The development of successful non-GMP material supply chain strategies is the result of sound planning. The ability to devise a plan for the supply of raw materials and Registered Starting Materials (RSMs) depends on an understanding of how the need for these materials evolves and changes over the development cycle, the regulatory requirements that need to be addressed, and the role of sponsors in defining and justifying the non-GMP materials used in their API manufacturing processes.
Determining practical sources of raw materials and regulatory starting materials (RSMs) that are not produced under good manufacturing practices (GMP) is often far from a trivial pursuit. In recent years, a number of factors have further compounded the task of sourcing of these compounds:
A discussion of the significance of these factors, and how they impact creation and execution of non-GMP sourcing and supply chain strategies is discussed in the remainder of this article.
Sourcing of raw materials and intermediates in early development tends to be expedient and tactical, as opposed to strategic. In many cases, a medicinal chemistry synthetic route to the API is all that is available, and if possible and practical, this synthesis is adapted and taken forward as the early enabling route for the first stage of development, including Phase I clinical supply. A key question to be addressed in early API development is the availability of starting materials and key reagents.
The trend in NCE APIs is one of increasing structural complexity, with regard to scaffold backbones, combinations and placement of functional groups and stereochemistry. Complexity traces upstream in a synthesis to the raw materials for a given API. There is an inverse relationship or trade-off between structural simplicity in raw materials and RSMs and increasing molecular structural complexity. If the materials used to manufacture a complex API are structurally uncomplicated, then the necessary chemical transformations are more demanding and sophisticated. Conversely, if complexity is purchased, in the form of advanced raw materials or RSMs, the GMP process is simpler. Purchase of raw materials and RSMs that are structurally complex means that there is heavier reliance on third party suppliers (i.e., other than the GMP API manufacturer) to shoulder the technical demand of providing these materials with the required quality. As a result, more oversight of third party suppliers of complex non-GMP materials is necessary.
A historically relevant example of the use of starting materials possessing sufficient complexity to act as templates for the synthesis of complex final molecules is the Chiron 1 or chiral synthon approach, which was formalized and advanced by Hanessian. In the Chiron approach, a “chiral pool” of optically pure small molecules, including amino acids, carbohydrates, hydroxy-acids and other naturally occurring compounds are used as synthetic starting materials. Although initially directed primarily toward the total synthesis of natural products, the Chiron approach was and is also adopted and implemented, where applicable and practical, by industrial medicinal and process chemists.
An illustrative example of the Chiron approach as applied to industrial chemistry is the sequence used to generate Fragment B, the side chain precursor, for the first generation Pfizer commercial process for Atorvastatin (Lipitor)2, shown below:
In the last 20-25 years, advances in asymmetric synthetic methodology, including chemocatalysis and biocatalysis, have progressed considerably beyond the manipulation of chirons. In addition to the considerable advances made in asymmetric synthesis, catalytic functional group interconversion, transition metal-mediated cross coupling reactions, C-H activation and ring closing olefin metathesis, among other synthetic methodologies, have enabled an expansion in the diversity of chemical space explored.3 This expansion has expectedly given rise to an increase in the structural novelty and complexity of drug candidates advanced from discovery into development.
As more development candidates are nominated that bear novel scaffolds and combinations of functionalities, a challenge arises – when the required quantity of a complex material jumps from a few grams to a kilogram, how is it secured? Some precursors are available in small quantities from catalog companies, but often they need to be custom produced to ensure sufficient quantities and quality. Almost as often, unconventional and/or expensive reagents are needed to prepare them, and these reagents may also need to be custom-prepared. The increasing inability to secure raw materials “off the shelf” adds time and cost to the synthesis of even modestly scaled up batches of complex APIs. The additional time and cost is associated with practicality and quality. Practical, scalable syntheses of complex raw and starting materials must be developed. The materials need to be adequately characterized in order to determine attributes (purity, impurity profile), and use-tested to correlate those attributes with material performance. This challenge is usually not insurmountable at early stages of chemical development and manufacturing. However, as the need arises to develop a process capable of providing increasing quantities of material, corresponding requirements for increases in process understanding, control, a reliable supply chain, and cost of goods (COGs) are factors that must be confronted and addressed.
When it is clear that sourcing of materials for a given API manufacturing process may not be routine, a sponsor has several options. The first option is to allow the CDMO to handle identification and qualification of suppliers, and then procurement of the necessary materials. Many sponsors will initially defer to the CDMO to procure raw materials and RSMs. All CDMOs in the API manufacturing space have experience in this area, however their resources may be limited for particularly difficult to source materials.
Going forward from early development, the most convenient situation is that the CDMO, by itself, is able to find reliable sources that are able to produce materials in the required quantities and quality. However, supply planning has become more complex, and supply strategy evolves over the course of development. It is up to the sponsor to monitor the situation as development proceeds from early to mid and late stages, in order to gauge if and when a point comes where the limits of the CDMO to source key materials are being approached. At this point, it is necessary for the sponsor, themselves, or with the aid of a sourcing specialist, to do the work necessary to complement the capability of the CDMO in order to establish a reliable supply chain. This is always a collaborative effort, since a critical aspect of establishment of a supply chain is qualification of the suppliers by the CDMO, and this entails analytical, QC and use-testing of materials from suppliers under consideration.
Whereas many raw materials and reagents are available from third party suppliers, the RSM is often custom-produced in-house at the CDMO, given that they are often initially intermediates in the GMP API manufacturing process, and there is the need for significant process and analytical R&D to optimize the chemistry for scale-up and production at the scales required. Once developed, optimized and scaled, the chemistry for the production of RSMs may be transferred to a more cost-effective manufacturing site. Proceeding in this way affords the sponsor more control over the third party production of RSMs, since the processes are better understood, and this can be clearly communicated to potential suppliers in a technical package. Increased process understanding also enhances understanding of the quality requirements for RSMs, and this provides more clarity on the viability of a given precursor as an RSM.
As a drug development program transitions from Phase I to Phase II clinical trials, the number and size of the clinical trials tends to increase significantly. An increase in the quantity of API required usually necessitates an increase in process capability, as well as process controls to ensure consistent delivery. It is well understood that, from a quality point of view, the majority of risk associated with a given API manufacturing process resides in its final steps, in which the penultimate intermediate and its impurity profile, along with how the final API is isolated and purified, have the most significant impact on quality. For this reason, the early steps of a given API process are the most changeable, since their expected direct impact on the quality of the final API is low.
There have always been advantages associated with performing some chemical process development work on custom produced raw and starting materials. This work can improve quality of these materials, which also can raise the yields for production of the RSMs. An improvement in the economy of the production of RSMs reduces the volumes of raw materials, solvents and reagents required, resulting in a reduction of cost and cycle time. Process R&D and optimization for raw materials and RSMs also develops understanding that provides a means of control over these materials, including control of impurity profiles and carryover of impurities into the GMP API manufacturing process.
In the past, impact of the quality of the RSMs on the API was addressed by defining them far upstream in the synthesis, and preferably, as made commercially on a large scale, for multiple products and uses, outside of pharmaceutical applications. As a result, there was significant latitude given to the sponsors from regulatory agencies in how this was done. In recent years, with custom-produced RSMs often only a few steps from the API, oversight by regulatory agencies of sponsor proposal and justification of RSMs has become more stringent,4 and this has had the effect of moving these considerations to earlier points in the development cycle.
In particular, the European Medicines Agency (EMA) reflection paper on requirements for selection and justification of starting materials of chemical active substances issued in September 2014 has signaled a shift in formal expectations for the rigor and thoroughness with which syntheses of proposed RSMs need to be justified. The problem stated by the reflection paper relates to the perceived increase in risk to the quality of APIs from RSMs in new drug applications, due to three major factors:
The above three factors are compounded by insufficiency of information provided by some sponsors to justify thei
