Excipients Step into the Spotlight

During the past few years, industry has come to better understand excipient functionality and variability as well as excipients' role in the drug-product supply chain. As a result, excipient users and suppliers are looking for more even ground regarding the way in which excipients are used and regulated compared with active pharmaceutical ingredients (APIs) and other raw materials. Standard-setting bodies such as the US Pharmacopeia and US Food and Drug Administration are taking notice and starting to widen the curtains when it comes to the use of novel excipients and the qualification of excipient supply and suppliers.

To address these issues, Pharmaceutical Technology moderated a Speakers' Roundtable at the May 2010 ExcipientFest-Americas and International Pharmaceutical Excipients Council (IPEC) Regulatory Conference in San Juan. This article highlights key points made by the panelists*: Rosa Motta, acting branch chief of international compliance at FDA's Center for Drug Evaluation and Research (CDER), Division of Manufacturing and Product Quality; Catherine Sheehan, director of excipients in the Documentary Standards Division of the US Pharmacopeia (USP); Dale Carter, director of global quality, silica, at Huber Engineered Materials and chair-elect of IPEC-Americas; Ranga Velagaleti, manager of regulatory affairs, North America, BASF Corporation; William Busch, senior applications development specialist at Dow Wolff Cellulosics and member of IPEC's quality-by-design (QbD) committee; and Eric Berg, director of supplier quality at Amgen, member of IPEC-Americas Executive Committee, and Rx-360 consortium volunteer.

ILLUSTRATION: DON FRASER/PHOTOS: GETTY IMAGES

Excipient usage evolves

PharmTech: Given the recent changes to the excipient industry, from a regulatory perspective, what core challenges arise with the use of excipients in pharmaceuticals?

Motta: Globalization of the excipient supply chain and the variable degree to which excipient quality is managed by drug manufacturers seem to pose the greatest risks. In more complex global supply chains, excipients can readily change ownership multiple times without proper documentation, accountability, or traceability. There is a higher risk to conduct less frequent audits of the most remote sites of excipient manufacturing. The risk of accepting an unsuitable excipient can be magnified by the use of a non-specific identity test and inadequate excipient manufacturer qualification and monitoring programs aimed to support the level of established credibility. Excipient manufacturers are not required to register as drug manufacturers and it remains relatively easy for an ingredient not intended or suited for pharmaceutical use to be introduced into the supply chain.

Panelists (l to r): BASF's Ranga Velagaleti, Dow's William Busch, Amgen's Eric Berg, and USP's Catherine Sheehan. (PHOTO: COURTESY EXCIPIENTFEST)

PharmTech: How is industry using excipients today compared with 10 years ago?

Busch: The biggest change has been the improved understanding of the role excipients play in the final performance of the API. Excipients have been defined as an inactive substance used as a carrier for the active ingredients of a medication. This is, in fact, the first sentence when one looks up 'excipient' in Wikipedia (May 21, 2010). IPEC defines excipients as any substance other than the active drug or product that is included in the manufacturing process or is contained in a finished pharmaceutical dosage form. Today, it is well understood that excipients provide a range of functionality—from process aids for lubricity, flowability, and compressibility to finished dosage-form functionality aids, which may improve the availability or control the dissolution rate of an API. The US Pharmacopeia-National Formulary (USP-NF) includes extensive categorizations of excipients.

FDA's Rosa Motta. (PHOTO: COURTESY EXCIPIENTFEST)

With the advent of FDA's QbD initiative, drug manufacturers are being asked to provide proof of their understanding of the role each excipient plays in their finished formulation. This requires the drug manufacturer to run a design of experiments (DOE) to understand the role that each ingredient in the formulation plays in the final dosage-form functionality. In the ideal case, the manufacturer can develop a design space to predict the finished dosage-form performance based on properties of the individual formulation components. Because there is inherent variability in any raw material, the key challenge is to develop robust formulations that will be able to use the excipient within its variability. Can a manufacturer use any excipient that meets its specification limits? If so, the manufacturer has a robust formulation.

Excipient variability is compounded, however, when purchasing material from different suppliers, who may use different processes and unit operations to produce the excipient. Two excipients may not be interchangeable, and thus, it is important to understand the differences and how they affect processing and final dosage form.

To correct for inherent variability, both formulation flexibility and process flexibility are needed, the degree of flexibility being dependent upon limits determined during the design space development. Excipient variability is compounded when purchasing material from different suppliers, who may use different processes and unit operations to produce the excipient. Two excipients may not be interchangeable, and thus, an understanding of the differences and how they affect the processing and final dosage form must be achieved.

PharmTech: Why is industry's understanding and control of excipients important to FDA?

Motta: Excipients generally comprise a significant portion of a dosage form and can potentially compromise drug product quality if their quality is not adequately controlled. A single batch of an excipient can be used to manufacture many batches of drug products. Thus, an excipient manufactured or held under subpar conditions can cause a large number of drugs to be adulterated, potentially putting patients at risk or resulting in a shortage of a medically necessary drug. Although excipients are not pharmacologically active, many excipients play a key role in drug bioavailability. Even excipients that are less prominent in their functionality have quality attributes that, if not adequately controlled, might compromise the quality, stability, or performance of the drug product. In the worst case—demonstrated by recurring events in which diethylene glycol (DEG) was added to an excipient to increase its market value—when excipients are not controlled, the result can be a widespread outbreak of serious adverse events.

Supply security dictates transparency

PharmTech: IPEC recently developed a guide for excipient qualification that addresses GMPs and GDPs. In addition, as reported in Pharmaceutical Technology's May 2010 supplement, International Pharmaceutical Excipient Auditing (IPEA), an IPEC subsidiary, received ANSI accreditation of its excipient supplier GMP certification program. How can industry benefit from these programs?

Carter: The focus of the guide is to help excipient users make correct decisions about the proper steps during drug development to formulate with the correct excipient grade. This goes a long way toward having a successful supplier relationship throughout the product's life cycle. The guide helps excipient manufacturers understand what information is important to share and why it is needed. This guide also highlights key information needed from both parties to select and qualify the correct grade for the user's formulation and finished drug-manufacturing process. Excipient makers typically offer several USP-NF grades of excipients designed to optimize performance in different processes or formulations.

PharmTech: There's been ample talk throughout industry about auditing, including shared and third-party audits, and related challenges. What is truly needed to move forward in this direction?

Berg: A key topic here is transparency of the original manufacturer. Some suppliers are not the original manufacturer. They provide value by repackaging and testing, and they accept responsibility for the quality. For these suppliers, it is critical that pharmaceutical customers know who the original manufacturer is and verify that a robust supplier-quality program is in place. I would expect this review of original manufacturers and the review of the company's supplier-quality controls to be a part of the supplier audit.

Pharmaceutical companies need to request transparency and treat the information honorably to earn a supplier's trust and, in turn, suppliers need to provide transparency. All three parties need to come together in business review meetings, so that each one can appreciate the total value chain for the material and ensure that there is a shared commitment to protecting material authenticity.

PharmTech: Will FDA provide any guidance on the use of paper audits? Does the agency recommend auditing every single supplier and distributor in one's supply chain-and if so, should those be on-site, in-person audits?

Motta: A vendor questionnaire provides some preliminary indication that a supplier can be qualified and can be used to gather information in advance of doing a site audit. Accuracy and integrity of information received from suppliers can be established through an ongoing program for supplier monitoring, which should include periodic site audits. FDA supports the product manufacturer decision to use an accredited third-party whose auditors possess adequate qualifications to perform audits of excipient manufacturers to replace or supplement the drug manufacturers' own audit. However, the manufacturer must determine whether the audit performed by the third-party is adequate. Manufacturers might need to perform complementary audits to gather enough information to satisfy their internal procedures for supplier quality management. Manufacturers should implement a comprehensive risk-management system approach through the entire product life cycle to include how often and how in-depth to audit their suppliers. A supplier that has never been audited by the drug product manufacturer may be considered a "higher risk." We believe site audits are an integral part of assuring ingredient quality and supply-chain integrity. An adequate on-site in-person audit of the excipient manufacturer process and practices may be the best way to get an accurate assessment of the capability of the excipient manufacturer to manufacture under CGMP conditions and to meet the quality requirements of the product manufacturer for the particular excipient.

Novelty finds its way

PharmTech: IPEC recently completed a pilot program involving a novel excipient safety evaluation procedure to promote regulatory acceptance of new excipient usage outside of the new drug application (NDA) process. BASF's Solutol HS 15, a new solubilizing excipient, went through the process and was ultimately published as an official monograph in USP–NF (see PharmTech's November 2009 issue for the full story). Why are novel excipients so necessary today and why is industry reluctant to use them?

Carter: Because the approval of an excipient for use in a drug product occurs in the FDA review and approval of a finished drug product, pharmaceutical companies tend to stick with excipients that have already been approved in other drugs to limit the chance of delaying the approval process. The result is that new drug products that could benefit from the functionality of new excipients end up being formulated with old technology and the patients are deprived the benefit of advancements in science that could deliver better medicines. IPEC recognized this problem and our safety committee developed a process for novel excipient review whereby an independent group of recognized experts could review the manufacturing and safety data provided by an excipient company and make a recommendation as to the safe use of the excipient. This information can then be submitted along with the panel's review as part of the manufacturer's application. While the evaluation process is not an official approval, a favorable review using a process similar to that used by an FDA reviewer provides confidence to the pharmaceutical company that the excipient will not cause a delay of the drug approval process, thus encouraging the use of novel excipients to make better medicines.

PharmTech: What role did USP play in this pilot?

Sheehan: BASF collaborated with USP in the development of this compendia monograph (Polyoxyl 15 Hydroxystearate NF, the USP-NF official title for Solutol HS 15). One of the major challenges at that time was that Solutol HS 15 was not used in an approved dosage form in the US and as a result was not listed in the FDA's /CDER /Inactive Ingredients database (IID). There is no independent approval or evaluation procedure for new excipients used in an approved dosage form in the US because they are evaluated only in the context of an NDA or biologic license application (BLA). FDA only permits the use of an excipient in an FDA approved dosage form marketed in the US. Once the drug product is approved by FDA, the excipient is listed in the IID and usually followed by the development of the compendia monograph standard. The IID listing includes the name of the excipient, the dosage form, and the amount per dosage unit. Drug product names are not mentioned in the IID database. Solutol HS 15 was considered novel or new as it had no prior use in a human drug product approved in the US. The term, "new excipient" is defined by FDA's 2005 industry, Non-clinical Studies for the Safety Evaluation of Pharmaceutical Excipients as follows:

"In this guidance, the phrase new excipients means any inactive ingredients that are intentionally added to therapeutic and diagnostic products, but that: (1) we believe are not intended to exert therapeutic effects at the intended dosage, although they may act to improve product delivery (e.g., enhance absorption or control release of the drug substance); and (2) are not fully qualified by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration."

The term, "novel excipient" is also defined in FDA's 2004 guidance, Drug Product, Chemistry, Manufacturing and Controls Information:

"Novel excipients are excipients used for the first time in a human drug product in the United States or by a new route of administration. Any novel excipient should be identified and its specification included in this section of the application (P.4.6)."

As a result, new drug product manufacturers are reluctant to risk drug approval with the use of new excipients because it adds additional risk to the drug application process; the entire application could be rejected if the excipient is considered unsafe.

The IPEC-Americas Novel Excipient Safety Review Procedure required BASF to submit a safety evaluation package to an independent toxicology consulting firm for novel excipient evaluation. BASF also submitted the independent safety evaluation report and all components to FDA through the IPEC –Americas safety committee chair. BASF informed USP about Solutol HS 15 safety evaluation by FDA under the IPEC-Americas Novel Excipient Safety Evaluation Procedure Program and their plan to submit a new monograph proposal. USP subsequently collaborated with FDA resulting in the publication of the draft monograph in the USP Pharmacopeial Forum (PF) Jan.– Feb. 2009 edition, followed by publication of the monograph in USP 33-NF 28 Reissue (official Oct. 1, 2010).

Recently, USP has expanded the USP Pending Monograph process to include excipients. Excipients that satisfy the Pending Monograph requirements listed on the USP website qualify for this approach. Requirements include submission of a drug master file (DMF) for an article to FDA. The purpose of pending monographs is to have an official USP-NF monograph ready as soon as possible after FDA grants final product approval (with associated excipients(s)). To this end, the pending monographs approach lets monograph development begin before FDA's approval process is complete, resulting in an official USP-NF monograph more rapidly than would be possible if monograph development started only after final FDA approval. Pending monographs are considered authorized rather than official text because they are approved by the USP Council of Experts, but are not part of an official compendium of the U.S. (USP or NF). For more information on the Pending Monograph approach and the USP-NF standards setting process, visit the USP websites: www.usp.org/standards/pending/ or www.usp.org/USPNF/submitMonograph/.

PharmTech: Since the pilot, what feedback has BASF received in terms of clients willing to use a novel excipient that hasn't appeared in an NDA?

Velagaleti: First-time use of a novel excipient in a drug product is very critical due to understandable apprehension by customers if not previously used in a FDA-approved drug (as noted, FDA does not approve or reject excipients). Under IPEC's Novel Excipient Safety Evaluation program and discussions on this program with FDA, the agency as we understand from IPEC has agreed to to look at only one novel excipient ahead of time, before being used in a drug product (before appearing in an NDA). Even though Solutol HS 15 has gone through the IPEC program, FDA will review it again within an NDA. Hopefully, because of this review and the submission of the BASF toxicology DMF to FDA subsequent to the agency review under this program, the Solutol HS 15 safety review in the context of a drug application may move faster. More importantly, the agency review enabled BASF to request from USP an official monograph, which USP published. This has made it easier for us and the program should open door for more novel excipients to enter the market.

PharmTech: Based on this pilot, is FDA becoming more open to the use of new excipients in pharmaceuticals outside of the NDA process?

Motta: It is not FDA's intent to preclude industry from developing new technologies that have been proven to improve the quality of the drugs offered to consumers. As a matter of fact, in 2005, the agency published a guidance for industry, Non-Clinical Studies for the Safety Evaluation of Pharmaceutical Excipients to provide guidance regarding developing safety profiles to support use of new excipients as drug components.

Elemental impurity proposals affect excipients

PharmTech: USP has been actively involved with FDA and industry in discussing new general chapters and requirements for testing metal impurities. ICH has formed a working group on the development of a Q3D Metal Impurities guideline to address a global risk-based approach to controlling metal impurities. Excipients will be impacted significantly by the outcome of these efforts. Do you foresee harmonization helping to minimize the testing required for products that are marketed around the world? Will USP wait for the results from the ICH working group before moving forward with its proposed general chapters?

Sheehan: USP proposed three new General Chapters on Elemental Impurities Limits, Methods, and Dietary Supplements Metals Limits in the January-February 2010 issue of the PF for public comment and review. Other related information appeared in PF 36(1), including a draft General Notices statement about the applicability of the standard to all monographs and two Stimuli articles outlining the rationale for the limits chosen by USP and a summarizing the comments received from an original Stimuli article and Heavy Metals Workshop and USP's response to the comments. The new elemental impurities proposed General Chapters were available for public comment until Apr. 15, 2010.

The revisions focus on two areas of work: updating the methodology used to test for elemental impurities in drugs and dietary supplements to include procedures that rely on modern analytical technology; and setting limits for acceptable levels of metal impurities (including, but not limited to, lead, mercury, arsenic, and cadmium) in drugs and dietary supplements. The USP Metal Impurities Advisory Panel, which reports to the USP General Chapters Expert Committee, worked with USP staff and stakeholders to assess methodologies and limits that provide greater patient/consumer protection and can reasonably be deployed across industry laboratories. The limits for exposure are toxicologically based and developed by an expert process to provide quality standards that reflect consensus views about potential health/toxicity concerns. These new approaches are intended to replace the existing methods in General Chapter <231> Heavy Metals. The proposal aligns well with the current European Medicines Agency (EMA) guidelines on the specification limits for residues of metal catalysts. USP believes that the elements and limits proposed in PF will align with what the ICH Q3D guideline will propose.

USP is currently evaluating the PF comments and will subsequently make a decision on how to move forward based on comments received. These comments should allow USP to provide a better and more informed response on the ICH draft proposal once it is published. USP's perspective is that given the public health issues involved, it is inappropriate to wait until ICH releases their first draft proposal before moving forward with the proposed USP chapter revisions, although USP understands that a delayed implementation date will be important to allow time for industry to comply with the new standard. USP agrees that the harmonization of elemental impurities will lead to reduced testing required for products that are marketed around the world.

ICH's Q3D Expert Working Group is working to come to an agreement on an appropriate list of metals and their limits but will not include testing. The working group is scheduled to meet during the June, 2010 ICH meeting in Tallinn, Estonia. The three Pharmacopeia Discussion Group members (European Pharmacopoeia, Japanese Pharmacopoeia and the United States Pharmacopeia), will attend the meeting. Three FDA representatives along with USP representative, Antonio DeStefano, vice-president of General Chapters will also attend. According to the ICH process, the Q3D working group will commence work on the development of the harmonized tripartite guideline and prepare an initial draft of the guideline, based on the objectives set out in the Concept Paper, and in consultation with experts designated to the EWG. Upon reaching Step 4, the harmonized tripartite guideline moves immediately to the final step of the process that is the regulatory implementation.

Pricing remains an eternal challenge

PharmTech: Many in industry are questioning whether all pharmaceutical companies fully and equally qualify every supplier in their excipient supply chain and whether the prices or the quality evaluations dictate the decisions on whose material gets used. How can industry work through this?

Berg: Quality evaluations definitely dictate the decisions about whose material gets used. Quality of the material is key and the quality systems and processes under which the materials are made are crucially important. On the price side, I want to advocate that industry-purchasing individuals consider the total cost of ownership of the materials. Effective change control, deviation management, and so forth, take resources and money to do well. In our business, we should expect prices to reflect the total cost and we should be willing to pay. In my opinion, companies that treat these materials as commodities and squeeze for the lowest cost should not be in the business of making medicines because they are promulgating insecure supply chains.

Busch: This is a somewhat difficult question for me to answer as an excipientsupplier, but the need for a good reputable supplier is second to none. This goes well beyond the GMP requirement under which the excipient is produced and includes the entire supply chain through which the material flows. While price is always a factor, the cost of any specific ingredient must be weighed against how critical that excipient is in the final dosage form. If its use is critical, then the functionality of the excipient and supply-chain integrity must trump any savings that may be incurred by using a questionable supplier. If alternate suppliers are desired, it is, in my mind, better to try to do so early in the formulation development so that, if needed, flexibility can be built into the formulation to account for the use of alternate materials with potentially different functionality. At Dow Wolff Cellulosics, we have several manufacturing sites and we are constantly confirming the interchangeability of the same grades of product produced between them. If the plants do not produce equivalent or interchangeable products, we are sure not to claim such, and will sell those products under a different designation.

Velagaleti: We recognize that users of excipients are under regulatory scrutiny to make sure suppliers are qualified for GMP compliance and that raw materials produced are of high quality. The qulaification of suppliers by users may include, but is not limited to, testing incoming raw material, on-site inspections for GMP compliance of manufacturing facilities, and so on. From a supplier's point of view, we encourage that kind of scrutiny, but there is one challenge. Take BASF, for example. We manufacture several excipients in our facilities in the US and Germany, and if all of our customers were to visit us each year or every other year for an audit, that would be an enormous drain on our resources in the plant, which are primarily dedicated to manufacturing and GMP compliance. We have been innovative by conducting group audits at our excipient manufacturing facilities in US. We provide specified dates that companies can come and audit our facility. We do a joint group presentation of our quality systems, and arrange for plant and laboratory visits. Beyond this, customers can look individually at topics of specific interest to them. This helps to fit, for example, audits from six different customers into one day. We are also trying to be innovative by using qualified third-the party auditors, and USP Verification and Certification program.

Carter: IPEC's function is the safety of excipients and the organization is focused on standards that are based on objective regulatory and scientific criteria. Price issues are not a focus of the organization. However, I hope that when looking at the cost of an excipient, a pharmaceutical company will evaluate the total cost of using the excipient compared with the risk and cost of the excipient. When you look at the total cost of manufacturing a drug, excluding the development and R&D cost, the most expensive part may be the packaging, followed by the API, operational manufacturing cost, and lastly, the excipient cost. When I am cooking for dinner guest, I would never risk spoiling an enjoyable evening by using a cheaper unfamiliar spice or ingredient whose cost time quantity is less than the meat, a pharmaceutical company should not let the price of an excipient risk the security of supply by using an excipient that can not be qualified throughout the entire supply chain.

The reality is that, in many companies, the procurement group that works with excipients is separate from the API procurement, quality, and regulatory groups, and sits is a small section of operations with isolated goals for price savings in a silo that prevents them from truly seeing how their choices fit into the overall cost and risk picture. In my opinion, all pharmaceutical companies should change their organization so that the procurement organization reports to the quality unit organization.

*Janeen Skutnik, director of quality and regulatory policy at Pfizer and chair of IPEC–Americas, and Sherry Ku, former senior director of pharmaceutical development at Wyeth Research, also participated in the live roundtable, which can be listened to on the PharmTech Podcast Page.