Susan J. Schniepp is a fellow at Regulatory Compliance Associates, Inc. and a member of Pharmaceutical Technology's Editorial Advisory Board.

Susan J. Schniepp

The United States Pharmacopeia (USP) held its Annual Scientific Meeting in Toronto in September.  At the meeting, USP released a series of whitepapers (all seven are available at 

) that discuss the role the pharmacopeia's public standards play in an "era of healthcare crisis and reform" (1, 2).  

USP's Council of the Convention (CoC) assembled the whitepapers. Established in 2005 to facilitate and educate United States Pharmacopeial Convention (USPC) representatives, CoC is responsible for examining the purpose, role, and composition of USPC membership, including voting procedures. These responsibilities are critical to defining a revision cycle.  A revision cycle is defined as the five-year period between conventions in which the Expert Committees set standards (i.e., develop and revise monographs and general chapters) of the USPC. Convention representatives are responsible for selecting USP committee chairs and voting on the resolutions that will define USP's strategic direction. The 2010 convention will take place Apr. 21–24, 2010, in Washington, DC, and the 2010–2015 revision cycle will commence on July 1, 2010. 

Envisioned as a liaison between USP's Council of Experts, scientific staff, and convention members, CoC also holds responsibility for reviewing with key stakeholders the progress on resolutions adopted at annual meetings. These annual interactions are expected to result in a more educated membership that is prepared to deal with the complex issues facing USP when all parties meet at the convention every five years. USPC meets every five years to set the goals, objectives, and direction for USP during the upcoming revision cycle.   

USP was founded in 1820, long before the pharmaceutical industry came into existence. At that time, medicines were prepared by pharmacists, making them the pharmaceutical manufacturers of the day. Because of this and other historical developments, USPC membership is based heavily in the pharmacy community.  The pharmaceutical industry is represented in USPC by trade organizations such as the Generic Pharmaceutical Association, the Parenteral Drug Association, and the Pharmaceutical Research and Manufacturers of America. Each member organization sends a representative to the convention, where he or she is expected to vote on changes to the USP Constitution and bylaws, select (by vote) the members of the Board of Trustees as well as the Council of Experts Chairs, conduct business meetings, debate, and vote on resolutions. 

Fast forward to September 2009 when CoC released seven whitepapers at the USP Annual Scientific meeting. The seven papers address areas of interest for USP (e.g., food ingredients and dietary supplements), but three are of special interest to the pharmaceutical industry, as summarized below. 

Whitepaper: "USP's Role in Setting Enforceable Quality Standards for Medicines." 

 The content of this CoC whitepaper discusses USP's ongoing mission to establish standards for all pharmaceutical products approved for sale in the US. According to this paper, USP's monograph universe consists of 5720 articles. Of these 5720 products, 1960 (34%) do not have monographs and 583 (10%) have monographs that do not meet current standards and need to be updated. The paper justifies the out-of-date monographs by stating that, "USP has no way to compel information and receipt of candidate materials to support a public monograph." The paper further indicates that the US Food and Drug Administration's Freedom of Information Act prevents USP from obtaining the necessary information to establish monographs from companies' new drug and abbreviated new drug applications. The paper  explains some of the efforts undertaken to establish missing monographs, including establishing performance-based monographs (3) and developing monographs from existing sources outside the US. In addition, CoC explores USP's potential role in supply-chain management to prevent economically motivated adulteration through the convention's standards-development process.  

Whitepaper: "Importance of Standards in Assuring Good Quality Food Ingredients and Foods." 

 During the 2005–2010 revision cycle (August 2006), USP purchased the Food Chemicals Codex (FCC) from the Institute of Medicine (IOM). In February 2008, under the auspices of USP, the sixth edition was published, followed by supplements in February 2009 and August 2009. USP also established a web-based publication, the 

, for users to review and comment on proposed changes to FCC monographs. This whitepaper indicates that the industry has been slow to respond to the standards in FCC and discusses potential avenues for enhancing the use and prestige of the FCC on a global basis.  

The pharmaceutical industry uses the FCC because it contains monograph information for some common ingredients  that are used in drug-product formulation but that are not subjects of USP monographs. The industry needs to monitor the international activities of the FCC to ensure they are consistent and appropriate. 

Whitepaper: "USP's Role in Assuring Global Access to Quality Medicines." 

During the 2005-2010 revision cycle, USP made concerted efforts to expand its global presence. This whitepaper describes USP's current international efforts and identifies possible ways to advance  this initiative. One unique concept presented in this white paper is a proposal to establish an independent Global Health Care Secretariat as a means to secure and control global registrations of products and medicines. As stated in the paper, this initiative would be "based in a vision of a collaborative global health care secretariat with multiple components, involving representatives from all countries and yielding decisions suitable for national adoption. The components would focus on a) discovery, b) research and development, c) sound regulatory decision-making and, when appropriate, rapid registration decisions, d) optimal pricing–payment strategies, e) evidence-based healthcare delivery based on outcomes/pharmacoeconomic studies, f) quality of care, and g) safe medication use."  

What does all of this mean? In April 2010, USPC will convene and vote on resolutions that will effect the next five years of USP activities. These whitepapers may set the stage for those votes. It is important for industry to read these papers in their entirety and be prepared to engage in debate on the pros and cons during the open-floor discussion of the convention. This is the best way to assure that USP will appropriately represent all parties of the pharmaceutical-products process, and it may be your best opportunity to influence the direction of USP as it strategizes the next five  years.  

Many of the ideas brought forth in these whitepapers appear to be altruistic. It is hard to argue with the concepts of securing safe food, providing safe medication, and establishing appropriate standards for the global community. However, other organizations such as the International Conference on Harmonization and the Pharmaceutical Inspection Cooperation Scheme are trying to address many these same issues. It would seem appropriate for USP to engage them in dialogue so that efforts are not duplicated and to prevent a divergent set of standards from evolving.   

 is vice-president of quality assurance at Javelin Pharmaceuticals, 125 CambridgePark Drive, Cambridge, MA 02140, tel. 617.499.4709, 

 1. USP whitepaper, USP's Role in Patient Safety, Sept. 23, 2009. 

 2. USP whitepaper, Opportunities for Drug Information and Use Standards, Sept. 23, 2009. 

Articles

With a five-yar revision cycle around the corner, USP will hit or miss the collaboration mark.

Insider Solutions: A New Direction for USP?

It was only one and a half years ago that a leading pharmaceutical company recalled several lots of a life-saving product after receiving numerous reports of adverse events, namely allergic reactions. The company ceased production of the drug and began investigating the cause of the incidents. Approximately one month later, the US Food and Drug Administration issued a Public Health Advisory to the medical community, warning them not to use this product. The company, Baxter (Deerfield, IL), recalled all lots of the product, heparin, which was ultimately linked to more than 350 serious adverse reactions and several patient deaths. Contaminated active pharmaceutical ingredient (API) supplied by a manufacturer in China caused the reactions.  

One of the most important issues facing the pharmaceutical and biotechnology industries today is securing the supply chain. None of us want to experience a similar event like the one described above. The problem is figuring out how to manage the supply chain with existing or dwindling company resources. Big companies have large auditing staffs, but even they are unable to audit all of their suppliers on a sufficiently frequent basis because of their diverse product line. Smaller start-up companies often do not have personnel with expertise in supplier qualification and auditing because they are focused on early-stage development, thereby leaving them to trust their contract research and manufacturing organizations (CROs and CMOs) with the integrity of their supply chain.  

If the industry learned nothing else from the heparin incident, it learned to verify, qualify, and document everything regarding the suitability of all suppliers. The upside of this learning experience is that there is plenty of help available to companies that want to learn more about shoring up their supply chain. 

The Parenteral Drug Association (PDA) offered a two-day conference in September 2008 in Washington, DC, to discuss the pharmaceutical supply chain from a global perspective. The initial conference was so successful that it was refined and repeated three more times: December 2008 in San Diego, March 2009 in Munich, and June 2009 in Shanghai. This series of conferences focused on identifying issues related to supply-chain management and discussing perspectives on how to address identified deficiencies. One key contributor to the series' content was the International Pharmaceutical Excipients Auditing (IPEA) organization.  

 Founded in 2000, IPEA is an independent subsidiary of the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas). The organization's mission is "to facilitate the assessment of excipient manufacturers to appropriate GMP [good manufacturing practice] standards." 

To achieve this goal, IPEA audits pharmaceutical and nutriceutical excipient manufacturing facilities following US Pharmacopeia (USP) and IPEC guidelines on a worldwide basis. IPEA's audit reports provide a basis for confirming that the quality systems used to produce the audited excipient meet the appropriate current GMPs. The leaders of IPEA hope that, "through CGMP audits, deficiencies in excipient manufacturing and packaging can be identified early and potential industry tragedies can be avoided," according to their mission statement. In additon, IPEA has been training industry professionals in CGMP auditing for excipients for several years, demonstrating how far ahead the organization was in recognizing vulnerabilities in the supply chain.  

Also stemming from the PDA conferences was the desire of industry supply chain representatives to unite and stay informed of developing standards and current FDA thinking. This desire led to the formation of a new industry group called Rx-360, an international pharmaceutical supply chain consortium whose mission is to: "Create and monitor a global quality system that meets the expectations of industry and regulators that assures patient safety by enhancing product quality and authenticity throughout the supply chain."  

This new group held its first formal meeting on June 4, 2009, in Washington, DC. It is unclear what the final role of the consortium will ultimately be, but its leaders indicate they intend to serve in four different capacities: Adopting standards and best practices, technology development to detect tampering in the supply chain, monitoring the supply chain for suspicious activities, and establishing auditing services which may ultimately lead to shared supplier audits. 

In September, PDA will hold its annual PDA/FDA Joint Regulatory Conference in Washington, DC. Conference planners are devoting a plenary session and an entire two-day track to discussions about the supply chain. Guidance on constructing quality, technical, and cooperative agreements as well as discussions about products and services available for conducting supplier audits, and good distribution and import practices will be featured topics at the conference. Regulatory authorities are expected to speak in all the sessions to provide their perspective on industry initiatives. 

It is important for the industry to secure the pharmaceutical supply chain from starting materials to final-product distribution so that patients can rest assured that they have received safe and effective medicine that does what it is intended to do.  

 is vice-president of quality assurance at Javelin Pharmaceuticals, and a member of the PDA/FDA Joint Regulatory Conference 2009 Planning Board, 125 CambridgePark Drive, Cambridge, MA 02140, tel. 617.499.4709, 

Determined to prevent further supply-chain breaches, industry takes charge, offers proposals.

Insider Solutions: Preventing the Next Heparin Scare

The US Food and Drug Administration recognizes more than 20 standard-setting organizations. There are also several organizations recognized by the medical device industry as producing standards easily referenced in 510(k) filings and whose procedures are equally beneficial and applicable to the pharmaceutical industry. Take, for example, the International Organization for Standardization (ISO), which publishes sterility and air-quality standards, and the American Society for Testing and Materials (ASTM), which publishes packaging material standards. 

211.194(a)(2) on laboratory records, requires companies to indicate the procedures they use to release their product to the market. The regulation also asks companies to document the "location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested." This concept seems straightforward enough. But additional text in the regulation in parenthesis is more intriguing: "(If the method employed is in the current revision of the 

], AOAC International, Book of Methods, or in other recognized standard references, or is detailed in an approved new drug application and the referenced method is not modified, a statement indicating the method and reference will suffice)." 

Many people in the pharmaceutical industry are familiar with 

, and have heard of AOAC, but how many of us know the names of the organizations that collectively make up the "other recognized standard references" category? FDA's Center for Devices and Radiological Health (CDRH) website provides some insight. CDRH runs a Standards Program through which companies can access the Center's FDA-Recognized Consensus Standards Database. This database allows individuals to search by the name of the standards organization, the type of standard, or the standards category. 

This database is important to those outside the device industry because the information contained in CDRH's database applies to products regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). To exemplify, I did a test search in the database for USP sterility standards and got nine results meeting the defined criteria. Of these results, four standards were for evaluating drug products, all commonly used in CDER and CBER registrations. However, when clicking on the title of the standard in the database, the resulting information only pertains to medical devices. Other searches yield similar results. 

I went on to test the simple search feature for the term "air classification." As expected, ISO 14644-1 on Cleanrooms and Associated Controlled Environments displayed. Many pharmaceutical companies use this standard to determine air quality when manufacturing injectable products. There was no mention, however, of this standard applying to anything other than "...medical devices where processing in controlled environments is a component of the development and manufacture of the product." 

Many standards included in the database are considered "recognized consensus standards," which CDRH defines as one that "...FDA has evaluated and recognized for use in satisfying a regulatory requirement and for which FDA has published a notice in the 

." Organizations developing consensus standards for FDA recognition must follow a process in which "the standard development is transparent (i.e., open to public scrutiny), where the participation is balanced, where an appeals process is included, where the standard is not in conflict with any statute, regulation, or policy under which FDA operates, and where the standard is national or international in scope." 

211.194(a)(2) on laboratory records, which allows for use of recognized standards beyond those included in 

, the Office of New Drug Quality Assessment has begun to recognize other standards through its 

(MAPP). The manual states that it may sometimes be appropriate to reference monographs contained in these publications in investigational new drug and new drug applications. CBER and CDER seem to be moving in the direction of CDRH with respect to recognizing consensus standards and this direction is definitely positive for industry. It will be exciting to watch their programs develop. 

Organizations Monitored by the Center for Devices and Radiological Health

AAMI: Association for the Advancement of Medical Instrumentation 

AIUM: American Institute of Ultrasound in Medicine 

ANSI: American National Standards Institute 

ASME: American Society of Mechanical Engineers 

CEN: European Committee for Standardization 

CLSI: Clinical Laboratory Standards Institute 

ESD: Electrostatic Discharge Association 

IEC: International Electrotechnical Commission 

IEEE: Institute of Electrical and Electronic Engineers 

IESNA: Illuminating Engineering Society of North America 

ISO: International Organization for Standardization 

NCCLS: National Committee for Clinical Laboratory Standards 

NEMA: National Electrical Manufacturers Association 

NFPA: National Fire Protection Association 

RESNA: Rehabilitation Engineering and Assistive Technology of North America 

USP: United States Pharmacopeial Convention, Inc. 

Check out the following citations to obtain more information on the agency's participation in standards organizations: 

http://standards.gov/standards_gov/a119.cfm

2) FDA Policy Statement: Participation in the Development and Use of Voluntary Standards: 

http://www.fda.gov/oc/guidance/voluntarystandards.html

10.95 Participation in outside standard-setting activities. 

 is vice-president of quality assurance at Javelin Pharmaceuticals, 125 Cambridge Park Drive, Cambridge, MA 02140, tel. 617.499.4709, 

Standards data is helpful, but FDA needs to apply its information across the board. This article contains bonus online-exclusive material.

Insider Solutions: Device Database Can Help Pharma

Nuclear magnetic resonance (NMR) spectroscopy has been used as an analytical tool since the 1950s. It allows scientists to view single atoms and molecules in various media solutions and in the solid state, and this capability makes the technique an invaluable tool in pharmaceutical development. A new book titled 

NMR Spectroscopy in Pharmaceutical Analysis 

offers readers a comprehensive look at NMR spectroscopy and its use as a practical tool for the pharmaceutical industry. The book is divided into three parts that describe fundamentals and techniques, general applications, and special applications. 

NMR Spectroscopy in Pharmaceutical Analysis, U. Holzgrabe, I. Wawer, and B. Diehl, Eds., Elsevier, Amsterdam, 2008, 528 pp., ISBN: 978-0-444-53173-5

The first chapter of Part I, "Fundamentals and Techniques," establishes the basis of understanding for the rest of the book. This chapter educates the reader about the various parameters used in high-resolution NMR spectroscopy to determine the unique structure of molecules. These parameters are described in topic-specific discussions that are enhanced with tables and figures to demonstrate the intricacies of this methodology. 

The chapter is logically organized and includes sections discussing chemical shift, spin–spin coupling, heteronuclear spectra, molecular dynamics, chemical derivatization, and stereochemistry. These chapter sections are divided into specific topic discussions within the major category. For instance, Section 3 on chemical shift includes discussions of electronic density, anisotropy, mesomerism, and steric  effects. The author analyzed the chemical rifamycin to generate the data presented in the sections, thus maintaining continuity. 

The subsequent chapters in Part I build on the concepts presented in Chapter 1 and discuss quantitative NMR from the solution and solid-state perspectives. These chapters also discuss the applicability of microcoil NMR technology in today's analytical environment. The chapters are of particular interest to analysts because they discuss the applicability of NMR technology and the advantages it offers over current preferred methodology such as high-performance liquid chromatography (HPLC).  

One author noted that the decisive advantage of NMR spectroscopy is that it requires almost no preparation time. Eliminating extensive preparation time would allow more samples to be analyzed in a shorter period of time. If adopted as a release procedure, NMR could help companies get close to attaining real-time release for their products.  

Part II of the book, dedicated to general applications, comprises seven chapters that focus on NMR technology as a practical laboratory tool. Topics in this section include using NMR to analyze multicomponent drugs, determine polymer characterization, identify and characterize natural substances, and perform metabolic profiling. 

One of the more interesting chapters in Part II is the chapter titled "Investigation of Multi-Component Drugs by NMR Spectroscopy" because it shows readers that NMR spectroscopy can be an efficient way to analyze complex drug mixtures. One data table compared HPLC results and NMR spectroscopy results that were obtained using two methods for each technique. The table showed an excellent correlation between the results and reiterated the virtual lack of preparation time needed for NMR analysis. 

Yet the information in the table would have been more powerful if the author had included a column that listed the overall time it took to obtain a result using each of the methods. This information would clearly demonstrate the time advantage that NMR offers over traditional HPLC procedures. Another interesting item would have been a comparison of the time required to perform NMR spectroscopy and that required for the fast LC methods being developed. As in Part I, these chapters include supporting tables and  figures that enhance the reader's understanding, as well as individual references for each chapter. 

Part III, "Special Applications," is unique and makes this book a must-have for pharmaceutical development and analytical laboratories. Although some of the topics seem to have limited application, they stimulate the reader to think of how these special applications could be developed and used for their specific business purposes. 

For example, Part III, Chapter 1 describes how to use statistics and quantification to determine the quality of fruit juice and encourages the reader to imagine the possibility of employing this approach for complex pharmaceutical products such as total parenteral nutritional mixtures. One of the most intriguing topics of Part III is the application of NMR spectroscopy as a process analytical technology tool to monitor complex pharmaceutical reactions and processes online. This concept is examined in the last chapter of the book, which leaves the reader asking, "How can I use and adapt NMR to continually monitor and improve my manufacturing process?" 

Overall, this is a comprehensive book that explores NMR technology from theory to practical application. The book would be helpful to analytical scientists and manufacturing professionals alike and would be a valuable addition to any pharmaceutical library. 

 is a pharmaceutical consultant at Schniepp and Associates, 379 Burroughts Rd., Boxborough, MA 01719, tel. 978.264.3273, fax 978.266.9538, 

A new book inspires readers to seek ways to apply NMR spectroscopy to their own purposes.

An Analytical Technique with Special Resonance

I have been participating in activities of the US Pharmacopeia (USP) for several years, and I am continually disappointed by those in industry who claim that USP's standards are antiquated. The USP process is voluntary and relies on industry participation for setting, updating, and maintaining its monographs. By taking a proactive role in helping to establish the specifications, test procedures, and general test requirements published in 

, industry can have a voice in setting standards and ensuring those standards are appropriate for their intended purpose. 

It is especially critical for industry to participate in the USP public review and comment process when the proposed revisions impact a broad range of products. The pharmacopeia recently adopted, for example, new requirements for residual solvents that took effect July 1, 2008. There are many other proposed changes that will affect broad-scope procedures and methodology such as harmonizing the chapters for microbiological tests with the European and Japanese Pharmacopoeias, making revisions to the heavy-metals test chapter, and redesigning monograph formats. 

Figure 1: The US Pharmacopeia review-and-comment process. 

The impact industry can have on these public standards by taking advantage of the commenting process can be demonstrated  by reviewing the steps associated with the adoption of the new residualsolvents requirements. 

Residual-solvent revisions began in 1988 when USP proposed a general test chapter for organic volatile impurities (OVI), ultimately adopted in 1990. In 1997, the International Conference on Harmnization ICH) finalized Q3C 

 The European Pharmacopoeia (Ph. Eur.) subsequently adopted this guideline in 2000. In 2003, USP published a proposal to align the OVI chapter with the ICH and Ph. Eur. documents. The official adoption date for this revision was set for April 1, 2004, but feedback from industry prompted a major revision, ultimately delaying adoption of the standard. 

The original USP proposal for residual solvents would have changed every monograph to include a line item for residualsolvent testing. Industry publicly commented that this requirement would result in unnecessary testing. Based on the public feedback, USP revised its initial proposal and formed a project team, involving the pharmaceutical community, to make new recommendations. The collaborative effort culminated with the adoption of the new standard last July, with little or no comment from industry. Although some concerns remain among industry, they are related more to the standard's applicability than to its content. 

Industry has been commenting to USP for many years that its monograph format is difficult to decipher. Many companies have transcribed monographs into their standard operating procedures so that analysts can easily understand and perform the required tests. Other companies have used the 

monographs, commenting to USP that the European style is easier to follow. 

USP listened to these concerns and unveiled plans to redesign the format of its monographs by the time the 2010 edition of the 

 is issued. Over the past two years, the organization has been rewriting some 3000+ monographs in the new format. Because of the enormous volume of work associated with translating test procedures, there are bound to be occasional errors. Industry can help eliminate potential errors before the transcribed monographs become official by performing a technical review of the monographs' contents. USP has posted completed redesigned monographs on its website for this purpose. 

The public-review process is an important mechanism for USP to obtain necessary feedback from industry regarding changes to its official standards. Participation is optional, but having a say in the quality of the standards one uses in everyday testing is clearly beneficial. In December, 

) on potential implementation issues associated with 

's microbiological testing chapters, which become official in May. In the September/October 2008 edition of 

USP published a paper on potential revisions to the heavy-metals test chapter. Now is the time to comment on both. It is only through the proactive participation that everyone in industry can be assured USP standards are appropriate and applicable to their work. 

 is a pharmaceutical consultant at Schniepp & Associates, LLC, 379 Burroughs Rd., Boxborough, MA 01719, 

The USP public-comment process exists for a reason. Industry needs to take advantage. This article contains bonus online-exclusive material.

Insider Solutions: Have a Say in USP Standards

The global supply chain for the pharmaceutical industry has expanded during the past decade as companies have striven to be competitive and harness emerging technology. Foreign markets have emerged to offer lower costs for various products. Many companies find managing global suppliers and product-quality issues to be challenging. Recent industry events such as the contamination of batches of heparin demonstrate that a lack of control in the global supply chain can lead to patient harm and death, product recalls, loss of integrity, and significant financial liability for a company. Current good manufacturing practice (CGMP) regulations state that companies that design and manufacture pharmaceutical products must ensure that all components, raw materials, and product from suppliers meet predetermined specifications and that suppliers and their operations are in a state of control. 

In today's climate, companies should use a risk-management program to assess their suppliers' ability to provide material suitable for the manufacture of medicinal products. A risk-management program should help companies evaluate and control the quality of their suppliers and of the supply chain. The US Food and Drug Administration's Pharmaceutical CGMPs for the 21st Century initiative is intended to enhance and modernize the regulation of pharmaceutical manufacturing and product quality. Its goal is to bring the pharmaceutical industry in line with the risk-management activities the medical-device industry uses to reduce patient and business risk. FDA's expectations are outlined in the International Conference on Harmonization's Q7, Q8, Q9, and Q10 guidelines. Several key elements can help control and limit risk throughout a global supply chain. This article will discuss risk prioritization, risk assessment, risk control, risk communication, and risk review in detail. 

Deciding how to begin implementing a supplier risk-management program can be challenging for established companies, let alone for startups. A risk-prioritization matrix outlines a systematic and objective approach that helps companies select the best starting point. 

One approach to developing a specific company's matrix is to create a list of manufactured and distributed products that includes key data. The following data may be considered in developing a risk-prioritization assessment:  

Patient risk (i.e., sterile, parental, nonsterile)

Quality data such as nonconformances, corrective actions/preventive actions (CAPA), deviations, and customer complaints

These data can be entered into a table similar to that in Figure 1. The individual data categories are assigned a numerical risk-ranking value as in the following example:  

Figure 1: Example risk-prioritization matrix. (ALL FIGURES ARE COURTESY OF THE AUTHORS.)  

Key quality data such as nonconformances, CAPA, deviations, and customer complaints should receive values equal to their number of occurrences. 

Likewise, the risk value for the volume of product manufactured is equal to the number of lots or units produced. Typically, this value is weighted to reduce the chance that a low-risk product with a high production volume will become the highest priority. Values are multiplied to obtain a risk-prioritization score. The product with the highest score gets top priority. 

Once the products have been prioritized, a risk-assessment technique can be used to evaluate, control, and communicate the associated risk related to a given product. Failure mode effects analysis (FMEA) is currently used to assess supplier risk. A supplier FMEA does the following things:  

Lists each component of the product along with its function.

Identifies possible supplier-failure modes.

Assesses the severity of the supplier failure modes based on their effect on the end user. Product characteristics are identified as critical if patients are harmed when the characteristics are not controlled.

Lists possible causes of the supplier failure modes and estimates the number of occurrences for each cause.

Lists current controls to prevent or detect the supplier failure modes or causes and estimates how effective the current controls are.

One obtains a risk priority number (RPN) by multiplying predefined rankings for severity, occurrence, and detection. These rankings are typically numbers from 1 to 5 or 10. A threshold RPN should be identified, and suppliers whose risk exceeds the threshold should be considered unacceptable. Figure 2 provides an example of a supplier FMEA template (1, 2).  

Figure 2: Example supplier failure mode effects analysis template. RPN is risk priority number. 

Suppliers with RPNs that exceed the threshold value should be audited. Companies can conduct a full or modified audit, depending on the severity of the risk that prevented the supplier from achieving an acceptable RPN ranking. Key items to focus on during an audit include the quality of the supplier's risk-assessment program and how the supplier controls critical characteristics. Supplier audits are discussed in more detail below.  

The manufacturer and its supplier should work together to establish a plan to reduce the risk of quality nonconformances and agree on an approach for communicating and reducing risk. Approaches to reducing risk generally fall into two categories. 

 The industry prefers the easier approach, which is for the manufacturer and supplier to agree on a joint cooperative plan that reduces the identified risk to an acceptable level. This plan frequently necessitates further risk analysis of the supplier's suppliers and components (i.e., Tier 2 analysis, or analysis of a secondary supplier) to understand where the sources of risk enter the supply chain. In some cases, improved controls at the Tier 1 (i.e., primary) supplier, combined with improved inspection or processing by the finished-goods manufacturer, reduces risk to an acceptable level. Tier 3 or Tier 4) suppliers might be investigated to achieve acceptable finished-good product risk levels if the Tier 1 controls and mitigations are not sufficient. 

During the implementation of the corrective actions or risk mitigations, the supplier FMEA should be updated, and residual risk should be assessed. All revisions and updates to formal risk-management documents and reports should be reviewed and stored in a risk-management file established for that product. If risk controls and mitigations at the supplier and finished-goods manufacturer are exhausted and the risk remains unmitigated, alternative approaches to achieving robust quality may become necessary. 

Category 2: Establish an alternate supplier.

 A longer path toward achieving robust quality and low risk is to qualify an alternate supplier or to change the design or process so it achieves a higher level of quality. Category 2 is generally chosen only if the all plans for reducing risk at the current supplier have been exhausted or if the supplier does not cooperate in implementing a risk-reduction plan. It is useful to apply tools such as design for Six Sigma to the component's critical characteristics during the development of new or modified processes or component designs. 

If the finished product has a level of residual risk that is above the threshold of acceptability, even after all opportunities for risk mitigation and control have been exhausted or found to be economically infeasible, a company should perform a medical risk–benefit analysis to determine whether the product's benefits outweigh the harm that could result from using the end product. Figure 3 provides a flow diagram that shows the supplier-assessment process using FMEA and RPN.  

Figure 3: Supplier risk-assessment process. FMEA is failure mode effects analysis, and RPN is risk priority number. 

After the supplier risks have been identified, reduced to acceptable levels, and communicated, it is important to establish a formal agreement to ensure that the supplier maintains a state of control and the manufacturer is an active participant in the supplier's quality- and risk-management programs. An effective way to establish this relationship is through a quality agreement. The quality agreement is a contract between the pharmaceutical manufacturer and its supplier of critical components or materials used during the development and manufacturing processes. The purpose of a quality agreement is to clearly define supplier qualification requirements, product and process specifications, regulatory-compliance requirements, management responsibility, a risk-management plan and a comprehensive communication plan. 

The quality agreement should also specify the manufacturer's expectations for processing changes that the supplier considers. The supplier should inform the pharmaceutical manufacturer of proposed changes to their manufacturing process in a "Notification of Change." The pharmaceutical manufacturer can thus evaluate the impact of the change on its final product. The manufacturer's previously identified management team should approve the change before the supplier implements it. Even the smallest change to a supplier's process can have an immense effect on a manufacturer's product or process. Establishing and maintaining a quality agreement is essential to controlling this potential risk. 

Once established, the quality agreement should be periodically reviewed and monitored for effectiveness. Predetermined quality criteria such as the number of products out of specification, CAPA, and the number of product complaints should be measured, and trends should be investigated. The quality agreement must be evaluated regularly to ensure that required updates are implemented and communicated to each party in a timely manner. 

In addition to monitoring quality criteria, it is recommended that the manufacturer conduct periodic supplier audits to ensure and verify that the supplier is maintaining a state of control, meeting the pharmaceutical manufacturer's requirements, and employing a quality-management review system. The manufacturer should evaluate its suppliers according to defined criteria and procedures. Results should be documented. Each supplier that a manufacturer selects should have a demonstrated capability of providing products or services that meet the established requirements specified in the quality agreement. Once a supplier is selected, its performance must be monitored periodically. The frequency of monitoring should be commensurate with the significance of the product or service the supplier provides. The complexity of the service and its potential effect on the finished product's performance also should be considered. 

Planning for a supplier audit is critical. Supplier audits should be scheduled according to the product and process risk assessments. The interval between audits should be established according to the significance of the material for final-product performance and the supplier's demonstrated ability to manufacture to the specified requirements consistently. An evaluation of the supplier's past history in providing similar products or services should be included in the assessment when possible. Written mail surveys or questionnaires frequently are used to assess the supplier's quality plan, test and inspection procedures, validation history and references, and the results of previous regulatory inspections or registration audits. Often, one set of questions will not fit all suppliers. Also, the focus of supplier audits can evolve as the relationship between the manufacturer and supplier matures. Though previous relationships with a supplier and registration to a specific industry standard such as ISO 9001 are important to manufacturers, they should not rely solely on previous audits and certifications as evidence that a supplier can provide acceptable products. Instead, manufacturers should conduct on-site supplier audits to assess supplier risk and establish conformance. 

The supplier audit helps identify nonconformances that occur in many processes throughout the product life cycle—from the design process to the manufacturing process to the distribution process. Supplier audits can build both parties' confidence and provide a system for high-quality technology transfer. 

In addition, an audit helps the supplier understand the pharmaceutical manufacturer's expectations. Supplier audits generally provide objective analyses of the vendors and can be fact gathering tools to ensure that the supplier meets the manufacturer's expectations, thus enabling control over the quality of the product.  

Because of the rapid growth of the global supply chain for the pharmaceutical industry, increased risk management is essential to ensure regulatory compliance and consumer safety. By implementing the ideas and tools described in this article, the pharmaceutical manufacturer will reduce risk, enhance patient safety, and ensure long-term success for its products.  

 is the director of product and process development, all at Regulatory Compliance Associates, 7401 104th Ave., Suite 160, Kenosha, WI 53142, tel. 262.842.1250, fax 262.842.1251, 

 is the president of Schniepp and Associates and a member of 

*To whom all correspondence should be addressed. 

Failure Mode and Effect Analysis: FMEA from Theory to Execution,

 (American Society for Quality, Milwaukee, WI, 2nd ed., 2003). 

Guidelines for Failure Modes and Effects Analysis (FMEA) for Medical Devices,

The growth and globalization of the pharmaceutical supply chain make risk assessment more important than ever for pharmaceutical manufacturers. The authors describe a program to identify, prioritize, mitigate, and communicate risks in manufacturer–supplier relationships.