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Regulatory Landscape for Raw Materials: CMC Considerations

A reliable supply of raw materials is critical to maintain a robust supply chain to serve patients globally. With shortages, regulatory complexity is compounded due to differences in submission and data requirements from various regulatory agencies. Therefore, there is an increasing need to implement a harmonized regulatory infrastructure that is both flexible and predictable to provide more agility without product delays.

The pharmaceutical manufacturing supply chain starts with the raw materials, which are needed to ensure drug availability for patients. With ever-increasing supply chain challenges, raw material shortages have become a point of discussion. In this article, the term “raw material” refers to a material used in the manufacturing and packaging of a drug substance (DS) or a drug product (DP).

For a synthetic drug, the DS is chemically synthesized in multiple ordered steps from the starting materials using a range of chemicals. This is followed by DP manufacturing, where the DS is formulated with excipients. Finally, the DP is packaged in a suitable container to ensure continued quality.

For a biologic drug, the DS is manufactured upstream in cell culture media followed by downstream purification, which requires chemicals, filters, and resins. The DP formulation and filling processes use excipients, filters, vials, and syringes. In addition, single-use technologies have been increasingly employed throughout manufacturing because of the advantages they offer, including reductions in cost, manufacturing footprint, contamination risk, and processing times (Figure 1).

Although they have been historically overlooked as a key element, raw materials are a critical component at every stage of the drug manufacturing processes. Recent US FDA data show that the lack of raw material availability contributes to 27% of drug shortages (see Appendix ).

There is undoubtedly a need for improved supply chain flexibility to address shortages. In cases where raw materials are single sourced, supplier manufacturing problems or product facility closures could result in manufacturing delays and/or stoppages. Similarly, an increased demand forecast could lead to a raw material shortage. One possible mitigation strategy is to build sufficient inventory to ensure continuous product supply. However, large inventories increase the cost of production and the risk of scrapping raw material lots that exceed their shelf life before they can be used.

Diversification and redundancy of raw material supplies by qualification of new raw material sources ensure a geographic footprint of manufacturers providing flexibility and supply resiliency. However, use of alternative raw materials may require approvals from multiple health authorities. Waiting for approvals can significantly delay implementing a change, and the timelines vary between regions, adding further complexity to supply management. For example, implementation of an alternative vial would typically require 4 to 6 months for approval in the EU and US but more than 18 months in other countries. In some cases, to meet the forecast, DP manufacturers manufacture at risk while waiting for approvals for second-source supply.

During the pandemic, the pharmaceutical industry faced challenges in the production of COVID-19 therapeutics and vaccines to meet global demand, as well as mitigation of drug shortages for non-COVID-19-related products, without compromising product quality or patient safety. Lessons learned during the pandemic could be leveraged for future procedures and regulatory submission requirements. This article highlights the regulatory expectations of raw materials, the challenges of postapproval changes. and the impact on supply resiliency. Case studies are presented that demonstrate the importance of defining the raw material attributes that are critical to product quality and how this could support increased postapproval flexibility (including the use of ICH Q12 principles).

Regulatory Expectations

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines contain information regarding regulatory requirements for raw materials. There should be a system for evaluating critical suppliers and a specification agreed upon with the supplier and approved by quality. Upon receipt, incoming raw materials should be tested against specifications that include critical attributes, analytical procedures, and acceptance criteria. Additional requirements are described in ICH Q7. 1 The Common Technical Document (CTD) for the Registration of Pharmaceuticals For Human Use: Quality—M4Q guidance covers the minimum requirements for submission of raw materials; however, certain regions have additional requirements. 2

Raw materials used in the manufacture of the DS should be listed in CTD section 3.2.S.2.3, Control of Materials. The name of each material, where it is used in the process, and information on the quality and control should be provided. The material manufacturer is not required for all cases but is often requested by some health authorities for critical materials such as filters. A compendial or multicompendial grade should be listed where applicable; for all noncompendial materials, specifications should be included. Information demonstrating that the quality of the raw materials meets standards appropriate for their intended use should be provided. For example, biologically sourced raw materials may require careful evaluation to establish the presence or absence of deleterious endogenous or adventitious agents.

Per ICH Q11, the potential for material attributes that impact DS critical quality attributes should be identified. 3   Raw materials used near the end of the manufacturing process have greater potential to introduce impurities into the DS than raw materials used upstream; therefore, tighter control of quality should be evaluated. A risk assessment to define the control strategy of raw materials can include an assessment of manufacturing process capability, attribute detectability, and severity of impact. For example, the ability of the DS manufacturing process to remove an impurity or limitations in detectability (e.g., viral safety) should be considered. The risk related to impurities is typically controlled either by raw material specifications or robust purification steps later in the synthesis.

An excipient is formulated with the active pharmaceutical ingredient and is typically not chemically or physically altered prior to use; therefore, all components are likely present in the DP. The intended end use of the excipient should be considered when determining the appropriate regulatory and GMP requirements for the excipient and its manufacturing facility. The quality of the excipients and the container/closure systems should meet pharmacopeial standards, where available and appropriate. Otherwise, suitable acceptance criteria should be established. The use of a noncompendial mate-rial may be considered acceptable with strong scientific justification. For a multicompendial excipient that may be marketed for global use, the DP manufacturer should demonstrate conformance of the excipient to the monograph requirements found in specified compendia.

A description of the DP and its composition is provided in CTD section 3.2.P.1, Description and Composition of the Drug Product. More details regarding the quality of excipients are provided in CTD section 3.2.P.4, Control of Excipients. For the European Medicines Agency (EMA), functional related attributes should also be considered, and it may be necessary to include additional tests and acceptance criteria, depending on the intended use of the excipient (see Appendix). For excipients of human or animal origin, information should be provided regarding adventitious agents in CTD section 3.2.A.2, Adventitious Agents Safety Evaluation. For novel excipients (i.e., excipients used for the first time in a DP or by a new route of administration), full details of manufacture, characterization, and controls, with cross-references to supporting safety data, should be provided according to the DS format in CTD section 3.2.A.3, Novel Excipients. 4

Additionally, excipients and primary container components may be subject to regional regulatory requirements. For example, the National Medical Products Administration (NMPA) requires registration of high-risk excipients and primary container components using a master file that is referenced by the DP sponsor.

Postapproval Change Management

When a drug manufacturer intends to introduce a change, the potential impact on the process and product quality must be assessed.  1 , 5 , 6 A change is classified as major, moderate, or minor depending on its nature and impact. A major change is one that requires submission and approval by a health authority prior to distribution of post-change material. A moderate change is one that typically requires submission to a health authority but may not require approval prior to distribution of post-change material. A minor change is reported to the health authority after implementation and does not require a submission prior to product distribution. The classification helps determine the data required to demonstrate comparability (pre- and post-change) and confirm no adverse impact on product quality.

A formal change control system under the company’s pharmaceutical quality system (PQS) is required to evaluate all raw material changes, with established procedures for identification, documentation, review, and approval. A quality risk management system provides assurance to the health authorities that the applicant can ensure process consistency and product quality while continuously monitoring, verifying, and mitigating identified risks. After approval and implementation of the change, there should be an evaluation of the first batches produced post-change.

Health authorities have divergent classifications for changes in terms of risk to product quality and documentation/data requirements. Table 1 shows the classifications assigned (based on published guidance) to three distinct types of raw material changes for biologics (B) and synthetics (S) across six regulators (FDA, EMA, Health Canada, Therapeutic Goods Administration [TGA], Pharmaceuticals and Medical Devices Agency [PMDA], and NMPA) and the World Health Organization (WHO):

• Relaxing acceptance criteria or deleting a test for a raw material. Although this change is not explicitly described in the TGA guidance, a change category requires that any change to raw material specifications be submitted as a Category 3 application requiring prior approval. The PMDA classifies such a change as a partial change application requiring prior approval if the acceptance criteria or test is registered in M1.2. It is considered a moderate change by the FDA (CBE30) and NMPA. In the EMA, Health Canada, and WHO, such a change would be considered minor, provided the deleted parameter was redundant or obsolete. In the case of deletion of an attribute specification that may have a significant effect on product quality, the EMA classifies it as a major type II variation requiring approval before implementation. Health Canada classifies this type of change as level 2 for biologics, which requires approval prior to implementation, or level 3, which requires immediate notification for synthetics, which allows implementation prior to reporting to the agency.
• Relaxing acceptance criteria for compendial excipients to comply with changes to compendia. This change ranges from a moderate change (CBE-30) by the FDA to a minor change not requiring prior approval by the WHO.
• Change to manufacturer or supplier of excipients or raw materials. Classifications vary widely by region depending on the raw material involved and route of administration. Consistently a change in the source of an excipient to one that carries a risk for transmissible spongiform encephalopathy (TSE) is considered a major change. This classification can be reduced to a minor change according to Health Canada and the WHO if supported by a valid TSE Certificate of Suitability (CEP).

Some health authorities do not include all three changes described in their postapproval guidance; for example, the FDA provides guidance for synthetics, but not biologics. Changes not covered need case-by-case management. In addition, submission categories vary between health authorities, making it very challenging to manage the submissions for a raw material change globally. In some guidance documents, changes require associated conditions to be met and documentation/data to be provided in a specified submission category. If a condition cannot be met, then the submission category may be upgraded to a higher category.

Additional examples of postapproval changes for FDA, EMA, Health Canada, TGA, PMDA, NMPA, and WHO are described in detail in the Appendix. The categories in the Appendix assume all conditions are met, required documentation is available for submission, and they are aligned with health agency expectations. The absence of any of the listed documentation should be scientifically justified.

Due to global regulatory requirements, many postapproval changes cannot be implemented until the health authorities have reviewed and approved the change, which can take considerable time. During technical review, additional time and resources may be required to address requests for information from agencies. Because of the lack of harmonization across regions, it is difficult to predict the time that it will take for approval by each health authority. The estimated global approval times for major changes vary considerably—from less than 6 months in some major markets to greater than 18 months in others—resulting in periods of several years before full global implementation of a change can occur. 7

This results in a lack of supply chain agility to implement changes when faced with immediate supply shortages. Managing a strategy to accommodate varying global approval timelines is a challenge. Similarly, there are regulatory hurdles to implementing raw material improvements postapproval to proactively improve raw material reliability (e.g., innovative technologies and raw material specification changes enabled through scientific understanding of raw material attributes and their impact on product quality).

Addressing Challenges for Postapproval Changes

Multiple asynchronous reviews of the same information with varying approval timelines across global health authorities result in a more complex supply chain, without improving safety, quality, or efficacy. Currently, a streamlined data package for fast global implementation of a change is unlikely to be accepted due to differing regional data requirements.

The implementation of a global regulatory infrastructure that is harmonized, flexible, and predictable would provide drug manufacturers the agility to expedite raw material supplier qualifications to be better equipped to face raw material challenges while maintaining product quality and supply to patients. The identification of the critical raw material attributes and appropriate setting of specifications is a crucial first step.

Attribute-focused Approach to Developing Material Specifications

A robust raw material control strategy can be achieved with an attribute-focused approach to identify critical material attributes. This approach facilitates the development of science-based raw material specifications and phase-appropriate decisions across the life cycle of a material. It is important to engage in material attribute understanding early in commercial process development when raw materials are being selected. A well-defined material target profile can be used to conduct a material attribute assessment, and based on that profile, a control assessment can be completed. This can be executed in several stages:

• Define the role of the raw material. Determine how it will be used in the process and what functions it needs to perform its intended use.
• Assess the attributes that the raw material requires to perform the desired function and identify the critical material attributes that impact the process performance and product quality.
• Define the desired target and allowable range for each material attribute based on the knowledge and understanding of the process tolerance.
• Build a control strategy to define the material attribute controls required, from the raw material manufacturing to the receipt and testing at the drug manufacturer.

The attribute-focused approach enables identifying critical material attributes and developing science-based specifications, which are established based on the intended use of the material and the process requirements; for example, avoiding the use of compendial-grade specifications when noncompendial material will suffice or avoiding the use of technical-grade raw materials when more control is required. In addition, having clear user requirements facilitates more informed supplier selection and can support the identification of established conditions (ECs) for raw materials in regulatory filings.

Once the critical material attributes have been established, specifications defined, and suppliers onboarded through the pharmaceutical manufacturer's quality management system, raw material performance can be monitored using attribute data analytics. This enables the predictive assessment of raw material variation, identification of the source of variability, and implementation of proactive mitigations strategies to prevent failures. 7

Regulatory submissions preferably include only the critical material attributes. For postapproval raw material changes, the material target attribute profile can facilitate a strong scientific justification based on the knowledge and understanding of the process and the critical material attributes. Some examples of noncritical details include registering trade names, listing part/catalog numbers, and information included in the supplier certificate of analysis that is not relevant to ensure product quality. Registration of these details may limit options of second sourcing, especially in the worst-case scenario when a supplier discontinues a material.

Utilization of Regulatory Tools in ICH Q12

ICH Q12 helps streamline postapproval change implementation by establishing harmonized change categorization, including the identification of the portions of an application requiring a submission if changed postapproval. 8 The level of submission category for a change is determined by the level of risk associated with making the change. ICH Q12 provides a framework to enable the modification of some submission categories for changes based on scientific understanding and the level of risk associated with the change.

It includes regulatory tools such as ECs, postapproval change management protocols, and the product life-cycle management document to enhance the manufacturer’s ability to manage chemistry, manufacturing, and controls (CMC) changes effectively under the company’s PQS. 9 Adoption of the principles of ICH Q12 could result in fewer postapproval submissions and the ability to implement more changes prior to notification.

According to ICH Q12, “ECs are legally binding information” within an application considered necessary to assure product quality. Any change to an EC requires a submission to the health authority. Identifying ECs enables a risk-based framework, allowing the use of scientific knowledge and risk mitigation to justify the submission category of a change.

The number of ECs for a raw material, how narrowly they are defined, and the associated submission category depend on several factors:

• Characterization of the product and detection limits of product quality attributes: Development approach adopted, which dictates the level of process and product quality understanding.
• Performance based: High level of scientific understanding of the material attributes that have an impact on process performance and product quality. Data-driven enhanced control strategy primarily focused on the control of process outputs and an improved understanding of the risk.
• Parameter based: Limited understanding of relationship between inputs and resulting product quality attributes. A larger number of material attributes are considered potentially critical.
• The potential risk to product quality when implementing changes to the EC: Risk assessment activities should follow approaches described in ICH Q9 and must consider the overall control strategy and any possible concurrent changes. 10

In general, enhanced knowledge and understanding of the relationship between raw material attributes, process parameters, and product quality enable the identification of parameters critical to product quality, leading to a reduction in the number of ECs. For example, employing a performance-based approach to development can demonstrate that a material attribute that was initially considered potentially critical (in a parameter-based approach) is not actually critical and has no impact on product quality.

A decision tree (Figure 2) was modified from ICH Q12 that illustrates the stepwise approach to identifying ECs for raw material attributes and the as-sociated submission categories (in the context of process parameters). For parameters that are not ECs, postapproval changes are not reported.

Overall, agreement with regulators on the ECs and associated submission categories can reduce the number of postapproval submissions to only the changes most critical to ensuring product quality. This provides more flexibility to implement changes and thus the ability to react more quickly to supply chain challenges. In the long term, a collaboration between regulators and industry stakeholders to develop and implement harmonized guidelines for raw materials would help address flexibility challenges, prevent delays in implementing process improvements, and ensure that both regulator and industry resources are devoted to the most critical issues.

• 1 a b International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. “ICH Harmonised Tripartite Guideline Q7: Good Manufacturing Practice for Active Pharmaceutical Ingredients.” Published November 2000. https://database.ich.org/sites/default/files/Q7%20Guideline.pdf
• 2 International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. “ICH Harmonised Tripartite Guideline M4Q(R1): The Common Technical Document for the Registration of Pharmaceuticals For Human Use: Quality–M4Q(R1).” Published 2002. https://database.ich.org/sites/default/files/M4Q_R1_Guideline.pdf
• 3 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. “ICH Harmonised Tripartite Guideline Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities).” Published May 2012. https://database.ich.org/sites/default/files/Q11%20Guideline.pdf
• 4 The International Pharmaceutical Excipients Council (IPEC). “Qualification of Excipients for Use in Pharmaceuticals.” Published 2008. https://ipecamericas.org/sites/default/files/ExcipientQualificationGuide.pdf
• 5 US Food and Drug Administration. “Guidance for Industry. Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products.” 2021. https://www.fda.gov/media/109615/download
• 6 US Food and Drug Administration. “Changes to an Approved NDA or ANDA.” 2004. https://www.fda.gov/files/drugs/published/Changes-to-an-Approved-NDA-or-ANDA.pdf
• 7 a b Burke, S., M. Hammond, and T. Wang. Raw Material Control Strategy. BioProcess International. October 2020. https://bioprocessintl.com/wp-content/uploads/2020/10/18-10-eBook-RawMaterials.pdf
• 8 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. “ICH Harmonised Tripartite Guideline Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management.” Published November 2019. https://database.ich.org/sites/default/files/Q12_Guideline_Step4_2019_1119.pdf
• 9 Lo Surdo, J. L., N. S. Cauchon, C. Langer, S. Ramdas, and E. Zavialov. “A Vision for ICH Q12: Current Experience, Future Perspectives.” Pharmaceutical Engineering 41, no. 5 (September/October 2021). https://ispe.org/pharmaceutical-engineering/september-october-2021/vision-ich-q12-current-experience-future
• 10 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. “ICH Harmonised Tripartite Guideline Q9: Quality Risk Management.” Published November 2005. https://database.ich.org/sites/default/files/Q9%20Guideline.pdf

Case Studies

This section describes case studies of postapproval changes to raw materials and the regulatory challenges. The examples highlight the value of well-characterized raw materials and the importance of only including critical material attributes in regulatory submissions. They are representative of issues manufacturers face when attempting to address supplier and quality aspects of raw materials.

Case Study 1: Polypropylene Glycol—Removal of Noncritical Attribute from Specification

The original molecular weight (MW) specification for polypropylene glycol 2000 (PPG) of 1800–2200 was based on the Food Chemical Codex monograph (90%–110% of label) and not based on a scientific understanding of the process/product requirements. By employing an attribute-focused approach, an assessment of MW was performed based on a review of literature, process understanding, process performance, and historical PPG release testing data. The analysis showed no correlation between antifoam performance and MW, and a wider MW range of 1200–3000 was deemed acceptable for use in the processes. Based on the process performance and robustness of the raw material supply quality, it was concluded that the MW attribute is not critical and can be removed from the PPG specification to reduce the business risk without impacting the quality of the DS.

At the time of assessment, removal of the MW specification could be reported without requiring approval in the US and Canada and required prior approval in four regions: Australia (3 months for approval), EU (up to 6 months for approval), China (up to 10 months for approval), and Israel (required EU approval first, up to 1 year for approval). The same rationale for the change was submitted globally.

Case Study 2: Betaine—Widening of Raw Material Specification Criterion

Betaine has no compendial monograph, and the original specification included water with an acceptance criterion of ≤ 2.0%. It is a hygroscopic material that transitions to the monohydrate form on absorption of water. This results in water uptake during standard material handling and a risk of failing in-coming quality control testing for the water content attribute.

A technical assessment was performed, demonstrating that increased water content is not expected to have any impact on process or product quality. Based on the chemical properties of betaine and its functional use in the process, a specification of ≤ 3% for water content was considered appropriate. In addition to specification changes, several mitigations were put in place regarding material handling.

At the time of assessment, widening of the water specification was reportable as a notification in Australia, China, and Canada. For many markets, this change did not require reporting to the health authority. This is an example of a change involving a well-characterized raw material resulting in shorter timelines to implementation.

Case Study 3: Sodium Deoxycholate—Removal of Noncritical Attribute from Specification

Sodium deoxycholate is a noncompendial white crystalline powder manufactured by neutralizing deoxycholic acid with sodium hydroxide (NaOH). The amount of NaOH added during the raw material manufacturing determines the conversion to the more soluble sodium salt and the pH in solution. The pH specification for a 10% solution was set at 8.2–10.0 to avoid precipitation at values below 8.2 caused by residual deoxycholic acid.

It was recognized that this specification for pH was not aligned with the raw material supplier specification of 7.0–9.5. Historically, the pH (average of 8.4) comfortably met the supplier specification but was close to the in-house specification 8.2–10.0. This was a supply risk due to the high probability of failing pH testing upon receipt.

A technical evaluation was performed to evaluate the impact of the pH attribute on the process performance and product quality. Because a titration step was added to the preparation of the sodium deoxycholate solution during DS manufacturing, it was recommended to remove pH from the sodium deoxycholate specification. This change improves the robustness of sodium deoxycholate supply with no impact on the DS manufacturing process or product quality.

At the time of assessment, removal of the pH specification required prior approval in Australia and New Zealand; was reportable with no restrictions in the US, Canada, EU, Great Britain, and Switzerland; and was not reportable in the rest of the world.

Case Study 4: Urea—Change from Noncompendial Pellets to USP Powder

Urea is typically the main component in the oxidation buffer in a DS process. The supplier discontinued urea in pellet form, which required a transition to USP compendial-grade powder (from the same supplier). This resulted in a raw material specification change in which all of the specifications for the pellets were included for the powder with the same limits (except appearance) and additional tests were added to comply with the USP monograph. Buffer preparation using urea powder was evaluated, and it was determined there was no impact on dissolution, pH, or conductivity parameters. However, because the pellet form was filed with the appearance of “small colorless or white pellets,” the change to powder required submission and approval of a variation by several health authorities before it could be implemented. Prior approval was required in EU, Great Britain, Australia, Switzerland, Turkey, and Israel, whereas notifications were submitted to the US, Canada, Brazil, Gulf Coast Cooperative, Egypt, and Colombia. The remaining countries considered the change as not reportable. The wide range in filing categories worldwide delayed global approval and implementation to manufacturing, which in a worst-case scenario could cause restrictions on supply.

In summary, if raw material attributes are not critical, they should not be included in the specification, because changing or removing filed specifications can take months to years, making supply more challenging to manage. Also, attributes that have high variability have an increased risk of testing failures and risk to supply. Because not all attributes with high variability are deemed critical, a risk-based approach to testing should be taken to avoid risk to supply. Therefore, it is important to identify the critical attributes early during development and mitigate any risks upfront. Defining the raw material target attribute profile could enable the identification of ECs and submission categories when using ICH Q12 principles. For example, in the case of sodium deoxycholate, the pH of the solution may have been considered an EC because it is critical to ensure material solubility and the ability to perform its function. However, through the control of pH in the DS manufacturing process, the sodium deoxycholate pH attribute is not actually critical and was determined to have no impact on product quality.

As mentioned, it is critical to have a reliable supply of raw material to maintain robust drug supply in order to serve patients. Because of short-age-related challenges, implementing a global regulatory infrastructure is increasingly needed, specifically an infrastructure that is both flexible and predictable to provide more agility to react efficiently without product delays. Leveraging ICH Q12 principles such as ECs can streamline the number of postapproval submissions. In the future, more innovative regulatory approaches, as well as supply chain approaches to manage raw materials, could be envisioned. The use of structured content and data management in CMC regulatory submissions could potentially provide a direct link to proactively manage risks in the supply chain and communicate with regulators. 11

In addition, employing the idea of quality management maturity to evaluate raw material manufacturing sites could perhaps enable an FDA rating system based on supplier excellence. 12 Ideally, a sponsor could gain some regulatory flexibility if they were to switch suppliers to one that had an “excellent” rating. Finally, through convergence and reliance, a collaboration between regulators and industry stakeholders to develop and implement harmonized guidelines for raw materials could address multiple reviews of the same material and ensure that both regulator and industry resources are dedicated to only the most critical issues, ensuring uninterrupted supply of medicines to patients worldwide.

Reader note: This article was originally submitted to Pharmaceutical Engineering® in January 2022.

• 11 Ahluwalia, K., M. J. Abernathy, J. Beierle, N. S. Cauchon, D. Cronin, S. Gaiki, A. Lennard, P. Mady, M. McGorry, K. Sugrue-Richards, and G. Xue. “The Future of CMC Regulatory Submissions: Streamlining Activities Using Structured Content and Data Management.” Journal of Pharmaceutical Sciences 111, no. 5 (May 2022): 1232–1244. doi:10.1016/j.xphs.2021.09.046 2021
• 12 US Food and Drug Administration. “Quality Management Maturity for Finished Dosage Forms Pilot Program for Domestic Drug Product Manufacturers: Program Announcement.” Federal Register. 16 October 2020. https://www.federalregister.gov/documents/2020/10/16/2020-22976/quality-management-maturity-for-finished-dosage-forms-pilot-program-for-domestic-drug-product

Acknowledgments

The authors acknowledge Jette Wypych, Mike Abernathy, and Satoshi Nagayama for their helpful discussions in the subject matter discussed in this article.

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• Published: 07 June 2021

Analytical quality by design methodology for botanical raw material analysis: a case study of flavonoids in Genkwa Flos

• Min Kyoung Kim 1 ,
• Sang Cheol Park 2 ,
• Geonha Park 2 ,
• Eunjung Choi 2 ,
• Yura Ji 2 &
• Young Pyo Jang 2 , 3  

Scientific Reports volume  11 , Article number:  11936 ( 2021 ) Cite this article

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The present study introduces a systematic approach using analytical quality by design (AQbD) methodology for the development of a qualified liquid chromatographic analytical method, which is a challenge in herbal medicinal products due to the intrinsic complex components of botanical sources. The ultra-high-performance liquid chromatography-photodiode array-mass spectrometry (UHPLC-PDA-MS) technique for 11 flavonoids in Genkwa Flos was utilized through the entire analytical processes, from the risk assessment study to the factor screening test, and finally in method optimization employing central composite design (CCD). In this approach, column temperature and mobile solvent slope were found to be critical method parameters (CMPs) and each of the eleven flavonoid peaks’ resolution values were used as critical method attributes (CMAs) through data mining conversion formulas. An optimum chromatographic method in the design space was calculated by mathematical and response surface methodology (RSM). The established chromatographic condition is as follows: acetonitrile and 0.1% formic acid gradient elution (0–13 min, 10–45%; 13–13.5 min, 45–100%; 13.5–14 min, 100–10%; 14–15 min, 10% acetonitrile), column temperature 28℃, detection wavelength 335 nm, and flow rate 0.35 mL/min using C 18 (50 × 2.1 mm, 1.7 μm) column. A validation study was also performed successfully for apigenin 7- O -glucuronide, apigenin, and genkwanin. A few important validation results were as follows: linearity over 0.999 coefficient of correlation, detection limit of 2.87–22.41, quantitation limit of 8.70–67.92, relative standard deviation of precision less than 0.22%, and accuracy between 100.13 and 102.49% for apigenin, genkwanin, and apigenin 7- O -glucuronide. In conclusion, the present design-based approach provide a systematic platform that can be effectively applied to ensure pharmaceutically qualified analytical data from complex natural products based botanical drug.

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Introduction.

Interest in high-level analytical system for complex pharmaceutical ingredients such as plant extract is increasing in the reality that drug development using natural extracts is increasing worldwide. Botanical drug guidelines of the United States Food and Drug Administration (USFDA) which was revised in 2016, recommends a ‘Totality-of-the-Evidence’ approach that comprehensively utilizes fingerprint analysis, chemical identification, and quantification of active or chemical constituents in the drug substance to characterize the complexity of the botanical sources to ensure consistency in drug quality 1 , 2 .

In order to achieve high standard of analytical methods of quality control, quality by design (QbD) approach have been adopted during analytical method development of various pharmaceutical practices 3 , 4 , 5 , 6 . The QbD is a disciplined approach to understand and control new drug products, based on sound science and quality risk management in diverse pharmaceutical processes 7 , 8 . Analytical methods play a significant role in drug product development in the control scheme of constant quality system monitoring of a product lifecycle 9 . The International Conference on Harmonization (ICH) is preparing to develop a new ICH Quality Guideline (ICH Q14) on Analytical Procedure Development, which will include the QbD concept for analytical methods, termed Analytical Quality by Design (AQbD) 10 . The AQbD approach begins with determining the analytical target profile (ATP), which is the prospective target of the analytical method development process and relates performance elements based on the intended target criteria 11 . The selection of critical method attributes (CMAs) is also performed, which directly represent a strong link to the intended criteria such as selectivity, precision, or accuracy in the desired analytical quality. Secondly, parameters that may affect analytical results are identified through a risk assessment approach 10 . Those highly selected risk factors are known as critical method parameters (CMPs) which should be tested with design of experiment (DoE) methodology and statistical screening. Thirdly, the polynomial relationships between CMAs and CMPs were studied in order to understand the in-depth cause-effect aspects that were statistically designed to identify the influential input variables affecting the representative output variables 12 . Meanwhile, the DoE is usually conducted twice by screening factors and then response surface methodology for optimizing the analytical method. The purpose of the screening study is to find the high-risk factors through fewer experiments, which is usually performed with designed two-level models such as full factorial design (FFD), fractional factorial design (FrFD), and Plackett-Burman design (PBD) 8 , 12 . In addition, an optimization process is conducted to ensure that proper quality is attained in the analytical method by considering the selected high-risk factors during design. The results are interpreted through response surface methodology (RSM) which is a potent statistical technique in mathematical modeling to interpret the designed-responses. Optimized strategic design responses include Box–Behnken design (BBD), central composite design (CCD), Taguchi design (TD), Mixture design, and Doehlert design 8 , 12 . Finally, the most appropriate designed point or method operable design region (MODR) is calculated from the RSM and confirmed by the method validation processes 13 .

While quality control systems based on the AQbD approach are applied widely in the field of pharmaceuticals, few application studies have been conducted on botanical extracts 14 , 15 , 16 . Since botanical extracts have complex and diverse phytochemicals as active ingredients, the selection of optimal analytical conditions is not simple. Also, it is quite challenging to screen the analytical parameters (i.e. buffer pH, organic solvent type, gradient slope, column temperature, etc.) that must be optimized by DoE technique.

In this paper, a systematic design-based approach to optimize a liquid chromatographic analytical method for major constituents of Genkwa Flos was investigated to suggest an analytical platform for how to consider CMAs and identify CMPs in an integrated case study with a botanical source. Compared to the routine One-Factor-At-a-Time (OFAT) approach, which tried one variable and collected one response, the current total quality approach utilizes scientific designing models and statistic expertise to finally obtain less experiment time, robust, precise, and easily validated analytical method 9 .

The flower buds of Daphne genkwa (Genkwa Flos, Thymelaeaceae) have been widely used as traditional oriental medicine in East Asia, China and Korea, and continue to draw great attention for their diverse pharmacological efficacy 17 , 18 , 19 . Previous phytochemical studies on D. genkwa revealed diverse chemical components including diterpenoids, flavonoids, lignans, and coumarins 20 , 21 , 22 . In recent years, genkwa flavonoids, as the main active constituents of Genkwa Flos, have been reported to exhibit remarkable pharmacological activities such as anti-inflammatory 23 , immunoregulation 24 , anti-tumor activity in colorectal cancer 25 , and anti-rheumatoid arthritis activity 26 . In order to exploit Genkwa Flos as a main ingredient of botanical drug, it is necessary to develop a robust and reliable analytical method for quality control, which is able to identify and quantify multiple components in botanical extracts in order to assure the consistency of pharmacological efficacy of herbal drug products.

CMPs were determined by risk assessment and factor screening experimental data in sequence. CMAs were established by equations that can be expressed as a single number by collecting the resolution of multiple peaks. After developing the optimized method by central composition design (CCD), the method validation was carried out in order to evaluate the soundness of the methods.

Results and discussion

Characterization of flavonoids using uhplc-pda-ms analysis.

UHPLC-PDA-MS system was utilized for the identification of flavonoids in Genkwa Flos. High-resolution mass data from Time-of-Flight (TOF) analyzer combined with UV–Visible absorption spectral pattern enabled to identify known flavonoids from Genkwa Flos extracts by direct comparison with those of previous researches 22 , 23 and/or reference standard solutions. A total of eleven identified flavonoids were listed in Table 1 providing their retention time, λ max , quasi-molecular ion, observed mass, mass difference, and molecular formula. Those were also tagged as peak 1 to peak 11 in the UHPLC chromatogram obtained at 335 nm (Fig.  1 A) which are apigenin 5- O -glucoside, apigenin 7- O -glucoside, yuanhuanin, apigenin 7- O -glucuronide, genkwanin 5- O -primeveroside, genkwanin 5- O -glucoside, genkwanin 4′- O -rutinoside, tiliroside, apigenin, 3′-hydroxygenkwanin, and genkwanin as eluted in order.

Representative UHPLC chromatogram of Genkwa Flos extract tagged with characteristic 11 flavonoid peaks ( A ) and their chemical structures ( B ). Kinetex-C 18 50× 2.1 mm, 1.7 μm column; mobile phase-A: 0.1% formic acid in water, mobile phase-B: acetonitrile; 335 nm detection; column temperature 28 ℃; 0.35 mL/min; gradient Time (min):%B, 0:10, 13:45, 13.5:100, 14:10, 15:10 used for the chromatogram.

Analytical target profile (ATP) and critical method attributes (CMAs)

The first step in AQbD-based method development is to define the ATP for stepwise and scientific procedures 7 . An analytical procedure which is able to quantitatively determine the specified eleven flavonoids in Genkwa Flos is a target of this study. Various elements of ATP such as analytical technique and instrument requirement were summarized as the intended target criteria (Supplementary Table S1 ). After ATP set-up, the potential CMAs were considered based on preliminary studies and review of the literature 8 , 9 . The general key CMA is the resolution ( R s ) of critical peaks 4 , 15 , 27 , which may be a critical attribute to avoid peak overlap for selective identification in liquid chromatography. Finally, the CMAs, corresponding to ATP, were established as countable peak number (Y n ) and resolution (Y 1–11 and Y sum ) after substantial consideration based on the modeling of experimental studies.

Preliminary studies

To carry out design-based method development studies, several preliminary tests were performed in different columns (i.e., length, particle size, manufacturer), using various solvents (i.e., acetonitrile, methanol), and acidified water (i.e., non-acidified, 0.1% acetic acid, 0.1% formic acid). Also, the detection wavelength for analyte was tested to acquire the greatest specific detection. The purpose of these attempts is to reduce variables by fixing those three parameters, but guarantee the best peak symmetry with the least working time. The achievement results were organized in Supplementary Table S2 , and final decision to C 18 (50 × 2.1 mm, 1.7 μm) column, acetonitrile and 0.1% formic acid water solvent system, and 335 nm detection wavelength, respectively.

Risk assessment studies

Quality risk management (QRM) allows us to control the entire process and recognize high-risk parameters that will affect the final quality of the analytical method 28 . We endeavored to establish QRM through risk assessment studies including experimental instruments and analytical parameters as shown in Fig.  2 , an Ishikawa fishbone cause-effect diagram. From the cause-effect diagram, potential factors in performing liquid chromatography could be identified and a subsequent step, the organized failure effect in each of the potential factors were calculated with a risk priority number (RPN) to sort out the high risk factors 29 . Following the guidance of ICH Q11 30 , RPN numbers were calculated with the equation ‘Severity \(\times\) Probability \(\times\) Detectability’ to allocate risk in each failure mode. The risk assessment and control strategy are summarized in Table 2 . Those parameters, column temperature (X 1 ), flow rate (X 2 ), injection volume (X 3 ), and gradient slope, indicate highly influential factors, which are calculated greater than 10 RPN. Practically, when designing the models, the gradient slope was converted into run time (X 4 ), because the initial and final percentages of acetonitrile solvent were fixed at 10 to 45 (Table 3 ). Thus, these four parameters were thereby selected for the further factor screening studies. The parameters counted less than 10 RPN were controlled as the constant.

Ishikawa Fishbone in Six Sigma of the UHPLC-PDA performance.

Factor screening studies

A (4 2 ) full factorial design (FFD), 4-factors and 2-levels, was performed for finding relatively fewer significant parameters from a list of higher risk potentially affecting the chosen CMAs, peak numbers (Y n ). Since Y n generally reflects the integral quality of chromatographic separation, we chosen it for the FFD which is roughly executed at just 2-levels (Low and High). The selected high risk factors during risk assessment studies were identified as column temperature (X 1 ), flow rate (X 2 ), injection volume (X 3 ), and run time (X 4 ). The main effect(s) were estimated by selecting the first-order polynomial models, which were drawn out per Eq. ( 1 ):

In the equation, Y n is the studied CMAs, which is number of countable flavonoid peaks, when examined in each of 19 runs as depicted in Table 3 . Those experimental runs were constructed randomly. A Pareto chart and Main effect plots (Fig.  3 ) show the significant influence of column temperature (X 1 ) and run time (X 4 ) on the studied CMAs, as these parameter frequencies were found to cross the corresponding α -value. As observed in Fig.  3 B, the countable peak numbers (Y n ) showed a negative correlation to column temperature (X 1 ), but a positive effect by run time (X 4 ). According to the statistical results (Table 4 ), the fitted model was very suitable to the experimental data by p -value under 0.05 with lack-of-fit larger than 0.05. Thus, factors such as column temperature (X 1 ) and run time (X 4 ) were selected as the CMPs for further optimization studies, and the other minor effective factors were kept as constant values. The flow rate (X 2 ) was adjusted to 0.35 mL/min, while the injection volume (X 3 ) was fixed at 1.0 μL.

Pareto chart ( A ) and main effect plots ( B ) obtained during factor screening of critical method attributes (CMAs), Y n peak numbers.

Response surface analysis

The subsequent chromatographic method optimization was executed by selecting the second-order quadratic polynomial model, where a central composite design (CCD) model designed with level 1.41421α were conducted with fourteen experimental runs (Table 5 ). The analyzed CMPs were column temperature (X 1 ) and run time (X 4 ) and studied at five different equidistant levels, i.e. low axial (− 1.41421), low factorial (− 1), central (0), high factorial (+ 1), and high axial (+ 1.41421). Meanwhile, the potential CMAs were newly chosen as Y 1–11 , which are the resolution ( R s ) of each of the identified eleven flavonoid peaks listed in Table 1 . Since botanical extracts have numerous phytochemicals, the resolution of each eleven peaks were defined between the closest eluted peaks. In detail, when calculate Y 8 for the peak number 8 shown in Fig.  1 A, the closest peak is just behind one eluted at 7.326 min. Besides, the first peak resolution (Y 1 ) and second peak resolution (Y 2 ) were of equal value, because the peaks are not totally separated or completely resolved by the UHPLC system and the closest eluting potential interference was each other. Furthermore, in several experimental runs (Table 5 ), the Y 1 and Y 2 were R s  = 0, indicating that those two peaks completely overlapped or co-eluted. The USP resolution equation using the baseline peak width drawn by lines tangent to the peak at 50% height was conducted for absolutely divided peaks, but USP Resolution (HH) using the peak width at half-height multiplied by a constant was utilized when calculated for overlapping peaks 31 .

In order to evaluate efficiently the total quality of separation in chromatographic fingerprints derived from each experimental run, one hypothetic score was introduced as total summation of Ys values of each peaks. In the design space, the Y 1 to Y 11 peaks were integrated as one value of Y sum by Eq. ( 3 ), which represents the estimated response for the experimental correlation with the two selected CMPs. Also, in order to prevent the value of a few peaks from dominating the overall result, it was necessary to determine the maximum value of each variable. A resolution over 1.5 usually indicates great separation, and when it is greater than 2, the peak is considered to be completely separated 32 . Hence, before integrating, the resolution values greater than 2 were set to 2 as shown in Eq. ( 2 ):

where Y i represents i th peak resolution after normalizing by Eq. ( 2 ), and the minimum to maximum response followed by Eq. ( 3 ) is 0 to 22, respectively. The randomly experimented fourteen runs to the selected CMAs are tabulated in Table 5 with the studied CMPs levels and designed experimental schedule. To clarify the CCD results, Minitab software ver. 18 was utilized for deriving ANOVA analysis and statistical optimization. Equation ( 4 ) is obtained by substituting the experimental data into a mathematical mode encompassing both main effects and interactions reflecting the second-order quadratic polynomial model.

ANOVA analysis was performed to statistically verify the model, which illustrates a statistically highly significant model ( p  < 0.05) and reasonable values of R 2 (95.09% for determination and 90.89% for adjusted). The results are given in Table 4 , it is also apparent that two CMPs in the first-order (X 1 , X 4) and second-order (X 1 ·X 1 , X 4 ·X 4) terms were significant, whereas the interaction correlation (X 1 ·X 4 ) was not significant. Those statistical results are also confirmed by observing the Pareto chart, Main effect plots, and Interaction plot shown in Fig.  4 .

Pareto chart ( A ), main effect plots ( B ), and interaction plots ( C ) obtained during center composite design (CCD) studies of critical method attributes (CMAs), Y sum ; summarizes the eleven resolutions.

Selection of optimum chromatographic solution

To obtain the optimized chromatographic method, the CCD design space was further studied in response surface analysis by using Statistica software ver. 13.3.0, carried out for the specific CMAs, Y sum . The 3D response surface (Fig.  5 A) and 2D contour plot (Fig.  5 B) revealed individual and plausible interaction(s) in factors and responses. Both column temperature (X 1 ) and run time (X 4 ) have a similarly curved plot, which is gradually increasing and decreasing at around the central level (0). Specifically, the central level of column temperature (X 1 ) was 35 ℃ and run time (X 4 ) was 14 min, respectively. As observed from Eq. ( 4 ), those patterns also may be inferred to be parabolic curves, which mean the response with a maximum value can be calculated by mathematical computing works. Finally, the optimum UHPLC-PDA performance solution with a maximum response Y sum of 18.80 was adjusted mathematically to the column temperature of 28.2861 ℃ and run time of 13.1784 min as portrayed in diagrams in Fig.  6 . The verification step was studied to appraise model suitability and the repeatability results were near the predicted value of Y sum with a very acceptable %RSD and %RE (Table 6 ).

3D response surface plot ( A ) and 2D contour plot ( B ) depicting the interaction of two critical method parameters (CMPs) on the Y sum .

Optimization diagrams calculated mathematically.

Analytical method validation studies

The purpose of validating an analytical method is to demonstrate that the proposed method is suited for its intended use by satisfying the expectations of ATP. At first, method validation of UHPLC fingerprint was performed to determine the precision and stability. The same test solution (30 mg/mL) of the Genkwa Flos, which was injected six times in one day for precision test. Next the same test solution was analyzed 0 and 24 h after the preparation of test solution for stability test. The results were summarized in Supplementary Table S3 as calculated %RSD values of relative retention time (RRT) and relative peak area (RPA) of each peak which were calculated relative to the selected marker peak, apigenin 7- O -glucuronide (peak 4). All %RSD values of RRT and RPA of eleven peaks were under 1%, indicating the commendable precision and stability of the fingerprint method.

Next, we studied the quantitative method validation using three standard compounds of apigenin 7- O -glucuronide, apigenin, and genkwanin, which were identified as major components by chromatography (Fig.  1 ). Since the assigned eleven flavonoids were all 2-phenylchromen-4-one backbone flavones, those three peaks with the highest % area in the Fig.  1 were selected as representatives for verification of the optimized analytical method. Standard calibration curves of three compounds for linearity were derived in the range of 0.9765–500.00 μg/mL or 31.25–2000.00 μg/mL with the high values of the coefficient of correlation (0.999), respectively (Table 7 ). The linear calibration plots with corresponding residual plots are depicted in Supplementary Fig. S1 , where none of the points were observed as outliers in the studied range of each concentration. Detection limit (DL) and Quantitation limit (QL) were also drawn out from the linearity test, indicating a sensitive method for quantification of those flavonoids. Precision, a measure of repeatability, was evaluated by intra-day and inter-day variability. As shown in Table 7 , the %RSD value of content in the intra-day and also inter-day variability tests were found to be with a reasonable value as under 0.22, respectively. Accuracy of the method was confirmed by spiked and triplicate injections of known standard concentrations into the sample solution. Percentage recovery for the three compounds’ test concentrations studied ranged from 100.13% to 102.49% (Table 7 ), with their %RSD values less than 0.85.

System suitability has been checked with the systematically optimized chromatographic method and found to be well within ICH criteria 11 except resolution, as represented in Fig.  1 . Among the eleven flavonoid peaks, resolution of peaks 1, 2, 3, 6, and 9 were under 1.5, which is the remaining challenge for a detailed trial of the isocratic and gradient mixed solvent system or to consider other factors. Meanwhile, an accurate and precise chromatographic method also depends on the %RSD values for injection repeatability precision, tailing factor 9 , plate count 13 , and capacity factor distribution 11 , so those criteria also must be considered as CMAs. However, the only criteria of resolution was selected for CMAs because %RSD and tailing factor were estimated to great precision and symmetry over the entire experiment. Also, when performed CCD studies of those parameters, plate count (> 2000), and capacity factor (> 1), were evaluated as proper in the overall 14 runs of experimental design work as tabulated in Supplementary Table S4 .

To apply the AQbD approach, a thorough study on the characteristic of the analyte must be accomplished. The risk assessment studies were conducted carefully to achieve the optimized analytical method that is able to quantify diverse flavonoids from all of the other detected interferences with a substantial acceptable resolution, selectivity, and good efficiency. Thus, optimizing the selected CMPs as column temperature (X 1 ) and run time (X 4 ) the resolution of eleven identified flavonoid peaks were well resolved as mentioned and represented in Fig.  1 .

The present study adopted a novel AQbD approach to develop a sensitive, robust, and accurate UHPLC-PDA-MS method for the identification and quantification of flavonoids in Genkwa Flos extract. In this approach, a methodical data collection process was conducted to identify the CMPs and CMAs through serial experiments of preliminary tests, risk assessment, full factorial design, and central composite design (CCD). Moreover, a new attempt to express target multiple peak resolutions as a single value was proposed by integrating all analytical peak data, and it provides a direction of how to handle CMAs in developing an analytical method of botanical extracts containing diverse components. The quantitative models depicted by a 3D surface plot with a 2D contour plot between two potential parameters, column temperature (X 1 ) and run time (X 4 ), were successfully constructed to facilitate finding the most suitable conditions for the chromatographic analysis. In conclusion, an AQbD-based quantitative multi-component analytical method is successfully developed and can serve as a template for other herbal medicinal product cases.

Material and methods

Standards and reagents.

Apigenin (CAS no. 520-36-5, > 98.6%), apigenin 7- O -glucuronide (CAS no. 29741-09-1, > 98.8%), and genkwanin (CAS no. 437-64-9, > 98.0%) were purchased from Chem Faces, Wuhan, China. All of the other reagents were supplied by Duksan Pure Chemicals Co., Ltd., Ilsan, South Korea. For the analytical studies, HPLC-grade water, methanol, and acetonitrile were purchased from Fisher Scientific, Waltham, MA, USA; high purity nitrogen gas was provided by Shinyang Oxygen Co., Ltd., Seoul, South Korea.

Plant material and preparation of extracts

The flower bud of Daphne genkwa, which is a MFDS (Ministry of Food and Drug Safety of Republic of Korea) certified herbal medicine, was purchased from the Kyung-dong drugstore in Seoul, South Korea. The botanical origin was identified by Prof. Young Pyo Jang who is the head of Medicinal Herb Garden of College of Pharmacy, Kyung Hee University. A Voucher specimen (KHUP-2103) is deposited at the Herbarium of College of Pharmacy, Kyung Hee University, South Korea. Acquiring all plant samples and manufacturing extracts were carried out in compliance with the IUCN Policy Statement on Research Involving Species at Risk of Extinction ( https://portals.iucn.org/library/efiles/documents/PP-003-En.pdf ) and the Convention on International Trade in Endangered Species of Wild Fauna and Flora https://cites.org . The sample was ground and then powdered with 850 μm mesh sieves. Using 56% acetone in water as the extraction solvent, all flavonoid components were extracted by a shaking extraction procedure. The detailed list of extraction parameters are as follows: agitation speed of 150 rpm, shaking time of 12 h, and extraction temperature of 65 ℃. The concentration of the sample solution was fixed in all experimental sections as 30 mg/mL.

Instrumentation and UHPLC-PDA-ESI/MS conditions

A Waters AQCUITYTM H-class UPLC system (Waters Corp., Milford, MA, USA) was used for the UHPLC analysis. The system composed of a photo diode array (PDA) detector, quaternary solvent and sample manager, cooling auto sampler, and column oven. The operating software was Empower-3 software (Waters Corp.). A Kinetex-C18 column (2.1 mm × 50 mm i.d., particle size 1.7 μm, Phenomenex, Torrance, CA, USA) was used for all the chromatographic analysis. The sample was maintained at 25 ℃ and the UV/Visible detector wavelength was fixed at 335 nm in all experiments. The mobile phase was composed of acetonitrile and acidified water with 0.1% formic acid. The column oven, flow rate, injection volume, and solvent gradient system were screened by experimental design.

To identify and assign flavonoids, the mass spectrometric studies were carried out on an AccuTOF ® single-reflection TOF mass spectrometer (JEOL, Tokyo, Japan) equipped with an ESI probe. Some important parameters of mass spectrometry were as follows: positive ion mode, mass range m/z 100—1500, needle voltage—2000 V, orifice-1 voltage—80 V, ring lens voltage—10 V, orifice-2 voltage—5 V. Nebulizing and desolvation gas was nitrogen. The desolvation temperature was 250 °C and the orifice-1 temperature was set to 80 °C. Mass Center System (version 1.3.7b, JEOL, Tokyo, Japan) was operating software and mass calibration was conducted using the YOKUDELNA kit (JEOL, Tokyo, Japan).

Statistical analysis

In current study, two design of experiments, full factorial design (FFD) and central composite design (CCD), were constructed and also statistical analyzed using Minitab software ver. 18 (Minitab Inc., State College, PA, USA). The statistically significant coefficients ( p  < 0.05) per analysis of variance (ANOVA) were used in framing the polynomial equation followed by the evaluation of the fit of the two models. Parameters evaluated for appropriate fitting of the models including coefficient of correlation (R 2 ), lack of fit, F-value, and P-value are listed, respectively. Among them, the result of CCD was also studied in response surface analysis utilizing Statistica software ver. 13.3.0 (TIBCO Software Inc., Palo Alto, CA, USA).

Chromatographic method validation analysis

After defining the design model, the analytical operating point was validated per the International Conference on Harmonization (ICH) guideline Q2 (R1) and the parameters are described below 33 . Among the eleven identified flavonoids, three major eluates were chosen for study in this validation process, which are apigenin 7- O -glucuronide, apigenin, and genkwanin.

Linearity and range

To confirm linearity, working standards of apigenin 7- O -glucuronide in the range of 31.25–2000.00 μg/mL, apigenin and genkwanin in the range of 0.9765–500.00 μg/mL were prepared by a serial dilution process and then analyzed. From regression analysis, three regression lines along with the regression equation and least squares were derived by each of the standard compounds, respectively.

Detection limit and quantitation limit

Following the guideline Q2 (R1), there are several approaches for calculating Detection limit (DL) and Quantitation limit (QL), we chose the method “Based on the Standard Deviation of the Response ( s ) and the Slope (α) 33 ” for this study. In Eqs. ( 5 ) and ( 6 ), the slope ( α ) was derived from each slope of the three analytical curves. The standard deviation of the response ( s ) was determined based on the residual standard deviation of each regression line.

Repeatability and Intermediate Precision were performed with a known concentration of the analyte (30 mg/mL) to investigate precision. On the same day, two samples at 100% of the test concentration were studied by six determinations each for the repeatability test. One sample was prepared for chromatographic analysis by six determinations on the next day testing for Intermediate Precision. All results were assessed as the percentage relative error by converted reference contents.

Calculating the percentage recovery of analyzed spiked samples was used for the accuracy test. Three known amount of each standard solutions: 125, 250, and 500 μg/mL of apigenin 7- O -glucuronide; 15.625, 31.25, and 62.5 μg/mL of apigenin; 31.25, 62.5, and 125 μg/mL of genkwanin were spiked with respect to the analyte (30 mg/mL) solution. The recovery studies were carried out three times showing that the percentage recovery and also percentage relative error were calculated to be accurate.

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Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (Grant Number: 2018M3A9F3081538).

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M.K.K. contributed conception, design of the study, and performed the experiments; S.C.P. conducted statistical analysis; G.P., E.C. and Y.J. performed the experiments and data; M.K.K. wrote the original draft of the manuscript; Y.P.J. administrated project and acquired funding. All authors contributed to manuscript revision and approved the submitted version.

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Kim, M.K., Park, S.C., Park, G. et al. Analytical quality by design methodology for botanical raw material analysis: a case study of flavonoids in Genkwa Flos. Sci Rep 11 , 11936 (2021). https://doi.org/10.1038/s41598-021-91341-w

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A Case Study in Pharmacopoeia Compliance: Excipients and Raw Materials

The authors present a case study with raw materials and excipients, where a consistent, cross-functional approach is needed to ensure the appropriate selection, sourcing, testing, and filing of the materials used to manufacture bio/pharmaceutical products in a global environment, ensuring compliance with applicable compendial and regulatory requirements.

Throughout this series of articles, it has been emphasized that the bio/pharmaceutical industry must comply with requirements published by pharmacopoeias around the world. Several considerations have been presented to illustrate that pharmacopoeia compliance can be difficult. A previous article (1) highlighted compliance challenges resulting from the elaboration of monographs for drug substances and products. These challenges can be considered externally-based, driven by decisions made by the pharmacopoeias during the monograph development process. There are other compliance challenges that are internally-based, resulting from decisions made by one functional area in the company without consideration of the broader impact to other functional areas throughout the organization. One such example can be found with raw materials and excipients, where a consistent, cross-functional approach is needed to ensure the appropriate selection, sourcing, testing, and filing of the materials used to manufacture bio/pharmaceutical products in a global environment, ensuring compliance with applicable compendial and regulatory requirements. This case study is based on the experience of one of the authors (2) but is applicable to all companies across the broader industry, illustrating the potentially surprising point that some compliance difficulties may be of the company’s own making.

The challenge of compliance

During early development in the product lifecycle (3), various raw materials are used to prepare the drug substance, with the goal of consistently providing this active pharmaceutical ingredient (API) with appropriate quality and purity. Many of the raw materials are completely consumed during the manufacturing process, serving as building blocks that are converted into intermediate materials prior to the ultimate drug substance. Other materials may not be completely consumed, carrying over into the drug substance or drug product as residual materials or impurities. These residual materials may be an especially important consideration for complex biotherapeutic products (BTP). Continuing in the product lifecycle, the subsequent development of the dosage form involves the addition of excipients to the drug substance, with the goal of providing safe and effective delivery of the API in the drug product to achieve the intended therapeutic outcome. Appropriate product development information, along with safety, clinical, stability, and other data, are provided to regulatory agencies around the world to gain marketing approval for the drug product.

This article focuses on the raw materials and excipients used in the manufacture of drug substances and drug products. A company must comply with their approved product registrations and with appropriate compendial requirements, according to the expectations of regulatory agencies (3). The pharmacopoeias also provide information about the need for compendial compliance. For example, the General Notices in the European Pharmacopoeia ( Ph. Eur. ) indicate that drug substances and excipients must comply with all the requirements stated in the applicable monograph (4). The General Notices in the United States Pharmacopeia-National Formulary (USP–NF) state, “Official products are prepared … from ingredients that meet USP or NF standards, where standards for such ingredients exist” (5). Clearly, APIs and excipients used to manufacture the drug product must meet compendial requirements. The USP General Notices continue, stating that the drug substances and excipients are themselves prepared “from ingredients complying with specifications designed to ensure that the resultant substances meet the requirements of the compendial monographs.” Again, the active ingredients and excipients clearly must meet the monograph requirements. Information is lacking, however, as to the ingredients used to prepare the drug substances and excipients. In particular, what are the appropriate specifications for the raw materials that will ensure compendial compliance for the resultant APIs and excipients?

This lack of clarity about the control of the raw materials may lead to compliance challenges. The drug development/approval process takes many years and involves a large number of wide-ranging functional areas across the entire company, including research and development, procurement, supply, quality, and regulatory. It is essential for these groups to remain connected and aligned throughout the entire process, with sustained communication and appropriate documentation, to deliver an effective and efficient outcome for the company overall. It can be especially important for decisions made early in the development process to be communicated and understood across all departments. Equally important, the responsible groups making early decisions should have visibility, or line-of-sight, to the strategy and expectations of other groups involved later in the product lifecycle, as part of an end-to-end approach to the overall process (6). The situation is made even more complex as more bio/pharmaceutical companies outsource the production of drug substances, and contract manufacturers work with many customers having different material requirements.

There are important and fundamental questions about the materials used in product development and manufacturing that need to be considered throughout the product lifecycle. How does a company ensure the suitability and compliance of the raw materials and excipients used to support a broad product portfolio in a global environment? Are acceptable materials being used? Is appropriate testing being performed? How is this information communicated internally, across impacted functional areas? How is the information communicated externally, to external partners and suppliers, as needed? How is the information communicated externally to regulatory agencies around the world? These important questions can be expressed in simpler terms, as follows:

• What do you need?
• What do you buy?
• What do you test?
• What do you file?

These questions relate to the selection, sourcing, testing, and filing for excipients and raw materials, and the interplay among them is shown in Figure 1 . Each area is connected to, and impacts, the others, but one key aspect is the potential disconnect that can occur between what is sourced and what is filed for these materials. A consistent, cross-functional approach is necessary for a company to answer the questions in a way that ensures compliance with appropriate regulatory, compendial, functional, and quality requirements. Without a consistent approach that is understood and followed across the entire company, compliance problems can emerge.

Why differences emerge

The level of understanding about the materials used to prepare drug substances and drug products increases as a company moves through the product lifecycle ( Figure 2 ). Beginning in early development, the focus is on ensuring the materials are “fit for purpose”, with appropriate functionality of the materials (“what do you need?”) to support their intended use in the drug substance or product. At this stage, there are also questions about possible sourcing of the materials (“what do you buy?”) and appropriate quality (“what do you test?”). As development continues toward product registration, launch, and supply, the functionality of the material is better understood, and quality and compliance considerations now become most important. The situation is increasingly complicated in today’s global industry, with additional regulatory expectations arising in important markets. Appropriate sourcing and testing are still key considerations (“what do you buy?” and “what do you test?”) that bridge product development to supply, but a critical focus now surrounds the specific details that will be included in the product registration (“what do you file?”).

The differences that emerge in this case study are internal to the company, based on misalignment of expectations and requirements for raw materials and excipients between different functional areas. Without a line-of-sight or end-to-end perspective across the product lifecycle, different areas will likely have different understanding and definitions for the materials used during development, continuing into product launch and supply. Although a definition is provided in the International Council for Harmonization (ICH) Q6 guidelines for an excipient used in a drug product, there is no information about the ingredients that are used in the preparation of the drug substance (7). To enable a consistent process for the selection, sourcing, testing, and filing of excipients and raw materials, it is critical to have clear, practical, and specific definitions, not just for the materials themselves, but also for the grades that may be available. The definitions used for materials throughout this article are listed in Table I and are summarized as follows:

• Raw materials are used in the manufacture of the drug substance and should not be present in the final drug product.
• Residual materials may be used during the manufacture of the drug substance or drug product, but may not be completely removed, and as a result may still be present in the finished product.
• Excipients are ingredients added to the drug substance during manufacture of the drug product and intended to be present in the final product.

While these terms and definitions may differ between different companies, the important point is to have the discussion and reach a common understanding within a company to establish a consistent, cross-functional approach to compliance.

The definitions for materials are based on their use in the manufacture of the drug substance and drug product. The definitions for material grades are based on the materials that are purchased and the testing performed on them. The definitions for grades used in this article are listed in Table II and include compendial grade, multi-compendial grade, supply grade, and reagent grade. Compendial and multi-compendial grade relate to the availability of one or more monographs for the material in the pharmacopoeias. Supply grade is a term used when there is a need for a company to have visibility to the supply chain and change control for the material. As an example, for a material purchased from a distributor, a company may need to be notified if the distributor changes their supplier of the material, as this could have an impact on the drug product manufacture. Similarly, for a material purchased directly from a manufacturer, a company may need to be notified if changes are made to the manufacturing process of the material as this may also impact the manufacture and quality of the drug product. The notification from distributors and manufacturers can be very important for control of the materials used in the highly-regulated bio/pharmaceutical industry. Finally, reagent grade applies to materials not covered by the criteria above. The use of reagent grade materials should be carefully considered to ensure their acceptability in the manufacture of a drug substance or product, from a quality and regulatory perspective.

It is now possible to look at the four questions posed earlier in greater detail, with the common understanding provided by the definitions for materials and grades given above. The underlying questions will enable discussion and drive decisions that are consistent across the various functional areas. Many of the underlying questions are the same  but are examined from different perspectives by different functional areas. The goal is to align on the approach used throughout the product lifecycle for the selection, sourcing, testing, and filing of the materials.

Functionality: what do you need?  The question, “what do you need?”, arises at the very beginning of development, and the answer depends on how the material will be used. Is it an excipient used in the drug product, or is it a raw material used in the drug substance? This is a fundamental question that should be easy to answer.

If the material is intended as an excipient, its safety must be confirmed. Is safety or toxicology data available in the literature? Does the material have generally recognized as safe (GRAS) status? Is it listed in the FDA Inactive Ingredient Database showing the maximum level that has been approved in drug products for a particular route of administration or dosage form? When looking at the functionality of the material, it is important to identify the unique characteristics that contribute to its suitability for the intended use. What specific materials and grades should be considered? Will the material support a quality-by-design approach to manufacturing? Is viscosity or particle size important? Are there impurities that can impact the overall quality of the material itself or the quality of the product that will be made from it? Are there residual solvents or elemental impurities present? Depending on its use, is there a need to consider microbiological quality or sterility?

The functional and quality requirements for the materials determined during development are important to other groups involved later in the product lifecycle. These requirements will be tested by the quality groups to ensure the identity, purity, and performance of the materials. The requirements may eventually be listed and justified in product registrations, with potential impact on post-approval change control. At a certain point, questions arise as to the availability of the material. These sourcing considerations are not necessarily fundamental during early development but are critical in late development and commercialization.

Sourcing: what do you buy?  The question, “what do you buy?”, builds on the decisions made in new product development and evolves throughout the product lifecycle. Again, you start with the question of how it is used because that, in many ways, determines what you buy. The development scientist may pull a raw material or excipient off the laboratory shelf to start their work. The material may have been purchased through a chemical catalog or it could be a promotional sample from a potential supplier. The scientist might check what is available in the chemical stock or manufacturing area that can be used in development studies.

There is still a need to understand the critical quality attributes (CQAs) for the material to enable discussion with potential suppliers. At this stage, there is a focus on what is available. Is there only one supplier or are there multiple sources that can provide the material? Is visibility to the supply chain or change control necessary and possible for the material?

As product development proceeds, considerations of the cost and available quantities become important. If there are multiple sources for the material, what is the basis for choosing one supplier over others? Is there a need to qualify more than one supplier in case of material shortages? What experiments are needed to ensure suitability of materials from different suppliers for use in the specific formulation? Have the suppliers been previously audited by the company? Were the audit findings acceptable? Are specific materials with different characteristics available (e.g., hydroxypropyl cellulose with different molecular weight and viscosity properties) and is one better suited for the intended function? All of these questions lead to the ultimate determination of the materials and suppliers that will be used in the manufacture of the drug substance and product. These decisions also impact the testing performed and provide information about what may be filed in product registrations. Typically, the purchased materials should be compendial, multi-compendial, or supply grade. In some cases, reagent grade materials may be considered, although the ability to use reagent grade materials in drug product manufacture is fairly limited due to quality and regulatory concerns, in the authors’ experience.

Quality: what do you test?  The question, “what do you test?”, depends again on how the material is used. If the material is used as an excipient and there are applicable monographs, the quality groups need to ask whether they will perform all tests in one or more pharmacopoeias. In which countries will the product be filed? This determines which pharmacopoeias may be applicable when ensuring compendial or multi-compendial compliance. What if the material is used as an excipient but is non-compendial, meaning there is no monograph for the material in the pharmacopoeia?

Understanding CQAs for the intended use is again important so that quality testing can be performed to control these characteristics in releasing the material. What tests are performed by the supplier? What are the supplier’s acceptance criteria? One key point in going through the exercise at this stage is that there must be discussion and agreement with the supplier for any additional tests or different limits that will be required based on the use of the material. A company making these decisions in a vacuum or without interaction with the supplier can put the availability of the material at risk and create potential challenges for the company. Release tests should include analytical and microbiological controls to evaluate overall quality, ensuring the identity, purity, and functional suitability of the material. Control of specified impurities is a key consideration. Some tests for the functionality-related characteristics of the material may be performed as “internal tests” and not included in the product registration. These internal tests are performed for release of the material but do not represent a regulatory commitment. This leads to the final question to be considered.

Registration: what do you file?  The question, “what do you file?”, also depends on how the material is used because this determines what may be listed in the product registration. One key lesson is that the answers to the prior questions (“what do you need, buy, test?”) do not necessarily have to correlate with what you file. What is listed in the registration does not have to match what is sourced or even tested. This returns to the potential disconnect that was presented earlier in Figure 1 .

At a practical level, how the material is used determines which section of the Common Technical Document (CTD) will contain the information about the material that is provided to regulatory agencies. Recall that the bio/pharmaceutical company must comply with approved product registrations, including applicable compendial requirements. What is listed in the registration becomes a regulatory commitment. Based on how the material is used, does the company need to commit to compendial testing in the registration per the applicable monograph? If used as an excipient, the answer is “yes.” For which pharmacopoeias is the company claiming compliance? It is recommended that compliance with only one pharmacopoeia be listed in any product registration, according to which particular pharmacopoeia is applicable for the specific country to meet regulatory expectations in the filing. This idea will be further detailed in the following strategy section. Are there additional tests, such as quality attributes and functionality testing, that are critical to product manufacture and should be included in the registration?

In determining what to list in the product registration, a company must choose wisely because the decision essentially locks you in. Considering what may be an extreme example, imagine an ingredient used as a “raw material” as defined in this article, and that it is an important component in the preparation of the drug substance. Imagine further that the company wishes to control the particle size of this material, not as a CQA, but to aid in processability during manufacture of the active ingredient. In this example, because it is an important component in the manufacturing process, visibility is needed for the supply chain and change control of the raw material. This situation is consistent with the use of “supply grade” material.

Imagine, however, that the supplier will only assure supply chain visibility if the company purchases “compendial grade” material. It must be stressed that procuring compendial grade material does not mean that compendial compliance must be listed in the registration; nor would particle size testing necessarily need to be included. Perhaps the company has determined that only assurance of the identity of the material is required for quality testing and in the registration to support the material’s intended use in manufacturing. The particle size might be an additional internal test for control, while the company gains more experience with the manufacturing process. If, however, there are disconnects between the different functional groups in the company and in their decisions, it is conceivable that the registration might list compendial compliance (based on the material procured) and the particle size test (based on the testing performed) because a consistent approach was not followed.

The result is an unnecessary regulatory commitment with which the company must now comply. This situation can create challenges for many groups, including quality (“why do we now have to perform testing per the compendial monograph?”), manufacturing (“after scale-up, we no longer need to control particle size for the material”), and procurement (“we would like to change to a lower-cost supplier who provides supply chain visibility for the material without reference to the monograph”). Any changes to address these challenges will require that the company make updates to the product registrations, with the associated difficulties typical of the change control process. This situation illustrates the intersection of the four questions considered and enables discussion of principles and strategies that can help avoid the potential challenges.

Aligning on  principles and strategies

The goal is for a company to establish a consistent, cross-functional approach for the selection, sourcing, testing, and filing of materials used to manufacture drug substances and products, in compliance with applicable compendial and regulatory requirements. Consistent principles and strategies should be established that will be followed throughout the product lifecycle by all functional areas in the company. Using the definitions provided earlier, the following principles are proposed:

• Principles for excipients
• An excipient should be compendial grade, unless a monograph for that material is not available in the pharmacopoeia.
• If there is more than one applicable monograph in the multiple pharmacopoeias, the material may be multi-compendial grade.
• An excipient without a compendial monograph should be supply grade.
• Principles for raw materials
• A raw material should be supply grade.
• Even if there is a monograph in the pharmacopoeia for the material, its use as a raw material does not require sourcing, testing, or filing as compendial grade.
• A raw material may be procured as compendial grade (to have supply-chain and change control visibility), but the filing should only include the minimum requirements to ensure the quality and suitability of the material. The filing should not reference the compendial monograph.
• Principles for residual materials
• A residual material may not be applicable in all small-molecule or complex biotherapeutic processes. Whether the material needs to be compendial grade or supply grade should be addressed on a case by case basis.
• The strategy for a residual material would generally align with the raw material strategy.
• Testing and filing should reflect appropriate, minimum requirements for the material.

As stressed before, in establishing the principles within a company, it is important to have the discussion with colleagues from all functional areas involved throughout the drug product lifecycle to develop a consistent approach for the appropriate selection, sourcing, testing, and filing for the materials used.

Strategies for  excipients: compendial  vs. multi-compendial

The principles given above enable a company to establish their strategy based on the fundamental use of the material as an excipient or raw material. Figure 3 shows an appropriate strategy for the case where the selection process determines an ingredient will be used as an excipient. The other functional area decisions for sourcing, testing, and filing are shown in the three columns, with the corresponding choices for material grade shown in the colored boxes. Assuming there is an applicable monograph in one or more pharmacopoeia, the sourcing decision for an excipient is either compendial or multi-compendial. The testing decision is also compendial or multi-compendial. The filing decision is compendial, with the recommendation that only one pharmacopoeia is referenced for the material in any registration. The decisions in this strategy can be better understood by looking more closely at specific situations.

It is instructive to look at the interplay of the decisions for sourcing and testing when considering whether compendial or multi-compendial grade is the better choice for an excipient used in a particular drug product. It will cost more for a company to purchase an excipient sold as multi-compendial grade because the supplier of the material must perform additional testing to ensure compliance with more than one monograph. The user of the excipient may be able to leverage the multi-compendial testing performed by the supplier to reduce their own testing of the material, by accepting some results from a qualified supplier’s certificate of analysis (COA). This can be done provided the user of the excipient performs at least one specific test to verify the identity of the material. Additionally, the user must establish “…the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals”, as stipulated in the US Code of Federal Regulations (8).

Alternatively, the excipient user can perform all testing needed to ensure multi-compendial compliance for the material. This can be accomplished even if the material is purchased to comply with the monograph in only a single pharmacopoeia. This approach is not “testing into compliance”. To be considered compendial grade, a material must be prepared according to recognized principles of good manufacturing practice (GMP) and meet the requirements in the pharmacopoeia monograph, as noted in the USP General Notices (5). With this understanding, a material may be purchased, for example, as “ Ph. Eur. grade”, meaning it has been manufactured under appropriate GMPs and meets the Ph. Eur. monograph requirements. This material can be further tested by the user of the material according to the USP monograph. If the material meets the additional USP requirements, it can be considered to be multi-compendial, because it has been prepared under appropriate GMPs and complies with the monograph requirements in both Ph. Eur. and USP . With this approach, there is a potential business risk that must be understood by the quality and procurement functions in the company. The excipient user may be unable to return material to the supplier if they obtain a failing result for an additional test in the USP , when the supplier has not indicated that the material complies with the USP monograph requirements. Alternatively, there is no need to reject the material if it fails USP testing, but the company would need to control the material inventory, so it is not used where USP compliance is required.

There are, in fact, a wide range of options that a bio/pharmaceutical company may take to ensure multi-compendial compliance for an excipient intended to support global product registrations (9). The most conservative approach is to perform full testing according to the specific tests, methods, and acceptance criteria contained in each monograph. Full multi-compendial testing demands significant resources and time, and, accordingly, will not be the preferred approach in many instances, particularly once the product has reached the supply stage of the lifecycle. There are earlier times during the product lifecycle, however, where this might be a good approach to take. For an excipient used in a drug product biobatch or formal stability batch, demonstration that the material has been tested to comply with applicable pharmacopoeia monographs for the United States, Europe, Japan, and China markets, for example, enables this information to be communicated to regulatory agencies in these countries and may avoid delays in product approval. Obviously, testing would not be required for a national pharmacopoeia if there is no intention to file in that particular country.

Other approaches involve reduced testing as noted earlier, by accepting some results from a supplier’s COA or establishing an appropriate skip-lot testing program. A company may be able to leverage the outcome of excipient harmonization completed by the Pharmacopoeial Discussion Group (PDG) to perform testing per one monograph in the USP, Ph. Eur. , or Japanese Pharmacopoeia (JP) to ensure compliance with all three. There is also a strong case to be made for a company to leverage their own “internal harmonization” for excipient testing to ensure multi-compendial compliance. This concept was presented in a different context in the previous article for a drug substance (1), where a company demonstrates equivalency between their currently approved method and a different method published in a new monograph. In the case of excipients, internal harmonization would demonstrate and document that the same results would be obtained using different methods in the different monographs for a particular quality attribute, to reach the same overall accept/reject decision for the excipient. This determination of method equivalency between the different monographs enables a company to perform testing per one pharmacopoeia to ensure compliance with the others used in the equivalency studies. The use of a method other than the one in Ph. Eur. requires prior approval from regulatory agencies in Europe (10). In the case of internal harmonization of excipients, it is recommended that the Ph. Eur. test method be performed to ensure multi-compendial compliance while avoiding this regulatory burden.

Turning to the strategy for the regulatory decision, it is important to keep in mind that a company must comply with pharmacopoeia requirements to which they have committed in their product registrations. To ensure global acceptance for compendial grade excipients used in a drug product, a company should demonstrate compliance with USP and Ph. Eur. monograph requirements, at a minimum. These global pharmacopoeias are accepted by many regulatory agencies well beyond the geographical boundaries covered by the pharmacopoeia (11).

A few additional points are necessary. If the product will be marketed in Japan and there is a JP monograph for the excipient, then compliance with the JP is required for Japan. Filing USP or Ph. Eur. in this case would not be accepted by the Japanese health authority. A similar situation is now clear for China. If there is monograph for the excipient in the Chinese Pharmacopoeia (ChP) , then compliance with the ChP is mandatory for the excipient used in product going to China. The situation for other countries with their own national pharmacopoeia should also be considered, although the broad acceptance of USP and Ph. Eur. standards may be suitable to regulators in these countries.

Looking more closely at multi-compendial compliance with USP and Ph. Eur. monographs for excipients, what should the company actually file in their product registration? This question relates to the pharmacopoeia reference listed for excipients in CTD section 3.2.P.1 for the composition of the drug product. In an effort to maintain a single product registration for use globally in 150 or more countries, some companies choose to indicate multi-compendial compliance by some combination of the applicable pharmacopoeias, such as “USP/Ph. Eur.,” “USP, Ph. Eur.,” or even “USP or Ph. Eur.,” perhaps with a footnote indicating compliance with one or the other “as applicable to the particular country”. While the meaning of this regulatory commitment may be apparent for the US and European countries, it is not as clear to regulators in many other countries around the world. Nor is the meaning necessarily clear to the quality group in a company that needs to test an excipient for use in a product intended for one of these countries. Recall that for Japan and China, compliance with the JP and ChP , respectively, is required if they contain a monograph for the excipient. This means the goal of a single registration is not possible for a global bio/pharmaceutical company.

As shown in Figure 3 , it is the authors’ recommendation that only one pharmacopoeia is referenced for the excipient in any registration. This means listing USP compliance for excipients in one registration, which may be filed in 75 or more countries that accept USP compliance. Another registration would list Ph. Eur. compliance for excipients, to be filed in another 75 or more countries, including all of Europe. The benefit of this approach becomes clear when considering the potential impact on global product registrations resulting from an update to the pharmacopoeia monograph. Executing the change control process to implement the monograph update typically requires some degree of regulatory impact assessment by the chemistry, manufacturing, and controls (CMC) function of a company to determine if any actions are necessary. Assume, for example, the update is to the USP monograph. If the company has filed the somewhat ambiguous “USP/Ph. Eur.” compliance in 150 countries, then the company will need to complete regulatory impact assessment for product registrations in all 150 countries. By contrast, if the company has filed specific compliance to USP in 75 countries, then the impact assessment is only needed for the registrations in these 75 countries. No change control or impact assessment is needed for the other 75 countries where Ph. Eur. compliance has been filed. This approach reduces by half the number of regulatory impact assessments needed by a company as a result of compendial updates. This workload reduction is significant given the time and complexity of looking at so many individual product registrations. Adding the country-specific registration needed for Japan that lists JP excipient compliance and for China that lists ChP excipient compliance, there are a total of only four different registrations needed for global use, acceptable in essentially every country in the world.

There are other approaches that may be taken to ensure appropriate compliance for excipients with monographs in the pharmacopoeia. In Europe, the excipient supplier can apply for Certification of Suitability to the Monographs of the European Pharmacopoeia (CEP). The CEP procedure has been in place for more than 25 years to provide assessment of the manufacturing and quality controls used for an excipient (12). Another approach introduced by USP, the Ingredient Verification Program for Excipients, provides a complete evaluation of an excipient company’s quality system to ensure control of the material’s quality and includes review of manufacturing batch records and release data, a GMP audit, product testing, and continuous surveillance monitoring (13).

Strategies for excipients:  Non-compendial

There are some instances where there is no monograph in the pharmacopoeia for an excipient that will be used in a drug product. These so-called “non-compendial” excipients could be novel materials that have not previously been approved in a drug product or simply a material where a pharmacopoeia monograph has not been established. Non-compendial excipients introduce another set of considerations to help guide a company’s strategy. As noted previously, the safety, toxicology, and/or GRAS status must be assessed for the non-compendial excipient. Because compendial grade is not an option, the sourcing decision defaults to supply grade to ensure visibility to the supply chain and change control for the excipient.

The questions now center on the appropriate testing and filing for the material. Looking first at testing, how does the excipient user establish appropriate specifications when there is no compendial monograph for the material? The starting point is the supplier’s specifications, but there are additional questions to be considered. Should the excipient user include all tests from the supplier’s specifications? Should the same methods be used, if they are available from the supplier? Are there tests or methods in the general chapters of the pharmacopoeia that could be used for the material? Should the company apply the same acceptance criteria to the material, or is there a particular range for a quality attribute that is needed for their manufacturing process? Are there other functional requirements that should be added to ensure appropriate control for the excipient? Because the excipient supplier will likely have no visibility to the specific use of the excipient in the drug product, the user must ensure agreement with the supplier on any additional tests or limits for the material. Not doing so could result in the supplier being unable to consistently provide material that meets the user’s specifications, putting the supply of the drug product at risk. The ultimate goal, as emphasized previously, is to establish overall testing requirements that ensure the excipient has appropriate quality, is fit for purpose in the drug product, and can be procured on an ongoing basis.

Once the specifications have been established for the non-compendial excipient, consideration turns to the product registration. In this case, there is not the ability to make the simple but specific reference to quality requirements listed in a monograph for the material. Which of the tests established for the non-compendial excipient should be included in the filing? Clearly, there are tests that are required for the excipient that should be listed, becoming regulatory commitments to control the quality of the material. There may also be some tests that can be maintained as internal tests, as described earlier. Additional information, beyond quality requirements, will also be needed in the registration for a novel excipient.

An interesting situation experienced by one of the authors helps to illustrate the subtlety of the considerations that can enter into a company’s strategy for excipient testing and filing. A new product under development included an excipient that had not been previously used by the company. On searching, the CMC group found there were no monographs for the material in either the USP or Ph. Eur. , but there was a monograph in the French Pharmacopoeia (Ph. Fr.) . The CMC scientist wanted to take the simple and seemingly appropriate action of filing the excipient to comply with the Ph. Fr. monograph. In discussion with the compendial affairs group, however, it was pointed out that the Ph. Fr. was not included in the company’s pharmacopoeia surveillance process, for a variety of reasons, including available resources and the need for translation. This raised the risk that any future change to the Ph. Fr. excipient monograph could jeopardize the company’s compliance for the material, as committed in the registration. Should the material be filed with the Ph. Fr. reference, which would likely be acceptable throughout Europe, but perhaps not as widely accepted by other countries? Is there another approach that could be taken? The compendial affairs group recommended the material be filed as a non-compendial excipient to avoid the compliance risk. However, the specifications listed in the Ph. Fr . monograph at the time of filing would be used to establish the tests, methods, and acceptance criteria to control the material, becoming manufacturer’s specifications rather than compendial specifications. If questioned upon review by a health authority, the alignment with the Ph. Fr. monograph could be shown. By listing the requirements as manufacturer’s specifications, however, the compliance risk was removed with no additional surveillance activities required by the company to monitor potential changes to the Ph. Fr. monograph. It is conceivable that another company would have made a different decision and filed the excipient to meet the Ph. Fr. requirements. This points to the reality that, taking all considerations into account, there is not always a single decision that is best for all companies. The lesson is that the affected groups should come together and discuss the functional requirements, quality requirements, and regulatory expectations for the material to determine the appropriate strategy.

Strategies for raw materials

The strategies and functional area decisions for the case where the selection process determines an ingredient will be used as a raw material for the preparation of the drug substance are presented in Figure 4 . As shown in the columns, the recommended sourcing decision is supply grade or compendial grade, either of which can provide the desired supply chain and change control visibility for the material. Sourcing compendial grade for the raw material does not mean it would be tested or filed as compendial grade. It is unnecessary to consider multi-compendial grade material as this will simply be more costly to purchase. If compendial or supply grade material is not available, or if it is otherwise suitable for the material to be purchased as a commodity, then reagent-grade material can be considered, with the cautions mentioned earlier taken into account. The testing decision is to include only the minimum requirements that are needed to ensure the raw material is fit for purpose, in terms of its quality and functional attributes. The filing decision is also to include only the minimum requirements necessary, with no reference made to a compendial monograph, if one is available for the material. In establishing the specifications for the material, some tests from an available monograph or from general chapters in the pharmacopoeia might be included, since these can be useful. There should be no commitment to comply with the monograph, however, because that is neither necessary nor appropriate for the intended use of the raw material in drug substance manufacture. Recall the product lifecycle can span many years from development to registration to supply, with many functional areas involved in decision-making throughout the process. With this in mind, in the authors’ experience, the decisions made for raw materials pose the greatest risk of internal disconnects between what is filed and what is sourced or tested, as represented in Figure 1 . Committing to more than is necessary for the raw material in the product registration has unfortunate practical and long-lasting impact to other functional groups in the company.

Strategies for  residual materials

As noted in Figure 4 , the strategy for a residual material would generally align with the raw material strategy. Similar to raw materials, the decisions made for residual materials pose a risk of disconnects between what is filed and what is sourced or tested. Consistent application of the principles and strategies described in this article can help avoid these disconnects, ensure appropriate testing, and reduce the potential compliance burden and risk.

Principles and strategies have been provided to help companies develop a consistent, cross-functional approach for the appropriate selection, sourcing, testing, and filing of raw materials used in the preparation of drug substances and excipients used in drug products. Having a common understanding of definitions based on how the materials are used and for material grades based on what is purchased and how it is tested can facilitate appropriate decisions by impacted groups across the product lifecycle. The decision of what is included in the product registration is particularly critical. The often-complex answers to seemingly simple questions-What do you need? What do you buy? What do you test? What do you file?-help guide a company’s decisions that can provide less complexity and ensure compliance with applicable compendial and regulatory requirements.

Acknowledgment

The authors gratefully acknowledge the contribution of Susan J. Schniepp for her technical review and helpful suggestions during the preparation of this series of articles. Sincere appreciation also goes to representatives from the development, quality, regulatory, and compendial affairs functions at Merck & Co., Inc. for valuable discussions over many years that helped shape the concepts, principles, and strategies described in this article.

J.M. Wiggins and J.A. Albanese, “A Practical Approach to Pharmacopoeia Compliance,” BioPharm International Regulatory Sourcebook eBook, xx-xx (March 2020).

J. M. Wiggins, “Excipients: Appropriate Selection, Sourcing, Testing, and Filing in a Global Environment,” Presentation at Excipient World Conference, National Harbor, MD (May 6–7, 2019).

J.M. Wiggins and J.A. Albanese, “Why Pharmacopoeia Compliance Is Necessary,” BioPharm International Regulatory Sourcebook eBook (September 2019).

EDQM, General Notices, Section 1.1 General Statements-Demonstration of Compliance with the Pharmacopoeia, Ph. Eur. 10th Edition (Jan. 1, 2020).

USP, General Notices, Section 3.10 Conformance to Standards-Applicability of Standards, Second Supplement to USP42-NF37 (Dec. 1, 2019).

J.M. Wiggins and J.A. Albanese, “Why Pharmacopoeia Compliance Is Difficult,” BioPharm International Regulatory Sourcebook eBook (September 2019).

ICH, Quality Guidelines, ICH.org .

Code of Federal Regulations, Title 21, Chapter I, Subchapter C, Part 211, Subpart E, Section 211.84 (d), “Testing and approval or rejection of components, drug product containers, and closures” .

J. M. Wiggins, American Pharmaceutical Review 6 (3), 10–14 (Fall 2003).

EDQM, General Notices, Section 1.1 General Statements-Alternative Methods, Ph. Eur. 10th Edition (Jan. 1, 2020).

J.M. Wiggins and J.A. Albanese, “Revision Process for Global/National Pharmacopoeias,” BioPharm International Regulatory Sourcebook eBook (December 2019).

EDQM, “Certification of Suitability-About the Procedure-Background & Legal Framework,” EDQM.eu .

USP, “Ingredient Verification Program for Excipients,” USP.org .

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The raw-materials challenge: How the metals and mining sector will be at the core of enabling the energy transition

The transition to a net-zero economy will be metal-intensive. As the move toward cleaner technologies progresses, the metals and mining sector will be put to the test: it will need to provide the vast quantities of raw materials required for the energy transition. Because metals and mining is a long lead-time, highly capital-intensive sector, price fly-ups and bottlenecks will be unavoidable as demand outstrips supply and price volatility creates uncertainty around the large up-front capital investments needed for production. Supply, demand, and pricing interplays will emerge across different commodities, leading to feedback loops followed by a combination of technology shifts, demand destruction, and materials substitution. Metals and mining companies will be expected to grow faster—and more cleanly—than ever before. At the same time, end-user sectors will need to factor potential resource constraints into technology development and growth plans.

About the authors

This article is a collaborative effort by Marcelo Azevedo, Magdalena Baczynska, Patricia Bingoto, Greg Callaway, Ken Hoffman, and Oliver Ramsbottom , representing views from McKinsey’s Metals & Mining Practice.

By the end of the November 2021 United Nations Climate Change Conference (COP26), it became clear that momentum had shifted. Climate commitments made in Glasgow have entrenched the net-zero target of reducing global carbon emissions (aimed at preventing the planet from warming by more than 1.5°C) as a core principle for business. At the same time, another reality became apparent: net-zero commitments are outpacing the formation of supply chains, market mechanisms, financing models, and other solutions and structures needed to smooth the world’s decarbonization pathway . Even as debate continues over whether the conference achieved enough, it is evident that the coming decade will be decisive for decarbonizing the economy. While every sector in the global economy faces common pressures—such as stakeholder and investor demands to decarbonize their own operations— metals and mining companies have been presented with a special challenge of their own : supplying the critical inputs needed to drive the massive technological transition ahead.

Raw materials will be at the center of decarbonization efforts and electrification of the economy as we move from fossil fuels to wind and solar power generation, battery- and fuel-cell-based electric vehicles (EVs), and hydrogen production. Just as there are several possible trajectories through which the global economy can achieve its target of limiting warming to 1.5°C, there are corresponding technology mixes involving different raw-materials combinations that bring their own respective implications. No matter which decarbonization pathway we follow, there will be fundamental demand shifts—and these will change the metals and mining sector as we know it, creating new sources of value while shrinking others.

Requirements for additional supply will come not only from relatively large-volume raw materials—for example, copper for electrification and nickel for battery EVs, which are expected to see significant demand growth beyond their current applications—but also from relatively niche commodities, such as lithium and cobalt for batteries, tellurium for solar panels, and neodymium for the permanent magnets used both in wind power generation and EVs (Exhibit 1). Some commodities—most notably, steel—will also play an enabling role across technologies requiring additional infrastructure.

Rare-earth metals

Rare-earth metals’ existing global reserves (in aggregate across different metals) are believed to be 120 million metric tons of rare-earth-oxide (REO) equivalent, representing 500 years equivalent of the global estimated production of 240,000 metric tons in 2020. 1 “Mineral commodity summaries: Rare earths,” United States Geological Survey, January 2021. However, when looking closer, a number of factors stand out. First, these elements occur in relatively low concentrations; therefore, identifying and bringing assets to production would likely come with higher investment needs and lead times. Second, specific elements (for example, neodymium), which are critical for the transition, occur at very different proportions within those deposits. This makes the availability and economics of specific metals much more nuanced than a superficial analysis can reveal. Third, there is a significant geographical concentration of known reserves: 40 percent of REO-equivalent reserves are estimated to be in China. Therefore, additional geological exploration would be needed to identify other economically viable deposits in specific geographies. Finally, in addition to the availability of raw materials, processing and separation of the specific elements is crucial. To date, most of the processing and separation capacity, as well as the technical capabilities, are also concentrated in China. Energy transition will therefore require a regional redistribution of processing capacity and reorganization of supply chains.

The required pace of transition means that the availability of certain raw materials will need to be scaled up within a relatively short time scale—and, in certain cases, at volumes ten times or more than the current market size—to prevent shortages and keep new-technology costs competitive (see sidebar “Rare-earth metals”).

Economic growth, technology development, and material intensity as drivers of demand growth

Mine supply and solar-panel production.

Tellurium, a relatively niche metal used in certain types of solar panels, has a global mine production of approximately 500 metric tons. 1 “Mineral commodity summaries: Tellurium,” United States Geological Survey, January 2021. A tellurium-only mine does not exist, as it is exclusively produced in small quantities as a by-product of the smelting and refining of other metals (more than 90 percent of tellurium is produced from anode slimes collected from electrolytic copper refining 2 “Mineral commodity summaries: Tellurium,” United States Geological Survey, January 2021. ). As such, while demand growth driven by solar capacity may be prodigious, growth in supply is expected to be capped at the growth rates of metals such as copper. Even though copper demand is also expected to experience significant growth due to the energy transition, its mine supply is unlikely to expand at the rates that solar-panel production needs in a net-zero-transition scenario.

Road-transport and power-generation are examples of sectors that are relatively advanced with respect to their technological readiness to reduce greenhouse-gas (GHG) emissions. But building a low-carbon economy and reducing the emissions intensity within these sectors will be materials-intensive (Exhibit 2). For example, generating one terawatt-hour 1 This comparison is made on a per-terawatt-hour basis and not on a per-gigawatt (GW)-capacity basis, as commonly seen in literature, since the different technologies will have different capacity factors and lifetimes; therefore, the amount of electricity generated from one GW capacity would not be the same when comparing technologies. Equally, for vehicles, the comparison is done on a per-kilometer basis and not on a per-vehicle basis. Emission intensity factors can vary greatly depending on location and choice of materials. of electricity from solar and wind could consume, respectively, 300 percent and 200 percent more metals 2 Here we are only measuring metals needs. In addition to metals, other materials (most notably, concrete) will have different requirements depending on the power-generation technology. than generating the same number of terawatt-hours from a gas-fired power plant, on a copper-equivalent basis, 3 Copper-equivalent conversion used 2015–21 average prices for each metal. The conversion is used to emphasize the need for smaller-volume metals, such as palladium, which otherwise appear irrelevant when compared with steel, for example. while still drastically reducing the emissions intensity of the sector—even when accounting for the emissions related to the materials production. 4 For more information on materials-production-related emissions, see “ Pressure to decarbonize: Drivers of mine-side emissions ,” McKinsey, July 7, 2021; MineSpans by McKinsey. (See sidebar “Mine supply and solar-panel production” for more on how supply of an essential raw material is currently limited.) Similarly, producing battery or fuel-cell EVs will be more materials-intensive than building an internal combustion engine (ICE) vehicle.

When building new power-generation capacity or producing new vehicles, factors other than material intensity also influence each technology’s carbon footprint. 5 Emission intensities within the same technology can vary greatly (see examples on Exhibit 2). First, there are the emissions derived from use of the technology throughout its life cycle (such as the burning of fossil fuels in power generation, or the use of electricity in running a battery EV). Second, the emission intensity of each technology will depend, to a certain extent, on the choice of material (for example, steel versus aluminum in the case of vehicles). Third, even when using the same material, choice of supplier can make a significant difference, since the carbon footprint of the same commodity can vary greatly depending on its origin. Finally, each sector will have its own specificities. In the case of power generation, renewable capacity has lower capacity factors than fossil-fuel-based capacity. As such, more generation capacity and, hence, more metals are needed to generate the same amount of electricity. In the case of road transport, the average mileage of different powertrains could also play a role (for example, if battery EVs and fuel-cell EVs were to be driven for longer distances over their lifetimes compared with ICEs).

How quickly can supply react?

Looking ahead, under a scenario in which materials are required at steadily growing levels to meet evolving needs but markets fail to adapt to varying technology mixes 6 For more on McKinsey’s scenarios for decarbonization of the power and road-transport sectors, visit McKinsey Center for Future Mobility, Power Solutions and Energy Insights. and materials intensities over time, hypothetical shortages of raw materials would emerge—as demand is expected to grow significantly faster than supply. Under the scenario presented in Exhibit 3, lithium mine supply, for example, would need to grow by around a factor of seven versus today’s required growth. Meanwhile, metals with smaller mine supply (such as tellurium) would need to show even faster growth—as such, these are the main candidates for required substitution and technological innovation. Other metals, such as copper and nickel, would also need to see accelerated supply growth compared with what has been observed in the past. While the required growth in such metals may seem less ambitious, this should be considered relative to the significantly larger-scale industries surrounding them, as well as the significant capital required, increasingly challenging geological conditions (such as smaller deposits and lower grades), long lead times, and growing processing complexity involved. For copper and nickel alone, we estimate that meeting demand growth of the order of magnitude shown in Exhibit 3 would require $250 billion to $350 billion cumulative capital expenditures by 2030, both to grow and replace depletion of existing capacity. Despite a relatively large pipeline of projects to scale up supply in some of these commodities, and efforts to reduce the capital and operating costs associated with a number of them (such as direct lithium extraction), the task at hand is not trivial. In fact, in the scenario presented in Exhibit 3, we could see copper and nickel demand exceeding supply by five to eight million and 700,000 to one million metric tons, respectively. As such, incentives for new supply growth will be necessary.

Price incentives

Nickel and battery production.

Nickel, which is used in battery production, is widely available in the earth’s crust. However, it is subject to a number of commodity-specific factors. First, while battery-suitable nickel (that is, class 1 nickel) can be produced from the various deposit types (sulfides, laterites), relatively long lead times of ten years or more from discovery to feasibility, construction, and ramp-up, along with the high capital intensity of greenfield assets, could lead to short-term deficits. Second, nickel is a relatively established market , but it is primarily used in stainless-steel production (around two-thirds of the global nickel supply was used in stainless-steel production in 2020). The fast growth in nickel demand from batteries, therefore, may potentially lead to a fly-up in prices and require large-scale substitution and technological innovation to rebalance the market—either in batteries themselves, forcing a move to different battery chemistries, or in established markets such as stainless steel, driving a shift in stainless-steel-series production, or both—unless capacity starts to rise quickly, combined with conversion of lower-grade class 2 nickel into class 1 nickel.

Thus, while there may not necessarily be physical resource scarcity for some of these raw materials in the earth’s crust, and acknowledging that recycled materials will play an increasingly important role in decarbonization in the future, the trajectory toward materials availability will not be a linear one. We expect materials shortages, price fly-ups, and, given the inability of supply to react quickly, the need for technological innovation and substitution of certain metals (possibly at the expense of performance and cost of the end-use application). While raw-materials needs will grow exponentially for certain metals, lead times for large-scale new greenfield assets are long (seven to ten years) and will require significant capital investment before actual demand and price incentives are seen. At the same time, with increasingly complex (and largely lower-quality) deposits needed, miners will require significant incentive (for example, consistent copper prices of more than $8,000 to $10,000 per metric ton and nickel prices of more than $18,000 per metric ton) before large capital decisions are made (see sidebar “Nickel and battery production”). Without slack in the system (such as strategic stockpiles and overcapacity), the industry will not be able to absorb short-term (less than five to seven years) exponential growth. As seen, for example, with past reduction of cobalt intensity in batteries, a combination of technological development on the supply side and large-scale substitution and technological development on the demand side will occur. Substitution in noncritical applications will take place and new extraction and processing technologies will emerge. An individual sector’s ability to rapidly ramp up supply, as well as other factors such as continued technological development and performance, available material alternatives and carbon-footprint implications for end-use applications, to name a few, could all impact the extent of substitution for individual commodities. Hence, we see commodities such as tellurium, with its small volumes and by-product nature, likely requiring substitution, while lithium, despite the fast expected growth, perhaps not as much, given the relatively large pipeline of projects and continued development of new production technologies.

How market balance is achieved

Despite the potential for shortages, as discussed above, supply will always equal demand. As sectors and countries decarbonize, each individual commodity market will face specific supply-and-demand balances. The resulting picture will not mirror any specific forecasted commodity demand, including the scenario outlined in Exhibit 3, but what we will see is a constant feedback loop between supply, demand, and prices. We believe that commodities facing an upside in demand from the energy transition will follow one of three trajectories, as demand accelerates (Exhibit 4):

• Supply responds to prices. As demand accelerates and prices react, the industry is able to bring in new supply (for example, lithium) relatively quickly. In such cases, the technological transition follows the “expected” growth, where the commodity does not become a structural bottleneck, even if there is short-term volatility.
• Demand accelerates, prices react strongly, and materials substitution kicks in. The industry is unable to bring in new supply fast enough and technological innovation leads to materials substitution within that application (for instance, cobalt after a price spike). In such cases, performance of the technology deployed may be compromised, with implications for overall needs, for example, lithium iron phosphate (LFP) batteries being less energy dense than NMC 7 Lithium nickel manganese cobalt oxide (LiNiMnCoO2). batteries.
• Demand accelerates, prices react strongly, and technology substitution kicks in. In this case, rather than materials substitution within the application, the end-user sector is forced to shift its technology mix. In such a scenario, a different bottleneck may emerge. For example, non-tellurium-based solar panels may have lower performance, which may lead to a shift toward more wind-generated power, adding pressure on neodymium.

We have observed the second trajectory within the battery sector, where there are three very distinct phases in the feedback loop. Initially, batteries with a relatively high cobalt content were common. As adoption began to accelerate, and cobalt prices reached $100,000 per metric ton in 2018, batteries with cathodes containing more nickel started gaining share. This substitution was in the end seen as a win–win result for the industry, leading to lower battery costs and higher energy density.

Subsequently, as high-nickel-containing batteries started becoming more common, the industry began to realize the scale of the task ahead: a large growth in class 1 nickel demand in an industry that has faced capital-expenditure overruns, delays, and in several cases, failure to reach design capacity. Nickel prices also started going up as consumers tried to secure supply.

Today, battery producers and OEMs speak about optionality, with a tiered approach to battery technology. LFP batteries have started gaining share again, while high-manganese-content batteries are also expected to be developed. Manganese is a compelling alternative, as its global production of approximately 20 million metric tons 8 “Mineral commodity summaries: Manganese,” US Geological Survey, January 2021. is four to five times greater than nickel production and 140 times greater than cobalt production. Meanwhile, manganese reserves of 1.3 billion metric tons are 16 times greater than reserves of nickel and 140 times greater than reserves of cobalt. 9 MineSpans by McKinsey.

This cycle is likely to keep evolving, as battery technology moves ahead, adoption accelerates, and possible new bottlenecks arise. And as other sectors make the energy transition, individual commodity sectors’ ability to ramp up quickly will be put to the test. With power generation, a similar cycle could follow, for example, with tellurium and silver potentially becoming a bottleneck for production of solar panels; with neodymium and praseodymium, for the rare-earth-based permanent magnets used in wind power generation; and potentially even with the extra uranium needed for additional nuclear-generation capacity.

Implications for producers and end-user sectors

The energy transition will force every sector of the economy to adapt, each with its own specific challenges.

As the raw-materials supplier to the economy, the mining sector will need to grow at an unprecedented pace in order to enable the required technological shifts. The sector will be expected to move at a faster pace, despite its traditional reputation as a long lead-time, highly capital-intensive industry. As metals will undoubtedly play a crucial role in keeping the planet within a 1.5°C warming scenario, producers of metals commodities will need to undertake the following:

• (Re)build a growth agenda. In the context of shifting commodity value pools and rebalancing portfolios, the mining sector has underinvested for several years—an issue accentuated in 2020 by the COVID-19 pandemic. With the expected demand growth ahead, miners will need to rebuild their growth portfolios. This can take multiple forms, from grass-roots exploration to selective M&A and creating exposure to recycling. The sector’s financial health has improved significantly since 2015, with lowering debt-to-equity ratios and significant cash generation, although balance-sheet health will remain a key priority for most boards and executive teams, given the sectors’ cyclicality.
• Innovate for productivity and decarbonization of operations. Technological innovation will be an important lever both to enable debottlenecking and growth (for example, advanced analytics in mining and processing) and to facilitate reduction of the carbon footprint in operations (for example, fleet electrification, water management).
• Embed themselves into supply chains. Due to both the specific requirements of a number of decarbonizing technologies and the strict emission-footprint-reduction targets from end-user sectors, a number of metals will become less commoditized. Just as procurement by end-user sectors will change, so will the marketing and sales of metals. Understanding customers’ product specifications and requirements and partnering with consumers will be key, as will capturing quality and green premiums in the context of tightening supply–demand balances. In addition to placing volume on the market, this lever will help to manage downstream Scope 3 emissions from raw-material producers.

At the same time, consumers of raw materials will need to factor potential resource constraints into technology development and growth plans. The following solutions are on the table  for consideration:

• Adapt technology rollout plans. In response to raw-materials price volatility and supply constraints, companies will need to identify and distinguish between hard and soft constraints around technology rollout—and then engineer raw materials that may be difficult or expensive to source.
• Send clear demand signals and secure raw-material supply. Clearly signaling growth, technology mix, and material needs will be an important mechanism to enable raw-material suppliers to approve large capital investments. This will take place (and is already doing so) in multiple forms: from off-take agreements with producers and partnerships with raw-materials suppliers to equity ownership of raw-material production. Irrespective of the strategy used, companies along the supply chain, such as cathode-active material producers, EV OEMs, and battery producers, will need to secure raw materials to enable aggressive growth plans, while also decarbonizing their own supply chains.

Marcelo Azevedo is an associate partner in McKinsey’s London office, Magdalena Baczynska is a research science analyst in the Wroclaw office, Patricia Bingoto is a senior knowledge expert in the Zurich office, Greg Callaway is a consultant in the Johannesburg office, Ken Hoffman is a senior expert in the New York office, and Oliver Ramsbottom is a partner in the Hong Kong office.

The authors wish to thank Jochen Berbner, Nicolò Campagnol, Julian Conzade, Stephan Görner, Michael Guggenheimer, Benoît Petre, Humayun Tai, and Michel Van Hoey for their contributions to this article.

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This case details The Boeing Company's raw material supply chain risks and explores appropriate strategies to mitigate them. Aluminum and titanium accounted for about 75% of the weight of a typical large commercial aircraft, so Boeing and its suppliers bought hundreds of millions of pounds of these metals every year in order to manufacture structural parts. But Boeing's forecasting methodologies for aluminum and titanium consistently underestimated true demand, which cost the company significant time and money. The case describes an ineffective scrap recovery process which failed to recover millions of dollars of precious scrap material, as well as a disproportionately low allocation of risk mitigation resources to raw material mills. Students will analyze purchasing policies pertaining to supplier evaluation and develop new strategies to minimize raw material costs.

Learning Objectives

1) Understand the risks of raw material flow interruptions in the supply chain.

2) Examine external versus internal causes of suboptimal supply chain performance.

3) Identify internal processes in need of improvement to ensure efficient supply chain functionality.

4) Analyze purchasing policies pertaining to supplier evaluation and develop new strategies to minimize raw material costs.

Apr 5, 2019

Discipline:

Operations Management

Geographies:

United States

Industries:

Aerospace sector, Fabrication and manufacturing

WDI Publishing at the University of Michigan

W58C01-PDF-ENG

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• Case Studies

The ‘Raw’ Case Approach

When Yale SOM developed the integrated curriculum, a case writing team was formed to create materials in support of this new approach to management education. In the subsequent years, the SOM Case Research and Development Team (CRDT) has contributed nearly two hundred pieces of material to the SOM curriculum on a wide variety of topics and from numerous global locales. CRDT has also pioneered a new type of case study, the “raw” case, that better reflects the new curriculum—and actual management practice. 

In 2007, the SOM faculty and CRDT began experimenting with using multi-media on the web to deliver case materials. These experiments led to an entirely new paradigm, the raw case, that improved upon the traditional case method and afforded new pedagogical opportunities.

Raw cases replicate the way that individuals access and use information in the real world: management dilemmas do not manifest themselves in neat 10–15 page narratives, but rely on an individual’s ability to synthesize information from a variety of channels. The web-based platform also allows students to view, search, absorb, and analyze the material in a non-linear manner. Determining what information is relevant and how it relates to the questions at hand is part of the learning experience. It also allows students to tailor their experience of the case to their own interests, in that they may choose to skim some topics while going into greater depth on other issues.

Consider the SELCO raw case. SELCO is an Indian company that specialized in bringing solar electric products to the poor. In 2009, the company needed a new growth strategy. As students consider the company’s dilemma, the raw case allows them to view video interviews with company leaders and customers, inspect maps of SELCO’s service areas, see videos describing how SELCO’s products were being used, consider articles on India’s electricity grid and socio-economic conditions, read about the company’s founding, consult the company’s organization charts, income statements and balance sheets, inspect the company’s innovative products, review the company’s business models, read news articles about the company’s success, and so on.

Raw cases are also designed to enable faculty to break through the traditionally “siloed” approach to business problems. In the SELCO case, students have to analyze marketing, design, financial, organizational, government relations, and financing problems in the context of a growth strategy. At Yale SOM, raw cases are often co-taught by faculty from different disciplines.

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From the first, SOM case writers and film crews have ventured to numerous locations in the United States, as well as international settings that include India, South Africa, Sweden, and China. Casting a wide geographic net allows CRDT to bring back management dilemmas from a number of contexts and cultures, as well as to spotlight trends in emerging and established markets, all for the benefit of preparing SOM students to lead across sectors and regions. Launched in 2012, the Global Network for Advanced Management consists of 28 business schools from around the world.

The creation of the Global Network for Advanced Management has increased the ability of the CRDT to offer global content through case-writing collaborations with other schools. For example, the Yale SOM team collaborated with EGADE Business School (Tecnológico de Monterrey) to focus on Walmart of Mexico’s sustainability efforts and relationship with the Mexican electricity grid. In another Global Network collaboration, Yale CRDT collaborated with faculty at the National University of Singapore to produce a case about the burgeoning palm oil industry and its relationship to environmental regulation and the Indonesian labor market.

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For those management challenges that do call for a more discipline-focused approach to a particular topic, the CRDT has produced more than 75 traditional-format cases for use in Yale classrooms. Many of these cases have been adopted at other business schools in the United States and elsewhere. In addition to cases, the team has produced technical notes and other pedagogical materials to support the school’s curriculum.

Though initially developed for use only at Yale SOM, the majority of CRDT cases are now available to other accredited business schools and management programs. Some cases are available under Creative Commons licensing. Others are available for purchase through one of our  publishing partners  or the  Yale Management Media store . 

Case spotlight: Boeing’s Strategic Initiative: Raw Material Supply Chain Risk Mitigation

This case was featured in  Connect , issue 43, January 2020 .

Author perspective

Who – the protagonist.

Andrew Burgess, Senior Manager of supplier performance for aircraft materials and structures at The Boeing Company .

Boeing is a global leader in the design, manufacture and sale of commercial and military aerospace equipment.

Aluminium and titanium are key to Boeing’s raw material production, so if they couldn’t obtain the material they needed to produce parts, airplanes couldn’t be built.

The risks urgently needed to be mitigated as Boeing were at risk of losing supply from one of its largest titanium mills in Russia, with the US Government looking to ramp up trade sanctions on the country.

In 2014 and 2015 Boeing paid over $2.6 million in penalty charges for failing to meet minimum mill scrap recycling requirements.

By 2017, Boeing was collecting almost all of its recoverable titanium scrap, but around 60% of the scrap was classified as non-recoverable.

Boeing is the top US manufacturer exporter, supporting airlines and government customers in 150 countries.

“Boeing relied on suppliers to deliver millions of parts on time and at an acceptable quality standard to assemble airplanes for timely delivery. If even one part was missing, planes could not be delivered, making supply chain risk assessment a critical part of Boeing’s strategy.” Excerpt from the case.

Andrew faced a number of questions. How could the company better forecast its raw material needs? How could it rework its PRA process to better suit raw material mills? Could it better limit errors in the ordering, processing and shipment steps of the supply chain?

AUTHOR PERSPECTIVE 

Placing things into context

Prakash said: “Students really enjoy the realistic context of the case study. This case provides adequate facts and data, so that students can quickly grasp the serious threat to Boeing of raw material supply disruption from aluminium and titanium mills. They appreciate how a large, global, high technology company like Boeing can be quite vulnerable to basic metal supply and demand. Also, the name “Boeing” itself adds to the cache of the case.”

Perfect case

Prakash continued: “The case was written and published prior to the public disclosure of the full extent of the 737 Max problems. In retrospect, I think it is a perfect case to analyse.

“The analysis reveals that Boeing is an extremely well-run company and has good management systems in place to run their business, albeit these management processes can always be improved. The case provides students opportunities to identify these improvements.”

He concluded: “I think cases in the Production and Operations Management field have certain vigour and vitality. They are data rich and usually describe real life situations that students can relate to.

“Personally, I am biased towards Production and Operations management issues because this is where “all the action is.” This is where companies produce products, provide services and contribute to the well-being of society.” 

The protagonist

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The strategic procurement of raw material: a case study

Sanjita Jaipuria , M. Jenamani , M. Ramkumar

Sep 3, 2016

Influential Citations

International Journal of Procurement Management

Key takeaway

This study proposes a quantitative approach to develop kraljic's sourcing matrix, combining spend analysis, kraljic's purchasing portfolio model, and market analysis to optimize raw material procurement strategies..

Strategic procurement is essential to ensure uninterrupted availability of raw material at a competitive cost for the smooth production operation. Kraljic's purchasing portfolio model is widely used in strategic procurement practice. However, hardly any quantitative model has been discussed in existing literature to develop Kraljic's sourcing matrix. Hence, in this study a quantitative approach has been proposed to develop Kraljic's sourcing matrix. Many times the market condition affects the procurement activity. The total procurement cost generally comprises of different cost components and through adopting strategic approach the controllable cost components can be reduced. Therefore, including Kraljic's purchasing portfolio model, two techniques such as spend analysis and market analysis is applied to identify the strategic issues based on the cost structure and market condition. In this study the framework to develop procurement strategy using spend analysis, Kraljic's purchasing portfolio model, and market analysis is described through a case study.

THE EFFECTIVENESS OF IMPLEMENTING AN ERP SYSTEM FOR RAW MATERIAL (Case Study at PT. Pharmacy)

• Salsabila Taufanti, Viera Sree Rahayu, Moch Irsyad Effendi, Nurtika Indria, Rainer Agustinus, Veronica Christina

Inventory is an asset of great value in a company, the ineffectiveness of inventory management will cause problems for the company. This study is intended to evaluate the effectiveness of implementing Enterprise Resources Planning (ERP) in order to find solutions to problems faced by pharmaceutical companies that have very large types and quantities of inventory. This research is a descriptive study, by collecting data using questionnaires distributed to ERP users as well as conducting observations and interviews. The results showed that the ERP applied to the company was effective in terms of system quality, information quality, service quality, user satisfaction, and employee performance.

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Friday, May 24, 2024

High H5N1 influenza levels found in mice given raw milk from infected dairy cows

Mice administered raw milk samples from dairy cows infected with H5N1 influenza experienced high virus levels in their respiratory organs and lower virus levels in other vital organs.

Mice administered raw milk samples from dairy cows infected with H5N1 influenza experienced high virus levels in their respiratory organs and lower virus levels in other vital organs, according to findings published in the New England Journal of Medicine. The results suggest that consumption of raw milk by animals poses a risk for H5N1 infection and raises questions about its potential risk in humans.

Since 2003, H5N1 influenza viruses have circulated in 23 countries, primarily affecting wild birds and poultry with about 900 human cases, primarily among people who have had close contact with infected birds. In the past few years, however, a highly pathogenic avian influenza virus called HPAI H5N1 has spread to infect more than 50 animal species, and in late March, the United States reported a viral outbreak among dairy cows in Texas. To date, 52 cattle herds across nine states have been affected, with two human infections detected in farm workers with conjunctivitis. Although the virus has so far shown no genetic evidence of acquiring the ability to spread from person-to-person, public health officials are closely monitoring the dairy cow situation as part of overarching pandemic preparedness efforts.

To assess the risk of H5N1 infection by consuming raw milk, researchers from the University of Wisconsin-Madison and Texas A&M Veterinary Medical Diagnostic Laboratory fed droplets of raw milk from infected dairy cattle to five mice. The animals demonstrated signs of illness, including lethargy, on day one and were euthanized on day four to determine organ virus levels. The researchers discovered high levels of virus in the animals’ nasal passages, trachea and lungs and moderate-to-low virus levels in other organs, consistent with H5N1 infections found in other mammals.

In addition to the mice studies, the researchers also tested to determine which temperatures and time intervals inactivate H5N1 virus in raw milk from dairy cows. Four milk samples with confirmed high H5N1 levels were tested at 63 degrees Celsius (145.4 degrees Fahrenheit) for 5, 10, 20 and 30 minutes, or at 72 degrees Celsius (161.6 degrees Fahrenheit) for 5, 10, 15, 20 and/or 30 seconds. Each of the time intervals at 63℃ successfully killed the virus. At 72℃, virus levels were diminished but not completely inactivated after 15 and 20 seconds. The authors emphasize, however, that their laboratory study was not identical to large-scale industrial

pasteurization of raw milk and reflect experimental conditions that should be replicated with direct measurement of infected milk in commercial pasteurization equipment.

In a separate experiment, the researchers stored raw milk infected with H5N1 at 4℃ (39.2 degrees Fahrenheit) for five weeks and found only a small decline in virus levels, suggesting that the virus in raw milk may remain infectious when maintained at refrigerated temperatures.

To date, the U.S. Food and Drug Administration (FDA) concludes that the totality of evidence continues to indicate that the commercial milk supply is safe. While laboratory benchtop studies provide important, useful information, there are limitations that challenge inferences to real world commercial processing and pasteurization. The FDA conducted an initial survey of 297 retail dairy products collected at retail locations in 17 states and represented products produced at 132 processing locations in 38 states. All of the samples were found to be negative for viable virus. These results underscore the opportunity to conduct additional studies that closely replicate real world conditions. FDA, in partnership with USDA, is conducting pasteurization validation studies – including the use of a homogenizer and continuous flow pasteurizer. Additional results will be made available as soon as they are available.

The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, funded the work of the University of Wisconsin-Madison researchers.

G Lizheng et al. Cow Milk Containing H5N1 Influenza Viruses—Heat Inactivation and Infectivity in Mice. The New England Journal of Medicine DOI: 10.1056/NEJMc2405495 (2024).

NIAID Director Jeanne Marrazzo, M.D., and Lauren Byrd-Leotis, Ph.D., with NIAID’s Division of Microbiology and Infectious Diseases’ Viral Respiratory Diseases Section, are available to discuss the findings.

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

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Effect of Raw Materials on Hardness and Metallography Test of Aluminum Matrix

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• First Online: 05 June 2024
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• Lutiyatmi Lutiyatmi 16 ,
• Eko Surojo 16 ,
• Nurul Muhayat 16 &
• Triyono Triyono 16  

Part of the book series: Lecture Notes in Mechanical Engineering ((LNME))

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• International Conference and Exhibition on Sustainable Energy and Advanced Materials

The use of aluminum is increasing because it is lightweight, wear-resistant, ductile and friction resistant. However, the waste generated is also increasing, for example, piston waste and other aluminum product waste. This aluminum waste can be recycled through a remelting process, but the quality of the product changes in its physical and mechanical properties. Aluminum waste consists of piston waste and aluminum waste as the main composite material (AMC). The reinforcement uses 10% slag from cast iron casting waste containing SiO 3 . The purpose of this study was to analyze the physical and mechanical properties of AMC waste piston products (Piston/SiO 3 ) and AMC waste aluminum (Waste Al/SiO 3 ) with 10% slag. The research was conducted by remelting AMC products using a crucible furnace. Hardness and metallographic test samples were prepared and then tested. The results show changes in test results in the remelting process of AMC products. Analysis of chemical composition tests with a spectrometer showed an increase in the value of the elements Ni, Cu and Mg which could increase the strength and hardness of the AMC material. It was observed that the results of the hardness test with microvickers showed an increase in the hardness value. Metallographic testing results in finer grains and increases the value of the product's mechanical properties. These findings indicate that the AMC material has better properties than the AMC raw material.

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Mechanical Engineering Department, Universitas Sebelas Maret, Surakarta, 57126, Indonesia

Lutiyatmi Lutiyatmi, Eko Surojo, Nurul Muhayat & Triyono Triyono

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Fakulti Kejuruteraan Mekanikal, Universiti Teknikal Malaysia Melaka, Malacca, Melaka, Malaysia

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Teknologi Kejuruteraan Mekanikal, Universiti Teknikal Malaysia Melaka, Malacca, Melaka, Malaysia

Najiyah Safwa Khashi’ie

School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore

Kit Wayne Chew

Faculty of Engineering, Mahasarakham University, Maha Sarakham, Maha Sarakham, Thailand

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Lutiyatmi, L., Surojo, E., Muhayat, N., Triyono, T. (2024). Effect of Raw Materials on Hardness and Metallography Test of Aluminum Matrix. In: Salim, M.A., Khashi’ie, N.S., Chew, K.W., Photong, C. (eds) Proceedings of the 9th International Conference and Exhibition on Sustainable Energy and Advanced Materials. ICE-SEAM 2023. Lecture Notes in Mechanical Engineering. Springer, Singapore. https://doi.org/10.1007/978-981-97-0106-3_23

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