will require a holistic, thoughtful approach. This will involve the collection of information needed to form an understanding of the molecule and process, assessing the risk of the change to the product and manufacturability, and collecting comparability data with suitable analytical tools and methods.

Information to strengthen understanding

Incorporating multiple datasets in a stepwise fashion to generate a comprehensive analysis is critical when approaching comparability assessment; this will initially involve building a:

• Thorough understanding of the previous process (and control points within this);
• In-depth understanding of the product;
• Description and justification of critical process parameters (CPP) and Critical Quality Attributes (CQAs);
• Description of the therapeutic window and how the current product meets the needs of the patient population (mode of action, safety, and dosing data);
• Detailed process map/workflow including a clear definition of changes to the previous process; and
• Justification for the establishment of CPPs within the revised process.

Sometimes, a paper-based comparability assessment could be utilized instead of an analytical comparison, possibly saving time and costs. This highlights the importance of accessing and collecting this data early. However, if the comparison focuses on a critical data set, analytical testing will be needed.

Understanding risk

Once a thorough background on the molecule, previous processes, and proposed changes are formed, developers and manufacturers should perform a risk assessment. Risks resulting from bioprocessing changes can be distilled into two areas:

1. Risks to the manufacturability of the drug
Assessing manufacturability risk will focus on determining how changing existing processes could impact the state of control for the process and whether it could result in a less consistent product. It will also involve examining whether those inconsistencies could have an impact on known CQAs and/or the therapeutic window of the revised product. 

2. Risks to patient safety and drug efficacy
Considering patient safety, qualifying, and quantifying the risk of changes that impact known CQAs and the therapeutic window of the revised product are critical. The nature of the change drives the safety discussion, for example, when the therapeutic window is narrow, minor changes can significantly impact patients and are associated with higher risk. On the other hand, when the therapeutic window is large, changes in CQAs may not alter the benefit-risk proposition of the molecule and would necessitate the implementation of a residual risk determination strategy.

Determining the risk that you’re willing to take is a key part of risk assessment, and requires an understanding of the implications of any changes to determine if the possible outcomes are worth the risk. Additionally, the quality of the risk assessment will heavily depend on experience, as teams with 35 years of experience, for example, will have witnessed the implications of bioprocessing changes more often than those with significantly fewer years.

Carrying out risk assessments will then help to guide where analytical testing is needed.

Meeting analytical requirements

Strong analytical development capacity is a critical function for teams performing comparability protocol testing. The analytical techniques and approaches must accommodate and carefully evaluate the general and product-specific CQAs with appropriate replicates being included for CQAs deemed critical to safety and efficacy. Risk-based approaches should also be used to determine which CQAs require closer inspection. Developing an effective sampling plan will also go hand in hand with analytical techniques.

In some instances, it may be necessary to develop additional analytical methods because changes in product CQAs are so subtle that they necessitate higher precision or orthogonal approaches to measure these changes. While analytical methods and instrument sensitivity continue to advance, care must be taken to clearly understand these subtle changes to link their effect with possible clinical performance and risk to patient safety. These new approaches can be utilized in measuring process intermediates and the final product.

Potential outcomes of a comparability study

Following analytical assessment, one of four possible outcomes of the comparability exercise will be decided:

1. Highly similar with no adverse impact to safety or efficacy
2. Highly similar with differences that do not adversely impact safety or efficacy
3. Highly similar with differences that have the potential to impact safety or efficacy, requiring further characterization or non-clinical/ clinical studies
4. Highly dissimilar in a way which is likely to impact safety or efficacy requiring clinical studies

For most projects, the comparability study will highlight that process changes have resulted in a product that is highly similar with differences that may or may not have the potential to impact safety or efficacy (1, 2, or 3). If the evidence collected from the study suggests that there is a potential that the changes will impact safety or efficacy, having a complete understanding of the CQAs and manufacturing processes is critical.

When additional clinical studies might be necessary, like in outcome #3, a smart study design can help to minimize the challenges involved. By having a study design that focuses on understanding the molecule, the CQAs, and how they could confer clinical performance, the study will be more informative, with a lower risk of spurious results. Consequently, this could help developers determine where there could be alternative options to clinical trials, such as suitable animal models to assess immunogenicity and in vitro testing to validate changes.

Key lessons

Reliance on specifications and release criteria is not enough to satisfy the comparability exercise. Comparability should incorporate a holistic approach to the product and the process, with data generated and evaluated around both to determine comparability. 

Having a strategy built on forming a strong understanding of the product and process will enable the risks to the performance to be identified. With this information, developers and manufacturers will have more choices at their disposal for alternative options, helping to mitigate the risk. Supported by integrated analytical capacities or services, this strategy can therefore help prevent projects from going down the wrong path with changes that could cause future challenges.