Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

With a quality-by-design approach, robust processes consistently deliver quality product. Small drug manufacturers looking to adopt a quality-by-design (QbD) approach aim to scientifically determine product and process characteristics that will meet specific criteria set after careful analysis of the intended drug application. These critical quality attributes (CQAs) of the final drug product (and often of the API) include the physico chemical properties and performance behavior of the formulated drug (drug substance). The manufacture of small-molecule APIs often requires the production of multiple intermediates using different processes. To consistently achieve these CQAs, it is necessary to ensure that each of these processes is robust. Critical process parameters (CPPs) are, therefore, important components of an effective control strategy for ensuring that the API process consistently delivers product with the appropriate CQAs.


While true CQAs are found in the final specification for a drug product, there are several different aspects of a formulated drug, and particularly the API, that are affected by process parameters. These aspects, therefore, must be linked to the CPPs for each manufacturing process required for the preparation of an API, according to Chris Senanayake, vice-president of chemical development for Boehringer Ingelheim Pharmaceuticals. These characteristics include, but are not limited to, total purity, individual impurity levels, the polymorph(s), solvates, pH, water content, and particle size.

For the API, the most common CQAs are related to impurities from chemical processes and the solid-state properties (e.g., particle size, polymorphism) of the drug substance, according to Gert Thurau, group leader, Technical Regulatory at Roche. It is essential to control impurities for the safety of the drug product, while control of the solid-state properties of the drug substance is necessary to achieve consistent product properties, including bioavailability. “Once these attributes have been defined, it is possible to define what is important to the process and build a process that comes closer to quality by design and is, therefore, highly robust,” he says. The assay and impurity profile of an API are essentially inter-related and are important because low impurity levels translates to safety for patients, while a high assay indicates appropriate efficacy, according to Vishwanath Nadig, associate director of quality assurance for Dr. Reddy’s Custom Pharmaceutical Services (CPS). Nadig adds that moisture content is also important because, in some cases, the presence of moisture may accelerate degradation of the drug substance.

These CQAs should be selected such that if the final product has these attributes, then it will work for its intended purpose. CPPs should then be selected because they have a relationship to the final CQAs and, when controlled, will assure the manufacture or a product with the right CQAs, according to Senanayake. “CPPs are the process parameters that affect the critical quality attributes of the API, and it is important to determine the range for each critical process parameter expected to be used during routine manufacturing and process control,” adds Mark TePaske, director of regulatory affairs, quality, and compliance for Cambrex. Most importantly, it is essential to establish appropriate CPPs for each individual process step because they will ultimately affect the quality of the drug, which in turn can impact efficacy, according to Nadig. “Establishing and meeting CPPs and CQAs allows quality to be built into the process and affords robustness beyond release testing,” adds TePaske.  He also notes that well-defined CPPs ensure that a process operates in a state of control and in a validated state, which is crucial, because process validation is a cGMP requirement.

The definition of the CQAs for the final drug product and API is the first step in a comprehensive risk-based approach to product and process development, according to Thurau. “The starting point of the analysis is typically the quality target product profile, which leads to defining the critical quality attributes for the final product, and in turn, the critical quality attributes for the drug substance. Since the most important CQAs of the final API are the process-related impurities, which mostly result from the starting and raw materials, it is essential to understand the chemistry of the individual process steps,” he explains. In addition to risk assessment, Senanayake adds that prior knowledge, designed experiments, and regulatory expectations all play a role in determining CQAs and CPPs.


Once CQAs are defined, typically during the initial scale-up phase, it is necessary to identify the appropriate CPPs. “At Boehringer Ingelheim, we believe that using a design of experiment (DOE) approach is the best method for demonstrating the interdependency of CPPs and the CQAs for individual process steps,” Senanayake says. Along with general risk assessments, the use of design failure mode and effects analyses (FMEA) is also effective for defining critical parameters of drug products, drug substances, and production processes, according to Nadig. “When applied appropriately, these two approaches are sufficient for defining the important attributes,” he says.

While orthogonal experiments can also be used, Senanayake notes that with DOE, knowledge is gained about the design space for each process that cannot be obtained using screening experiments, although they are useful when determining certain aspects of processes, such as the most effective solvents or catalysts. TePaske adds that once defined, critical attributes should be affirmed experimentally and control limits established, with processes, procedures, equipment and/or facilities revised as needed.

It should be noted that the risk-assessment methods used today are much more rigorous than the processes used in the past. “Historically, process and CQA definition was driven by the process development chemist, and the depth and breadth of the investigations were chemist-dependent,” observes TePaske. As a result, process development was primarily viewed as a laboratory exercise.  He goes on to note that current approaches are more disciplined, and studies are defined by multidisciplinary project teams. “These teams review and reconcile findings and risk assessments, and the concerns of the production, materials, quality, engineering, and other departments involved in manufacturing are integrated into the development process.  In effect, CQA definition and process development have evolved from a laboratory exercise to a global preparation for process validation and commercial GMP manufacturing.” He concludes that this team-oriented approach is the best practice because it integrates the needs of all of the disciplines involved in commercial manufacturing and virtually eliminates the possibility that CQAs and CPPs that cannot be performed in the available facilities and equipment will be defined.


  Based on the results of the quality risk assessment, various reaction and work-up conditions can be investigated, and the products from each process step can be carefully analyzed with regard to their impurity profiles and other properties, according to Thurau. “For example, the structures of the impurities can be determined, and consequently the process conditions can be adjusted to minimize the impurities and/or their fate in downstream steps can be determined. The result is the elimination of the impurities or the determination of safe limits for them,” he explains. He stresses that it is important in this part of the process to be systematic, and to consistently maintain a link between the CPPs being evaluated and the drug product and drug substance CQAs.


  While there are many benefits to a QbD approach and the establishment of CPPs that are linked to final product and drug substance CQAs, there are challenges to implementing such an approach. For Senanayake, the time and resources required remain the biggest barrier to obtaining a useful understanding of a process. “These barriers must be overcome, though, because having thorough knowledge of a process once it has reached commercial manufacturing is critical for success, and therefore, it is necessary to take the time to fully understand the design space,” he asserts.  Thurau agrees that the major limitations are practical in nature and can typically be overcome. He does, however, note that there are some open questions on the definitions and differences in the applicability of the concept by various health authorities. “As registrations for products developed and manufactured using the QbD approach become more detailed and explicit about criticality, the hope is that the increased knowledge will lead to more flexible approaches to change management (do and tell) as opposed to the current set approach (tell and do).

Both Nadig and TePaske point to the need for participation of knowledgeable team members from across different functions of the organization as a challenging aspect of QbD and the establishment of effective CQAs and CPPs. “The multidisciplinary approach requires up-front involvement of disciplines whose primary job responsibility has historically been manufacturing and requires a new way of thinking,” says TePaske. He also adds that the risk-assessment approach often focuses on what can be done, which can stifle innovation.


Despites these barriers and limitations, many companies have recognized the value of a QbD approach and the importance of linking critical process parameters for individual process steps with the critical quality attributes of small-molecule APIs and the corresponding formulated drug products. Boehringer Ingelheim, for example, is monitoring process robustness at each development stage and focusing on understanding how this robustness translates to the commercial scale using batch histories, according to Senanayake. In addition, the company is trying to complete DOEs on the important steps in its manufacturing processes. “Our success to date is demonstrated by our validation efforts and the control charts we have established for individual steps,” he says.

At Dr. Reddy’s CPS, when defining CPPs for each process step, a cross-functional team meets to discuss the key sensitivities of the process parameters and material attributes, which are first weighted in importance, and then tolerances on the variables are established, according to Nadig. DOE screening is then performed to identify the critical parameters, followed by optimization and definition of the design space to understand what will happen to the CQAs under different parameter settings. “Importantly, we are trying to engage senior members from cross-functional teams during these pre-planning meetings so that an exhaustive risk assessment is conceptualized and a mitigation plan worked out,” he comments. The company also emphasizes the importance of clear communications, participation with the customer, and giving weight to all stakeholder concerns throughout the process.


The consequences of not establishing CPPs that are effectively linked to CQAs can be severe. “If the proper controls for an intermediate step in the manufacturing process are not in place, then it is possible for a material to be produced that does not meet specifications for unknown reasons. Such a situation can in turn result in a recall if the intermediate is carried through the entire commercial process. In addition, without proper controls, processes often deliver poor quality product or product of inconsistent quality,” asserts Senanayake. In addition, according to Thurau, if inappropriate process parameters or in-process material attributes are established, the quality of the final product may appear high, but it is the result of testing quality into it, and not of process design and process understanding. Finally, TePaske stresses that operation in a state of control is fundamental to process validation and continued process performance in a validated state. 

Articles

With a quality-by-design approach, robust processes can help deliver quality product consistently.

QbD Facilitates Robust API Development

Although significant attention has recently been directed towards biocatalysis as the way forward for commercial-scale asymmetric synthesis, chiral transformations mediated by traditional metal-based and organic catalysts remain important for the manufacture of pharmaceutical intermediates and APIs. In addition, much effort continues to be invested in the development of novel enantioselective methods for the synthesis of building blocks necessary for the manufacture of biologically active molecules. A brief survey of recent literature underscores the breadth of chiral chemocatalysis and interesting new techniques for the selective preparation of asymmetric compounds. Selected examples are highlighted in the following.


Many natural and non-natural amino acids and derivatives contain both nitrogen and sulfur substituents, thus the synthetic methods for the enantiomeric synthesis of building blocks containing these two elements are of significant interest. Scott Denmark and Hyung Min Chi reported an enantioselective route to chiral pyrrolidines, piperidines, and azepanes bearing thiol substituents (1). In their method, terminal and trans disubstituted alkenes with a pendant tosyl-protected amine group are converted to the desired products through the formation of a thiiranium intermediate via Lewis base-catalyzed intramolecular sulfenoamination using a chiral BINAM (1,1’-binaphthyl-2,2’-diamine)-based selenophosphoramide catalyst.

Tsuyoshi Mita and Yoshhihiro Sato at Hokkaido University in Japan reported the asymmetric synthesis of α-amino acids via the stereopsecific carboxylation of optically active α-amino silanes, which were obtained through the enantioselective silylation of N-tert-butylsulfonylimines using a Cu-secondary diamine complex (2). The carboxylation proceeded under 1 atmosphere of CO

. Spirocyclic oxindolo-β-lactams were prepared in high yields with excellent diastereo- and enantioselectivities by Song Ye at the Chinese Academy of Sciences (3). In this case, ketenes were subjected to an N-heterocyclic carbene (NHC)-catalyzed Staudinger reaction with isatin-derived ketimines using NHCs with free hydroxyl groups as the catalyst.


  Chiral fluorinated compounds are also of interest, because incorporation of the highly electronegative fluorine atom can have an impact on the physico-chemical properties of APIs. Gregory Fu and colleagues at the California Institute of Technology tackled the challenge of preparing chiral tertiary alkyl fluorides, and particularly α-fluorocarbonyl compounds (4). They reported a method for the asymmetric synthesis of tertiary α-fluoroesters via the catalytic asymmetric coupling of aryl alkyl ketenes with commercially available N-fluorodibenzenesulfonimide and C

ONa as a nucleophile using a chiral ferrocenyl PPY (4-pyrrolidinopyridine) catalyst. The alkoxide was crucial for freeing the catalyst from an acylated intermediate. Meanwhile, Qing-Yun Chen and Yong Guo at the Chinese Academy of Sciences reported the asymmetric synthesis of tertiary α-fluoro ketones via the Tsuji-Trost reaction of racemic acyclic α-fluorinated ketones using a palladium/phosphinooxazoline catalyst (5). The desired products were obtained in up to 90% yield with up to 90% enantiomeric excess (ee). 
  
  The preparation of chiral compounds with trifluoralkyl groups is also important for drug development. Liang Hong and Rui Wang at Lanzhou University in China developed a practical method for the enantioselective introduction of a monofluoroalkyl group into the oxindole framework (6). The reaction of a wide range of 3-bromooxindoles and α-fluorinated β-keto gem-diols afforded the desired products with diastereoselectivities of >20:1 and enantioselectivities of 93-99%. Xufeng Lin and colleagues at Zhejiang University reported the first highly enantioselective iso-Pictet-Spengler reaction of C-2-linked 

-aminobenzylindoles with trifluoromethyl ketones (7). The reaction is mediated by chiral spirocyclic phosphoric acids as organocatalysts, and the benzazepinoindoles bearing trifluoromethylated quaternary stereocenters were obtained in up to 98% yield and up to >99.5% ee.


  Asymmetric hydrogenation is one of the most widely used enantioselective chemocatalytic reactions used at commercial scale. Even so, advances in this technology, including its application to a widening range of substrates, continue. A recent example was reported by Xumu Zhang at Wuhan University in China (8). His group developed a Rh-DuanPhos ((1

-(1,1′)biisophosphindolyl) complex for the synthesis of chiral cyclic allylic amines with up to 99% ee from cyclic dienamides. The products are ideal building blocks for the preparation of chiral, cyclohexane derivatives with multiple substituents. Meanwhile, Virginie Ratovelomanana-Vidal at PSL Research University and Zhaoguo Zhang at Shanghai Jiao Tong University reported the enantioselective synthesis of γ-hydroxy amides with up to 99% ee via the asymmetric hydrogenation of γ-ketoamides in the presence of a Ru-Xyl-SunPhos-Daipen catalyst (9).


  Functionalization of chiral intermediates can also be achieved via asymmetric C-H insertion reactions. In 2013, the H.M.L. Davies group at Emory University reported the enantioselective synthesis of highly functionalized 2,3-dihydrobenzofurans from derivatives of veratrol and anisole via two sequential enantioselective C-H insertions involving an intermolecular carbene insertion catalyzed by rhodium followed by an intramolecular C-H alkoxylation reaction catalyzed by palladium (10). The products could also be further functionalized via a palladium-catalyzed intermolecular Heck-type sp2 C-H functionalization reaction.


Carbon-carbon (C-C) coupling reactions have become key tools in the synthesis of pharmaceutical  and other fine chemical intermediates, and chiral C-C coupling reactions are highly valued. Several new methods have been reported recently, including the diastereo- and enantioselective coupling of alcohols and vinyl epoxides to form asymmetric quaternary carbon centers, which was developed by Michael J. Krische at the University of Texas at Austin (11). In this iridium-catalyzed reaction, primary alcohol oxidation leads to reductive C-O bond cleavage in isoprene oxide to generate aldehyde-allyliridium pairs that combine to form products of tert-(hydroxy)-prenylation, many of which are observed in terpenoid-type natural products. Notably, the reaction proceeds without the use of premetalated reagents or unwanted stoichiometric byproducts.

Meanwhile, Brian M. Stoltz at the California Institute of Technology prepared (trimethylsilyl)ethyl ester protected enolates via fluoride-induced “thermodynamic” enolate formation and used them in palladium-catalyzed asymmetric allylic alkylation reactions to obtain α-quaternary six- and seven-membered ketones and lactams (12). The reaction expands the scope of allyl substrates beyond traditional β-ketoesters and has a high tolerance for reactive functionality.

Two rhodium-catalyzed enantioselective C-C coupling reactions were also recently reported. Vy M. Dong at the University of California, Irvine reported the enantioselective cross-coupling of aldehydes and α-ketoamides via intermolecular hydroacylation to provide α-acyloxyamides using a new Josiphos ligand (13). Separately, Chen-Guo Feng and Guo-Qiang Lin developed the enantioselective rhodium-catalyzed 1,2-addition of arylboronates to cyclic N-sulfamidate alkylketimines, which provides chiral sulfamidates that can be readily reduced to chiral β-alkyl-β-aryl amino alcohols (14).

Finally, Amir Hovedya at Boston College reported the copper/NHC-catalyzed enantioselective allylic substitution of di- and trisubstituted alkenes with readily accessible (pinacolato)alkenylboron compounds to generate 1,4-dienes bearing an asymmetric tertiary carbon (15). The reaction tolerates a wide range of olefins and provides the desired products in up to >98% yield with >98:2 selectivity for the SN2′ vs. SN2 addition and a 99:1 enantiomeric ratio (er). The group also demonstrated the applicability of the reaction in the synthesis of several natural products.


  Multicomponent reactions are attractive because they often enable the synthesis of complex intermediates in an atom-economical manner from basic starting materials. These reactions are even of more interest when they proceed with high stereo- and regioselectivity. At the Universidad de Oviedo in Spain, Francisco J. Fañanás and Félix Rodríguez developed a one-pot, gold phosphate-catalyzed, three-component coupling reaction of alkynols, anilines, and glyoxylic acid that generates sprioacetals with incorporated α-amino acid functionality (16).


  Cascade reactions, like multicomponet reactions, are attractive because they provide direct access to complex structures in one pot with few or no undesirable byproducts. Adrien Quintard and Jean Rodriquez of Aix Marseille Université developed a cascade reaction involving the enantioselective reaction of allylic alcohols with diketones catalyzed by an iron catalyst with iminium activation followed by chemoselective acyl transfer (17). The γ-chiral alcohol products (3-alkylpentanols) are obtained in up to 96% yield with a 96:4 er and are useful for natural products synthesis.

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A literature survey underscores the breadth of chiral chemocatalysis and interesting new techniques for the selective preparation of asymmetric compounds.

New Techniques Advance Asymmetric Synthesis

A survey of the recent literature reveals numerous advances in asymmetric chemocatalysis.

Asymmetric Synthesis Continues to Advance

With a quality-by-design approach, robust processes consistently can help deliver quality product.

QbD in API Manufacturing

Supply chain transparency, or the ability to see into the various levels of the supply chain, is an acute need in the biopharmaceutical industry, largely due to regulatory pressures on manufacturers to protect the quality of the final products they sell to end consumers, according to Bindiya Vakil, CEO and founder of supply chain resiliency solutions firm Resilinc. 

FDA and equivalent global organizations regulate drug companies to better understand their sources of supply and thus better control the quality of the final drugs being manufactured and sold to consumers. “Today, most suppliers operate in many different countries and thus have global supply chains. In addition, they often use subcontractors that actually own and operate the factories. This type of complex supply chain structure introduces risk; sub-tier suppliers and subcontractors may not follow the stringent regulatory requirements that govern product quality, which is necessary for protecting the efficacy of drugs,” Vakil notes. Consequently, there is a critical need for biopharma manufacturers to gain and maintain deep knowledge of their direct suppliers and their global and sub-tier dependencies, particularly in situations where drug efficacy can have human life or health consequences.


  Typical biopharma supply chains are increasingly global and complex, and the complexity continues to expand each year. A drug manufacturer typically purchases active ingredients for a single drug from more than 50 direct suppliers that might have 300 manufacturing sites globally in aggregate, according to Vakil. She adds that the direct suppliers also leverage their own complex supply chains. Direct suppliers can range in size from a relatively small operation with one factory to a large chemical company with more than 80 sites worldwide that supplies thousands of customers across all industry verticals. Each of these suppliers may have hundreds of suppliers of their own, and the entire supply chain across the multiple tiers is critical to the efficacy of the final product. 

“Supply chain transparency involves identifying the global supply chain dependencies of all direct suppliers; determining which subcontractors are used; and understanding the customs, norms and issues in the parts of the world where these firms operate and manufacture the various raw materials and ingredients,” Vakil says. The purpose is then to ensure that all of the sites in the full supply chain, including manufacturers providing basic raw materials, comply with regulatory standards around quality as applicable she notes. 

To achieve supply chain transparency, biopharma companies need to proactively work with suppliers to map the supply chain in order to proactively identify any dependencies that may create compliance issues, as well as identify sites and companies that may need to be audited.

 
  “Given the complexity of the manufacturing process, the quality controls required for conformance, and the regulatory process for obtaining FDA certification, proactive supply chain mapping is a must have for today’s biopharma companies to achieve long term success,” Vakil states. More specifically, she explains that if suppliers shift manufacturing to different sites or source raw materials from different subcontractors, without supply chain transparency, it is possible that the end customer will not know that a change has been introduced somewhere in such an extensive supply chain. Consequently, if a change results in an adverse impact on the final drug product, the end customer could spend many millions of dollars trying to identify the root cause of the problem. In a worst case scenario, Vakil stresses that such changes may negatively affect patient health or put the drug manufacturer at risk for litigation because of a decision that it had no knowledge or control over. 


  Achieving supply chain transparency is a challenge in the biopharma industry. The first hurdle that biotherapeutic manufacturers must overcome is mapping and understanding the inter-dependencies of their multitier global supply chains, which involves collecting data from suppliers. “Each supplier may have many manufacturing sites worldwide and manufacture hundreds of different raw materials, and the biopharma company may have hundreds of such suppliers providing various products. In addition, these suppliers generally sell products to multiple biopharma manufacturers that each require slightly different formulations/versions of the same raw material or active ingredient, and therefore different part numbers must be maintained for each customer for a given raw material. If each of the end customers tries to collect information about the suppliers’ supply chain at a raw material level in different formats, a huge burden would be placed on each supplier to support these different requests and formats,” Vakil observes. Furthermore, it is not sufficient to initially collect the supplier information; it is critical that the information be kept up to date, which requires periodic reviews.

Second, biopharma manufacturers must overcome the unwillingness of suppliers to provide full transparency and visibility due to concerns that customers may design them out or use the information to squeeze them for cost savings. The first issue is somewhat alleviated by the fact that a new source would need to go through the FDA approval process, which can take as much as two years, according to Vakil. She notes, however, that while the FDA approval process creates a major barrier against the rapid switching of suppliers, this concern is frequently cited as a reason why suppliers are unwilling to share information with their customers.

The lack of an industry standard around supply chain transparency is the third challenge, and has resulted in the need for each company to create its own methodology and process. “Industry organizations such as BioPhorum, Rx360, and others, will play an important role in addressing this issue,” Vakil says. In fact, these organizations are working together with the FDA to streamline the entire process by developing and publishing a standard that solution providers such as Resilinc can adopt.


  Resilinc, along with its biopharma clients, has adopted specific strategies and approaches to creating a more transparent supply chain. These strategies focus first on identifying the existing and potential risks, followed by mapping of the possible weak spots in the supply chain and then implementing more sophisticated sense-and-respond capabilities that strengthen the organization’s supply chain flexibility and agility, according to Vakil. “By proactively tracking and managing existing and potential risks, biopharmaceutical and life sciences companies will be in a better position to use vital supply chain data to handle disruptions and respond more effectively,” she states. Such a “sense-and-respond” supply chain approach also gives companies an edge over the competition. “Biopharmaceutical manufacturers that can identify potential trouble spots early on, monitor and respond to potential risks, and create transparency with multiple tiers of supply chain partners will mitigate risks that frequently cause financial damage to the top and bottom line,” Vakil adds.


  Resilinc has focused on addressing supply chain transparency and developed over the last four years a very large repository of supply chain transparency information that enables biopharmaceutical manufacturers and their suppliers to seamlessly share information with minimal effort, according to Vakil. “Our publish once, share multiple times methodology creates real time savings for suppliers using the system to share information across many customers. In addition, we emphasize extensive supplier training, onboarding, and data cleanup, which saves time and effort for the customers, who can then use their valuable resources for enhanced intelligence gathering, rather than for basic data collection,” she says. 

A fundamental aspect of Resilinc’s approach has been the creation of a “network effect” in the biopharma industry, which has expanded as more clients and their supply chain partners join the Resilinc platform. “This network effect comes into play quickly,” asserts Vakil, “and each successive new client and supplier derives faster time to value and lower total cost of ownership as they securely, and with their suppliers’ approval, leverage data already existing on the platform.”

In addition, over time the depth and breadth of information on the Resilinc platform increases. Today the company has modules for supply chain visibility at the site, operations, part level, and supplier site level for business continuity planning (BCP), as well as a conflict minerals compliance module and supplier corporate social responsibility (CSR) survey modules.

Amgen’s Executive Director, Supply Chain Patricia Turney mentioned in a recent Supply Chain Brain video that “We see Resilinc as a way to move the entire industry’s collective supply chain forward. With Resilinc, Amgen is able to gain new insights into our sub-tier supply chain that we were unable to see before. And if we do see a potential issue, we have the enhanced intelligence needed to take action before it can impact the company.”

Adds Vakil: “With industry leaders such as Amgen paving the way and actively bringing their suppliers and sub-tier suppliers to the Resilinc platform, the biopharma industry should begin to see the challenges above begin to diminish along with greater transparency and information sharing between supply chain partners.”

Continued need for secure information sharing


  Supply chain transparency is only the latest requirement for which companies must reach out to their suppliers and collect a wide range of information at the site, activity, and/ or part number level, according to Vakil. In addition, she notes that new regulatory requirements, risks, and other operational initiatives continue to create an acute need for a secure information sharing capability between customers and their suppliers. “The industry needs to examine this problem holistically and adopt solutions that will be successful at bridging the combined needs of customers and supplier information sharing for many years to come,” concludes Vakil.

Biopharma manufacturers must reduce risk in their complex supply chains and establish effective monitoring and control systems.

Need for Supply Chain Transparency is Acute

For approximately 100 years, a wet chemical method with visual evaluation of the results has been the standard test for determining the total quantity of heavy metals in APIs and excipients. Both the 

 (USP) and the International Conference on Harmonization (ICH) have updated, or are in the process of updating, analytical requirements for controlling elemental impurities. The new risk-based approach will result in significant changes, including new proposed limits, all of which are challenging pharmaceutical companies, contract manufacturers, contract laboratories, and suppliers to the industry. As a consequence, USP extended the deadline for compliance with   USPGeneral Chapters <232> Elemental—Impurities Limits and <233> Elemental Impurities—Procedures to December 1, 2015. The ICH Q3D guidelines are not yet finalized, but there presently remain some differences in the limits required by the two standards.


Revisions to USP’s standards for elemental impurities (heavy metals) were proposed in the interest of better protecting public health, according to Kahkashan Zaidi, USP principal scientific liaison. Elemental impurities include environmental contaminants such as arsenic, cadmium, lead, and mercury, and other elements that appear in drug products for various reasons. Some are present in naturally-derived APIs and excipients, such as those that are mined or extracted from plants. Others, such as catalysts, are intentionally added during the synthesis, while some are introduced unintentionally through interactions with processing equipment and/or container closure systems.

 General Chapter <231> Heavy Metals has several limitations. Most importantly, it is a qualitative method that involves the reaction of metallic impurities with sulfide ions to generate a colored precipitate. A visual comparison of the precipitate is made to a standard to determine if the sample exceeds specified limits. For insoluble materials, aggressive digestion is required that may lead to evaporation of the target metal species and thus lead to underestimation of the impurity content. In addition, the method is only effective for metals that react with sulfide ions, and therefore, other contaminants are not detected.

“Better understanding of the limitations of the current methods in 

 General Chapter <231> Heavy Metals made it very clear that a revision was needed,” states Zaidi. Significant advances in testing methods and our understanding of the toxicity of various elements often found in excipients and APIs has occurred since the traditional method was developed, according to Janeen Skutnik-Wilkinson, vice-president of NSF Health Sciences’ Pharma/Biotech division. “Comprehensive, globally harmonized guidelines for all elemental impurities are essential given the global sourcing that occurs today in the pharmaceutical industry,” she adds.


USP began the standards-setting process in 2008. Several public meetings and USP Pharmacopeial Education courses were held to gather and share user input. The proposed standards were developed by an advisory USP Expert Panel, which considered comments from all stakeholders including industry (e.g., manufacturers of APIs, excipients, and drug products), FDA, and other relevant analysts and toxicologists.

Pharmaceutical manufacturers and laboratories have been concerned about the substantial changes that accompany implementation of the new USP standard for elemental impurities and appealed to the organization for extension of the initial deadline for compliance. Because the new analytical method requires advanced instrumentation, many laboratories have needed time to acquire and qualify the necessary equipment and train staff on the digestion process.“USP’s standards revision process involves international collaboration among USP experts, industry, regulators, and other stakeholders. We wanted to allow ample time for careful deliberation and scientific dialog in order to reach conclusions that are supported by a maximum number of interested stakeholders,” says Zaidi. In addition, she notes that because the new elemental impurities standards represent a significant change from existing standards, it was important to provide sufficient time for manufacturers to incorporate the changes necessary to implement the new standards into their processes. As a consequence, USP responded to industry concerns, with the deadline for implementation extended more than once.

 chapters include limits for 15 specific elemental impurities (rather than determining a total amount) and analytical procedures based on modern analytical technology. The limits for acceptable levels of elemental impurities in drug products are included in General Chapter <232> Elemental Impurities--Limits. Manufacturers must demonstrate that the levels of lead, mercury, arsenic, and cadmium are below the limits. The remaining 11 elements, which are derived from common catalysts, must be considered if their presence can be expected based on catalyst use. Notably, according to Zaidi, unlike the previous General Chapter <231>, which applied to drug substances and excipients, the limits in <232> will apply only to drug products that are subject to a USP drug product monograph. “This requirement is a major change, because previously testing for elemental impurities only applied to APIs and excipients,” she says.

The limits for each elemental impurity in drug products are expressed as permissible daily exposure (PDE) values, which are determined after evaluation of toxicity data. For most drug products, the product itself can be analyzed. Manufacturers also do have the option of analyzing all ingredients in a formulation rather than the formulated product, but must be able to provide assurance that additional contaminants cannot be unintentionally added from product manufacturing processes or container closure systems for the product, for example. For large-volume parenterals (daily dose > 100 mL), however, each ingredient must be evaluated to determine if it meets the specified limits.


The procedures in General Chapter <233> for the evaluation of elemental impurities in drug products use inductively coupled plasma-atomic (optical) emission spectroscopy (ICP-A(O)ES) or inductively coupled plasma-mass spectrometry (ICP-MS), depending on the instrument and sample used, according to Zaidi. Alternative procedures may be used as long as they meet the validation criteria in chapter <233>. 

Sample preparation is crucial for these analytical techniques. Some samples may be analyzed directly, but many will require dissolution in water or an organic solvent prior to analysis. Others that are not soluble in either water or organic solvents will require digestion using acids, which USP recommends be performed in a closed-vessel digestion apparatus.


The new requirements for elemental impurities will greatly affect both pharmaceutical manufacturers and their suppliers. “The changes will be significant, because the traditional wet chemistry test will no longer be acceptable unless it has been validated for each analyte element. While switching to an instrumental technique will be easier and enable companies to run more samples in a shorter amount of time, companies may need to purchase analytical instrumentation that they don’t already have, or find a contract laboratory that has the instrumentation necessary to perform the analyses,” says Nancy Lewen, a senior principal scientist in pharmaceutical development for Bristol-Myers Squibb (BMS). She does, however, also appreciate the emphasis on using a risk-based approach rather than a sweeping requirement for analyses for every single sample. “Once companies perform their initial product assessments, then the workload should drop off quite a bit, unless there are changes in the way their products are made,” Lewen observes.

While the new requirements do represent a significant change for the industry, the use of the risk-based approach for determination of elemental impurities will allow companies to prepare, according to Terry L. Harper, supervisor of pre-formulations at AAIPharma Services. “The key to success is for companies to conduct their risk assessments in a logical manner and to plan and design an efficient process. If that can be achieved, it should be a relatively straightforward process to meet the requirements,” adds Joseph Bordas-Nagy, director of structural chemistry with AAIPharma.

Contract laboratory Exova has observed that some pharmaceutical companies are looking to outsource elemental impurities analysis, while others are investing in new ICP-MS or ICP-OES instruments for in-house testing, according to metals group leader Samina Hussain. On a positive note, she comments that the majority of final drug products the company has tested for elemental impurities are below the specifications set in USP <232>.  She does note, though, the process of validating for elemental impurities by ICP-MS or ICP-OES is a relatively new concept for pharmaceutical companies, and understanding this process is a crucial step in assuring pharmaceutical products are compliant by December 2015. “The process should involve: method development, drafting of a method validation protocol for review, and the actual execution of the validation,” according to Hussain. “Pharmaceutical companies need to be aware that this will take time for a contract lab to successfully develop. While we have the base capability to carry out this level of testing, it will take time to develop these methodologies to meet specific industry needs,” she notes.

The need to evaluate raw materials for the various elemental impurities will also require supply-chain resources, according to Patty Benson, director of quality assurance at SAFC. “Products such as those derived from plant sources or those that are mined will pose the greatest challenge in that they may vary from batch to batch or year to year,” she notes. Engaging in discussion with suppliers is very important; they don’t need to comply with the guidelines, but manufacturers of finished products must be able to obtain raw materials that meet certain specifications to ensure that they can comply with the requirements for elemental impurities, according to Skutnik-Wilkinson. “It is best to view suppliers as partners, particularly for suppliers, such as excipient manufacturers, for whom the pharmaceutical industry is an insignificant portion of the business. Such a situation presents special challenges and requires a bit of diplomacy,” she says.


BMS has had considerable experience using ICP-OES and ICP-MS, so is already ahead of the curve in that regard, according to Lewen. BMS has also followed the updates and proposed updates and tried to modify its analytical methods to meet the requirements that are announced through publicly-available venues.  In some cases, that has meant back-tracking and changing a method procedure, particularly when limits have decreased or an element has been added. “Our goal is to perform an assessment on each of our products to be prepared for compliance, whatever the requirements end up being,” she says.

Exova also has extensive experience with ICP-MS technology and currently has seven ICP-MS instruments and one ICP-OES at its US site, and additional ICP-MS instruments in Canada and Scotland to serve the global market, according to Hussain. “Testing for elemental impurities is not new to us, and we have successfully validated many diverse matrices. The challenge will be to offer timely turnaround on method validations if most companies choose to continue waiting,” she observes.

AAIPharma has two ICP-MS instruments to provide redundant capabilities and has developed conditions for effective solubilization and methods for quantitative screening analyses that are designed to generate data for risk assessment. The quantitative screening method is effective for providing quantitation of elements of interest without prior knowledge of the sample matrix. Quantitation is based on calibration curves established for each element. The method includes assessment of method performance based on spiked recovery at two levels. “We have had good success with 26-27 elemental impurities in a number of drug products and excipients to date and are enthusiastic about applying this method to a wider number of substances and assisting clients in their efforts to comply with the changing standards,” notes Bordas-Nagy. “The key,” says Harper, “is to get as much data as possible as quickly as possible in order to determine a specification is not needed or that a validated method is required.”

To prepare for compliance with new elemental impurities standards, SAFC has developed a draft procedure and checklist to evaluate its raw materials, process water, equipment, and container closure systems with respect to the identification of potential sources of elemental impurities in its regulated products. The company is also working with its biopharmaceutical customers to develop a process to evaluate raw materials that pose the greatest risk to their cell-based processes. “We will follow the regulations with regard to thresholds and have begun to use ICP-MS to systematically monitor many of our raw materials—specifically to develop a good baseline understanding of the trace elements and the levels that we are likely to see in various raw materials. Salts (mined raw materials) have been shown to be more variable in terms of trace metals, and we have been continuing to develop this type of baseline data,” says Benson. She adds that working closely with vendors to determine how much control the company can exercise over this measured variance has been important.


USP recently posted proposed revisions to General Chapters <232> for public comment in Pharmacopeial Forum 40(2) with a comment deadline of May 31, 2014. The revisions to <232> convey USP’s review of and subsequent partial alignment with the ICH Q3D Step 2b limits. “USP’s proposed limits reflect a review of published toxicological data and studies, as well as expert review by toxicologists serving on USP’s Elemental Impurities Expert Panel. In some cases, USP’s proposed limits diverge from the Q3D Step 2b limits, and USP has notified ICH of these divergences via a comment letter on the Q3D Step 2b document,” Zaidi notes.

“Our approach to the lack of full harmonization is to take the most conservative approach and select the lowest limits in all of the existing and proposed standards,” comments Bordas-Nagy. “With such a strategy, we ensure that both our own products and those of our clients are in compliance,” he concludes.

Changing regulations are impacting the identification and monitoring of variable materials in excipients.