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The authors discuss expectations of regulators on the selection of drug substance regulatory starting materials (RSM) and the justification of their designation in the pharmaceutical supply chain, the scope of the RSMs' presentation required in regulatory filings, and how to mitigate and prepare for "push backs" in the event of a major objection to the sponsor's RSM designation.
Pharmaceutical businesses are rapidly becoming global, with approximately half of the industry’s growth in emerging markets (1). A pharmaceutical company’s objective is, therefore, to build a sustainable and cost-efficient supply chain that meets global regulatory requirements. The selection of drug substance regulatory starting materials (RSMs) and justification of their designation in the pharmaceutical supply chain has become an industry-wide focus as a measure of mitigating regulatory risks and preventing unexpected rises in cost when transitioning from clinical to commercial supply chain. This article discusses the expectations of regulatory agencies, the scope of the starting materials’ presentation in the filings, and the risk and readiness for a “push back” (i.e., extension of the GMP portion of the API process upstream) in the event of an agency’s major objection to the sponsor’s RSM designation.
The pharmaceutical supply chain can be divided into four segments, as shown in Figure 1, from starting materials (i.e., the RSM), to the drug substance, the formulated drug, and ultimately, the packaged and labeled finished product.
Commonly, the emphasis during pharmaceutical development is on the portion downstream of the RSMs. The part of the supply chain upstream of the starting materials does not receive the same level of attention--less time is allocated for development of process and specifications, which can, therefore, present a regulatory risk and potential for an unexpected rise in cost when transitioning from clinical to commercial supply chain. One particular risk factor is the development of RSMs, or the lack thereof.
Typically, at the time of marketing application submission, the sponsor would have validated the production processes of the drug substance, formulated drug, and finished product. This validation involves successfully conducting at least three consecutive commercial-scale batches for each segment of the supply chain and releasing each batch against pre-defined acceptance criteria (i.e., commercial specifications). If, at this advanced stage of development, the proposed RSM designation is not accepted by a regulatory agency, then the entire supply chain that stems from this RSM is essentially invalidated. The sponsor will likely experience lengthy delays to address RSM designation issues before the marketing application is approved.
One of the most underrated risks is for sponsors to assume that RSM designations used throughout clinical trial applications will be accepted in the marketing application without justification. An industry-wide disagreement on terminology--resulting in a plethora of names related to starting materials, such as raw materials, key raws, critical raw materials, key raw materials, critical raws--further confuses the role of starting materials in the supply chain. To clarify, an API RSM could be a raw material, a manufacturing process intermediate, or even an API. The material could be an article of commerce that is available from multiple sources, typically in large quantities and often sourced under commercial agreement. The material could be produced in-house and manufactured using custom-designed process. The RSM should be used in the production of API and it should represent a significant structural fragment of the API’s chemical structure. The sponsor of the clinical or marketing application should designate the RSMs and document rationale for their selection (2). The RSM’s designation marks the point at which GMP production (described in Section 3.2.S.2.2 of CMC module 3) (3) of the API begins, as shown in Figure 2.
In 2014, the European Medicines Agency (EMA) published a reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substances (4). EMA felt that the current guidelines lacked detailed specifics, thus leading to a variety of interpretations. Proposed starting materials specifications were often insufficient. EMA even encountered instances where starting materials were not discussed in the application or processes by which the starting materials prepared were not part of the overall criticality appraisal. More recently, the International Council for Harmonization (ICH) Q11 guidelines implementation group published two documents of questions and answers to clarify the ambiguity and provide additional examples for the selection and justification of starting materials (5). These documents are extensions of the original Q11 guidelines (6).
As a guidance to industry, EMA included seven examples of critical manufacturing steps that should be performed under GMP:
While the last example in this list pertains to the final isolation and purification step of drug substance, which should be performed under GMP setting, the first six examples are quite broad and could apply to the non-GMP portion of the drug substance process where RSMs are produced. For instance, “careful control of parameters” is expected in any manufacturing process. Furthermore, the definition of “complex chemical transformation” is somewhat subjective because any chemical reaction will have its own intricacies. Thus, the probability of EMA’s push back of a proposed RSM designation is quite high.
Figure 3 shows the API portion of the supply chain and frequently encountered reasons for regulatory agencies to reject proposed RSM designations. It is important to note that the whole supply chain is impacted.
The most common reason for rejection of a RSM designation is the insufficient number of steps (#1 in Figure 3) in the API manufacturing process (CMC Section 3.2.S.2.2) (3). Lack of in-process controls or inadequate acceptance criteria for formally released GMP intermediates (CMC Section 3.2.S.2.4) (3) represent inadequate quality control and is another common reason (#2 in Figure 3) for the rejection of a RSM designation.
The insufficient presentation of synthesis and controls for RSMs (CMC Section 3.2.S.2.3) (3) could also be the reason (#3 in Figure 3) for rejection of a RSM designation. Regulatory agencies expect API-like acceptance criteria for RSMs, thus insufficient scope of specifications is another reason (#4 in Figure 3) for major objection to a RSM designation. Lastly, the reviewer may determine that there was insufficient appraisal of criticality in the full synthetic route (i.e., from raw material or building block to API), leading to rejection of the RSM designation (#5 in Figure 3) (7, 8).
Successful defense of RSM designation is not guaranteed; therefore, the sponsor should preemptively work on three areas to prepare for possible push back: chemical synthesis, analytical controls, and manufacturing.
Chemical synthesis plays an important role because the extent of push back will depend on the synthetic route. As part of the synthetic route scouting strategy early on in process development, the sponsor should identify an earlier intermediate as a back-up RSM. The push back will result in an increased number of GMP steps upstream, requiring in-process analytical controls and adequate scope of acceptance criteria for the back-up RSM.
The rejection of RSM designation can lead to two scenarios. If the RSM was produced at a non-GMP plant, the sponsor would have to transfer production to a GMP plant, which can be stressful, especially if the sponsor learns about the major objection to the RSM designation in a pre-new drug application meeting or during marketing application review. The sponsor would be in a more favorable situation if the rejected RSM was produced at a GMP plant. They would then have an opportunity to retroactively validate RSM process at the same manufacturing site, in the same equipment, and on the same scale, and retain all commercial inventory, including all drug substance and formulated drug batches already derived from this RSM.
The following case study is presented to illustrate use of a back-up RSM. A schematic presentation of validated commercial process for the preparation of API is shown in Figure 4.
The proposed RSMs 1 and 2 were produced using a custom designed manufacturing process (i.e., neither of the RSMs was an article of commerce). RSMs 1 and 2 constituted 38% and 31% of the API’s core atoms, respectively. The core atoms are defined as all API structure atoms in the required connectivity and spatial orientation, excluding hydrogen atoms. Hence, RSMs 1 and 2 could be viewed as custom designed building blocks of similar complexity. Yet because RSM 1 was an additional step “away” from the API formation, the two RSMs had different propinquity to the API (see Figure 4). As a result, the API GMP process lacked symmetry in its synthetic hierarchy.
FDA accepted the proposed RSM 1 designation, but rejected the proposed RSM 2 designation, stating that the latter is used in the API making step, and thus is considered an advanced process intermediate and should be produced under GMP. The sponsor had anticipated a push back and had identified a precursor to RSM 2 as a potential starting material. As a risk mitigation measure, the sponsor developed appropriate GMP-level analytical controls and acceptance criteria as back-up preparation for RSM 2. Furthermore, the sponsor had produced all RSM 2 batches in a GMP plant, creating an opportunity to retroactively validate RSM 2 process in the same equipment, on the same scale, and at the same manufacturing site, hence, enabling retention of all downstream commercial launch inventory originating from RSM 2 to the API and formulated drug to the finished packaged and labeled product.
In the updated API process, RSMs 1 and 2 constituted 38% and 20% of API’s core atoms, respectively, and could be viewed to have similar complexity, custom-designed building blocks with identical propinquity to the API (see Figure 5). As a result, the API GMP process had symmetrical synthetic hierarchy.
In another scenario, there is a possibility that FDA could accept the proposed RSM designation, while EMA rejects that same designation. The sponsor could accept the major objection to the RSM designation and extend the GMP portion of the API process upstream. In this scenario, the sponsor would be forced into a complex, two-stream supply chain, one for the US market and another for the EU market. Alternatively, the sponsor could overcome objection by presenting a comprehensive assessment of the RSM’s impact on the CQAs of either API or formulated drug.
CQAs are justified by an impurities assessment. There are two types of impurities:
A laboratory-based R&D study, where high levels of process materials and impurities are purposefully introduced in the process (i.e., “spiking”), can assess an impurity’s fate by measuring their residual levels after one or more operations. Data from such studies can be used to calculate the estimated maximum level of any material in the API. Laboratory results are typically confirmed by analyzing manufactured batches of the API and corresponding process intermediates.
The fate analysis of a RSM in the process and assessment of its impact to the API’s CQAs is presented in the example in Figure 6.
The API manufacturing process consisted of four distinct manufacturing steps. A high quantity of RSM was spiked in each step and the amount that remained upon completion of the step was measured. Individual purging factors (see Figure 6) were calculated by dividing spiked quantities with the amount that remained. Iterative multiplication of all individual factors yielded a cumulative purging factor of 2.32 x 1013. To help reviewers appreciate how effectively the RSM is purged in the process, the maximum estimated level for this material in the API was calculated. The actual kilogram quantities of the RSM (100 kg) input and corresponding API (61.32 kg) output were used. A conservative assumption was made that only approximately 80% of the RSM will convert to the API, leaving approximately 20% of unreacted material, corresponding to 20.14 kg. Division of this residual amount by the cumulative purging factor (2.32 x 1013) yielded the maximum estimated level, 8.68 x 10-7 mg, in the API. This quantity was converted to a more common presentation of concentration for an ultra-low-level impurity: parts per million (ppm = mg/kg). Division of the maximum estimated level (8.68 x 10-7 mg) by the API batch output (61.32 kg) yielded 1.42 x 10-8 ppm.
The purging study findings were confirmed by analysis of eight API batches with a method that could detect residual RSM at a level as low as 0.05 ppm. In summary, the results from analysis of laboratory-scale purging studies and manufactured batches conclusively demonstrated that the proposed RSM was purged in the process and had no impact on the API’s CQAs. The study results enabled the sponsor to exclude the analysis for this RSM in the API acceptance criteria. Agencies worldwide accepted the justification for this RSM.
The lesson learned is that regulatory agencies tend not to challenge RSM designations in clinical trial applications because they do not want to impede clinical development. Thus, unless the GMP portion of the API process is very short (for instance, where there are no chemical bond-making reactions, but just purification steps), the agency is not likely to reject the proposed RSM designation in the clinical trial application. Expectations are, however, very different as sponsors transition from clinical to commercial supply chain. The sponsor should, therefore, be prepared to provide a rationale and evidence in support of the RSM designation.
In conclusion, the CMC sections in regulatory filings should first demonstrate that the sponsor understands the science and technology used to produce the drug and can provide quality data to support statements in the application. Second, the sponsor has to show that adequate controls are in place throughout the entire process and that at no point in the supply chain are patients put at risk.
1. P. Berk et al., “Rethinking the Pharma Supply Chain: New Models for a New Era,” Boston Consulting Group (May 2013).
2. FDA, Guidance for Industry, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, (Silver Spring, MD, September 2016).
3. FDA, Guidance for Industry: M4Q, the CTD, Quality, U.S. Department of Health and Human Services Food and Drug Administration (Center for Drug Evaluation and Research, 2001).
4. EMA, Reflection Paper on the Requirements for Selection and Justification of Starting Materials for the Manufacture of Chemical Active Substances (London, September 2014).
5. ICH, Q11 Implementation Working Group “Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities), Questions and Answers (regarding the selection and justification of starting materials) (October 2016).
6. FDA, Guidance for Industry, Q11 Development and Manufacturing of Drug Substances (Silver Spring, MD, November 2012).
7. M. Faul et al., Organic Process Research & Development, 18 (5) 594-600 (2014).
8. M. Faul et al., Organic Process Research & Development, 18 (5) 587-593 (2014).
Supplement: Solid Dosage Drug Development and Manufacturing
Pages: s12–s15, s22
When referring to this article, please cite it as V. Jurkauskas and M. Chen, “Transition From Clinical to Commercial Supply Chain-Regulatory Starting Materials," Pharmaceutical Technology Solid Dosage Drug Development and Manufacturing Supplement (March 2018).
Valdas Jurkauskas, PhD, is vice-president and head of Chemistry, Manufacturing and Controls (CMC) at Akebia Therapeutics and Minzhang Chen, PhD, is CEO of STA Pharmaceutical, a WuXi AppTec company.