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

Cynthia A. Challener

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.

Articles

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.

Taking Action on Elemental Impurities

Novel excipients in the United States are only reviewed in the context of a new drug application (NDA) or, more rarely, a new abbreviated drug application (ANDA). Even if a drug manufacturer is willing to accept the risks associated with the use of a new excipient in an NDA filing and manages to receive approval of the drug product, the excipient is only approved for use at the level used in that drug and for that particular route of administration. In addition, the time required for safety testing and the drug product approval process means that excipient manufacturers have a long wait to achieve a return on their investment, and often there are few years of patent protection left. As a consequence, it is difficult to make the business case for the development of novel excipients at a time when new classes of APIs that can treat as yet untreated diseases and meet unmet patient needs are being identified. The drug products that use these APIs will only reach the marketplace if novel excipients designed to overcome undesirable physical and/or chemical properties are available to enable their effective delivery.


New excipients and improvements to existing excipients are needed both for future drug-product development and for specialized applications such as pediatric-drug development, according to Chris DeMerlis, manager of regulatory affairs at Colorcon. While there are perhaps 300 to 400 different chemical entities used as pharmaceutical excipients, many are chemically similar, such as reducing sugars, clays, cellulosics, and carbohydrates. If one member of a class is unsuitable for a particular API, then generally none of the members of that class will be effective.

In addition, a number of excipients have recently been banned by FDA (dibutyl phthalate and di(2ethylhexyl) phthalate (1), and action on similar compounds may take place in the future. As analytical techniques advance, information about impurities in excipients that may be potential issues in certain applications is becoming available, such as formaldehyde and peroxide residues in microcrystalline cellulose and polyethylene glycol. According to Chris Moreton, vice-president of pharmaceutical sciences with FinnBrit consulting, “The imminent introduction of 


General Chapters <232> and <233> concerning elemental impurities may mean that some current excipients will no longer be suitable for certain applications.”

Perhaps most importantly, modern drug-discovery methods (including combinatorial chemistry and high-throughput screening), which target isolated receptors rather than whole animal models, have changed the paradigm regarding drug solubility, permeability, and stability, according to Moreton. “These new drug molecules are placing increasing demands on drug-delivery technologies and available excipients, and some of the more traditional formulation approaches simply are not adequate to deliver these poorly soluble compounds,” he explains.

Together, the challenges posed by newer drugs combined with the issues surrounding some of the more commonly used excipients means that the number of available excipients for a particular application (formulation project) can be considerably reduced. “We need new excipients to increase our options for the formulation and delivery of the newer molecules coming through the development pipelines, including both small-molecule and biologic drugs,” Moreton asserts. There is a particular need for excipients that can aid in the formulation of parenteral drugs, according to Nigel Langley, head of marketing for BASF’s pharma ingredients and services business. Keith Horspool, vice-president of pharmaceutical development with Boehringer-Ingelheim, adds that new functional excipients in particular have potential to address the solubility and other challenges presented by drug candidates in today’s pipelines.


In the past 1520 years, less than a handful of new excipients have been launched in the US, according to Moreton. There is no independent approval process for novel excipients. They are approved as part of an NDA and then only if the drug is approved and only for that particular route of administration and the level of use approved for the NDA. For pharmaceutical companies, it is risky to use a novel excipient because doing so complicates the regulatory issues, because any problem with the new excipient could hold up the approval of the drug product. Moreton points to one recent example: the use of Captisol (sulfobutyl ether betacyclodextrin, originally from Cydex) by Pfizer. “In this case, no other excipient was found to provide an acceptable finished product, so Pfizer was willing to adopt the risk of incorporating the safety testing for the excipient into the safety testing program for the drug and drug product. The technical need overrode the concerns over the risks,” he says.

It takes many years to develop a novel excipient and perform all of the necessary safety testing. Excipient manufacturers are then faced with the challenge of finding a pharmaceutical company that is willing to accept the risks of using a new excipient and then must hope that the drug progresses through clinical trials and ultimately receives approval. If the drug fails, the excipient does not receive approval, even if the failure was not related to the excipient (and the clinical trial data are not usable, even as a reference). “With the very high attrition rate for NDAs, the outlook for getting a novel excipient approved is pretty limited, and if an excipient is approved, often there is very little patent life left by that point,” Langley notes. Moreton adds that while there are provisions for patent term extensions for drug products, there are none for novel excipient compounds.

“As a result of these combined issues, it is getting more difficult to argue that there is a business case for investing in the development of new excipient technologies,” states Langley. Pharmaceutical manufacturers are concerned. “The current system is not only stifling innovation, it is creating an untenable business environment for excipient developers. The risks are becoming so great that excipient manufacturers are coming to the conclusion that excipient development is a nonviable proposition. Real change must be accomplished before excipient producers become unwilling to invest in innovation,” he asserts.


Modifying the approval process for novel excipients so that they can be approved on an individual basis without tying them to a particular new molecular entity (NME) would make excipients available for development efforts of other NMEs independently of the development success of any one NME program, according to Vinod Tuliani, director of product development with GlaxoSmithKline.  If this type of regulatory pathway can be established, the industry will be encouraged to develop the types of novel excipients that are required for the effective delivery of challenging new drug candidates, adds Dave Schoneker, director of global regulatory affairs at Colorcon. “An independent pathway for safety assessment of new excipients, new co-processed excipients, and new uses or levels of existing excipients would increase the likelihood for pharmaceutical companies to include new excipients into their formulations,” he says. He also believes such an approach would lead to improvements in the overall design quality of many pharmaceutical products (to address things like drug solubility issues), enhanced productivity, and reduced costs. “Such designed-for-purpose excipients would become critical tools in pharmaceutical formulation as the industry moves towards a quality-by-design world,” Schoneker comments.

Guidance for Industry, Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients 

(2), which became final in 2005, provides recommendations for the safety evaluation of new pharmaceutical excipients, but does not address their approval. The New Excipient Evaluation Procedure (3) established by the International Pharmaceutical Excipients Council (IPEC)-Americas in 2007 is run by Robert Osterberg, a former FDA toxicologist. Osterberg heads a panel of independent toxicologists that review the safety/tox package of a new excipient to assess whether or not, in their opinion, it would be acceptable to FDA. Several reviews have been conducted, most to justify the use of higher levels of a current excipient than is given in the FDA’s Inactive Ingredient Database (IID). The hope that the new procedure would be a major step towards the adoption and approval of new excipients has not been realized, however, in part because the review is not an official FDA assessment leading to regulatory approval of the excipient. The program has, however, been beneficial in providing good supporting information to pharmaceutical users based on the safety review by word-class experts, according to DeMerlis.


With widespread interest and concern over the issue of new excipient development in the industry, a new effort has been initiated that unites the forces of IPEC-Americas and the IQ Consortium, an organization of pharmaceutical and biotechnology companies with the mission of advancing science-based and scientifically-driven standards and regulations for pharmaceutical and biotechnology products worldwide. The group within the IQ Consortium working on the issue is the Novel Excipients Working Group, which comprises colleagues from the pharmaceutical development, excipient, regulatory, and other fields, according to Tuliani. Notably, the group has surveyed members and found that there is significant interest in finding a way to increase the development of novel excipients to overcome barriers in developing new drug products.

“With both pharmaceutical and excipient manufacturers working together to uncover gaps in understanding and expectations and address them, it is possible to identify best practices and the types of data that are needed,” Horspool notes. He adds that with its technology focus and large membership that well represents the pharmaceutical industry, the IQ Consortium is the ideal group to work with IPEC-Americas on this issue. “With these two organizations working together, we can present a much more powerful argument,” observes Horspool. “It is exciting that we have these two major associations representing the excipient and pharmaceutical manufacturers collaborating on this effort,” agrees Langley. “We believe that we have the opportunity to make real progress,” he adds.

The Novel Excipients Working Group and a similar group formed within IPEC-Americas are currently exploring the development of joint best practices for preclinical safety (testing and specification requirements) and creating a process for designing a well-defined pre-clinical data package for novel excipients. With IPEC-Americas, the group is assessing current challenges to excipient review and approval, and possible next steps to alleviate these challenges. Horspool and Langley are excited about the potential of these efforts. “We see unprecedented possibilities for advancing meaningful change to the adoption of new excipients for achieving the most important goal of enabling new drug products to reach patients,” says Horspool.

Guidance for Industry, Limiting the Use of Certain Phthalates as Excipients in CDER Regulated Products

 (Rockville, MD, December 2012).
  2.	FDA, 

(Rockville, MD, May 2005).
3.	C. DeMerLis et al., <em>Pharm. Tech</em>. 33 (11) 72-77 (2009). See also: 

http://ipecamericas.org/content/ipec-novel-excipient-safety-evaluation-procedure

New excipients and improvements to existing excipients are needed to facilitate access to new drugs for patients.

Exploring a New Approval Process for Continued Excipient Innovation

The drivers for the development of new raw materials are, as always, changing customer needs. At the top of the list in today’s industry, according to Douglas Bowman, program manager for PharmaGrade raw materials at SAFC, is risk reduction. Beyond that, he says that customers are looking for effective ways to increase performance and output and optimize productivity. 


“The demand for supply chain security and transparency continues to grow and is the number one concern of many drug manufacturers as they navigate the new market,” asserts Bowman. In fact, many manufacturers are still working to respond to guidelines implemented in 2012 that require final end-users to have visibility of their raw-material supply chain. “Biopharmaceutical manufacturers are faced, now more than ever, with the reality of global events that have threatened and breached supply chain security,” adds Beth Ann McLane, SAFC’s product manager for enhanced quality. Global threats to the security of the raw-materials supply chain have caused a public outcry, and regulatory bodies have demanded higher levels of compliance. “Manufacturers are now being held fully responsible for the raw materials that go into their products and they simply do not have enough capacity to test for all of the possible contaminants that could find their way into the materials,” she comments. 

In response, the industry is moving towards risk assessment and risk mitigation of raw materials from the early stages of drug development. Manufacturers are looking to their raw-material suppliers to provide them with the support of a secure supply chain, according to McLane. “The more that biopharmaceutical manufacturers know about their suppliers and the raw-material supply chain, the more confident they can then be about the safety of those raw materials,” she says. Achieving this goal requires tracing these materials back to the manufacturer and demonstrating that there is a stringent change-control process in place. 


At the same time, the push to reduce risk has caused many manufacturers to move away from animal-derived materials that provide high performance in cell-culture manufacturing, such as serum, which is creating additional challenges in maintaining productivity and yields. The need to optimize productivity has, therefore, led to increased scrutiny of other raw materials in the media, as well as other bioreactor supplements. “There is a much greater focus today placed on isolating extraneous matter or impurities that could have a negative effect on the performance of raw materials,” Bowman observes. “Where, as a result, having a controlled source in combination with meaningful specification is optimal.”


In the past, according to Bowman, manufacturers typically asked only for the name of the source of a raw material from their supplier and considered this information to be ample identification of the “source”.  Much has changed since then, because customers realize the amount of risk such an approach involves, particularly given the requirements of increasingly stringent global regulations. “Manufacturers are now looking to source higher quality--GMP or similar quality level, such as SAFC’s Elite--across the board. It is no longer just a handful of raw materials receiving attention; any material being used in drug manufacturing is receiving a greater deal of attention,” he notes.  


The drive toward plant-based materials brings greater inherent variability to the table. “When something comes from the earth, there are many factors that cannot be controlled--factors that can change a material from lot to lot,” says Bowman. SAFC, as a raw-material supplier to the biopharmaceutical industry, has met this challenge by increasing its levels of testing and working to chemically define materials if possible. For those substances that cannot be chemically defined, and particularly in the case of plant-based raw materials, the company works to secure its sources and control what it can. “The rest of the process,” comments Bowman, “involves continuous learning built on research and testing of the materials that allows us to capture and analyze critical data points.” 

He does stress, though, that meeting these challenges is not as simple as it may seem. SAFC, despite the difficulty, has chosen to view the situation as an opportunity. “We have worked on expanding our PharmaGrade line of high-quality, controlled, and documented materials to remove some of the pressure on manufacturers, but the process is grueling. We must identify how/where the product is made, conduct audits, establish quality agreements, ensure there is a stable change-control process, and obtain full documentation for customers, and of course, conduct extensive testing.” Through this comprehensive process, the company believes it can gain an understanding of the types and levels of contaminants associated with raw materials and use that information to mitigate their biological impact at different levels. 


SAFC’s PharmaGrade portfolio was created in response to urgent demand from customers for products they can count on to be consistent and that are from a source where the production is controlled and changes are limited, according to McLane. “These types of customers are not only looking for a guaranteed level of quality; they also want to know what is happening with the raw materials and be notified if/when any changes occur,” she observes. To provide a higher level of documentation and support, SAFC has invested significant resources into the identification and qualification of products for the line and established a strong change-control notification system.

Each product has a complete dossier of information about it, including the site of manufacture and the quality systems associated with the product. New materials must also meet seven key criteria that were developed based on customer requests and include manufacture under GMP (or SAFC’s Elite) quality guidelines, supply-chain transparency, formal vendor qualification, quality assurance review and release of each lot, change-control notifications, quality documentation, and availability as catalog items. The PharmaGrade range includes amino acids, buffers, and specialty chemicals that are widely used in biopharmaceutical manufacturing.


SAFC has also been focused on a stringent raw-materials characterization program to improve product/media formulations that involves the identification of impurities that impact productivity and product quality. “The goal here is to test and gather enough data that we can automatically identify performance issues and correlate them to a specific raw material. We also believe that if we can fully understand the biological effects of contaminants, we can then work to identify specifications that will enable more efficient biopharmaceutical production for our customers,” Bowman explains. 

On the customer side, the company is also taking time to educate customers so that they receive the grade of material that they actually need. “Our PharmaGrade raw materials are often not required for early development projects, while research-grade materials are not appropriate for commercial applications and could have grave effects on the final drug product,” he says. “We are, therefore, focused on aligning with our customers to really learn their processes and help them identify the right materials that are fit for purpose and ultimately fit for manufacturing,” he continues.


Supply-chain security is an issue that the entire pharmaceutical industry is grappling with. Both biologics and small-molecule pharmaceutical manufacturers, contract manufacturers, and raw-material suppliers are facing the same challenge of ensuring the quality and safety of the products they purchase and/or sell meet the standards set for drug product manufacturing and formulation.

 “The industry is coming together over this issue because these challenges are not just for one manufacturer; they are challenges for all manufacturers. Finding appropriate resolutions creates great opportunity for everyone,” Bowman asserts. Groups such as Rx-360 and the Parenteral Drug Association are working to define and standardize methods for achieving supply-chain security and raw-material quality, as well as educate their members. “Such industry-wide challenges require industry-wide answers to ensure that drug manufacturers are meeting and exceeding quality standards,” Bowman says. In particular, he points to the efforts of Rx-360 to encourage the use of more effective, shared audits that would allow the industry to take a significant portion of the time spent auditing to focus on these greater challenges. On a more global scale, Bowman believes that the International Conference on Harmonization (ICH) Q3 guidelines for elemental impurities, which are under development and will update the analytical requirements for heavy metals and other contaminants, will likely result in significant changes in detection methods and limits that can help the industry streamline raw-material standards. 


In the end, raw-material development for the biopharmaceutical industry is no different than new product development in any industry with respect to the importance of determining what customers really need and then working to meet those needs with a clear, educated, scientific approach, according to Bowman. “To that end, at SAFC we have honed in on identifying product characteristics that impact the performance and consistency of the formulated products we develop. We also want to make it simple for customers by offering the most commonly used products at an exceptionally high-quality level right off the shelf in order to eliminate the need for customization,” he says.


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

Biopharma are looking to reduce risk, increase performance, and optimize productivity in raw material development.

Supply Chain Security Tops Concerns for Biopharma Raw Materials

The African pharmaceutical market is growing at approximately a 10% compound annual growth rate and is expected to reach $42 billion by 2020, according to IMS Health. Such numbers are attracting pharmaceutical companies looking to expand their global footprint. To be successful in this very fragmented and emerging market, however, manufacturers of biologics must be aware of the many challenges that drug companies face when entering this region, as well as the issues specifically associated with these very sophisticated therapeutics. Most importantly, those firms that want to benefit from the anticipated growth in Africa must be willing to overcome the challenges and start investing in having a presence today, or risk being outcompeted by local and international firms in the future, says Dan Rosen, consultant with IMS Health’s Thought Leadership Group.


  “Africa is becoming a major emerging economy as growth in other countries in Asia, such as India and China, begins to slow. Even in just the last 10 years there has been a major shift in the economic and political conditions in many African countries,” notes Rosen. Unfortunately, he adds that many myths about the continent persist, and often the advances that have been achieved are not understood or recognized in the West. He points to the Ebola outbreak as a good example; while many assume it is a problem across the continent, the virus is only currently present in three countries, none of which are major growth markets in economic terms.

Making such general assumptions and ignoring the fact that Africa is comprised of more than 50 distinct countries is a big mistake for biopharmaceutical manufacturers looking to enter Africa. There are big differences between the countries in the northern, middle, and southern parts of Africa, differences from country to country, and even differences within countries on a tribal basis. The region can also be viewed from the perspectives of language, religion and cultural ties, English and French colonial histories, and trade blocks. Companies must also consider the public (government and non-government organization [NGO]-funded markets) and private markets within countries. 

In addition, because biologics tend to be very expensive, biopharma manufacturers must carefully consider their target markets, according to Sarah Rickman, director of the IMS Thought Leadership Group. “Except for vaccines and insulins, most biologics will only be purchased privately by wealthier individuals that have insurance,” she adds. Countries with such populations include Algeria, South Africa, and some sections of Egypt, and the larger sub-Saharan African countries. Within these countries, the facilities where the people who can afford biologics drugs can get treatment are typically concentrated in cities with larger populations.

Vaccines for the prevention of infectious diseases and insulin products, which are currently in demand due to a growing epidemic of Type II diabetes, particularly in Kenya and South Africa, are often purchased by governments and NGOs at reduced prices. Biologics manufacturers should not ignore the potential opportunities in selling to governments, though. “While the margins are often much lower, the volumes are much larger than is possible in the private sector and there is real potential to establish brand recognition,” Rickman explains.

She also suggests that biopharmaceutical manufacturers be prepared for the fact they won’t be doing “business as usual” in Africa and pick their battles very carefully. For Rosen, that means looking at the 5-10 largest markets and focusing on the largest cities within them.


  Both small- and large-molecule drug manufacturers face challenges in getting their products to the market and to patients. “The healthcare infrastructure is not established like it is in mature markets, and there are many issues that must be addressed regardless of the type of drug, such as the lack of patient awareness and limited access to healthcare,” Rickman observes. She adds that often patients prefer to receive treatment from local healers, even for serious illnesses, and thus early diagnosis does not often occur. Furthermore, many people prefer to receive local medicines rather than take drugs manufactured by western companies. 

The lack of an adequate distribution system is another factor that pharmaceutical companies must be willing to address, either by investing in the supply chain directly or finding partners to assist them. “Often people in Africa pay higher prices for original branded drugs than anywhere else in the world due to the numerous markups that occur as the products travel from the manufacturer to the patient. Therefore both availability and price are critical issues. Drug manufacturers must ensure that their products are not only getting to patients, but are at relatively affordable prices,” Rosen asserts.

There are added complexities for biopharmaceuticals. For example, supply chain concerns are exacerbated for biologics because of cold chain issues. “Often there are no facilities with reliable temperature controls, which complicates the shipment of many biotherapeutics,” comments Rickman. She adds that needle reuse/collection is another concern with biologics. 

There is also a lack of doctors that are trained to diagnose diseases that require treatment with biologics drugs, such as autoimmune and oncology-related diseases. “Highly trained specialists are required to prescribe biologics drugs, as are facilities with the capabilities to administer them, and there are very few of both in Africa currently,” says Rosen. He notes, however, that the latter issue is beginning to be addressed, with venture capital groups investing in the construction of private hospitals in large population centers. Nonprofits are doing so as well, such as Aga Khan Health Services, which has constructed health care facilities in Kenya, Tanzania, and Uganda, as well as many other developing nations. 


  The most successful western pharmaceutical companies operating in Africa today¾Sanofi and GlaxoSmithKline are two key examples¾have made sure that they have local people involved in the decision-making process, according to Rickman. “Whether setting up an affiliate with local offices or partnering with a domestic pharmaceutical manufacturer, biologics companies looking to participate in the African market must set up their businesses so that local people with knowledge of the market can make decisions without having to get everything approved by someone back at headquarters,” she adds. Of course, as the business becomes more decentralized, more local talent is needed, which can pose a separate challenge.


  The high cost of biologic drugs has created an opportunity for companies from low-cost regions of the world, particularly China and India, to provide non-original biologic drugs (not biosimilars, but copies) to the African market. While the quality of these drugs is typically below that of the originator products, they have made inroads in some areas and are expected to build market share over time.


  Despite the many challenges outlined above, IMS Health believes that the potential for real growth of the African pharmaceutical market is strong, and the environment is definitely positive. “The market is dynamic and changing very rapidly. Within just five years, we expect that the population in Africa that will be able to access and afford advanced drugs will be much larger. Companies that do not establish a presence now will find it very difficult to compete against manufacturers with established brands and low-cost suppliers in the future,” Rosen concludes.

Biopharma companies seeking to leverage opportunities in African market must adopt the right strategy to achieve success.

African Biopharma Market Presents Long-term Opportunities

Biopharma manufacturers must reduce the risk in their complex supply chains