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

Susan J. Schniepp

At the September 2010 recent PDA/FDA Joint Regulatory Conference, Howard Sklamberg, director of the US Food and Drug Administration's Office of Enforcement, discussed the agency's current enforcement strategy. The strategy is codified in a position paper dated July 15, 2010 (available on the FDA website at 

www.fda.gov/downloads/ICECI/EnforcementActions/UCM225183.pdf

) and signed by representatives from all primary FDA centers and offices including the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research.  

The document states, "The Food and Drug Administration (FDA) is articulating its enforcement strategy in order to ensure strategic alignment with in the Agency and express why enforcement is critical to protecting public health." The paper clearly defines FDA's areas of responsibility and the scope of their jurisdiction.  

One of the most important concepts presented in the paper concerns industry's seeming lack of ability to self-govern their operations to be in compliance with the laws that FDA oversees and enforces. In language leaving little room for interpretation, the document points out that, "Without effective FDA regulatory oversight and enforcement, some regulated entities will disregard even the clearest sregulations or will not be adequately vigilant to ensure compliance with the law, potentially harming the public." The paper goes on to say, "If, during an inspection, investigation and/or through laboratory analysis, a significant violation is identified, FDA will determine as quickly as possible what further agency action might be necessary." In addition, "FDA will use any and all available enforcement tools, as appropriate, based on the facts of the case and the nature and seriousness of the violation."  

So what should industry glean from these statements? In this new era of enforcement, it is far better to be proactive than reactive. Companies should routinely monitor the FDA website for 483 and Warning Letter postings. The information contained in these documents offers valuable insight into the issues the agency considers important. Companies should use these observations to assess their own practices and to identify any potential compliance gaps.  

If a gap is identified, the company should make the necessary change to remediate the issue and bring the system, process, or procedure into current compliance status. Drug manufacturers also should review their audit programs to ensure they are robust. Reviewing and evaluating one's suppliers—and making sure they can articulate the source and quality of the materials they provide—is another key element for proving to FDA that the firm is in control of its quality systems. In addition, if it is not already done, companies should consider implementing annual good manufacturing practice (GMP) training for all employees.  

Another important consideration to ensure current GMP compliance is to make sure the company, and its suppliers, is prepared to host a regulatory inspection. The concept of being "audit ready" has been around for years. Today, companies must challenge themselves to always be ready to host a timely and meaningful audit.  

Problems noted during inspections should be dealt with quickly and effectively. When faced with noncompliance issues, a firm should take care and time to properly outline its remediation plan.  

The steps to achieve compliance should be clear and specific, and a timeframe for completing each step should be included in the plan. In the event that remediation steps are delayed, the reason for the delay should be documented and a new completion date should be assigned. In such an instance, it would be wise for the company to communicate the reason for the delay to FDA and obtain the agency's agreement to the revised plan. 

Overall, drug manufacturers need to step up and take responsibility for their operations. They must ensure conformance to regulations and empower their quality personnel to act responsibly when assessing products and processes in order to meet safety and effectiveness requirements.  

By being proactive, firms will be able to maintain an efficient, compliant operation while working effectively with regulatory agencies. In the end, companies will save considerable time and resources by not having to remediate nonconforming and undesirable practices.  

 is vice-president of quality assurance at OSO BioPharmaceuticals in Albuquerque, NM, 

Articles

Drug manufacturers have to be more than just "audit ready."

Insider Solutions Rule #1: Be in Compliance

As the pharmaceutical landscape and its related supply chains become more global and complex, industry is in need of more quality agreements. There are several important issues that must be addressed before a company can transfer its product manufacturing to a contract manufacturing organization (CMO). In addition to the facility qualification process, there needs to be a document defining the ongoing relationship and responsibilities of the parties involved. A Technical Agreement, or Quality Agreement, that delineates each party's responsibilities is crucial for assuring that the processes will be controlled according to a mutual understanding. Although constructing a good quality agreement for cooperative manufacturing may seem somewhat predictable and repetitive, each agreement should be approached with a fresh outlook and take into account the strengths and weaknesses of each party.  

Recognizing the challenges and opportunities of the CMO model, the US Food and Drug Administration published in 2008 a guidance document, 

Cooperative Manufacturing Arrangements for Licensed Biologics,

 to provide information about the agency's expectations regarding quality agreements for biological products. Both FDA's Center for Biologic Evaluation and Center for Drug Evaluation and Research endorse the guidance, which describes four types of manufacturing arrangements: Short Supply, Divided, Shared, and Contract. 

A Short-Supply agreement is a specialized agreement used in situations where a necessary product is facing a potential out-of-stock situation. Divided manufacturing agreements are used when two manufacturers, each registered with FDA, are licensed to manufacture a specific product in its entirety and agree to jointly manufacture the product. Shared manufacturing arrangements are defined as agreements where two or more manufacturers are licensed to perform one or more parts of the synthesis of a product, but none of the companies are licensed to manufacture the entire product from beginning to end. Finally, Contract manufacturing arrangements, the most prevalent today, are, in essence, service agreements, where the license holder contracts with another company to manufacture the product for them.  

For the latter agreement, FDA's guidance spells out the responsibilities of the license holder and the contract manufacturer. Each party shares responsibility for ensuring the product's safety, purity, and potency, but the ultimate responsibility lies with the license holder. The license holder's responsibilities also include ensuring that the product complies with the biologic license application, current regulations, and product and established standards. In addition, the license holder is responsible for reporting proposed changes to the product or facilities being undertaken by the CMO.  

Table I: Responsibilities in contract-manufacturing agreements. 			

According to the guidance, CMOs must comply with current regulations. They are subject to FDA inspections and must be registered with the agency. The CMO should be prepared to provide pertinent information to the license holder, including facility floor plans and equipment validation. Both the CMO and the license holder should have robust procedures in place for informing and receiving information on deviations, complaints, adverse events, and the results of tests and investigations affecting the product(s) being manufactured. There are many more responsibilities discussed in the guidance document (see Table I), but the bottom line is that the license holder is responsible for the behavior and conduct of its partnering CMO.  

Regardless of which manufacturing arrangement companies use, it's important to understand the contents and recommendations of this FDA guidance and to structure quality agreements accordingly. One key element in this process is communication. The types of and speed with which information is communicated is vital to establishing a good working relationship between the parties implementing a quality agreement. Information-exchange is also pertinent to meeting FDA's expectations.  

 is vice-president of quality at Antisoma in Cambridge, MA, 

Before embarking on an outsourcing relationship, it's important to be aware of FDA's expectations.

Insider Solutions: The Quality Agreement

On Apr. 21–24, the United States Pharmacopeial Convention (USP) held its convention in Washington, DC. This gathering of pharmacopeial minds occurs once every five years and the outcome sets the direction and course of USP for the next five-year revision cycle (July 1, 2010 to June 30, 2015). 

Before discussing some of the significant happenings that took place at this convention, it's worth recapping some facts about USP. The independent, standard-setting organization was founded in 1820, long before the pharmaceutical industry came into existence. At that time, pharmacists were essentially the drug manufacturers of their time. Still today, many USP convention members are from the pharmacy community. Other members represent: US colleges and schools of medicine and pharmacy; state medical societies and pharmacy associations; national and state professional and scientific organizations; governmental bodies; health science and other foreign organizations and pharmacopeias; consumer organizations and individuals representing public interests; and manufacturers, trade, and affiliated associations.  

These member organizations name individuals to represent their specific interests at the convention. Delegates are responsible for voting on changes to USP's constitution and bylaws, voting on nominees to the Board of Trustees, voting on nominees to chair the USP expert committees, and debating and voting on resolutions. Of these responsibilities, the two that have the greatest significance to industry are electing the committee chairs—who then set the standards of the 

 (NF)—and voting on proposed resolutions, which define USP's strategic direction.  

For the 2010-2015 revision-cycle, USP cut in half its number of committees from 40 to 20. Forty individuals were slated to run for chairmanships, two for each available position. Of the 40 nominees, only 13 were from industry. In three instances, the two candidates running for the same position were both from industry.  

These numbers seem a little low for industry, considering that industry is the major contributor and user of the 

. Industry experts understand what elements are required of a method to optimize analysis and instill confidence that the pharmaceutical material—whether it is the drug substance, excipient, or dosage form—meets the necessary standards of identity, strength, potency, and purity. It is the industry experts who practice the performance of these methods on a daily basis and can understand when a method may not be optimal or suitable for inclusion in the pharmacopeia.  

There were nine resolutions proposed for the 2010 Convention—all were adopted. Three were of particular interest to the pharmaceutical industry as outlined herein. The first resolution calls on USP to strengthen its core compendial activities, working collaboratively with industry, regulators,and stakeholders to ensure relevant, timely, and accurate public standards. 

This should be USP's foremost activity and focus. The recent recall activities of 

 28, along with other issues (e.g., monograph redesign project, the confusing implementation of residual-solvents testing, the number of Errata in the 

) have left industry with a sense that USP is losing touch of its main objective and responsibility to the US pharmaceutical and medical community. The industry relies on USP to provide timely, accurate, and reliable standards. The specifications, methods, and general test procedures published in USP are used by industry to test and release product that is suitable for patient use. During the last five-year cycle, USP expanded operations to India and China and focused a considerable amount of effort on international activities. This growth appears to have stretched USP's resources, which may have potentially contributed to the unprecedented recall of the 

. For USP to regain industry's confidence, the organization must ensure it has the proper amount of resources devoted to monograph standards development. 

Second, a resolution on strengthening USP's relationship with the US Food and Drug Administration (Resolution 3) resolves to have USP work more with the agency and other public and private stakeholders to explore mechanisms that would enable USP to provide and maintain up-to-date national standards for legally marketed drugs and excipients in the United States. 

Overall, industry seems to supports this resolution and believes it is critical for USP and FDA to work together. However, such a partnership needs to consider the effect of their work on industry as it develops. FDA Commissioner Margaret Hamburg spoke at the convention. She indicated that FDA and USP will be working together to identify materials that should have additional tests to prevent adulteration with the intent of adding these mandatory tests to monographs. It is not readily apparent how adding tests to monographs will actually prevent adulteration. By the time the adulteration is discovered and the potential monograph test is discussed, adopted, and implemented the adulterators have gone on to different adulterants. The best way to stop the adulteration is to the focus on supply-chain knowledge, supplier qualification, and supplier auditing. These activities offer more security regarding the quality of material than does performing an additional monograph test on incoming material receipt. 

Industry is actively pursuing its understanding of the supply chain and has taken several steps to share information among themselves and their trade organizations to prevent adulteration. It would be more prudent for USP to let FDA and industry work together to prevent adulteration and be ready to assist if and when the need arises for additional tests to be included in monographs.  

Third, a resolution aimed at strengthening and expanding harmonization efforts (Resolution 5) urged USP to grow its collaboration with pharmacopeias, industry, regulators, international organizations, and other stakeholders around the world to develop global standards.   

A similar resolution was adopted during the last convention cycle but focused a bit more on USP's partnership with the Pharmacopeial Discussion Group and other pharmacopeias. The concept of harmonizing monographs has been around since 1989. It wasn't until the International Conference on Harmonization formed the Q4B Expert Working Group in 2004 that the industry saw progress made toward realizing the goal of harmonized standards. The new resolution offers a different twist on the international harmonization efforts by involving "regulators, international organizations and other stakeholders" to assist with the harmonization effort. While USP's activities in the international arena are welcome, the organization needs to make sure it has enough resources to manage the day-to-day operations of setting appropriate standards for the US pharmaceutical industry.  

A few additional resolutions are worth noting. One (Resolution 4) aimed to support and advance global public health by collaborating with national, regional, and global stakeholders. This particular resolution mentioned the expansion of USP's resources, something the organization should consider so as to not compromise its core business—that is, the publication of the 

Another (Resolution 6) revolved around establishing quality standards for food ingredients. The resolution indicated that "USP should continue and expand its commitment to quality standards for food ingredients, working to strengthen the role of Food Chemicals Codex (FCC) as a global compendium for food ingredients, increasing the number of documentary standards and reference materials available for food ingredients, and exploring the feasibility and advisability of expanding the scope of FCC." As with some of USPs other initiatives, this one is admirable but devoting the proper resources to this activity is paramount for success. The pharmaceutical industry occasionally needs to use food-grade materials for formulation due to the lack of a comparable pharmaceutical grade. It is important for USP to work with pharmaceutical experts as well as food experts to set the correct requirements for these ingredients. 

The next five years will be exciting for both USP and industry as the resolutions from the convention are addressed. Industry must demand that the quality and reliability of the 

 not be compromised as USP tries to assert itself as an international organization during the next revision cycle. 

A complete list of the organizations belonging to USP, the proposed resolutions, and Dr. Hamburg's address are available on the USP website at 

 is president of Schniepp & Associates, a pharmaceutical consulting firm, 

Inside USP: The USP Convention

On Apr. 21-24, the US Pharmacopeial Convention (USP) held its convention in Washington, DC. This gathering occurs once every five years, and the outcome sets the direction and course of USP for the next five-year revision cycle. USP's new revision cycle will begin on July 1, 2010 and last until June 30, 2015.

During the convention, delegates decided to cut its number of committees in half from 40 to 20. Forty individuals were slated to run for chairmanships, two for each available position. Of the 40 nominees, only 13 were from industry. In three instances, the two candidates running for the same position were both from industry.
 
Delegates also reviewed and adopted nine resolutions proposed for the 2010 convention. Three were of particular interest to the pharmaceutical industry. The first resolution called on USP to strengthen its core compendial activities, working collaboratively with industry, regulators, and stakeholders to produce relevant, timely, and accurate public standards. During the last five-year cycle, USP expanded its operations to India and China and focused a considerable amount of effort on international activities. This growth appears to have strained USP’s resources and may have contributed to the unprecedented recall of the 

 For USP to regain industry confidence, the organization may need to reassure industry that it has the proper amount of resources devoted to monograph standards development before it undertakes additional collaborative activities.
 
Second, a resolution on strengthening USP’s relationship with the US Food and Drug Administration (Resolution 3) pledged greater USP collaboration with the agency and other public and private stakeholders. The goal is to explore mechanisms that would enable USP to provide and maintain up-to-date national standards for legally marketed drugs and excipients in the United States. Overall, industry seemed to support this resolution and believe it is critical for USP and FDA to work together. Convention delegates also discussed, however, how a focus on supply-chain knowledge, supplier qualification, and supplier auditing could offer additional product security.
 
Third, a resolution aimed at strengthening and expanding harmonization efforts (Resolution 5) urged USP to increase its collaboration with pharmacopeias, industry, regulators, international organizations, and other stakeholders around the world to develop global standards. A similar resolution was adopted during the last convention cycle but focused more on USP’s partnership with the Pharmacopeial Discussion Group and other pharmacopeias. The new resolution offered a different aaproach to the international harmonization efforts by involving “regulators, international organizations and other stakeholders” to assist with the harmonization effort.
 
USP and industry will address the resolutions from the convention during the next five years. A complete list of the organizations belonging to USP, the proposed resolutions, and FDA Commissioner Margaret Hamburg’s address are available on the USP 

.
 
 Susan J. Schniepp attended the USP Convention and is a member of 

 Editorial Advisory Board. Read her full convention report and commentary in the May 2010 issue of 

The US Pharmacopeial Convention recently held its convention in Washington, DC.

USP Convention Sets Agenda for Next Five Years

The International Society for Pharmaceutical Engineering (ISPE) recently published the second edition of its 

Baseline Pharmaceutical Engineering Guide for Oral Solid Dosage Forms. 

This comprehensive volume takes a soup-to-nuts approach to guiding pharmaceutical manufacturers in building new facilities, and renovating existing facilities, to meet current global regulatory expectations. The book's layout is user friendly and includes visible tabs for easy reference. 

 ISPE Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities: Volume 2, Oral Solid Dosage Forms, International Society for Pharmaceutical Engineering, ISPE, Tampa, FL, 2010, 184 pp., ISBN 1-931879-67-2			

The various sections, including the introduction, are outlined in the same basic format, which helps readers to refer to other chapters and maintains the book's continuity. Each division opens with an introductory statement that highlights the chapter's content. A few of the guidance chapters have diagrams, tables, or charts that succinctly summarize much of the information presented in the chapter. In addition to these graphics, the authors have included cross-references to other chapters in the text so the reader can quickly refer to the appropriate chapters and obtain a clear and comprehensive understanding of a topic and its related requirements. 

It is worth the reader's time to peruse the introduction because it highlights the major changes that differentiate this new volume from the one published in 1998. The scope of the baseline guide is confined explicitly to solid oral dosage forms and key concepts that may be applied to clinical and commercial manufacturing facilities. In addition, the "Scope of this Guide" section tells the reader where to find similar information for facilities that manufacture excipients or injectables; readers don't need to guess about how to adapt this information to those specific operations. The introductory chapter has a subsection titled "Key Features of this Guide," which codifies the regulatory and compliance premises that form the basis for the information that follows in the subsequent chapters. 

After absorbing the introduction, the reader should review the appendices. All of the appendices are useful, but three in particular stand apart. Appendix 6 is a comprehensive glossary of the common terms used throughout the manual. The appendix also includes definitions that help readers interpret some of the information that the book provides. Appendix 5 provides a thorough list of references for readers who would like to know about the sources of some of the book's information. These references are cited throughout the body of the manual as well. 

Appendix 4, titled "HSE International Regulations and Standards Cross References," is the most useful. It displays in columns the regulatory references for many of the attributes that must be considered when building or renovating a solid oral dosage-form manufacturing facility. For example, if the reader needs to know the regulations that govern air emissions, he or she can locate this information in section 15.5 of Appendix 4, where the appropriate regulatory citations for this requirement for the United States, Canada, and the European Union are provided. Section 15.8 lists Japanese laws and regulations. This appendix emphasizes the global applicability and appeal of this manual. 

Section 11, titled "Risk-Based Approaches to Commissioning and Qualification," is new to the manual and offers basic concepts regarding risk assessment as it applies to this specific topic. This chapter guides readers through the commissioning and qualification processes and gives a synopsis of the various sections contained in the American Society for Testing and Materials (ASTM) standard that is the chapter's reference document. Although this chapter is not particularly useful on its own, it gives enough information about the ASTM E2500 standard for the user to determine whether it is worth purchasing. 

A few chapters in the manual could have benefited from more explanation and text. One example is Chapter 2, "Concepts and Regulatory Philosophy," which gives overly general examples of how certain philosophies apply to solid oral-dosage facilities. It might have been more beneficial to readers if a case study had been used to exemplify the issues and philosophies discussed. 

An even more interesting concept would have been to add a section to the introduction that described a fictitious company's need to retool an existing facility and build a new facility. The book could have followed these two scenarios through each chapter and given readers an idea of how the concepts and philosophies explained in the book work in practice rather than in theory. 

Overall, the ISPE manual is a valuable document that is well organized and informative. When the information is not as complete as the reader might need, the book offers numerous references to other information sources where more detailed data can be found. The international relevance of the book makes this a practical document for companies that seek to build or renovate their solid oral dosage-form manufacturing facilities, wherever they happen to be located. 

 is president of Schniepp and Associates and a member of 

New information improves an organization's guide to building manufacturing facilities.

ISPE Raises the Bar for Baseline Guides

Mergers, acquisitions, outsourcing, globalization, downsizing, and new technology. In other words, the pharmaceutical industry is undergoing immense 

. The environment today is one of merging and emerging cultures as companies combine workforces and globalize processes to be able to compete in the global marketplace.  

Merging companies must not only integrate their products but also their cultures—all while shrinking costs and maintaining control over their quality systems and regulatory compliance. Add to the mix the introduction of new technologies, which small and sometimes virtual companies must also manage within their quality systems across a variety of service providers and partners. With all of these changes, the criticality of an efficient change-control system that can track and ensure proper evaluation and implementation of changes is obvious. 

Envisioning a change-control system as a graph with ease of implementation on the X-axis and the complexity of the change on the Y-axis, it becomes easy to visualize why some changes may take years to implement (see Figure 1). As a change becomes more complex (e.g., a change that involves multiple products and country registrations), it becomes harder to implement. Complex changes are difficult enough for a single company with multiple sites, but they are even more exaggerated for virtual companies. For the latter,  multiple contract service providers are often involved and each one has its own processes and procedures for managing a requested change.  

Figure 1: Change complexity versus change implementation. (FIGURE IS COURTESY OF THE AUTHOR) 

Overall, changes can be categorized into four distinct levels of complexity: Level 1–Basic Change, Level 2–Straightforward Change, Level 3–Complex Change, and Level 4–Integrated Complex Change.  

Level-1 changes tend to be simple and easy to implement (e.g., changing a typographical error on an internal compliance document). Although these updates may affect multiple sites, there is no impact to regulatory filings or product quality and the changes do not require retraining.   

Level-2 changes are more challenging to implement. This second level of change (e.g., a change to a test method) often applies to more technical documents and systems. The changes being proposed may require validation activities and may affect multiple sites. Companies must assess how these changes will impact regulatory filings and product quality and strategize their implementation accordingly. Consideration should be given to the time required to train all affected personnel.  

A Level-3 change is often intricate, involving changes to technical internal documents that effect multiple products at multiple sites (e.g., a change to a test method for an excipient that is used in a variety of products, which  are manufactured at several facilities). Level-3 changes require personnel retraining at all affected facilities. In addition, the regulatory impact of these changes may be to multiple registrations in multiple countries with a possible impact on product quality, which can be  time-consuming and difficult to implement.   

A Level-4 change is the most integrated, most complex change. These changes can border on arcane and their implementation can take years to accomplish. They typically involve technical documents that require changes to processes, equipment, and/or facilities affecting multiple sites and/or multiple suppliers, and require employee training for both the company and supplier employees. The regulatory impact can affect multiple filings in multiple countries as well as product quality. An example of an integrated complex change may be the product transfer and subsequent decommissioning of an old manufacturing facility previously responsible for multiple products.  

The time required to transfer, validate, train, and obtain regulatory approval for multiple products requires enormous coordination. It is important to keep in mind that as the complexity of the change increases, the need for additional resources can also increase—as can the need to consider automating the change control process. In other words, although simple processes can be appropriate for uncomplicated changes, they can quickly become over-challenged when applied to the highest complexity of change. 

In today's environment, it helps to think of change as a continuum. The complexity of the change can impact the strategies for implementation, the tactics needed to effectively implement the change, and the time it takes for a change to be approved. At the same time, manufacturers will need to  establish consistency in their regulatory filings without affecting product quality. 

When dealing with this change, focus on the steps needed to effectively implement the change. Working closely with your contract research organizations to identify an accurate timeline for completion, including the necessary training required for employees, can help expedite the time it takes to complete the change request. Coordinating these activities with regulatory requirements also will help ensure necessary changes are implemented globally in an efficient and effective manner. 

 is president of Schniepp and Associates, LLC, 

We never thought implementing complex changes could become more cumbersome.