The Consultancy Expertise You Can Count On.
At CMC Innov, we are committed to providing innovative pharmaceutical solutions to ensure your project milestones are achieved on time every time. Let us be your trusted CMC partner.
About CMC Innov...
CMC Innov is a science-focused consulting company specializing in small molecule drug substance and drug product development. The company was created in 2023 on the solid foundations of 26 years’ experience in big pharma supporting small molecule and hydrogel dermal filler R&D projects at various stages in both the oncology and dermatology research areas.
We have a proven track record of enabling chemistry-focused R&D activities to meet their project milestones and with over 100 scientific publications, patents, prizes and international presentations, we are certainly not afraid of applying our savoir-faire to discover innovative solutions for our clients (when required of course)!
No problem is too small! Our services span from helping clients to solve individual chemistry-focused problems at any stage of R&D to leading the entire CMC activities of development projects at all stages with full RA support through our partners PharmDev Consulting (website) and Drais Regulatory Consulting LLC.
About Me...
CMC Chemical, Drug and Dermal Filler Development | People Leadership and Development | Continuous Improvement | Innovation | Problem-solving
In a nutshell, I am a NCE (new chemical entity) drug development leader and scientific advisor with more than 25 years’ experience in small molecule drug discovery & development working in big pharma alongside 5 years' experience in HA-based dermal filler R&D.
Throughout my career, I have been priviledged to have driven excellent discovery and CMC teams on >20 small molecule drug NCE discovery and development projects resulting in 14 transitions including 6 clinical candidates in the Oncology, Dermatology and Aesthetic & Corrective fields. In the past 5 years, I also expanded my horizons to trouble-shooting established products (eg., impurity management strategy, second sourcing of APIs, route improvement while remaining in the scope of DMF, CEP etc) resulting in several success stories, avoiding market recalls through sound scientific position papers and costly re-processing.
I am not afraid to innovate within the scope of the project or task in hand and have a strong track record of tangible creativity spanning from enabling access to hard-to-make design space in a drug discovery setting all the way to signficantly improving established API routes permitting net commercial gain.
Our Services
CMC Lead Case Study 1: Going lean and mean - virtual perfection?
Our first early development project operating in a fully externalized model where I assumed the CMC Leadership of both drug substance and product.
Often due to more and more demanding timelines and budget restrictions, we are obliged to sprint through the early tox phase with essentially the "medchem discovery" route to deliver the first 100 g of API while papering over the cracks as we go. This was the case for this particular project, the route employed for the first 100 g of API was a copy-paste of the medchem route and unsuitable for Kg scale-up. Major modifications in process and delivery strategy were required to deliver the technical and GMP batches on time for the POC.
Under the umbrella of COVID-19 and through a strongly collaborative approach with our CRO partners, we managed to shave off 5 months of lead time versus the first estimate and improve yield by 6 fold despite the 10 fold increase in scale. In fact, thanks to the yield improvement, we even made enough API to consider an alternative indiciation!
CMC Lead Case Study 2: How much!
API COGs (cost of goods) are sometimes overlooked particularly for innovative, first in class projects. However, when you are working on a non-life threating skin disorder, you must know what the payers are willing to pay for treating your target indication. Also playing against us was a high predicted maximum daily dose range and the cost of the API was very high (>19 chemical steps). So API COGs can matter even early on, and route improvement must be at least considered asap into the overall planning and project feasibility.
Here, we introduced 2 major modifications looking at the 2 costliest building blocks. One modification permitted us to avoid using an expensive palladium catalyst combo with no consequence on step count and yield. The other modification was the employment of an ambitious 3-step telescoped biocatalytic process to make the homochiral second building block, reducing the step count by 3 and improving yield by 4-fold. These 2 modifications permitted an estimated COG reduction of 55.4% and decreased lead time by about 15 weeks for synthesis of the API for the Kg-scale technical and GMP batches.
Discovery synthesis enabling design -Case Study 3: New trick for an old dog!
When our drug designers started to get more ambitious by desiring more sterically-hindered hydroxamic acid motifs, literature methods started to fail, often affording little hydroxamic acid product contaminated with carboxylic acid by-product that was difficult to purify. At one point in the program, only 2 final compounds were delivered sufficiently pure for assay during a period of 4 months for a back-up project!
As a lot of literature conditions had already been tested to improve throughput, we decided to test our own ideas and through an elegant "split/mix" approach, we found that the use of organic super bases (eg., DBU, DBN) in solution or supported on polystyrene permitted a very clean hydroxylaminolysis of even very hindered ester substrates to hydroxamic acid products. This new process was hugely impactful for our project, enabling the delivery of our complex design sets and eventually 4 candidates for development. For further reading, please consult: Tetrahedron Lett. 2016, 57, 2165-2170 (link); Bioorg. Med. Chem. Lett. 2017, 27, 1848-1853 (link); Bioorg. Med. Chem. 2018, 26, 945-956 (link); Syn. Lett. 2018, 29, 1102-1106 (link). Process highlighted on a popular internet site for organic & medicinal chemists in 2017: Organic Chemistry Portal (link) and cited many times.
Discovery synthesis enabling design - Case Study 4: Following fast!
We worked on the particularly challenging RORy target, fast-following several companies in what had become a patent minefield.
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Despite the fast-following approach, over 800 final compounds were prepared, requiring the development and optimization of a number of new chemical approaches "en route" to deliver our final compounds including a novel process to make benzoboroxoles. Our efforts were rewarded with the nomination of 4 candidates for development including our chiral sulfoximine-based candidate.
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If you would like to read more about our work on this RORy target, please consult the following: Tetrahedron Lett. 2017, 58, 3757-3759 (link); ChemMedChem., 2018, 13, 321-337 (link); Adv. Synth. Catal. 2018, 360, 2757-2761 (link); Bioorg. Med. Chem. Lett., 2018, 28, 1269-1273 (link); Tetrahedron 2018, 74, 2018, 5974-5986 (link); Lean delivery of a sulfoxime-based RORy inverse agonist for topical administration. Featured speaker & presentation given at BOS, Basel, Switzerland, 2019 (link).
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Discovery synthesis enabling design - Case Study 5: I am a (Caspase I) survivor!
From experience, when a drug discovery project has terminated with more synthesis papers (Tetrahedron, 2018, 74,4805-4822 (link); Tetrahedron Lett. 2018, 59, 256-259 (link); Tetrahedron Lett. 2016, 57, 2367-2371 (link); Tetrahedron Lett. 2016, 57, 5924-5927 (link) than design papers (Bioorg. Med. Chem. Lett. 2017, 27, 5373-5377 (link) & J. Med. Chem. 2018, 61, 4030–4051 (link)), it is usually a sign that the synthesis was complex and novel chemistry needed to be discovered to deliver the design sets and enable the Design-Make-Test-Analyse (DMTA) cycle to turnover. Indeed, not only were the synthetic routes long (19 linear steps per molecule at one point) but delivery of final compounds (achirally & chirally pure enough for pharmacological evaluation) was rendered particularly complex as we were obliged to prepare our final compounds equipped with a reactive, electrophilic hemi-acetal warhead (the drug-form) as the acetal warhead (the pro-drug form) was not hydrolyzed in the skin and was much less stable in topical excipients than the drug form. In spite of the added complexity, we delivered over 500 final compounds exploring and optimizing all key vectors (including a novel and intense study of the warhead) to finally deliver CD12694, a developable candidate for topical administration.
As the synthesis was often tricky with lots of unexpected twists, turns and challenges with long sequences, Caspase I became known internally as Project “Koh-Lanta” (the French version of Survivor, the tv survival series – we even gave a departmental presentation under the same theme including the music) ! I was fortunate to have had the pleasure of telling the story twice in London (link) and in Switzerland (link)...without the music though!
Discovery synthesis enabling design - Case Study 6: Diversity personified!
Working on the fiercely competitive target PI3K-alpha, we had to explore wide and quickly in what had become a saturated patent landscape. The synthesis teams delivered over 4000 finals in 3 years and supported what was the shortest LO phase in the company's history at the time, optimising 3 chemical series with little inter-route convergence at the same time! The team delivered and AZD8835 (15 linear steps but 29% overall yield with no chromatography - not bad for medchem!) for clinical development. This colossal effort earned the AZ quaterly prize for innovation in 2012.
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Obligatory innovation! There needed to be a massive investment from the synthesis team to permit access to effectively much new design space and we delivered! This phenomenal effort was compensated with acceptation of 5 individual print publications highlighting the novel synthetic chemistry required to deliver the final targets, please see: ACS Comb. Sci. 2011, 13, 449-452 (link); Tetrahedron Lett. 2011, 52, 6376-6378 (link); Tetrahedron Lett. 2012, 53, 5380-5384 (link); Tetrahedron Lett. 2012, 53, 6849–6852 (link); and Tetrahedron Lett. 2012, 53, 6078-6082 (link).
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Trouble-shooting -
Case Study 7: Slower is sometimes better!
One of our commercial API processes was not delivering right first time the final API without reprocessing since 2015 due to co-crystallisation of an impurity with an advanced intermediate. Through a collaborative approach with the CMO, a minor modification of the process was introduced involving slower addition of the anti-solvent, effectively holding the intermediate in the metastable zone for longer and permitting ultimately crystallization of the advanced intermediate effectively free of the impurity and without affecting solid state parameters.
As a result, the final API was delivered right first time since the minor modification was implemented avoiding wasteful and costly reprocessing.
Trouble-shooting -
Case Study 8: Finding needles in a giant haystack!
I guess old APIs can sometimes throw up some unwanted surprises as their processes were developed often before the introduction of the ICH guidelines when analytical methods were also very limited. This was the case for one of our older APIs, Lymecycline, first approved in 1963! After a period of instability with the drug substance and product, we decided to identify all the unidentified impurities in both the drug substance and drug product to better understand the degradation pathways.
Thanks to a phenomenal effort from all parties involved, we managed to identify and provide preparative methodology to 3 compendial and 4 non-specified impurities. Identification of compendial impurities enables preparation of analytical standards to quantify the impurities and better understand how to manage future OOS situations. For further reading, please consult: J. Pharm. Biomed. Anal., 2022, 220, 114993 (link)); Eur. J. Pharm. Sci., 2023, (link)); and our external talk entitled Transitioning towards a fully outsourced model in CMC - Showcasing Highly Collaborative Outsourcing Partnerships. Invited speaker & presentation to be given at BOS, Manchester, UK, 2022 (link), 2023 (link).
Trouble-shooting -
Case study 9: You CAN teach an old dog new tricks!
Through a super collaborative approach with a leading CMO, we put in place minor process modifications while remaining in the scope of the process conditions described in the regulatory dossiers of the commercial API. These modifications permitted not only a reduction of a troublesome impurity and avoid costly reprocessing but also improved yield by 1%.
Now, 1% percent might not sound much but given the large commercial volumes of API and the weak final concentration of the API in the final drug product, the impact of the few % was quite significant in terms of additional finished product volumes!
Marketed products support - Case Study 10: Nitrosamine topic(al)
As the responsibility (right or wrong!) for the nitrosamine risk assessments for both the drug substance and drug product fell upon the market-authorization holders (MAHs), we set about formalizing an approach (generic risk assessment templates, decision tree, questionnaires for API & excipients suppliers, keeping on top of the literature and evolution of the guidelines) to risk assess all our drug substance processes (not so easy to get information from API or excipient suppliers!) and our finished products for the presence of nitrosamine impurities. To finish off, we also asked ourselves an important question: What concentration of nitrosamine eg., NDMA would you actually need in a generic cream formulation to reach a systemic level of 96 ng / d? Through IVPT testing, we were able to confirm that actual topical bioavailibility is just ~1.5% primarily due to loss of volatile NDMA once applied on the skin. Extrapolated to a realistic dosing scenario of 2 mg of a generic cream formulation / cm2 with a signficant contamination of 0.3 ppm, we would need to cover 35% of the body surface area to reach 96 ng in the plasma! Let's not forget this data is likley to be very much a worst case v in vivo.
Overall, despite the challenging timelines, all the assessments (>100) were completed before the deadline including the topically-focused position paper supported by IVPT data.
Scientific writing and dossier support
Our scientific writing services provide comprehensive support for the entire drug development process with the help of our regulatory affairs expert partners PharmDev Consulting and Drais Regulatory Consulting LLC. Our services include authoring and reviewing scientific dossiers, answers to questions from health authorities, and writing science-based position papers to support established products after completion of any root cause investigation for quality assurance. We also have extensive experience in due diligence and patent support.
External publishing. You know the scenario - the patents are out there but your team is on another target or task already and you don't have time to write up the innovative work for external publication! We have been there! The external publication process IS very long eg., gather data, make a story, choose the right vehicle, write a draft, internal review, external review, corrections / resubmission, publication. CMC Innov has extensive experience in external publishing and can help with the leg work in the CMC / organic chemistry field.
Pierre Dubettier-Grenier, API Procurement Manager at Galderma, CH
“Craig worked for me mainly on process trouble-shooting activities to solve impurities formation and on out of specification root cause investigations. Craig’s outstanding achievements brought millions $ added value to the company, avoiding high-cost ingredients destruction and drug products recalls. His work allowed to characterize unknown impurities and to improve the scientific knowledge. That led to several scientific publications accepted by leading scientific journals."
Karine Charras, Raw Material & Industrialization Specialist at Galderma, Fr
"During the last 5 years, I had the great opportunity to have had the help of Craig on several trouble shooting projects related to API manufacturing at Galderma
Craig has got a very good vision of what is the problem and how to solve it quickly."
Stephen Desrosiers, Head of Global Operations & Commercial Quality at Galderma, CH
"I must highlight the quality of your work, your insights into chemical synthesis and great team work."
Emmanuel Vial PhD, Chief Development Officer at Granular Therapeutics
"I am truly impressed by his technical skills, depth of scientific knowledge and commitment to work which were key to the success of many projects he participated in. Lately, in my role of program leader I was also witness to his leadership skills in several projects and especially to his ability to keep his CMC team motivated and efficient through the right dosage of empowerment and trust and to his impeccable track record as a CMC lead and representative in projects, being always proactive, goal-oriented, reliable, providing solutions facing the inevitable challenges of a project and clear communications within and outside the team."
Frédérique Lantoine, QP at Galderma, Fr
"J’ai travaillé pendant 5 ans avec Craig au sein des Laboratoires Galderma. Ses compétences de chimiste m’ont été très précieuses. Je recommande chaudement son expérience dans le domaine du développement pharmaceutique."
Caroline Trognon, CMC RA Expert at Galderma, CH
"I had the privilege to work with Craig on different projects (from early development to troubleshooting resolution) on small molecules. Craig is a very talented chemist dedicated to his job who knows to drive projects to success with exceptional problem solving skills.
He is always enthusiastic, he likes to share his skills and is a very humble person despite his amazing knowledge in organic chemistry."
Héloîse Raynard PhD, Analytical Development Manager at Yopeski, Fr
"At Galderma he tackled issues ranging from but not limited to: impurities characterisation, new entities toxicity evaluation, manufacturing processes and formulation improvement and troubleshooting, novel drug delivery systems evaluation.... He identifies risks and acts quickly to mitigate them."
Laurent Hennequin PhD, President at MedChem Consulting, Fr
"Craig's ability to coach, to support and impact on the success and productivity of large chemistry teams is excellent and proven by his track record of contribution to clinical candidate drugs in the field of Oncology and skin disorders. His skills and delivery has led to an impressive record of international, peer reviewed publications. Craig is well known by expert in the art of synthetic chemistry and recognized internationally as demonstrated by the regular invitations he receives to give lectures at major international congresses. Craig is extremely creative and loves to find new solutions, explore new technologies, investigate yet unexplored avenues but always keeping in mind the initial team or project goal."
Anais Noisier PhD, Associate Principle Scientist, AZ, Sweden
He has this rare quality which prompts his collaborators to give the best of themselves and which makes him an exceptional team leader. He surely impressed me by his abilities to think outside the square and bring innovative solutions to the most challenging synthetic problems. Dr. Harris’ passion is an inspiration for all the students who had the privilege to be supervised by him. His dedication to organic synthesis, to his colleagues and students goes far beyond what one could dream of. Dr. Harris has never ceased supervising and encouraging me, and is still doing so many years after I have left AstraZeneca.
Gilles Ouvry PhD, VP at NRG Therapeutics, UK
"Craig is also a leader with a vision on how synthetic chemistry should function in the pharma environment. By applying lean principles (right first time synthesis, waste walks), coaching principals (forward planning meetings) and recognition of high quality contributions (authorship on publications), he shapes the teams he leads into goal-oriented, high performing units.
The most impressive thing for me however, was to see how in just a couple of years, Craig set up a research unit on hydrogels in the labs in Sophia-Antipolis and delivered what appears to be multiple truly novel concepts in this field.
I have yet to see a subject that leaves Craig without novel ideas et I can’t wait to see what he will invent next."
Dame Prof Margaret Brimble DZNM, FRS, University of Auckland, NZ
Craig brings real academic rigour to his work in the pharmaceutical industry. He appreciates that the underpinning science is valuable to achieve results in the competitive pharma industry and that ultimately this is what puts the companies he works for well above mediocrity.
Claire Bouix-Peter, Chief Operating Officer at Aldena Therapeutics, CH
“I was lucky to be part of your incredible journey at Galderma. You are a great chemist.”
Lisa Wang, Patent Attorney at Galderma, US
"It is my privilege to work with Craig who is an exceptional talent with rare expertise in the small molecule and aesthetics fields. In working with Craig, I am impressed with how comfortable he is navigating the technical and legal issues surrounding the small molecule development space from identifying and protecting innovation to interfacing, coordinating, and negotiating with third parties to provide critical project support. This quality manifests because it is gained through years of first-hand practice and knowledge. Craig is also a pleasure to work with due to his professionalism, work ethic, and responsiveness. It is so refreshing to work with Craig in that he is so humble given his exceptional qualities."
Contact
Craig S. Harris, PhD FRSC
CMC Innov Consulting SAS
+33 (0)6 84 99 04 87