API lifecycle management: A CDMO perspective

Didier Combis of Seqens CDMO explains why pharmaceutical companies should consider the specifics of the API when dealing with drug lifecycle management

The concept of product lifecycle management (LCM) is central to pharmaceutical companies when looking for profit maximisation. While the concept of LCM usually refers to the period from the product’s first launch into the market until its final withdrawal, as theorised as early as 1965 by Theodore Levitt in the Harvard Business Review, drugs are unique products, which have not one but three different life periods:

• An extensive development period, lasting a decade or longer
• A mid-life period where most of the revenues are generated, usually under patent protection
• A significant post-patent period, which can result in a long, steady decline or sometimes in new product launches through drug repurposing

Considering the extremely high level of regulations in this industry and the intensity of competition in the post-exclusivity period, pharmaceutical professionals need to take a holistic view of LCM and embrace the entire life of the drug, not just its branded marketing period, in order to make appropriate and timely strategic decisions to maximise cumulative lifetime sales.

The API is a key component of the drug lifecycle. It usually accounts for the main IP rights and represents the most important part of its tangible cost of goods. For the sake of simplicity, this article will focus only on small molecules APIs.

A close partnership between a pharma company and a CDMO drug substance specialist, capable of innovation and with a good understanding of LCM and the regulatory landscape, can be a significant competitive advantage. Indeed, wise timing and use of resources like analytical development, process chemistry and in-depth studies of solid state properties can make a real difference in speed-to-market, a regulatory derisking strategy or preparing the ‘ultimate generic battle’ with a smart second generation process.

Discovery to early phase II

Large CDMOs usually get involved two to five years after NCE inception. The first grams of the substance are often produced by the medicinal chemistry team of the innovative laboratory, or by specialised CROs. Speed is of the essence.

When the substance has successfully passed the first selection criteria, like toxicity and pharmacokinetic tests on animals, during preclinical studies, the chemical process used to produce very small quantities needs to receive a first round of optimisations or modifications. In anticipation of the first clinical trials, which imply the first administration of the substance to humans, cGMP is required to produce the API.

In addition, the synthetic route needs to be improved, so as to get a better control over impurities and to find a scalable process. Quantities become larger, usually in the kilo range, and safety and environmental constraints become  important drivers with the increase in production volume.

It is then time for the CDMO to get involved. For the CDMO, the time when the innovator enters the clinical phases is characterised by an intense use of chemical and analytical development capabilities, where speed remains the most critical factor. The purpose is to develop rapidly a chemical process with reasonable scalability features while controlling the impurity profile.

In addition, certain key CMC task must be completed like the identification of potential genotoxic impurities or the characterisation of the crystalline form of the API. At this point in the development phase, the only analytical method that needs to be validated is the one for the API.

The medicinal chemistry process is usually far from a realistic industrial process and sometimes needs a total redesign. Given the attrition rate in drug development and the time pressure at this stage, using special technologies like flow chemistry is not recommended, unless justified by fundamental technical or safety reasons.

The best choice for future value maximisation from a LCM perspective is probably quick process development with a professional industrial perspective. A certain degree of consultancy, without fancy chemistry, by an experienced team that knows the constraints of industrial API production can yield a major future gain in time and money. Some innovators can pay a high price two years later if the API-related work has been previously overlooked without ‘industrial lenses’.

Phase II-III: Taking the right decisions

The late phase of clinical studies has probably the most critical impact on the value generated by the collaboration between the CDMO and the pharma company (Figure 1). The future industrial process has to be fixed so as to become robust on dozens to hundreds of kilos scale, with a perfect control strategy for impurities. Analytical methods for the final API, intermediates and registered starting materials (RSMs) are validated in Phase III.

Most importantly, good decisions have to be taken during that stage to reduce API costs. The future manufacturing costs of drug substance production will be an outcome of both the quality of the process development work and decisions taken at this period of the API lifecycle. The R&D work is structured by ICH guideline Q11.

The involvement of senior chemical development teams in organisations with solid experience in complex multi-step synthesis and access to breakthrough technologies, like biocatalysis with gene-shuffling capabilities, can definitely help in taking the right process decision before the launch window is missed.

The costs of API-related tasks in the overall drug development programme usually peaks when multiple tasks run in parallel to generate high quality CMC data, such as Quality by Design (QbD) studies and the carry-over of the impurities to document the future NDA.

This is also the time to define the raw material sourcing strategy, which will define important economical and risk factors for the first commercial year. For the customer, especially cash-strapped emerging pharmaceutical companies, it is often a time of very difficult decisions on whether or not invest in a few extra months of FTEs for process improvement or polish the QbD studies.

The risk-averse approach is to retain cash to finance the coming validation batches or extra clinical studies but from an LCM perspective, this approach can be extremely costly. Multiple examples exist where three or four months of extra chemical development work to test a process modification, consolidate data by design space determination or fine-tune an enzyme which will cut two steps, have saved millions of euros over the first years of commercialisation.

Once a new medicine is filed in 50 countries, it gets harder for chemists to propose process improvement. Figure 2 shows the relative importance of process R&D spending on the API cost of goods. While it is very general and many counter-examples can probably be found, it underlines the importance of good process R&D at certain critical periods of the API lifecycle.

Late phase III-market launch

From a CDMO perspective, the beginning of the period from late phase III to market launch is defined by the production of the first registration batches, followed by the process validation campaign and the production of the launch quantities. This time is characterised, in most of the cases, by a decline in R&D activity as process validation freezes the manufacturing process.

Some exceptions exist when the innovator decides to launch a drug with a sub-optimal process for quick market access and finance a second-generation process to file in parallel after market launch. In that case the CDMO needs to have the critical size to offer sufficient chemical and analytical development resources to cope with the workload.

The regulatory teams, especially in QA, are strongly involved during this period where all validations have to be completed and the site has to be ready for pre-approval inspections.

The period can also be erratic in terms of industrial planning, while projected launch volumes may be significantly different from the initial marketing forecasts. A CDMO offering multiples sites and back-integration for certain key raw materials can help the innovator to reduce its up-front investment and facilitate a better use of its cash which ultimately maximise value creation along the drug lifecycle.

Commercial period

The commercial stage of the API lifecycle normally lasts for around seven to ten years. It is usually characterised by regular growth in production volume and is something of a ‘calm after the storm’ period.

The classic forces driving any industry for cost reduction are now in motion. The manufacturing site is gradually adapting and dealing with increasing volumes. Environmental, safety and quality compliance are key. Process optimisations are implemented softly within the constraints of the regulatory dossiers filed worldwide, which greatly limit chemists’ imagination. Cost pressure is not as strong as in the generic phase.

We are seeing significant improvements from authorities and the development of harmonised regulatory tools, enhancing the management of post-approval changes. For example, the development of QbD filing and the emergence of new guidelines like ICH Q12, published in December 2017, ‘Technical & Regulatory Considerations for Pharmaceutical Product LCM’, help to frame the possibilities of improvements for drug substance and drug product alike.

Q12 focuses on CMC changes in the commercial phase of the product lifecycle, to complement Q8 and Q11 guidelines on early stage aspects of LCM. It structures change control and introduces key notions like ‘established conditions’, post-approval change management protocols and product LCM, allowing more transparent and efficient communication between industry and regulatory authorities.

Certain powerful CMC changes leading to second-generation process, using, for example, biocatalytic steps to shorten the synthesis route can be implemented at any time during this period. However, the approaching generic battle, combined with the innovator company’s culture towards change and competition usually triggers the strongest evolution in CMC.

We are now in the middle of the API’s lifecycle. This period is characterised by fundamental changes, uncertainty and very different behaviour patterns among pharma companies. Some prepare actively for the ‘generic battle’, using CMOs to support them; some do not and prepare to manage a decline, which can be either very rapid or may last more than ten years.

Post-patent period

After a Darwinian selection process, which sees a dramatic reduction in the number of drug candidates and then, years later, of API manufacturers, the last API lifecycle stage usually starts with a period of relative stability for both customers and API producers.

The market has found a new equilibrium now, whether or not a CDMO is involved. Most CDMOs make catalogue API products and can offer ‘long-term generic API supply, but in some cases only pure API generic players stay involved.

Pharmaceutical laboratories working with good CDMOs will benefit from strong regulatory support and high quality compliance level, combined with strict EHS standards. This can make the first part of the maturity period long and smooth – as long as size of the business can justify sufficient resources to maintain a good supply chain.

Later, with the drug substance volume decreasing, problems quite often arise with the supply of non-GMP raw materials, where the original producers can no longer produce at the same price or face new environmental constraints, in China for example. In these situations, working with a CDMO that can back-integrate an early chemical intermediate offers more possibilities of creating a sustainable supply chain, even if the economics need to be reviewed.

The intrinsic therapeutic performance compared to the molecular entities already launched will strongly influence the length of this last stage of the lifecycle. Some APIs will continue to decrease in volume because of increasing manufacturing costs, which will drive the medicine out of the market.

In a smaller but increasing number of cases, either the originator or another creative pharma company will find a new indication, opening up a new round in the substance’s lifecycle. This ‘drug repurposing’ is now widely documented in the industry, with specialised companies like Harmonic Pharma in France offering in silico predictions to help make LCM decisions.

Given the extreme and growing costs (typically $1.7 billion) and the time (ten to 15 years) involved in bringing an NCE to market, and the fact that 90% of phase I candidates fail in development, repurposing is clearly an elegant way to add a new profitable block in the API lifecycle. 25% of the drugs being repurposed obtain a new market approval.

Conclusion

To develop a comprehensive and modern LCM strategy, a pharmaceutical company should have a good understanding of its drug substance component, which follows its own path over 30 years or more. This can lead to powerful value creation or result in the identification of new markets for extending the lifetime of small molecule drug products.

Contact:
Didier Combis – Commercial Director SEQENS CDMO
didier.combis@seqens.com