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.

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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 physical and chemical properties of an excipient can have an impact on the manufacture and performance of the pharmaceutical products. With regulators placing increasing emphasis on quality by design (QbD) in product development, the industry is now paying closer attention to the role of excipients in the formulation of drugs and the impact of excipient variability on the quality of the final drug product. Representatives of excipient development organizations addressed key aspects of excipient variability with 

Participants of this roundtable discussion include Bernhard Fussnegger, global development and technical marketing, BASF Pharma Ingredients; Dora Meissner, regulatory manager and Rick Mutchler, president, BioSpectra; Carl Mroz, director--global regulatory affairs, Colorcon; True Rogers, R&D pharma technology leader, Dow Pharma and Food Solutions; and Ann Gray, market segment manager oral excipients, Evonik Pharma Polymers & Services.

 What are common sources of excipient variability?

: Excipients come from two main sources: natural or naturally derived excipients, such as corn or potato starch, and synthetic or semi-synthetic excipients, derived through chemical processing of a feedstock source. Variability can be due to the feedstock source, which may be the growing conditions in the case of naturally derived excipients, or chemical processing for synthetic or ‘semi-synthetic’ excipients.
Batch-to-batch variability of the same material results from the combination of variances in the feedstock, process technology, process parameters, operator actions, and even environmental conditions. When different manufacturers produce the same excipient, this can lead to variability through the manufacturing processes, such as batch versus continuous processing and on the scale and/or location of manufacturing.

: Some common sources of excipient variability are inconsistent raw materials used during synthesis, inappropriate environmental conditions during manufacturing, packaging and storage, faulty or absent manufacturing controls, and skills/hygiene of operators handling and manufacturing the excipient. Additional sources of variability can be traced to manufacturing systems not designed for use to manufacture excipients and technology not designed for use to manufacture excipients. Multiple supply sources for raw materials with lack of equivalency can also lead to product variability. Further variability can be traced to lack of controls of in-process and finished goods during manufacturing stages.

 Product variability of excipients is mainly influenced by fluctuations in the specifications of starting materials. Critical are products derived from animal, vegetable, or mineral sources. Even seasonal and different regional provenance can have a remarkable impact. Also, variability of excipient properties is critically influenced by non-validated or manually performed production processes. The knowledge of critical product parameters and their link to the corresponding process parameters is key to help minimize fluctuations in excipient quality. Routinely maintained production equipment with well controlled and calibrated metering instruments will provide excipients with low variability.

: Raw materials and manufacturing processes are sources of excipient variability. Feedstock for naturally derived excipients can vary depending on species of crop, growing conditions, mining location, etc.  Higher natural feedstock variability can mean broader variation in functionalization, for example, the degree of substitution of natural polymers. The product specifications are often met by blending of batches.

In contrast, synthetic excipients are manufactured from synthetic substances and hence show limited risk of variability due to raw materials. Reliable functionality of synthetic polymers is integrated into the molecules by design and ensured through the use of predictable and tightly controlled conditions during manufacturing. 

: One source of variability is the manufacturing process to produce the excipient. Another is the inherent measuring variability of analytical methods used to characterize properties, such as those listed on a certificate of analysis (CofA). Yet another is the variability in the raw materials needed to produce the excipient. For example, one of the key components of cellulose ethers is the cellulose raw material itself. No two trees look identically alike, so it is naturally expected that there is some inherent variability from lot to lot of cellulose raw material.

: How significant is the impact of excipient variability on drug product performance? 

: The excipient is often one of the key enablers of drug product performance. For example, the excipient may enable the dosage form to release the API over an extended time period (i.e., 12- or 24-h release). Chemical properties of the excipient, such as molecular weight and structure, can dictate modified-release performance. Physical properties, such as particle size and shape, can impact the formulation processes during drug product manufacture. Lot-to-lot variations in excipient properties might impact processability and performance of the resulting dosage form. 

: The impact of excipient variability on drug product performance depends strongly on the function of the excipient in the drug product. Variability in a processing aid used in an immediate-release tablet, for example, may not affect drug product performance significantly. However, variability in a controlled-release polymer can, of course, strongly affect drug product performance. Examples of excipient properties that might affect manufacturability include viscosity, particle size, and flow properties; whereas parameters such as moisture content or impurities could possibly influence drug product stability, depending on the use and the API characteristics. 

: Excipient variability significantly impacts the performance of the drug product as 70-80% of the drug product can be composed of excipients. Excipients with unrecognized variability used in pre-final dose manufacturing can lead to mistakenly spending significant resources on investigating pre-cursor variability when the real variability was introduced earlier in the process.
Examples of excipient properties that may affect drug product performance are often tied to specifications that do not fully recognize the true impurity risk from the site of manufacture. Lack of uniformity in product characteristics, such as particle size, bulk density, trace impurities, moisture, and likely contamination from unidentified solvents and undesired chemicals used at the manufacturing site, can adversely affect recognized or expected solubility, manufacturing, stability, and bioavailability.

 FDA has presented recalls due to variability of excipients, resulting in poor dissolution. Examples are: 
  Variation in coating--Zein NF (a natural polymer derived from corn) resulted in variability of immediate-release profile of a coated tablet
Softgel capsules as result of cross-linking short-chain aldehydes--the interaction with API-affected bioavailability.

: As medical products are precisely characterized in regulatory documents with validated production parameters and product characteristics, any variability of the excipient can have a detrimental influence on drug manufacture and drug efficacy. In this respect, particle size distribution, morphology, or the specific surface area of a given excipient--all non-compendial parameters--may influence the final dosage properties. Even a simple parameter such as the pH value of a dissolved or dispersed excipient can affect the release character of a formulated API.


PharmTech: What guidance do the United States Pharmacopeia and European Pharmacopeia provide on excipient performance and functionality-related characteristics (FRC)?

; Excipient Performance suggests appropriate tests and specifications that ensure consistent and reliable performance should be added in a manner and at a level consistent with the risk level derived from a qualified assessment of the excipient. Additional specifications, even to those of existing monographs, should be added to reflect the required performance of the excipient when used in a drug formulation.

, Functionality-Related Characteristics of Excipients, in conjunction with the FRC section of each monograph, provides insight as to how the functionality of the excipients can be controlled and may require additional specifications based on the excipient’s critical role in a drug product formulation.

 General Chapter <1059> on Excipient Performance provides guidance on physical and chemical properties along with general chapters that could be useful in characterizing excipient critical material attributes (CMA). Ph.Eur. has added to selected excipient monograph sections “Functionality-Related Characteristics of Excipients” which are non-mandatory sections linking material attributes with intended function.

: For the time being, pharmacopeial monographs, as one traditional way to control and define the quality of an excipient, provide no binding guidance for an excipient’s functionality or performance. However, there are several concepts in monograph development or modification to address these aspects. Existing examples include family monographs (

., e.g., Macrogols), functionality-related testing 

, e.g., magnesium stearate) and attributes of different articles by type differentiation (

; e.g., ammonio methacrylate copolymer, Type A/Type B-NF). Proposed ideas include flexible- and performance-based monographs (both Ph.Eur. and USP-NF). All of these concepts can contribute to express excipient functionalities from an accepted pharmacopeial perspective.

. provide guidance on excipient definition and excipient safety, but provide little guidance on performance and functionality. These regulatory guidelines give manufacturers a set of boundaries within which to operate, while also providing flexibility to tailor solutions that may be required for a particularly sensitive formulation. Evaluation of excipient characteristics that impact the function of a drug product should be determined experimentally for each formulation and not dictated by pharmacopeial documents.

 USP intends to edit the General Chapter <1079> on excipient functionality. 

 has already started to define FRCs in some excipient monographs. As these are non-mandatory parameters and very much dependent on the dosage form an excipient is formulated in, they need to be considered as guidance only. Information deducted from QbD experiments in the course of medical product development will provide the best feedback on tolerances of product parameters and their variability. Whether or not they are congruent with compendially defined FRCs has to been proven for each and every finished dosage form.

: Not all excipients and not all properties of an excipient affect product quality and safety. How do you identify which ones are critical? What are the challenges in assessing the risk of excipient variability?

: Pharma companies are typically hesitant to share details on the exact use of excipients, especially in the early phase of projects. Exchanging information on the actual excipient application at an early stage is essential for the excipient manufacturer to identify parameters that can potentially influence the functionality of the drug product being developed. Risk assessment on the user and manufacturer side thus demands a mutual exchange of information on critical product properties and their acceptable and maintainable ranges.

: Critical properties are those that impact the chemical and physical properties of excipients and their end-use applications. Knowing the end use application of the excipient and its reactivity with other compounds will aid in identifying the critical quality and safety attributes to help eliminate negative impacts from excipient use. As excipients come closer to the ingredients found in the end product, the greater the need to identify them as critical. Challenges in assessing the risk of excipient variability are greatest when there is incomplete or mistaken communication or translation between the manufacturer and the user.

: A key is to link material attributes and process parameters to the drug product. Assessing the risk of excipient variability involves identifying which attribute or property has an impact on the performance of the finished dosage form and the extent of variation, then studying whether these influence performance or not. The concept of QbD is to understand variability, including excipients, to ensure the formulation is sufficiently robust to be able to withstand potential variability.

Risk assessment is a valuable science-based process used in quality risk management that can aid in identifying which material attributes and process parameters potentially have an effect on product CMAs.

: I have found that it is of paramount importance to tie drug product performance attributes back to both manufacturing process parameters and raw material properties. Doing this systematically enables one to hone in on the most critical process parameters and raw material attributes impacting processability and performance. Oftentimes, it is difficult to find raw materials exhibiting attributes at the edges of the specification ranges. Sound experimental design is essential for success. To address the challenges associated with QbD, excipient suppliers and drug product manufacturers should collaborate closely and earlier during the drug-product development process. 

: Proper risk assessment requires detailed knowledge of the excipient functionality in the finished drug product. The significance of a parameter such as size distribution of controlled-release polymer particles is different depending on whether the polymer is dissolved in an organic solvent to prepare a coating or used as matrix former in direct compression. We use our extensive polymer and formulation know-how as a base for helping our customers understand the effects of excipient variability in standard applications. Furthermore, in cases where our products are used in non-standard, novel ways, we work together with our customers to tackle the challenge of risk assessment.

The quality and composition of excipients can vary due to environmental factors, processing methods, raw material quality, manufacturing location changes, and even operator actions.

Meeting the Challenges of Excipient Variability

It is now more than a year since FDA brought out its 

 notice asking input from the industry on quality metrics. The goal is to stratify along increasing levels of quality all the manufacturing sites regulated by FDA. 

exemplifies the current view on the matter. This paper argues that while the direction is right, the approach is too complex and unnecessarily detailed. Moreover, two major ingredients are missing from the debate. First, quality culture is barely addressed. FDA, CEOs, and regulators in general have not devoted much attention to this primary driver of product quality. What is uppermost in their mind is the verification of compliance (i.e., the effect of quality), and the current debate seems limited to measuring quality system performance. Second, the willingness to learn from others is absent. There is no evidence that anyone wants to go beyond their comfort zone.

Over the years, FDA has been shown repeatedly to be a thought leader. For example, FDA demanded GMPs for APIs 40 years before such a requirement became law in Europe. FDA has also been behind process analytical technologies (PAT) and quality by design (QbD). Major medicine breakthroughs, such as Vertex’s Kalydeco (ivacaftor) for the treatment of cystic fibrosis patients, would not have been possible without FDA’s innovation of the breakthrough therapy designation. The stratification that FDA is seeking to implement must happen, but it needs a leap of faith and major innovative thinking in a direction that is different from current proposals.

FDA’s thermometer is one that only measures negative temperatures. FDA, as well as other regulators, tends to focus on the “floor” with medicine agencies explicitly defining a threshold level below which quality performance is deemed unacceptable. But what does FDA issue when it wants to say “Well done!”? Presently there is no FDA form for “Well Done.” Yet FDA is keen that we move in the direction of its 21st-century vision with concepts such as process understanding, risk management, and supply reliability. FDA has nothing in its arsenal to encourage the proactive pursuit of greater manufacturing quality.

At the same time, sanctions for non-compliance, especially when non-compliance is a business strategy, are insufficient to be an effective deterrent. Because the type of sanctions hurt primarily shareholders and not management, rogue behavior is encouraged by positive payback. Because non-compliance pays, rogue players often win. For example, has anyone been caught (let alone jailed) for causing hundreds of deaths in the heparin tragedy?

Safety and quality have much in common, with both being crucial aspects of industrial activity. Both depend directly on constant management attention and require the right tone at the top. Yet in terms of metrics, safety is easy (while quality is complex). The number of deaths, lost time due to accidents, the gravity and frequency indices are well-established metrics and are sufficiently comparable across all sectors. What we are trying to measure is simple. Research has also taught us to expect correlations between near-misses and accidents.


The Occupational Safety and Health Administration (OSHA) is the USA’s authority that enforces safety and health in the workplace. It performs regular compliance surveillance through surprise inspections. OSHA’s voluntary protection program (VPP) rewards workplaces that have consistently no lost time accidents by removing them from the inspection roster. VPP Star program recognition drives appropriate behaviors--a reduction in insurance premiums is a financial benefit, but paramount is the pride workers have in a safe workplace, and no effort is wasted in maintaining that status.

Just like FDA, OSHA has defined where the “floor” lies. Below such minimum acceptable safety level, sites get closed down and fines are levied. But OSHA’s thermometer also measures positive temperatures--the VPP Star program identifies the role models. OSHA thus has a three-level stratification of the safety performance of all the sites it regulates. The VPP Star program is an effective reward mechanism and a confirmation of a sound and vibrant safety culture.

The metrics used to assess the safety of workplaces exhibit the attributes that FDA is looking for, which include “not amenable to gaming, objective, cross all sectors, are non-intrusive and relevant” (1). It is simple, has virtually no cost, and enables the deployment of inspections of resources where they are really needed. The quality metrics currently under discussion involve setting up systems that are complex, require annual data input, need supervision and funding, and will necessarily introduce behaviors focused on improving “the site’s position in the league table” rather than just doing the right thing for the patient.

In accidents, harm to the worker is a simple common denominator. No comparable measure exists in quality. All the metrics that have been proposed may be objective and may ultimately correlate with recalls and adverse events, and elegant mathematics may make them comparable across sites and across all sectors of the pharmaceutical industry. Such metrics, however, are unable to measure whether the CEO is really committed to developing and nurturing a quality culture in his or her organization.

Sections 705 and 706 of the FDA Safety and Innovation Act (FDASIA) mandate that metrics be made available so that FDA can deploy its inspection resources appropriately. It does not say it needs to be complicated or costly, or that FDA cannot get inspiration from an OSHA-type VPP Star program. FDA could publish a simple list of manufacturing sites that are role models. When this list is published, FDA will have done enough to define the right behaviors and will have done so at a low cost.

The metrics being discussed tend to focus on the deciles from the bottom all the way to the top, which is both unnecessary detailed and costly. The only stratification the industry has today is a well mapped-out lower level, below which quality is unacceptable. What is needed now is a definition of an upper level, beyond which the quality performance is in the right direction and deserves recognition and applause (see


For FDA to establish a stratification of its sites in at least three classes, such as OSHA, it will need to define the border between “being in compliance” and “being ahead.” And those sites that make it beyond that threshold join what has been described as Commissioner Hamburg’s Dean’s List (2).

 It is unlikely that the shape of the distribution today approximates the normal distribution because there is nothing defining the right side of the bell shape. Once a driver of behaviors, such as a Dean’s List, exists, one could expect a normal distribution.

This paper argues that metrics pulled from a quality system alone will not help define where Commissioner Hamburg’s Dean’s List starts. The industry and regulators need to start acknowledging that what genuinely assures compliance and then takes an organization to levels of quality beyond the minimum is the organization’s quality culture. An organization’s quality culture is embedded in the values of the people that make any site function. A quality system will only assure quality if it is backed-up by a well-nurtured quality culture that permeates the entire manufacturing organization. Without a culture of quality, a quality system assures nothing. An article from

 magazine, “Dirty Medicine,” provides a good description of an organization where incidents of fabrication of compliance evidence were endemic (3). In other words, in an organization that has no culture of quality, it is not a system of controls and documents that will safeguard quality.

The large number of warning letters and import alerts issued to sites based in India in the past two years may not be statistically significant given the considerably large number of FDA sites in that country. What is both significant and of concern is that they are all related to data-integrity issues. The chief executive of an Indian drug maker was recently quoted as saying, “When a company is small, it can be managed by strong supervision. As companies get bigger, supervision can break down … You need systems and a culture to maintain proper supervision—and we are in that process of growing up, I think” (4). Indian generic companies’ grew at a rate so fast that the nurturing of such quality culture needed to be miraculous.

The agency should consider whether an organization that has a culture of fraud instead of a culture of quality can ever be reformed, or whether it should be given a second chance (5). The agency should also consider whether drug shortages are not inevitable when unscrupulous companies compete unfairly in the market through systematic non-compliance and destroy the competitiveness of compliant firms. A regulator’s job is not limited to the oversight of the quality of drugs. Regulators must take decisive action when non-compliance becomes an obvious competitive advantage that hurts the fabric of the industry. “A firm can have all the SOPs, systems, and controls required but, without a quality culture, product quality and business continuity are not assured” (6).


A quality culture is not the result of procedures, specifications, audits, a quality unit, or enforcement by regulators. Although some of these elements do help establish a quality organization, by themselves, they are insufficient.

It is surprising that of the 128 comments to FDA’s docket, only Pfizer’s refers explicitly to quality culture as preeminent: “The indicators mentioned above are only useful when coupled with a strong quality culture, which we believe is the foundation of consistent quality performance” (7).

The conditions where a quality culture  will develop are likely to include:

The right tone at the top, a focus on the right values

A constant display of concern for quality, for putting the patient ahead of everything else

An organization that consistently “walks the talk” 

An organization with great people skills and strong values 

Shareholders who expect more than just financial rewards.

 The indicators of a strong quality culture include: 

Quality-driven productivity brought about by sustained change through the introduction of improvements and innovation

Adoption of and investment in technology including IT to ensure a better state of control over systems and timeliness of event follow-up 

Prompt adoption of best practices, promotion of change, and continuous improvement in the quality system itself

Pro-active and transparent behavior with regulators leading to a rich relationship with regulators based on dialogue, sound science, and mutual respect 

Intense participation in the standard setting-process

Good performance in other areas such as safety, business conduct, and sustainability

  The degree of maturity of the quality culture will correlate with where the site is in terms of the following journeys: 

An evolving mind-set that accumulates as second nature habits such as deviation recording, change-control, trend analysis, risk management, process understanding that defines the space of process capability, and so on

Evolving from a rigid machine organization with inflexible quality systems towards a rationale-based approach that adjusts controls appropriately to each situation.

These aspects mirror the maturity of the quality culture in an organization. As the quality culture and system of an organization evolve and mature, the cost of quality diminishes and its capability becomes greater and more efficient. This approach can help map the progress of a quality culture and could be used to define the criteria and boundaries at the right of the bell shaped curve.

 An organization with a sound quality culture is easilyrecognized as it believes in the following two principles:

Product and process understanding (e.g., sufficient depth of science that provides an explanation of why a process deviation has or does not have impact on the quality of the product).

Sensible business management—Too fast growth and operating at the limit of capacity are often triggers of quality issues or of non-compliance. It is obvious that in many Indian generic-drug companies the product portfolio growth outstripped the company’s quality system. Senior management failed in its oversight. 


The following additional attributes of a manufacturing site could be used by FDA to set the bar for that site to be listed in Commissioner Hamburg’s Dean’s List:

A solid track record of consistent good performance at FDA inspections (frequency of successful inspection in the recent past)

Frequency of filings in the recent past that include a growing pattern of QbD approaches and the application of PAT controls

Providing FDA with IT access to perform at any time and in real-time remote inspection of all quality data related to commercial batch manufacturing and release (including seeing deviations, change control and analytical data, and trending thereof, and the measure of timeliness to close events)

Visible active participation in the standard-setting process 

Allowing FDA inspector training at the site.

Most importantly, FDA should add a further element to its compliance inspections. Inspectors should determine the existence and maturity of the quality culture in the inspected site. Simple cross-examination of operators and candid conversations with management at various levels will quickly tell what tone is set at the top, what costs of non-quality are accepted, and how much power the quality assurance department has over budgets, over purchasing, or finance departments decisions. An assessment of quality culture should be central to any quality metric assessment—this has to be done by FDA on-site during an inspection.

In lieu of the complex metrics that are being discussed, the industry and FDA could agree on what is the roadmap to reach the Dean’s List standard, what are the desired minimum attributes that would allow a site to apply to be invited into the program. It would be up to the site to check whether it meets the criteria, and application would be voluntary. To be accepted as an applicant would require a successful inspection that would assess the maturity of the quality system and the vibrancy of the quality culture. This accepted applicant status itself will be a great motivator to improve quality performance and inspection readiness, while also having a marketing value. It does not require much additional financial cost to the agency and allows any plant to set its sights on an ambitious goal.

Finally, for those that make it to the Dean’s List, FDA needs to go public and be able to say, “Well done!” and publish the names of those sites that made it onto the list. FDA has to decide how it will do this and also how it removes sites from the list (the same way as the Michelin or Zagat guides give and remove stars to restaurants and neither justifies it).

Being on this public list of role models does not need to trigger any special treatment as in the case of OSHA’s VPP Star program. Being listed will be in itself a worthwhile reward. Being listed will be a relevant element in FDA’s risk assessment and many new drug applications or abbreviated new drug applications are likely to be approved without pre-approval inspections if their product is produced in a listed site. FDA needs its best manufacturers to be profitable and to grow. A transparent and public three level stratification of quality performance will enable a better site to charge a price that rewards enhanced quality.

It is disappointing to hear that many in the pharmaceutical industry believe that a site’s quality metrics and ranking should remain confidential. When Deborah Autor of Mylan argued for a site’s ranking to be made public at a recent public meeting, other representatives of large multinational companies said that they were completely opposed. This is wrong. Transparency has become a motto of the 21st century. Our industry needs to change. Of course none of what is being proposed is in FDA’s comfort zone but as the breakthrough therapy designation and other examples illustrate, FDA’s greatest accomplishments happen when it innovates


1.	GPhA/FDA CMC Workshop Meeting (Bethesda, Maryland, June 2013).
  2.	Guy Villax, 

,” Fortune, accessed Aug. 19, 2014.
  4.	Reuters, “FDA bans imports from Sun Pharma plant in India crackdown,” Press Release, March 13, 2014. 
  5. 	IPQ, “

FDA Data Integrity Concerns Continue in India as Three More Firms Draw GMP Warning Letters

,” accessed Aug. 19, 2014.
  6. 	Mary Oates, Pfizer, “Risk-based approach to quality oversight in contract manufacturing - outsourced activities,” presentation at the APIC Annual Conference (Budapest, November 2011)
7.	Pfizer’s March 13, 2014 Response to Docket FDA-2013-N-2014. PT


Guy Villax is CEO of Hovione FarmaCiencia SA, Sete Casas, 2674-506 Loures, Portugal,

FDA is moving in the right direction in terms of implementing stratification by levels of compliance across pharmaceutical manufacturing sites. However, quality is a matter of culture more than metrics. In this opinion article, the author presents arguments for an FDA Dean's List as a means to nurture a quality culture within the industry.

A Case for an FDA Dean's List

The recent European Union Falsified Medicine Directive highlights the call for a secured supply chain for medicines. After years of legal debates on ways to address excipients control in Europe, the manufacturing authorization holder is finally accountable to develop a process along the principles of the International Conference on Harmonization on 

 (ICH Q9) to assess the suitability of the quality and safety of the excipients used. A guideline on a potential formalized risk-management process for ascertaining the appropriate GMP for excipients is expected to be published by the European Commission soon and should provide direction on the level of GMP to be expected for these materials. Using a model risk-management process proposed by industry, the authors discuss ways to apply this requirement, suggesting a strong emphasis on the nature of the “excipients industry” and the need for a close collaboration between the supplier and user prior to setting up any risk control strategy at the supplier manufacturing premises. The International Pharmaceutical Excipients Council (IPEC) and the Pharmaceutical Quality Group (PQG) GMP and IPEC GDP guidelines, as well as similar recognized GMPs and/or quality system standards, are used as a guide to implement the detailed practices.


In the EU, binding definitions are in place for medicinal products (1) and APIs (2, 3). It is an ongoing process to develop appropriate requirements for pharmaceutical excipients, which represent up to more than 90% of dosage forms.

A series of tragic incidents in the pharmaceutical supply chain caused the European Commission to propose an application of GMP for APIs (3) as guidance for the manufacturing of “potentially” critical excipients in 2007. The assessment report of this public consultation concluded that pharmaceutical companies defining the appropriate GMP for excipients, based on risk, would result in a more pragmatic approach. As a result, the European Commission adapted the legal basis for defining the appropriate GMP for pharmaceutical excipients using a risk-based approach: “The holder of the manufacturing authorization shall ensure that the excipients are suitable for use in medicinal products by ascertaining the appropriate good manufacturing practice on the basis of a formalized risk assessment” (4). A draft on 

Guidelines on the Formalized Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use 

(5) was submitted for public consultation.

 The risk-assessment model proposed and discussed in this article refers to these expectations (5). It also takes into account and provides links to existing guidance developed by industry and experts such as IPEC/PQG (6) and EXCiPACT (7), which are based on ISO 9001 and ICH Q7 (3).

Points for consideration on an appropriate GMP for excipients


Before excipient manufacturers are able to address implementation of an appropriate GMP for excipients, it has to be recognized that excipients are starting materials for medicinal products, which have not necessarily been designed exclusively to be used for medicinal purposes. Although accepted as safe to use in other consumer industries (e.g., food, cosmetics), the type of good practices in manufacturing may differ based upon design and practice by the company and technology used. This raises the essential need for a good interaction and communication between excipient manufacturers/distributors and users. Assessment of the appropriate formal level of GMP and GDP will have to be considered by both parties in a collaborative manner.

The user will have to determine the type of risks associated with their product, share the excipient functioning role, and communicate with the supplier/distributor potential critical quality attributes, which might impact its risk assessment. This kind of assessment may already occur today, although in most cases, informally. A good base for the primary assessment of the supplier (e.g., regulatory files, specifications, questionnaires results, audit reports) is complemented by transparency of available data from the user’s side. An appropriate form of agreement is typically required to address a supplier’s legitimate concerns in sharing its confidential information.

On the other hand, the excipient manufacturer should be able to obtain sufficient information on the potential end use of his excipient too, and only then assess his ability to meet GMP and/or GDP expectations. Information known to the user through its own supplier qualification scheme should allow him to initiate a risk assessment. This information that is known by the user, which will allow him to conduct its risk analysis, is usually reflected in a quality agreement or questionnaire, targeting the understanding of key elements on quality systems and GMP, such as change management, corrective and preventive action (CAPA), auditing, or third parties’ assessments.

Risk assessment for critical drug applications cannot occur without an appropriate dialogue between user and excipient supplier. Ignoring this essential step may lead to an inaccurate representation of the risks associated with manufacturing and supply of the material, and rank the risk/application/supply source inappropriately.

Assessing the risks through a proper user/supplier dialogue should allow better control of risks at relevant places during manufacturing and supply, resulting in a more effective risk reduction. Excipient suppliers may reasonably seek to limit their liability so that controls in a quality agreement mitigate risk without shifting it entirely to the supplier. Depending on the outcome of that assessment, certain sources of supplies may be seen as unacceptable. Actions are potentially to be taken to reduce identified risks. Such an approach should allow developing and documenting the relevant expectations for quality practices and the appropriate level of GMP/GDP.

It is, therefore, generally best practice for the user to develop, assess, and document the right key performance indicators (KPIs) to monitor the excipients quality in conjunction with the respective supplier according to the proposed overall risk-assessment model (see 

A potential implementation of a risk-based approach


GMP references for risk assessment. Excipients are regulated as starting materials for drug (medicinal) products. At this moment, the only GMP for starting materials, which is legally binding, is the ICH Q7 GMP guideline (3) for the manufacturing and distribution of APIs.

It can be argued that it may be neither adequate or appropriate to use ICH Q7 (3) requirements to define the GMP for excipients due to their complex nature. Guidelines developed by industry, such as IPEC/PQG GMP (6), IPEC GDP (8), and EXCiPACT (7), or equivalent guidance, provide appropriate quality systems and GMP standards reference. They are based on ISO 9001 quality systems concepts and provide an excellent foundation for the GMP and GDP gap assessment. The authors think that these guidelines provide a sufficient basis and no additional “what to do” nor a “how to do” guidance would be needed (see 

Quality risk-management principles as enabler. 

To comply with the expectation of implementing an appropriate “GMP for excipients” standard, the principles on quality risk management per ICH Q9 (9) can be used by the manufacturing authorization holder (MAH) as a reference to support the formal risk assessment of their excipient manufacturers/distributors. Excipient users, certification organizations, and regulators could use similar risk-assessment models when auditing excipient manufacturers.

As foundation of such a risk assessment and to determine the appropriate level of GMP and/or GDP for excipients, it is necessary to follow and keep in mind the two primary principles issued by ICH Q9 (9):

The evaluation of the risk to quality could be based on scientific knowledge and ultimately link to the protection of the patient

The level of effort, formality, and documentation of the quality risk-management process could be commensurate with the level of risk.

Understanding risk as “the combination of the probability of occurrence of harm and the severity of that harm” per ICH Q9 (9) is essential. Nevertheless, a list of hazards should not necessarily drive excipient users and/or regulators to potentially implement risk control measures for each and every hazard identified. All discussions and considerations should be linked back to risk levels (i.e., a combination of severity, probability, and detectability) with the main focus on the protection of patients.

Applying a risk-based approach, similar to the one described in ICH Q9, could be used to determine the level of good manufacturing and distribution practices (GMDPs) for excipients (see 

). This process could be implemented retrospectively for currently used excipients, as well as prospectively during pharmaceutical development.

Typical quality areas to consider for the risk assessment


In the context of manufacturing of excipients, five specific areas of potential risks should be considered, understood, and assessed when reviewing the excipient manufacturers’ quality management system, as applicable.

Assessing the quality management system (QMS). 

Many excipient manufacturers have already implemented a certified QMS according to ISO 9001 requirements, or similar quality systems. These basic principles (including management responsibility, management of resources, requirements for product realization, and concepts on measurement, analysis, and improvement) represent basic expectations for a QMS for pharmaceutical manufacturing purposes.

Another key source of risk is the complexity of the excipient supply chain, which may include different actors prior to reaching the user of the excipient. Considering the origin of the material is potentially critical, whether it is directly sourced from the producer or indirectly sourced throught a third party. Additionally, repackaging and relabeling operations are regarded as “manufacturing” activities and should also be performed under an appropriate GMP.

Assessing the manufacturing of the excipient. 

Several factors could be considered, based on the source of the raw materials, the manufacturing process type, the equipment used, and the site organization. Facility and layout of the manufacturing site are unlikely to be similar to the ones used by pharmaceutical industry. A pragmatic approach has to be taken when identifying hazards associated with the supply of these materials. Use of risk assessment may be already a standard practice in some organizations (e.g., hazard analysis and critical control points [HACCP], failure modes and effects analysis [FMEA], etc.), and could be used and/or referenced for other specific risk-assessment purposes.

Assessing the route of administration in the drug product.

 It is important to seek a dialog with the excipient users, if possible, to generate an understanding for the particular needs of the respective drug product. Often such discussions are limited or prevented for reasons of confidentiality. However, it is regarded as very useful to provide the excipient manufacturer with a basic understanding of its excipient use, especially when higher risk applications are foreseeable (e.g., in sterile products).

 Specific consideration should be given to the influence on bioavailability and the manufacturing process of the drug product, if known. This is particularly important if an enhanced development approach (based on quality by design) has been taken, for example, to assess the excipient’s impact on the drug product’s critical quality parameters.

Each of these key elements should to be considered during the risk assessment (see also information and references in 

). Should any of these hazards raise a specific risk flag, risk reduction measures could be considered during the risk control phase as a basis for an appropriate risk acceptance decision. The risk-management process should be completed by monitoring and reviewing quality indicators (e.g., KPIs) and CAPA measures from internal and/or external audits.  

Appropriate control elements might be already implemented by the excipient manufacturer; for example, they may use different terminologies or processes to achieve the expected risk control measures. These elements are essential and justify the discussion between excipient manufacturer and user.

Potential considerations to GMP for excipients

 provide reference lists and link to similar basic GMP elements for the manufacturing of excipients as described in the European Commission draft guideline (5), EXCiPACT (7), and ICH Q7 (3). The authors consider it helpful to review these tables as part of the risk analysis, taking into account the principles of quality risk management based on ICH Q9 (9) to fulfill upcoming expectations and requirements. Similar basic GDP requirements apply to most excipient distribution operations as well as potential national legislation on distribution of goods under the trade applicable law.

) could be considered as a potential source of examples during the risk assessment of the typical quality area mentioned in the previous section on typical quality areas to consider for the risk assessment.

Using a model quality risk-management process according to ICH Q9, the authors discuss ways to apply this guideline.

Pharmaceutical Technology-09-01-2014

Need for Supply Chain Transparency is Acute

Taking Action on Elemental Impurities

Exploring a New Approval Process for Continued Excipient Innovation

Meeting the Challenges of Excipient Variability

A Case for an FDA Dean's List

A Practical Approach of Implementing GMP for Excipients

API Developers Pass Inspections and Upgrade Capabilities