Biopharmaceuticals

What are the minimal requirements we need to ensure are in place for our program, for the stage of development we are in – to be sure to meet any critical regulatory requirements but are still able to run our program as lean as possible?

This is one of the most common queries we receive in one form or another. To provide a suitably comprehensive response we would typically conduct a multidisciplinary (CMC, nonclinical and clinical) gap analysis of the available documentation and plans to identify the most critical gaps in the program, highlighting the greatest risks to achieving the next project milestone.

Based on the gap analysis, we would then provide appropriate recommended actions/options for the identified gaps.

In order to ensure the program is as lean as possible, we may recommend approaches that are not in accordance with regulatory guidance’s but scientifically justified, in these cases we will advise that these are agreed in appropriate agency scientific advice discussions before implementing.

How do we prepare our TPP?

The target product profile (TPP) is useful to put in place early in development, although can also be established later in the program. We view this as a valuable multidisciplinary strategic set of targets for your product outlining the regulatory goals (included intended markets), presentation/indication, envisaged posology, clinical, nonclinical and quality expectations. It allows you to keep focussed on the end targets during development and to keep the project within scope during development.

There are a number of options with how to approach this, but we have example templates of the basic requirements which can be tailored for your program. The TPP is not set in stone and should routinely reviewed as part of your development program.

How do we define CQAs?

A critical quality attribute (CQA) is a physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality (ICH Q8 (R2)).

We normally assign CQAs by using our CQA assignment tool, which assesses the impact of each quality attribute on bioactivity, immunogenicity, PK/PD and safety. This activity normally involves details literature searches, review of available characterisation and CMC data alongside input from nonclinical and clinical teams.

Once the CQAs are established they can be monitored during the program and support the impact assessment of any changes/steps in the manufacturing process. The defined list of CQAs should be routinely reviewed and updated as more data is generated on the product and available methodologies.

How do we define CPPs?

A critical process parameter (CPP) is a process parameter whose variability has an impact on a CQA and therefore should be monitored or controlled to ensure the process produces the desired quality (ICH Q8 (R2)).

A common approach for assigning CPPs is using a failure mode effect analysis (FMEA). This is a risk-based assessment of the manufacturing process unit operations with regards to the potential severity of failure and likely hood of occurrence and ability to detect the occurrence. Various scoring guides are available and can be used, however it is important to ensure the overall scoring system allows for a ‘sense check’ that has provision for technical scientifically sound justifications to be used for the final assignment.

The final CPP assignment can be used to define process characterization requirements and eventually the acceptance criteria for process performance qualification.

How many lots required for biosimilarity assessment?

This is the most common question we are asked by biosimilar developers. And unfortunately no single number can be given for all biosimilars in development. From a guidance point of view this has not yet been fixed, and it is likely there will be no fixed number recommended by Agencies.

The final number of reference product lots required will need to be able to account for the potential variability in manufacture and age of the reference product. In addition one of the contributing factors is the complexity of the molecule under development. Of note, if any shifts are observed in the data set, this may increase the number of lots required to be sure sufficient data from at least one consistent data set is available.

It will be of course also important to consider regional reference product requirements and material requirements to support the analytical/nonclinical/clinical studies, including any 3-way pairwise bridging studies.

The final number of lots of the biosimilar drug substance/drug product may potentially be less that the number of reference product lots, but will also need to allow for potential variability in the manufacturing process and the final data set should be amenable to statistical evaluation, where applicable.

The PharmaLex family includes a team of biotech statistical experts (PharmaLex Arlenda) who support such statistical analysis and can ‘translate’ the statistical requirements to the development teams.

The final approach to biosimilarity assessment should be agreed upfront with the relevant agencies.

How should we approach a comparability assessment for our specific change?

Historically the traditional approach of full release and characterization on three lots before and after the change was taken. However, we recommend a risk based approach to omit unnecessary testing but to ensure high risks are evaluated. In addition, depending on your product and specific change we may recommend different approaches.

For example in the case of a change to manufacturing process step the plan will be different for a live attenuated vaccine, Chimeric antigen T cell receptor (CAR-T) product or a monoclonal antibody (mAb) product. These products will have different levels of process characterization and understanding and the level of specific methods that may correlate the impact of a quality change to efficacy or safety will be different.

Based on the available information we would recommend an approach to comparability assessment and depending on the approach recommended, we may also advice discussion with the relevant agencies regarding acceptability.

What is the most suitable approach for a risk assessment for our particular CMC scenario?

There are various approaches to risk assessment, a number of which are described in ICH Q9. Different tools are used for different scenarios and include the simpler risk ranking and filtering or more detailed FMEA. These evaluations can be supported with process maps/flow charts/checklists/statistical tools.

We would advise a risk assessment approach depending on the scenario with simpler processes for early and simple changes or more detailed comprehensive process for later and more complex changes.

What minimum controls and characterisation data are required for our process to support our first in human study?

In addition to the regional GMP requirements, you need to be able to demonstrate that your manufacturing process is reasonably well controlled.

Your specifications maybe wider than you would expect for later in development but must be suitably justified for your drug substance, drug product and any relevant intermediates.

Your test methods must be demonstrated to be ‘fit for purpose’.

Any concerns regarding impurities (process and product related) should be identified appropriately characterized and assessed as a low risk to safety.

Product stability for any in-use preparation and the duration of your planned study must be established based on real time data, you may be able to justify this using representative development lots.

What is the impact of this OOS stability result on our clinical batch shelf life assignment?

Out of specification (OOS) results during stability must be appropriately investigated before they are confirmed as OOS results. Even if all testing is outsourced to a contractor the sponsor is responsible for ensuring they understand the conclusions and the implications of the results.

Such information should be assessed immediately as depending on the result that is OOS and the timepoint the test was conducted, the shelf life of the product may be affected and this may also impact an ongoing clinical study.

Now we have reached pre-BLA / MAA stage, what particular CMC activities should we focus on to support filing/submission?

There are a number of pre-BLA / MAA activities that should be completed prior to submission and filing to avoid delays and review questions.

At PharmaLex we would conduct a gap analysis of the package available to identify a list of risk ranked requirements for successful BLA / MAA submissions. A few examples of the common CMC items identified from this review includes: compendial / GMP compliance, forced degradation studies, data-based justification of specifications, reference standard establishment and extractable and leachable studies.