There are significant interpretational differences between the European Medicines Agency (EMA) and US Food and Drug Administration (FDA)’s guidance on active pharmaceutical ingredient (API) starting materials. In this article, Dave Elder explores the ambiguity in guidance from both agencies and addresses why industry struggles to identify and justify starting materials that are likely to garner regulatory approval in both these territories.
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ONE OF the biggest challenges faced during API development is the “designation and justification” of the API registered starting materials (RSMs); ie, those stages in the API synthesis where current good manufacturing practice (cGMP) philosophies and practices are first introduced.1 Indeed, the FDA’s cautionary statement from the first guidance in still holds true: “What constitutes the ‘starting material’ may not always be obvious.”2
ICH Q73 defined an RSM as: “A raw material, intermediate or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement or produced in-house. API starting materials are normally of defined chemical properties and structure.” However, the guidance failed to provide insight into the “designation and justification” of the API RSM.1
Subsequently, ICH Q11 was introduced during to harmonise the criteria for selection and definitions of the RSMs.4 ICH Q11 covers the development and manufacture of APIs and provides guidance on these materials. Each branch of a linear or convergent API manufacturing process begins with one or more RSM. An RSM should be a material with well-characterised chemical structure and properties, as such, non-isolated intermediates produced via telescoped chemistry are usually not considered appropriate RSMs.
ICH Q11 was introduced during to harmonise the criteria for selection and definitions of the RSMs”
The definition of “significant structural fragment” in this guidance is intended to differentiate RSMs from “reagents, solvents or other raw materials”. However, in retrospect the terminology was often misconstrued and misinterpreted by industry to support the use of structurally complex RSMs; whereas the intent was the reverse and regulators wanted industry to designate significantly simpler molecules than the API to be used as RSMs.5,6 Commonly available materials used to create salts, for example methane sulfonic acid, esters (eg, ethanol) or other simple derivatives should be considered reagents.
The guidance indicates that the connectivity between overall risk and number of stages from the introduction of an RSM to the completion of the manufacturing procedure is a combination of two main factors. The first relates to the physical properties of the API; which are defined during the final crystallisation stage and any subsequent size reduction processes, eg, milling, micronising, etc. The second factor relates to the formation, fate and purge of impurities, particularly mutagenic impurities (MIs).7 Impurities that are introduced or generated in the early stages of the manufacturing process typically have significantly more opportunity for removal (or purging) during subsequent downstream purification operations, for example extraction, distillation, washing or isolation/crystallisation of isolated intermediates, than those impurities generated late in the manufacturing process. Consequently, late-forming impurities are more likely to be carried over into the final API.
The prime considerations for any analytical method are that it exhibits appropriate specificity and sensitivity”
Although ICH Q114 aimed to harmonise practises intended to identify appropriate RSMs, many companies still interpret this guidance differently. Equally worryingly, the “target of regulators is not aligned across regions and continuously reinterpreted”.1 In the EU, during the early years of the ICH Q11 guidance (-), “inconsistency of approaches” was seen from reviewers across the region. During this time period, two-thirds of all Certificate of Suitability (CEP) dossier applicants were requested to redefine their RSMs based on a failure to demonstrate “an appropriate control strategy”.1 The European Directorate for the Quality of Medicines (EDQM) issued additional guidance to their assessors during to try and harmonise the interpretation of the ICH Q11 guidance.4 This additional guidance, while mainly aligned with ICH Q11, argued that the number of steps between the RSM and the API can be related to the overall control strategy; therefore, there was an expectation that more supporting information was required for late-stage RSMs to demonstrate that the applicant has appropriate process understanding to demonstrate that the quality of the subsequent API can be adequately controlled. Thus propinquity (the number of GMP steps) was an important consideration within the EU region and remains so.1 Indeed, the EMA will often go beyond reduction in structural complexity and a robust impurity control strategy to request additional stages between the proposed RSM and the API.
The increased frequency of disagreements between regulatory agencies and applicants has led to both the EMA5 and FDA6 issuing question and answer (Q&A) supplements for ICH Q11. Both agencies indicated that “applicants should consider all the ICH Q11 general principles… rather than just choosing a few of the general principles”.5,6 They highlighted the importance of MI control when identifying potential RSMs. Non-MIs should be controlled to ICH Q3A(R2)8 identification thresholds; in contrast, MIs should be controlled to 30 percent of the toxicology-based threshold defined in ICHM7(R1).9 However, they did add the caveat that for drugs for advanced cancer indications (as per ICH S910) or APIs that are themselves mutagenic, ICH Q3A(R2) criteria8 would apply. Both agencies also stated that there should be “multiple steps” between a non-commercially available RSM and the API, unless the structural complexity of the proposed RSM is low, in which case it can be assessed in a similar fashion to a commercially available RSM.5,6
The key challenges still remain: suppliers are always trying to maximise yield, minimise the environmental impact of the process and reduce cost whilst still aligning to the designated quality specification; applicants will continually seek to ensure there is always more than one supplier capable of manufacturing the RSM to the designated quality criteria as part of business continuity strategies; and regulators will always seek to limit applicants choice of supplier and the ability of applicants to change RSM suppliers with the objective of ensuring consistent quality.11
The prime considerations for any analytical method are that it exhibits appropriate specificity and sensitivity, ie, the method is ‘fit for purpose’.12 The peak capacity (N), ie, the maximum number of peaks that can be resolved within the available retention space, is an important consideration for any RSM method.13 Both the EMA and FDA indicated that, “the inclusion of analytical methodologies in the specification of the proposed starting material that are designed to detect a wide range of possible impurities based on different physical and chemical separation and detection principles. Appropriate acceptance criteria for unspecified impurities should be included in the specification”.5,6 As such, high resolution high-performance liquid chromatography-mass spectrometry (HPLC-MS) is often utilised to identify and quantify unknown impurities found in the RSM.14
Therefore, in order to “future proof” the designated RSM method from the impact of potential upstream chemistry changes leading to new impurities, it is always prudent to develop a fully-validated analytical method (as per ICH Q2(R1)15) for the RSM, with sufficient specificity and resolving power to detect any new impurities that could arise from any future process changes. Method validation is recommended by both the EMA5 and FDA.6 Indeed, full validation of the methods is the typical practice within industry, ie, in 92 percent of all cases, with the remainder of methods qualified.16 The typical RSM method is ICH Q3A(R2) aligned8 from a sensitivity perspective, with most companies having a reporting threshold of 0.1 percent.16 Companies typically employ tighter analytical controls, including impurity fate and purge studies, for RSMs introduced late in the process, ie, closer to the API, due to “limited impurity purging opportunities”.16 Industry also has a strong focus on potential mutagenic impurity (PMI) control strategies. Most companies will perform a full mutagenic risk assessment on the upstream RSM processes and develop appropriately sensitive methodology to follow the downstream fate of any PMIs.16
Given the ambiguity facing companies when trying to “designate and justify” RSMs,1 some companies have tried to predict the risk and uncertainty using model-based approaches, typically focusing on RSM complexity, sourcing, process robustness and impurity controls.16 Wigman et al.17 focused on four main parameters: propinquity, impurity purging power, complexity and stability, where a high risk (>10) would indicate that the likelihood of regulatory approval was decreased. However, some commentators have observed that the weight given to impurity control parameters (and particularly MIs) does not accurately reflect the importance that this factor plays in gaining regulatory approvals. Although the purging factor was developed primarily to assess the removal of reactive, ie, MIs or PMIs from API syntheses,7 the basic physicochemical attributes that are important in purging are equally germane to normal impurities, ie, ICH Q3A(R2)8 designated impurities.
In the majority of cases, industry tries to mitigate this risk by initiating contingency strategies”
Reizman et al. performed a retrospective analysis of 34 small molecule RSMs where they had requested scientific advice from the FDA, 12 of which were also reviewed by the EMA; ie, a third were assessed by both agencies.18 They noted a reduction in regulatory endorsement over time. The team achieved 92 percent agreement over the time period -, but this dropped to 71 percent over the period -. However, they also noted that their figures were likely to be a “conservatively high approximation”.18 Using the methodology of Wigman et al.17 Reizman and colleagues demonstrated 91 percent success with scores of ≤12, whereas they only saw 58 percent approval for scores of ≥13. An important qualification to their approach was the increased focus on MIs or PMIs. They developed the model further and identified two important parameters linked with successful endorsement of RSMs: (i) complexity score and (ii) impurity risk score. The team reported that their success metrics were impressively high for both endorsement, ie, 100 percent or non-endorsement, ie, 87.5 percent when complexity and impurity risk scores were either met, or not met, respectively.18 However, the concern is that, elegant though the model is, it fails to take into account the cultural differences between the FDA (pragmatic, risk-based) and the EMA (more conservative in nature).These tools help development teams to “recognise risks early”, allowing them to appropriately focus valuable process development resources.17 Reizman et al. used this approach to assess four alternative routes to a very complex API, which was currently synthesised using 16 chemical transformations. They were able to significantly reduce the number of stages of chemistry down to seven, without meaningfully increasing the likelihood of regulatory push-back on their proposed RSMs.18 The team similarly used this risk-based model to decide between two alternative commercial synthetic routes for a development candidate, based on a comparative assessment of the likelihood that the designated RSMs would be approved.
Although both the EMA5 and FDA6 have issued supplementary guidance (in terms of Q&A) to ICH Q11 guidelines,4 industry still struggles to identify and justify RSMs that are likely to garner regulatory approval in both territories. In the majority of cases, industry tries to mitigate this risk by initiating contingency strategies whereby the stages immediately preceding the initially designated RSM, ie, n-1 or n-2, are also manufactured to GMP standards and if they fail to persuade the relevant agency of the merits of their initial RSM designation(s), then this alternative mitigation strategy can be initiated. However, this is an inefficient and expensive commercial strategy and it would be much better to be able to predict the likelihood of success.
Reizman et al.18 have claimed that their risk-based approach helps to answer the thorny question of what is “acceptable simplicity” with respect to RSMs. Both Reizman et al.18 and Wigman et al.17 have used risk-based modelling and identified that the molecular complexity of the proposed RSM is the most significant factor impacting on regulatory acceptance. The other related factor is control of impurities (particularly PMIs) in the RSM and the two factors are intrinsically linked as increased complexity may be indicative of more intricate chemistry that will require greater impurity control. Unfortunately, Reizman et al.’s risk-based strategy is probably too US-centric, ie, only about one third of the small molecules assessed were evaluated by both the FDA and EMA,18 and thus fails to adequately model cultural differences. As such, the two agencies still do not always agree on the choice of designated RSM.
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 Chiron1 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.
For more information, please visit Registered Starting Material (RSM) Pharma Service.
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 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 their selection of RSMs in their applications, particularly a lack of assessment of criticality of the synthetic steps for the RSMs, relative to those of the GMP API manufacturing process. Criticality is determined by the potential to impact the quality of the final API. What is required is a data-based justification of the distinction between critical steps that could potentially affect the quality of the final API, and non-GMP steps used to produce a proposed RSM, which are considered non-critical, because they are sufficiently controlled and distant (as regards number of transformations and purifications) from the API, and thereby do not possess significant potential to affect final API quality.
The current regulatory position on starting materials for API manu-facturing processes does not mean that complexity and RSMs are mutually exclusive. But it does mean that there are explicit expectations that, if complex starting materials are to be proposed, requiring multiple steps for their production, then it must be established by the sponsor that the demarcation between critical (i.e., GMP) and non-critical (i.e., non-GMP) steps can be adequately justified, from a scientific point of view.
The practical effect of current regulatory thinking on RSMs is the need for planning and execution that goes well beyond finding a supplier and placing an order for material. As an API process with complex starting materials is scaled up, sponsors need suppliers with the capacity to produce the foreseeable quantities of RSMs, and the skill to demonstrate that the quality of these materials is adequate, and they meet the criteria for being designated as distinct from GMP intermediates in the API manufacturing process. This adds an aspect to non-GMP material sourcing activities that has analogy to outsourcing of chemical development and manufacturing of APIs. Prior to ordering of bulk materials or executing a supply agreement, it needs to be established that each complex RSM is produced with at least a rudimentary understanding of formation, fate and purge of impurities, and of impurity profiles and carryover. This entails evaluation and optimization of synthetic routes, scale up, and analytical method development and validation. In addition to making possible the ability to consistently produce materials with the necessary quality, the rudimentary understanding and control of production of non-regulated materials also provides data that will be submitted in the NDA and is the basis for more in depth justification of RSMs, should the need arise due to push back by regulatory agencies.
For the purposes of this article, there are five elements of a successful material sourcing effort that would lead to a supply chain that enables late stage development and commercial launch:
A comparison of these elements during early and later stage development is provided in Table 1.
Sourcing of raw materials and RSMs has always been more demanding than assumed by the uninitiated. The challenge of procurement and establishment of a supply chain has been compounded in recent years by:
The result of existing and evolving challenges of sourcing and procurement of non-GMP materials for API manufacturing is that more work is required by suppliers, CDMOs and sponsors. This work consists of sufficient understanding of non-GMP production processes and sufficient characterization of non-GMP materials to justify their designation as being distinct from the GMP API manufacturing process. It is ultimately incumbent on the sponsor to ensure that adequate preparatory work is done by their suppliers to support the strategies they have chosen for proposal of RSMs in their regulatory submissions.
SGL thanks Sue Wollowitz (Wollowitz and Associates), Danny Levin (Norac Pharma) and Greg Reid (ChemDev Solutions) for helpful discussions and suggestions on content in this article.
1a) S Hanessian, Total Synthesis of Natural Products: The ‘Chiron’ Ap-proach, Pergamon Press, Elmsford, NY, , and subsequent editions
b) S Hanessian, Design and Implementation of Tactically Novel Strategies for Stereochemical Control Using the Chiron Approach, Aldrichimica Acta, , 22,3
2a) PL Browser, et. al., The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase, Tetrahedron Lett., , 33,
b) BD Roth,The Discovery and Development of Atorvastatin, A Potent Novel Hypolipidemic Agent, Prog. Med. Chem., , 40
3) O. Mendez-Lucio, J.L. Medina-Franco, The many roles of molecular complexity in drug discovery, Drug Discovery Today, August,
4) European Medicines Agency, Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substances, September,
5) ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities), Step 3, September,
If you want to learn more, please visit our website Key Starting Material (KSM) Pharma Service.