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The value of a Quality Target Product Profile in early development
Clinical trials make up a substantial portion of the overall drug development costs and pharmaceutical companies are intensely focused on ensuring that the trial is well designed and developed. The development of the actual drug product, the Chemistry, Manufacturing and Controls (CMC) section of Investigational Medicinal Products Dossiers (IMPDs) or Investigational New Drug (IND) applications, is often not given the same level of attention.
The lack of attention when it comes to sufficient planning, developing and verifying of the actual CMC section of any pharmaceutical project is most common during the very early development phase; from pre-clinical to clinical phase 2A.
To gain a competitive clinical edge, pharmaceutical companies may look to do the most minimal CMC work required while still maintaining an acceptable level of control, as required by the competent authority. However, the question that arises is whether such decisions truly accelerate the overall development project.
Drugs and biopharmaceuticals approved by the FDA, where Target Product Profiles (TPPs) are mentioned, are associated with more efficient regulatory review times, perhaps because of increased planning or the TPP promotes well-organised regulatory dialogue. A well-defined Quality Target Product Profile (QTPP) that considers key CMC issues is one potential way to obtain early regulatory approval.
CMC activities during development
CMC activities include establishing manufacturing processes and product characteristics, defining product testing methods to ensure the drug product’s safety and efficacy, and consistency between batches.
The regulators expect that there is consistency between the product tested during the clinical trials and commercialised batches produced years later. To minimise the risk of later-stage failure, several key CMC activities must be considered during the development of biopharmaceuticals, see Figure 1.
Figure 1 CMC activities during the development of (bio)pharmaceuticals
Pre-clinical | Phase 1 | Phase 2A | Phase 2B | Phase 3 |
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Create and characterise the master cell bank, if biological IMP Develop the drug substance and drug product manufacturing processes Define the quality of the raw materials Set initial release and shelf-life specifications Describe potential degradation pathways Develop analytical assays for product release and stability testing Qualify analytical methods. Validate sterility, endotoxin and other critical assays for the safety of the patient. Ensure assays are stability-indicating Manufacture pilot/engineering batches Conduct initial viral clearance studies, if biological IMP Develop and characterize a reference standard Initiate drug substance, drug product and reference stability studies (accelerated and long-term) Initiate compatibility studies (excipients) Manufacture clinical material according to GMP Scientific advice with competent authority (e.g. EMA, FDA) at key decision points Write and submit the IMPD/IND |
Justify and document all changes to manufacturing process and analytical methods Consider if potential future changes in raw materials and manufacturing process (e.g., scale-up) could impact product quality Gather and trend analytical batch data and stability data Demonstrate suitability of analytical methods Write and submit amendments to IMPD/IND |
Create a working cell bank, if relevant Reevaluate and refine the product specifications Evaluate stability data for indications of degradation products and product shelf life Establish the bioassay Conduct the elemental impurities and nitrosamine risk analysis Write and submit amendments to IMPD/IND |
Create and test an end-of-production cell bank if biological IMP Continue to reevaluate and refine the product specifications Finish validation of analytical methods Prepare drug substance and drug product process validation strategies Identify critical steps in the manufacturing process and their control Write and submit amendments to IMPD/IND |
Manufacturing processes and analytical methods must be finalised. Only minor changes until commercialisation are acceptable. Batches placed on stability should be tested with validated analytical methods. Continue to evaluate, refine, and justify specifications, also omission of redundant QC tests. Conduct forced degradation studies and establish the final degradation profile Validate the manufacturing processes and analyse the validation batches Conduct extractable and leachable studies Conduct packaging, in-use stability, photostability and transport validation studies Finalize viral clearance studies, if biological IMP Finalise compatibility studies (packaging materials) Analyse all batch data and stability data and set final product specifications Write and submit the Marketing Authorisation Application |
The main part of the CMC activities defining the quality characteristics of the commercial product is performed during early development, that is in the pre-clinical phase and further developed until Phase 2AB. It is during these phases of development that the quality characteristics of a drug product ideally will be achieved to ensure the desired quality, considering the safety and efficacy of the drug product.
Establishing the design criteria for the different CMC activities in a structured and strategic way minimises the risk of repeating studies or delaying product development.
The value of a Quality Target Product Profile (QTTP) in early development
The QTPP is an overview of all the elements during the product development process that have an impact on the quality, safety and efficacy of a product in a given clinical indication. The QTPP does not only focus on CMC issues but should also cover the specific product design, mode of action of the product, intended clinical use, dosing, route of administration, and so on.
The QTPP is part of the ICH Q8 (R2) enhanced approach as a more systematic approach to development including, for example, incorporation of prior knowledge, results of experimental studies using design of experiments or multivariate data analysis, establishment of a control strategy, use of quality risk management, and use of knowledge management throughout the lifecycle of the product, see Figure 2.
Figure 2 ICH Q8(R2) Enhanced Approach
The definition of a QTPP early in the development of a new biopharmaceutical can be useful in identifying potential areas of CMC risks and designing adequate (and inexpensive) remediation strategies.
For example, product instabilities in the form of aggregates, impurities or degradation products are often responsible for the incidence of immunogenic responses in patients. These criteria, therefore, are often closely linked to specific quality attributes, namely, aggregation levels (as well as other product impurities), product yields and biological activity. From these quality attributes, several design criteria can be used to define a suitable developability program.
The design criteria could include increasing product stability, reducing aggregation, maintaining adequate productivity and achieving all these requirements whilst maintaining acceptable affinity to target.
The design plan should include a risk assessment, mapping areas of the molecule potentially responsible for the observed behaviour, and the introduction of a mitigation plan that could involve the substitution of key residues in the molecule to improve the required parameters.
Finally, the resulting product candidates should be assessed using relevant experimental techniques to determine whether the remediation plans satisfy the requirements for the product. In this example, the QTPP defines the target as “minimise resistance to drug” that identifies the quality attribute “low immunogenicity” and points out that development of the drug should focus on minimising aggregation.
Building up the QTPP should start at the research phase and continue up to the Marketing Authorisation Application (MAA). The QTPP is a living document. Throughout the development process, when changes are done and new data are accumulating, the information should be used to update the QTPP to assess the need for comparability studies and to evaluate possible gaps that may need to be filled. If it is put together properly and regularly updated, it provides the skeleton for the entire CMC module of the IMPD and the end target - the MAA.
How can LINK Medical support establishing a QTPP?
LINK Medical’s Regulatory team of CMC experts can assist with identifying gaps in the regulatory CMC documentation and together with the client at a QTPP workshop identify the “minimal acceptable results” and “ideal results” for each CMC activity.
A QTPP workshop held early in development can identify regulatory CMC gaps that could have resulted in delayed initiation of Phase 1 clinical trial had the gaps not been identified.
Contact leading CMC experts via e-mail: info@LINKMedical.com
Please visit the company website for more information: www.LINKMedical.com
