Robin McCallum manages all aspects of CMC Operations for TapImmune’s cancer vaccine programs.
Thank you, Robin, for taking part in this Q&A.
First off, what are “CMC operations”, and how do they impact clinical trials and the drug development process?
RM: CMC stands for Chemistry Manufacturing and Controls. CMC operations come into play when drugs emerge from the drug discovery and lead optimization phases of drug development and enter the IND-enabling, preclinical phase. An IND is an Investigational New Drug. CMC is maintained as a drug goes through the clinical phase (Phase I, II, and III) of drug development and throughout the life cycle of the drug as it is approved by a regulatory agency (e.g., FDA, EMEA) and marketed.
CMC encompasses the nature of the drug, its manufacturing process, and the manner in which the manufacturing process is shown to be in control. Some of the critical elements of CMC include:
- how and where a drug is manufactured
- what control procedures are in place to ensure reproducibility in the manufacturing process
- what control procedures are there to maintain drug quality and consistency
- what critical quality attributes (CQA) have been identified and characterized for the drug
- are the CQAs appropriate for the drug and its phase of development
- how stable is the drug
- is the drug manufactured in an appropriate dosage form
Appropriate CMCs are essential to ensuring that drugs supplied to support human clinical trials are safe and tolerable, and will become more rigorous as a drug goes through early-stage clinical trials (Phase I and II) into late-stage clinical trials (Phase III).
What prior biotech and drug development experience do you bring to TapImmune?
RM: I bring more than 12 years of experience in biotechnology and pharmaceutical development to TapImmune. This include broad experience in most areas of drug development and manufacturing, including research & development, process development, scale-up, GMP manufacturing, analytical method development, qualification, and validation, quality control testing, and quality assurance. My particular expertise is in pharmaceutical and biopharmaceutical process development, GMP manufacturing, and analytical methods.
I also work closely with a technical consultant who has more than 25 years of experience and expertise in process development, analytical methods, formulation and dosage form design; technology transfer to GMP operations, GMP manufacturing, regulatory submissions and quality assurance with a broad range of drug types including small organic molecules, peptides and proteins, biologics, and combination products.
Does the FDA require documentation of a company’s CMC operations as part of the drug development process?
RM: Absolutely! Submission of an IND for first-in-human clinical trials (Phase I) requires submission of a CMC section as part of that IND to the FDA. The agency is chiefly concerned that a drug administered to humans has been manufactured and characterized in an appropriate and consistent manner, and meets quality standards. CMC along with preclinical and toxicology studies in animals ensures that any drug advanced to Phase I clinical trials is as safe as possible.
How do CMC operations change as drug development goes from phase I, into phase II, and beyond?
RM: CMC is one of the links connecting early non-clinical or toxicology batches (Engineering runs) to clinical batches and eventually commercial batches if the drug is deemed safe and efficacious, and is approved by the FDA or other regulatory agency. The requirements for CMC expand and become more rigorous as the drug moves along the clinical development pathway toward commercialization.
At the Phase I stage, safety is the primary concern. Typically, the drug lot that supplies this early stage trial will meet basic quality requirements; however, the manufacturing process is usually not yet optimized for yield, purity, efficiency, scalability, etc. Further, the formulation is adequate for the dosage form and route of administration, but is not the optimal or final formulation. Typically only one non-GMP lot (Engineering lot) and one GMP lot (clinical lot) has been manufactured; therefore, there is not adequate, statistically significant data on lot to lot variability and consistency. Moreover, analytical methods if not performed as per compendia, have been minimally developed and qualified (method-dependent) to meet Phase I requirements, but have not been optimized and validated. Broad, tentative specifications for CQAs are established and some tests simply have “report results”. Also, although overall product purity and impurity has been quantified, individual specific impurities and related substances have not been identified and characterized. Lastly, only about 1-3 months of stability data from the clinical lot will be available by the time the drug is dosed in the first patient for the first-in-man trial. This is all acceptable from a regulatory standpoint for a Phase I drug lot.
At the Phase II stage where both drug safety and efficacy are concerns, the manufacturing and formulation process will typically be refined and improved although not optimized to the final process. There is also usually a scale-up of the manufacturing process at this stage though not yet close to commercial scale. The CQAs for the product will be better defined and characterized. More stability data has been generated (12 months+) using stability-indicating methods, at multiple temperatures. Many firms elect to finalize and validate analytical methods at this stage.
At the Phase III stage (drug safety, efficacy, and consistency), the manufacturing process is optimized to be robust, reproducible, and scalable to commercial scale with fully established in-process controls. This will be the commercial process by and large. Using fully tested raw materials, at least three consistency batches are manufactured as part of process validation. These batches are often used for NDA or BLA filings to regulatory agencies. Analytical and microbiological methods are completed validated, CQAs are fully defined and characterized, and final specifications are set. The physical, chemical, and biological properties of the drug are fully characterized. Process impurities are fully identified, defined, and quantified. Stability data from multiple clinical or GMP lots is available and stress testing has been completed. Also, container closure integrity testing is completed for sterile products.
I’ve read that in order to gain a competitive clinical edge, some companies may look to do the minimum amount of CMC work required while still maintaining an acceptable level of control, as required by the industry. How do CMC operations managers like yourself balance the need to keep costs down while maintaining a high level of quality required by the industry?
RM: In the competitive industry of pharmaceuticals, companies will always seek to accelerate drug development, with first-in-man trials being a critical milestone. Whether large or small, any pharmaceutical company will have to balance three important and inter-related factors: time, cost, and quality. Fortunately, the FDA has defined certain basic CMC requirements for drug that supply first-in-man studies with safety being the main concern. In some ways, the need to meet those basic requirement for safety in Phase I trials (derived in part from quality in CMC) will predefine the minimum amount of time any CMC operations manager will need to spend on the development, GMP manufacturing, and characterization of the first clinical lot. Therefore, that mitigates some of the corporate pressures for accelerating what will be an already aggressive timeline and reducing an already streamlined budget for drug development. TapImmune is committed to product quality and patient safety first, and we will not compromise that in favor of a faster timeline or lower cost. Those who sacrifice quality often end up losing quite a bit more money and time in the long run.
How long does the process take of manufacturing TapImmune vaccines?
RM: The process to manufacture TapImmune’s vaccine can be broken up into two main parts: I) manufacturing of the peptide Drug Substances or Active Pharmaceutical Ingredients (APIs) and II) manufacturing of the Drug Product or vaccine. Part I consists of the synthesis, cleavage, and purification of the individual peptide Drug Substances (5 peptides) and this process typically takes 2-3 months depending on the peptide. Part II consists of the formulation, filtration, vialing, and lyophilization of the Drug Product, and typically takes 1 week for manufacturing operations. Pre-manufacturing activities such as batch record prep, etc. and post-manufacturing activities such as quality control testing will add around 1 month each. Overall, it takes around 4 months to manufacture and fully release TapImmune’s vaccines for clinical use.
Once the vaccines are created, where are they sent to? Do you have any clinical sites in the country? If so, where?
RM: Once the vaccines are manufactured, tested, and released, they are stored at our manufacturing vendor for clinical distribution via clinical drug couriers. At this time, all of TapImmune’s clinical sites are located in the USA in a number of states across the northeast, southeast, south, and midwest: Florida, Kansas, Michigan, New Jersey, New York, Maryland, Missouri, Ohio, Tennessee, and Texas.
For more information on TapImune see:
U.S. Department of Defense Funds Phase II Trial of TapImmune Breast Cancer Vaccine source: Breast Cancer News
TapImmune Improves T-cell Vaccine Ahead of Phase II Trials source: BioPharma Reporter