Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

The US Food and Drug Administration issued on June 25, 2010, a 

CMC Postapproval Manufacturing Changes Reportable in Annual Reports

, to provide recommendations to drug applicants about the types of changes that may be included in annual reports.

  The draft guidance focuses on chemistry, manufacturing, and controls (CMC) postapproval manufacturing changes that the agency believes “present minimal potential to have adverse effects on product quality and, therefore, may be reported by applicants in an annual report,” states the document.

  According to the draft guidance, the number of CMC manufacturing supplements for new and abbreviated new drug applications (NDAs and ANDAs) has increased greatly over the past few years. The agency, in line with its Pharmaceutical Product Quality Initiative and risk-based approach to CMC review, evaluated the types of changes submitted in CMC postapproval manufacturing supplements and “determined that many of the changes being reported present very low risk to the quality of the product” and therefore no longer should be submitted in supplements.  

  Certain items that used to be submitted to FDA in manufacturing supplements now may be reported in annual reports, pending a final guidance document. These items include changes related to the drug product’s identity, strength, quality, purity, and potency. A specific list of changes is included in Appendix A of the draft guidance, which is broken down into the following sections: components and composition, manufacturing sites, manufacturing process, specifications, container-closure systems, and miscellaneous items. Specific changes within each section include items such as the elimination of an overage from the drug product manufacturing batch formula that was previously used to compensate for manufacturing losses, the addition of barriers to prevent routine in-process human intervention in a filling area, changes to filtration process parameters that are within currently validated parameters, the addition of a specification for excipients, the use of a contract manufacturing organization for washing a drug product stopper, and extension of expiry based on real-time stability data from pilot-scale batches.

  Postapproval changes that must be reported to FDA are included in section 506A of the Federal Food, Drug, and Cosmetic Act. The agency notes in the draft guidance that if the drug applicant is submitting supplemental applications based on recommendations for CMC changes provided in FDA’s 

 guide, the applicant should now also refer to Appendix A of this draft guidance to determine whether a particular change may now be reported in an annual report. The agency also notes in the draft guidance that applicants must continue to comply with the CGMP for Finished Pharmaceuticals regulations within 21 

 Parts 210 and 211, and for API manufacturers, with the ICH 

Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients

  Comments on the draft guidance should be submitted to FDA within 90 days, or by Sept. 23, 2010.

Articles

The US Food and Drug Administration issued on June 25 a draft guidance for industry, "CMC Postapproval Manufacturing Changes Reportable in Annual Reports," to provide recommendations to drug applicants about the types of changes that may be included in annual reports.

FDA Issues Draft Guidance on CMC Postapproval Changes for Annual Reports

The US Food and Drug Administration announced plans to revise the current good manufacturing practice (GMP) regulations at a conference held jointly by the agency and Xavier University in Cincinati, Ohio, June 13-16. Brian Hasselbalch, representing the Office of Compliance’s Division for Manufacturing and Drug Product Quality within FDA’s Center for Drug Evaluation and Research, was speaking as part of the first joint annual Global Outsourcing Conference at the school.

According to Haselbalch’s presentation, which is available on the Xavier 

, a draft of new CGMP regulations focusing on component controls is expected before the year’s end. Potential revisions include requiring pharmaceutical manufacturers to physically audit their suppliers (i.e., no more paper audits), test containers in each shipment received, implement tamper-evident packaging and security features, notify FDA of contaminated shipments and lots, and to use only those components recognized as safe for their intended use or listed in an already approved application. 

In addition to increased enforcement and information-sharing, FDA also plans to play a stronger “guiding role” in corporate responsibility. Hasselbalch offered some recent guidance documents as examples of FDA’s role in encouraging corporate responsibility: process validation, pharmaceutical quality systems, and testing of glycerin for diethylene glycol. It seems the agency will go even further by issuing a second phase of revised CGMP regulations that focus specifically on corporate responsibility. These revisions might include requirements that management assures compliance, performs self-inspections, evaluates and investigates problems, implements change control, and documents training and effectiveness, according to the presentation.

What’s behind the proposed changes? Hasselbalch’s presentation noted growing gaps in quality control caused by factors such as globalization, new technologies and processes, distribution challenges, and increased outsourcing of production. Between 2001 and 2007, he pointed out, the number of products manufactured outside the United States and the number of manufacturing sites abroad doubled. Some of the new products being imported into the US come from countries with “less developed regulatory systems,” according to the presentation. Along with these more complex supply chains, there has been an increase in pharmaceutical cargo thefts and in drug counterfeiting. More preventative measures are therefore needed. 

Industry will have a chance to comment on the proposed revisions once they are issued.

Editor's Note: On June 24, 2010, an FDA press officer clarified that the agency is "

 requiring finished pharmaceutical manufacturers to conduct on-site audits of the original manufacturers for components (i.e., ingredients) that they use in manufacturing."

The US Food and Drug Administration announced plans to revise CGMP regulations.

FDA to Revise Current GMPs for Component Controls

Last week, the steering committee and expert working groups (EWGs) of the 

 (ICH) met in Tallinn, Estonia, to discuss progress on the ICH quality trio guidelines and other Step-4 documents.

  The ICH Quality Implementation Working Group, which focuses on guidelines Q8 

, held its first training workshop during the meeting. The workshop focused on how to use design space, control strategy, and quality risk management, among other topics. Approximately 240 individuals, including inspectors, from 34 countries attended the workshop. Additional workshops will be held in Washington, DC, and in Tokyo, in October 2010.

  ICH representatives also adopted Annexes 11 and 12 to the Q4B guideline titled 

Evaluation and Recommendation of Pharmacopoeial Text for Use in the ICH Regions

 to Step 4. The next phase, Step 5, requires each region to publish and implement the guideline. The annexes harmonize analytical procedures for capillary electrophoresis and sieving. Two additional Q4B annexes, Annex 13 on bulk and tapped density and Annex 14 on bacterial endotoxin, moved to Step 2, which means the six parties to ICH have reached consensus on a draft guideline.

  Also of note, the Q3D EWG held its first official meeting to set limits on metal impurities in drug products and ingredients. The group has been working with pharmacopoeias around the world on this controversial industry topic. The working group is not expected to address specific tests for heavy metals.

  Two new EWGs were formed to focus on genotoxic impurities and photosafety evaluation.

  The next ICH meeting of the steering committee and EWGs will be held in Japan in November 2010. 
 
  

Last week, the steering committee and expert working groups of the International Conference on Harmonizaton met in Estonia to discuss progress on the ICH quality trio guidelines and other Step-4 documents.

ICH Meets in Estonia

In April 2009, the US Pharmacopeial Convention (USP) and the Russian Federation’s regulatory agency, Roszdravnadzor,  signed a 

 to work toward protecting and improving the quality of medicines worldwide. Last week, USP and the Ukraine Scientific Pharmacopoeial Centre for the Quality of Medicines agreed to share standards for the quality, purity, strength, and identity of medicines. The Ukrainian center will have a five-year, renewable right to include written standards (as written or modified) from the 

US Pharmacopeia–National Formulary (USP–NF)

 in its own pharmacopoeia and companion journal, 

 “This agreement is a milestone in helping to promote public health internationally. The scientific exchange represented by the agreement with the Centre will benefit not only the citizens of the Ukraine, but also Ukrainian manufacturers wishing to export to other countries,” said USP chief executive officer Roger Williams in a 

. “USP will benefit from the experience of the Centre’s scientists, which in turn contributes to the strength of the standards published in the 

The Ukrainian center also will explore opportunities to use USP’s accompanying reference standards to help evaluate drug quality and identity, according to the release. 

 that it had completed a series of eight drug quality courses at Moscow’s Scientific Center for Expertise of Medical Products as part of ongoing collaborative efforts.

The original MOU from April 2009 called for USP and Roszdravnadzor to increase working relationships by   exchanging scientific staff, facilitating the exchange of information, developing and using reference materials, and establishing third-party certification programs to allow for the review, testing, and auditing of drug manufacturers in the two countries.

Last week, USP and the Ukraine Scientific Pharmacopoeial Centre for the Quality of Medicines agreed to share standards for the quality, purity, strength, and identity of medicines.

USP and Russia Make Headway on Improving Drug Quality

  About one month after the announcement of McNeil Consumer Healthcare’s recall of children’s liquid pain and allergy medications (see back story, “

J&J Voluntarily Recalls Certain OTC Products Because of Manufacturing Problems

”), the US Food and Drug Administration 

  before the US House Committee on Oversight and Government Reform about the issue. Representing FDA was Principal Deputy Commissioner Joshua M. Sharfstein.
  
On May 27, Sharfstein explained to the committee the agency’s quality concerns about McNeil, a division of Johnson & Johnson (J&J, New Brunswick, NJ). 

“Over the last several years, FDA has had growing concerns about the quality of the company’s manufacturing process,” said Sharfstein. “These concerns have led to a number of unsatisfactory inspections and consumer recalls. FDA has inspected the company’s facilities with an increased frequency, and in February 2010, the Agency took the extraordinary step of convening a meeting with the management of the parent company, Johnson & Johnson, to express concern about a pattern of non-compliance.”

  Some of the problems FDA identified before 2009 included laboratory controls, equipment-cleaning processes, and a failure to investigate identified problems. “The company generally fixed the specific problems, and the Agency inspected the firm regularly,” added Sharfstein. In May and June 2009, FDA found several violations of current good manufacturing practice (CGMP), including McNeil’s failure to meet its quality standard in an ingredient (microcrystalline cellulose) in its over-the-counter liquids, which led to a recall last summer of 8 million bottles of finished product.

  In the fall of 2009, added Sharfstein in his testimony, McNeil received reports of a musty odor in certain products. The company did not fully investigate the reports or notify FDA of the reports, he said. The odor turned out to be a chemical called 2,4,6-tribromoanisole (TBA) and more recalls were made.

  FDA issued McNeil a Warning Letter in January 2010 about the quality of its drugs and failure to adequately investigate and correct quality problems. Also in early 2010, FDA followed up on a report of the death of a 6-year-old child who died after taking several of the products in question that were manufactured by McNeil. No contamination in the products was discovered.

  The agency expressed its concerns to J&J management at an unconventional meeting in February 2010. “The Agency learned that McNeil was taking several major steps to address these issues, including implementing management reporting structure changes, hiring new managers, and engaging a third party manufacturing consultant,” said Sharfstein.

  In April 2010, FDA inspectors returned to one of the McNeil facilities in question-Fort Washington, Pennsylvania-but the facility was shut down before the inspection began due to manufacturing issues. Particulates were found in children’s liquid medications, which led to the major recall of Children’s Tylenol, Motrin, and Benadryl on Apr. 30, 2010.

  Looking ahead, Sharfstein said FDA is “closely monitoring the implementation of a corrective action plan developed by McNeil that includes significant enhancements to its quality system, organizational changes, and senior management oversight. FDA will continue to investigate issues related to the Fort Washington facility including oversight related to renewal of manufacturing operations at that facility, to evaluate the facility’s suppliers, and evaluate the compliance of all other McNeil facilities.” He added that FDA is considering additional enforcement actions against the company.  

  Sharfstein detailed a few lessons learned from this case, including that FDA needs to more fully consider “the corporate structure” of a company and that it needs to review its recall process. “A range of activities are underway at the Agency to bring this vision to reality, including strengthening our criminal enforcement of FDA’s laws,” he concluded. 

Some Recalled Infants’ Tylenol Had Too Much Acetaminophen

About one month after the announcement of McNeil Consumer Healthcare's recall of children's liquid pain and allergy medications , the US Food and Drug Administration testified before the US House Committee on Oversight and Government Reform about the issue.

FDA Testifies to Congress Regarding J&J Recalls, Quality Concerns

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.  

 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 

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 

) 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. 

PharmTech: IPEC recently developed a guide for excipient qualification that addresses GMPs and GDPs. In addition, as reported in 

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 

 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. 

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 

 (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 

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: 

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 

  for public comment and review. Other related information appeared in 

 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 

 will align with what the ICH Q3D guideline will propose. 

 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. 

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 

 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.  

Industry and regulatory experts discuss excipient testing, regulatory expectations, supply-chain challenges, and pricing in this Speakers Roundtable. This article contains bonus online material and podcasts.