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

Susan J. Schniepp

There are two topics in today’s pharmaceutical landscape commanding the attention of both the industry and the regulators: drug shortages and quality metrics. It is increasingly difficult to discuss one of these topics without discussing the other. Establishing, maintaining, and interpreting quality metrics to measure the suitability of pharmaceutical products and the capability of the manufacturer to provide these products consistently and without delay has become a high priority for the industry and FDA.


  The first piece of this puzzle emerged in 2012 when Congress passed the Food Drug Administration Safety and Innovation Act (FDASIA) enhancing FDA’s capability to proactively react to, prevent, and alleviate drug shortages. This direction is codified in the language contained in Title VII—Drug Supply Chain and Title X—Drug Shortages. Specifically, Title VII Section 705 of the Act states FDA “shall inspect establishments described in paragraph [1] that are engaged in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs (referred to in this subsection as ‘drug establishments’) in accordance with a risk-based schedule established by the Secretary” (1). Additionally, this section also describes the risk factors to be considered in establishing the inspection schedule. The last risk factor listed in this section is “Any other criteria deemed necessary and appropriate by the Secretary for purposes of allocating inspection resources.” Section 706 of the same act allows FDA to request certain information from companies in advance of or in lieu of inspections by stating “Any records or other information that the Secretary may inspect under this section from a person that owns or operates an establishment that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug shall, upon the request of the Secretary, be provided to the Secretary by such person, in advance of or in lieu of an inspection…” 

The next piece of this puzzle is found in Title X section 506C-1 (Annual Reporting on Drug Shortages). Title X section 506C-1 requires FDA to annually provide Congress “a report on drug shortages…”

The third piece of the puzzle fell into place in a February 12, 2013 

 Notice. FDA asked the industry to “assist the Food and Drug Administration in drafting a strategic plan on drug shortages as required by the Food and Drug Administration Safety and Innovation Act…” This notice asked a series of thought-provoking questions including “What metrics do manufacturers currently use to monitor production quality?” and “How frequently would such metrics need to be updated to be meaningful?” (2).

The last piece of the puzzle revolves around the industry reaction to this information. Many trade organizations responded to the questions in the 

. Some prepared white papers while others held meetings to discuss the issue with their members. The general consensus, and the easy part from this activity, was that industry needed to actively engage with the agency in defining suitable quality metrics to provide information to the agency supporting their efforts to eliminate drug shortages and determine the appropriate quality metrics to be used in establishing a risk-based approach to inspections. 


  Companies currently use a variety of metrics to measure performance including, but not limited to, corrective action and preventive action (CAPA), out of specification (OOS), batch rejection rate, complaints, field alerts, recalls, batch yield, training effectiveness, and environmental monitoring excursions. The goal is to review and define which of these metrics can be used to measure performance based on product quality and suitability as opposed to performance based on compliance standards. The hard part is trying to define them so they are not subject to interpretation: they are simple but comprehensive and applicable to traditional, biotech, virtual, contract manufacturers, drug substance manufacturers, etc. The industry needs to ensure the metrics chosen provide meaningful data while avoiding unintended consequences. The metrics need to be simple so they do not divert or dilute a company’s resources from daily activities associated with producing and delivering high quality medicines.

So, what might these metrics be? The Parenteral Drug Association (PDA) held their Annual Meeting in San Antonio in April 2014 (3). During this meeting, there was an open member session where PDA proposed seven potential metrics for consideration. For each metric proposed, there was a definition to consider, a calculation, a recommendation on how to report the metric to FDA, and a discussion of potential unintended consequences that might result from the implementation of the metric. The metrics proposed by PDA were:

The PDA recommendations included some guidelines and principles clarifying the reporting of these metrics. Product metrics were defined as items with the same formula regardless of their final packaging configuration. Under this model, drug substance manufacturers would consider each drug substance batch as a product batch. Site metrics would be a compilation of the product metrics for the site and would combine drug-product and drug-substance metrics for sites that manufacturer both. The recommendation for reporting was to collect the data monthly and report annually, perhaps using annual product reviews or annual report dates to determine the cycle.

The metrics proposed by PDA seem reasonable but there is a missing piece to this puzzle. The most important metric used to determine a company’s well-being is a measure of their quality culture. The culture of a company dictates the veracity of their metrics. Achieving a quality culture requires management and employees to establish an environment where responsibility, accountability, and reliability are paramount, and to understand the role each person performs in delivering a high-quality product to the customer and sustaining that performance on a continual basis. Management must educate employees and provide the tools and environment where they can perform their functions in an atmosphere that encourages excellence and continuous improvement. 

The trouble with using quality culture as a metric is determining how to measure it. An unhealthy quality culture is easy to identify. People in a poor culture do not understand their job and its importance to the business. They often appear stressed, and they hide their mistakes or blame others for their errors. There is no evidence of teamwork. People work in silos and rarely, if ever, seek input or advice from others. The metrics that could potentially be used to measure a poor culture include a large employee turnover, an overabundance of deviations attributed to human error, and lack of pride in the performance of their jobs. In contrast, a robust, healthy quality culture can be evidenced by alignment of goals between quality and operations, self-sustained work teams that focus on continual improvement, and employees who incorporate quality into their jobs on a daily basis. They are not afraid to speak up and offer suggestions for improvement to their colleagues. People understand the importance of their jobs and respect each other and their management. This culture welcomes inspections and views these inspections as another tool to use in their continual improvement initiatives.

The establishment of simple quality metrics that not only measure the quality of the product but also reflect the quality culture of an organization is required to assist FDA in establishing a risk-based audit program. 

, Vol. 78, No. 29 (Feb. 12, 2013) 9928-9929.
  3.	PDA Annual Meeting, Apr. 7-11, 2014, Session titled Quality Metrics Update and Proposed Definitions.


Susan J. Schniepp is vice-president of quality and regulatory affairs at Allergy Laboratories.

Articles

Industry players offer suggestions for quality metrics as FDA continues to try and solve the problem of drug shortages.

Linking Drug Shortages and Quality Metrics

Training represents one of the key elements that management can use to assure a consistent, high quality, product. Codifying the elements of the training program will help a company maintain compliance to the regulations and address regulatory concerns about employee qualifications that might arise during inspections. Some companies are fortunate to have either a training department or a training coordinator to define and administer the program. Companies that do not have either should establish a training team with representatives from the quality assurance, quality control, and operations departments at a minimum. There should be approximately four parts to any training program: the introductory training requirements for new employees, the annual training requirements for all employees regardless of function, the continuing education training expectations, and special training requirements that may be required for continuous quality and process improvements. The first three may be tracked with a training matrix.


  New employees should be initially trained on applicable GMPs, good documentation practices (GDPs), and any additional global requirements impacting their jobs. It is prudent for a company to develop a quiz or test to demonstrate the new employee’s comprehension of these basic requirements with an established minimum passing percentage. The minimum percentage must be achieved before the employee is considered to have the basic knowledge needed to work in the company. Incorrect answers should be discussed as part of the process. If the required minimum is not achieved, the prospective employee should be provided additional instruction on the material and a different test should be employed to measure comprehension. If the minimum required comprehension level is still not achieved, the quality assurance department should inform the hiring manager and indicate the new employee is not suitable for employment. Once new employees have passed the minimum understanding requirements on the quizzes, they should then be trained on company policies and specific job-related standard operating procedures (SOPs). 


  Companies should perform annual refresher training on a variety of topics. At a minimum, it is recommended that employees be retrained annually on cGMPs and cGDPs. Additional yearly training topics could be tailored to the type of operations being conducted at the facility. If the company is manufacturing parenteral products, the annual training program might include modules on microbiological control in aseptic manufacturing and conducting investigations/root cause analysis. This yearly training should also measure employee comprehension of the material. This comprehension might be measured in a variety of ways including but not limited to written quizzes, oral quizzes, and hands-on demonstration. Whichever way is chosen to assess the employee’s comprehension of the material, it should be noted on individual training records

Continuing education training requirements


  Employees should be encouraged to enhance their job-specific knowledge and skills by attending external training conferences, seminars, and activities. The training team should be responsible for reviewing literature and recommending which employees should attend specific courses to enhance their skills and knowledge. The benefits of the external training should be discussed with senior management. There are several organizations that provide seminars, training classes, and symposia including the American Society for Quality, the Parenteral Drug Association, the American Chemical Society, and for-profit organizations.


  Companies need to recognize there may be occasions when special training is required for employees. The responsibility for determining the need for special training will reside with the training team but should be performed using qualified trainers with recognized expertise in the specific discipline being addressed. Using qualified trainers in this situation assures the attendees will be trained by experts that will understand questions that may arise during training. As with all training, a record of the training should be put into the employee’s personnel folder.

When a company invests in the future of its employees by establishing a comprehensive training program, they need evidence that the monies were well spent. To assure continued funding for training, management should establish metrics to monitor performance as a practical measure of the ongoing effectiveness of training activities. By continuing to invest in training, companies invest in their employee’s futures 
  and develop a knowledgeable, skilled and experienced workplace as well as a culture supporting continual improvement and growth.

Establishing a well-defined training program is a crucial activity for any biopharmaceutical organization.

The Elements of Training

Establishing, maintaining, and interpreting meaningful metrics has become an emerging industry issue. This topic has risen to prominence based on an article (1) and a 

notice (2) that explored the question of what types of metrics should be applied to pharmaceutical operations, giving meaningful insight to their overall quality and compliance.  

There is no set requirement on what metrics a company should track to measure their overall performance. Each company should determine which metrics to track based on their operations, number of facilities they operate and where they are located, what types of products they manufacture, and what type of culture exists in their places of business. 

When establishing a metrics program, companies should evaluate numerous data input points including, but not limited to, product quality attributes, manufacturing site performance, people metrics, and quality system metrics. For product-quality metrics, companies should consider reporting on batch-specific data such as trending drug product, drug substance, and stability-test results against customer complaint rates. Indirect product quality metrics could include environmental monitoring, water trend results, and yield rates. When establishing site metrics the company could look at inspection history including internal audit findings and maintenance history such as equipment age versus defect failure rates. People metrics should consider ongoing job-specific training and education, skills and experience assessments, and employee turnover rate by job function and site. Quality systems metrics might look at change control, investigation root-cause trends, and release-testing cycle times.  

The metrics chosen must be meaningful and written to provide a clear analysis of ongoing activities. It is important for operations and quality to agree on the metrics and how to report them to management to avoid overreaction to the data. It is not sufficient to simply report the data. The interpretation of the data is of crucial importance because it may include a root-cause analysis of its own. 

Let's examine a simple metric and explore the hidden unintended behavior it might encourage: 

Time from completion of manufacturing to approval of batch records. 

All batch records are completed in 30 days or less after manufacturing.  

Realistically, not all batches will be able to be released in 30 days or less for a variety of reasons including the fact that some complex investigations into root cause may take longer to resolve than the allotted 30 days. When considering how to report this metric, the organization should consider all possible reasons for achievement or non-achievement of the goal. This includes, in essence, a root-cause analysis to interpret the meaning of the metric. Evaluation of the cause and effect relationships are necessary before determining whether or not to revise the goal. If the goal is met most of the time with a few exceptions the data might indicate the batch release system is operating as intended. If the 30-day period is exceeded on a regular basis, the organization needs to consider why the 30 days are exceeded. Some of the questions to be asked might include:  					

Were there too many errors in initial submission? 

Are people unable to prioritize their work?  

Asking and answering these questions may offer solutions that can be used to streamline the batch release process so the 30 days can be consistently achieved. 

Careful thought and consideration should be exercised when determining what to measure, how often to measure, how to interpret and communicate the data, and what the expectation is for using the data to drive positive change. Management needs to be cognizant of the fact that whatever metrics are chosen to be reported, they must be developed, evolved, and adjusted over time to maximize their impact on driving positive change.  

When choosing a metric it is important that the architects of the metric are aware of unintended consequences that may inadvertently drive negative behavior. Management attempting to incentivize achievement of the goal such as offering a financial award if the goal is achieved, for instance, may lead to inappropriate behaviors that do not address the real issue. In these cases, it is generally not the metric that will drive the behavior but rather use of behavioral rewards. Reward for achievement rather than analysis of the real underlying causes will not lead to sustainable positive change. When managed properly, metrics are an important tool to help drive positive change and quality process improvements. 

is vice-president of quality and regulatory affairs at Allergy Laboratories and is a member of the 

 2. Docket No. FDA-2013-N-0124, Food and Drug Administration Drug Shortages Task Force and Strategic Plan; Request for Comments, 

Companies can use metrics as a tool to help drive positive change and quality process improvements.

The Meaning of Metrics

Investigating deviations is an important element in cGMP compliance. Well-conducted and documented investigations are crucial to any company's manufacturing operation. There are numerous training classes and seminars intended to demonstrate how to conduct proper and thorough investigations. Even with all that is available, there remains an overuse of "human error" attributed as the root cause. This overuse represents lost opportunities to reduce future issues by identifying the true root cause of a deviation.  Herein is the human error in Human Error. The question that needs to be asked during the initial investigation into a deviation is what caused the employee to make the human error? Asking this question early in the investigation leads to better root cause identification and opportunities for continued improvement. 

How is the use of "human error" reduced as a root cause of issues? There are three key elements required to effectively minimize human error as a root cause behind a deviation: well-written and concise documentation (e.g., SOPs and batch records), effective training on those procedures, and appropriate performance execution of the steps. When these elements are in place and functioning then use of human error, as a root cause, should be few and far in-between. Looking at each of these elements in more detail to ensure they meet their purpose may help companies get to the real root cause of an issue instead of just dismissing an event as human error. 

Documentation is intended to outline in a concise, understandable manner a recurring set of instructions that, if performed properly and in order, should yield a predictable outcome. These instructions should be written in a clear and succinct manner with enough detail so the operation being described can be successfully executed by trained individuals. All documents associated with an activity need to be synchronized so the information is consistent between documents. For example, SOPs may contain sampling instructions but master batch records indicate when samples should be taken. The instructions between the two documents should not be ambiguous or contradictory. In addition, subjective text such as words like "immediately" should be avoided. Instead of using the word "immediately," the instructions should define the elements needed for the task to be performed appropriately. It is also important to write the instructions for the intended audience. In some cases, the work force may be educated in the English language, although it may not be the primary spoken language. Avoiding coloquial and slang terms will help to ensure all employees understand the instructions. 

Once document content is established, employees performing the function described must be properly trained. Thorough training of an employee should be a multiphase approach. Initially, the employee should read all the related documents defining the task and ask any questions they may have of their supervisor. Once the trainee has comprehended the written documentation, they should be partnered with an experienced employee. Many companies stumble at this step in the training department because they often just partner the new employee with the most convenient experienced employee without giving much thought to whether the experienced employee has the capability to properly train another in their area of expertise. Companies should spend time assessing which of their experienced people have the skill set and patience to teach an activity to a trainee. The supervisor should also remain in the loop through this phase of the training to help emphasize the importance of the activity in the manufacturing of the product. The supervisor and the designated trainer must both agree when the trainee is comfortable performing a function without constant supervision. When employees are properly trained and understand the activity they are performing, they are less likely to make a mistake.  

After the control documents are established and the employees are appropriately trained, the employees needs to monitor their own performance to the standard set during the training. The process for monitoring performance should include the use of metrics. The metrics might include tracking how often deviations are written for a particular operation or on a particular employee. The analysis of this data could lead to poor documentation or poor training as a root cause instead of "human error". In addition to metrics, the process should also provide a feedback loop where the employee (old or new) has an opportunity to identify areas of improvement in both the documents and the training. When control documents are revised, it is important to retrain the employees on the change and make sure they modify their behavior to be in line with the new instructions.  

Occasionally assigning human error as the cause of a deviation is valid if an employee simply made a mistake. However, other possibilities for the deviation should be exhausted before human error is attributed as the root cause. By using appropriate metrics, having clear and concise instructions, conducting detailed training, establishing performance feedback mechanisms, and using appropriate root cause analysis tools, a more precise root cause can be assigned and continuous process improvement can be achieved.  

is vice-president of quality and regulatory affairs at Allergy Laboratories, Inc. and is a member of the 

A thorough investigation of all possible causes of deviations should be performed.

The Human Error Behind Human Error

The relationship between a client and a contract provider is important and complex. At the recent PDA/FDA Joint Regulatory Conference, held Sept. 10–12 in Baltimore, participants were treated to an in-depth look at this multifaceted alliance.  

E.J. Brandreth, vice-president of quality and regulatory affairs for Althea, offered a CMO's perspective of this relationship. In his presentation, Brandreth stressed the significance for a contract provider to be as knowledgeable and up-to-date on the application and interpretation of the regulations as the drug product sponsor. He educated the audience on various sources that contract providers use to establish robust processes that meet the needs of providing safe medications for multiple clients who have products ranging from Phase I to commercialization. These sources include guidelines and reports from PDA, the International Conference on Harmonization (ICH), the US Pharmaceopeia (USP), and 

. He also raised a thought-provoking concept: that reputable CMOs have some of the most robust and compliant systems because of the frequency that clients and regulatory agencies—both domestic and foreign—audit them. Although time-consuming, these audits allow contract providers to benchmark against best practices and the cumulative knowledge of the auditors. Brandreth's presentation also discussed the ideal relationship between the two parties as one in which the CMO and sponsor work together to achieve success. Ultimately, a CMO needs to think of itself as an extension of the sponsor.  

CMOs are acutely aware of the concerns of their sponsors because they are documented through audit observations, but it is not often that the complaints of CMOs are voiced. Brandreth eloquently brought to light the biggest complaints of the average CMO: unrealistic timelines, skipping engineering runs, and trying to overcome major scientific limitations during the knowledge-transfer process. Finally, Brandreth unified the client–contract provider relationship by noting that both parties face the same emerging issues, including glass delamination, weak investigations, and insufficient corrective and preventive action programs.  

Christopher Masterson, senior director of quality for Cubist Pharmaceuticals, spoke as well, from the point of view of a contract provider. He shared with the PDA/FDA audience the problem that there are too many immature client–provider relationships. He iterated the numerous contract services available today, including providers for cell banks, drug substance manufacturing, drug product manufacturing, R&D, test laboratories, labelers, and distributors.  

There has been much discussion in the industry that guidance on client–provider relationships is needed. In his presentation, Masterson pointed out that guidance does exist and cited a little-known regulation that currently addresses contract facilities: 21 

 200.10. This regulation states that FDA "regards extramural facilities as an extension of the manufacturer's own facility." Additionally, the regulation goes on to say, 

 "The Food and Drug Administration reserves the right to disclose to the pharmaceutical manufacturer...any information obtained during the inspection of an extramural facility having a specific bearing on the compliance of the manufacturer's, applicant's, or sponsor's product with the Federal Food, Drug, and Cosmetic Act." 

Based on this regulation, Masterson provided concrete examples of some activities the client–service provider should consider in its relationship to demonstrate compliance to this regulation. Some suggestions include visits with the service provider (beyond the traditional annual GMP audit), establishing key performance indicators, participating in material-review board meetings as needed, performing joint investigations as needed, and sharing issues through regularly scheduled business review meetings. Masterson demonstrated the success of this approach by sharing some case studies in which the client and service provider worked together to turn potentially negative situations into positive outcomes. He concluded his presentation by advising the audience to use data, science, and logic to solve problems and that the goal of the client–provider relationship is "not to think alike but to think together."  

Allan Coukell, director of the Medical Programs Pew Health Group at The Pew Charitable Trusts, provided a global perspective on this issue. He pointed out that outsourcing has grown exponentially over the past 10 years, complicating the already complicated pharmaceutical supply chain. In discussing this complexity, he brought to light some disturbing facts, including  that FDA 483 observations to contract manufacturers have risen over the past three years. In addition, Coukell noted that "FDA has expressed concerns about deficiencies in supplier qualification programs and quality agreements and that current regulations do not require companies to assess supplier plants before purchasing ingredients from them, or to visit the plants at any time to ensure quality standards are in place." He further highlighted the steps being taken to address this gap in regulations through the passage of new laws such as the 2012 FDA Safety and Innovation Act (FDASIA) and Generic Drug User Fee Amendment (GDUFA). He also complimented industry on some of its initiatives aimed at resolving supply-chain issues, including the efforts of Rx-360 (the international pharmaceutical supply chain consortium), EXCiPACT (a voluntary international scheme to provide independent third-party certification of manufacturers, suppliers, and distributors of pharmaceutical excipients worldwide), and International Pharmaceutical Excipient Auditing (IPEA), which also provides third-party audits through a shared audit program and ANSI accredited certification program. 

It is important for industry to understand and work to improve their client–service provider relationships. Such re-evaluations make both sponsors and CMOs more effective in achieving the goal of improving public health and safety.  

 is vice-president of Quality and Regulatory Affairs at Allergy Laboratories, Oklahoma City, OK 73109. Tel. 405.235.1451,  

Key talks from the recent PDA/FDA regulatory conference highlight room for improvement.

Advice for Enhancing the Client–Sponsor Relationship

 in 1977, many regulatory and compendial initiatives have transformed the way the industry does business not only in terms of global partnerships and supply chain management, but also in the laboratory and on the manufacturing floor. PharmTech's reports and special-themed issues have offered invaluable guidance and interpretation to the industry over the years when new standards and guidances are released. Some of the events and issues discussed in this publication have had long-term impact with respect to how the industry operates today. This roundup article highlights some of the organizations and key influential events that have shaped the pages of PharmTech and the way our industry works.   

Tamper-resistant packaging regulations (1983). 

In September 1982, several deaths resulted from cyanide poisoning in Chicago, IL, and its suburban area. The investigation determined that the common denominator between the victims was taking Tylenol. Johnson & Johnson, the manufacturer of Tylenol, was ruled out as the source of contamination but on Oct. 5, 1982, the company issued a nationwide recall of an estimated 31 million bottles. This incident prompted the passing of tamper-resistant packaging regulations, which made it a felony to tamper with packaged consumer products. The industry developed standards for tamper-resistant packaging that are still used today.  

The Orphan Drug Act was passed in 1983 to encourage pharmaceutical companies to develop medicines for patients with rare diseases. Companies were given 7 years of exclusivity and tax incentives for pharmaceuticals that qualified for orphan-drug status. This act has lead to the successful treatment of or medical management of diseases such as multiple myeloma and cystic fibrosis. Before this law was passed, there were approximately 38 drugs approved to treat rare diseases. From 1983 to 2010, FDA approved 353 orphan drugs and granted orphan designations to 2116 active compounds.  

The generic-drug scandal began when a generic-drug manufacturer submitted a complaint to regulators after experiencing repeated delays in approval of its ANDAs. The complainant charged that FDA was discriminating against the generic-drug firm in favor of other companies. Three FDA officials plead guilty to accepting bribes from companies and two companies plead guilty to offering bribes to FDA officials. Ultimately, 13 generic-drug manufacturers were investigated for fraudulent practices and several products were recalled. This incident resulted in an increase in requirements for ANDA submissions. Today, about 65% of the prescriptions written are for generic-drug products, but it has taken this segment of the industry about two decades to recover from the 1989 scandal.  

The Barr decision was the direct result of FDA investigations into questionable quality control practices for the handling of out-of-specification (OOS) results. FDA took Barr Pharmaceuticals to court for the perceived practice of testing products into compliance. Judge Wolin of the US District Court for the District of New Jersey presided over the proceedings. The result of the Barr decision changed the practice of how manufacturers' investigate laboratory results that do not meet specifications, and on how the industry determines whether a product meets it quality attributes.  

In late 2006, a leading pharmaceutical company recalled several lots of life-saving heparin after receiving numerous reports of adverse events, namely allergic reactions. The company ceased production of the product and began investigating the cause of the incidents. Approximately one month later, FDA issued a Public Health Advisory to the medical community, warning the public and healthcare providers not to use heparin. The company recalled all lots of the product, which was ultimately linked to more than 350 serious adverse reactions and several patient deaths. Contaminated API supplied by a manufacturer in China caused the reactions. This incident impacted the industry because it expanded the definition of supply chain and made companies responsible for the quality of all the ingredients going back to their root source, which in some cases turned out to be several layers deep. New focus was given to the importance of supplier audits, and several trade organizations began focusing on developing third-party audit capabilities to assist the industry in dealing with the vast amount of suppliers sourcing material to the pharmaceutical industry. The incident, for example, spawned a new trade organization, Rx–360, an international supply chain consortium, and redefined the concept of supply chain integrity. 

In February 2012, FDA issued three draft guidance documents regarding biosimilars

 The agency announced that "the draft documents are designed to help industry develop biosimilar versions of currently approved biological products, which can enhance competition and may lead to better patient access and lower cost to consumers."  These documents opened the door to generic-drug products in an area where there has been little competition to innovator products.  

The US Pharmacopiea (USP) was established in 1820 and is the oldest continuously revised compendia in the world. The standards and information published by USP are recognized as the legal standards by FDA and by regulatory authorities in other countries that have voluntarily adopted them. This compendium contains monographs for excipients, APIs, drug products, biologics, biotechnology products, general test procedures, and general information all of which govern the strength, quality, purity, and potency of medicinal products marketed in the US.  

USP has a history of impactful events but none have been more significant than its efforts to harmonize monographs with its counterparts, the European and Japanese Pharmacopoeias (

, respectively). The harmonization process began in 1989, when representatives of the three pharmacopeias met with industry representatives in an open forum to discuss the need to harmonize like procedures to reduce the regulatory burden on pharmaceutical companies. Prior to harmonization efforts, companies were required to meet the specifications in the governing pharmacopeia for the region of the world where they wanted to market their product. To accomplish this goal, the three pharmacpeias established the Pharmacopeial Discussion Group (PDG) and developed a 7-step process for unifying monograph requirements. Under this model, more than 100 items have been harmonized. The efforts to harmonize monographs continue today.  

USP introduced stakeholder forums in 1999, and the events became an officially recognized component of the USP family by vote at the 2005 USP Convention. Stakeholder forums allow for a free interchange of ideas between USP and industry trade organizations. The Prescription/NonPrescription Stakeholder Forum is the most active bi-annual meeting with USP. Among the participating organizations are IPEC, PDA, the Midwestern Compendial Discussion Group, and the Western Compendial Discussion Group. Through PDG, several USP initiatives have been implemented across the industry with little or no disruption to compliance. An example is the collaboration to implement the residual solvents standard, which took effect in 2008. 

The pharmaceutical industry has long recognized there is more than one way to synthesize an API and that the impurity profile for the ingredient is dictated by the specific route chosen. To accommodate impurity profiles based on the route of synthesis, USP started adopting multiple impurity methods to ensure all manufacturers of an API or the subsequent dosage form are able to reference the USP standard. These are identified and "Method 1," "Method 2," and so forth in the monograph. This practice has provided pharmaceutical manufacturers flexibility and sourcing alternatives for their products. 

During the past decade, USP has changed its mission statement to indicate that it wishes to "improve the health of people around the world through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods." Its current vision is "...to be a leader in promoting the public health by creating a unique knowledge base—consisting of quality standards and information on proper use—for medicines and related products and practices. USP will ensure that people throughout the world have access to this knowledge base." USP has opened offices in Switzerland, India, China, and Brazil. In addition, at the USP 2010 Convention, the organization passed Resolution 4, which deals with supporting and advancing global public-health initiatives. USP is also expanding its role in India and China and exploring relationships with the Association of Southeast Nations and Middle East and North African nations.  

The International Conference  on Harmonization (ICH)

In this author's opinion, the establishment of ICH has had the most influence on the pharmaceutical industry. The first ICH meeting was held in 1990 and the body of work produced by this organization and its impact on the industry is staggering. ICH's work has changed our language and established global stability requirements, and GMPs for APIs, and laid the foundation for the modern quality system. 

ICH Q2 Validation of Analytic Procedures (1994). 

This document established validation requirements for analytical tests, including identifications, quantitative impurities, controlled impurities, and active moiety. It standardized industry terminology for the various parameters needed for validation, including definitions for specificity, accuracy, precision, repeatability, linearity, robustness, and reproducibility.  The EU, MHLW, and FDA adopted the document and it continues to define how the industry approaches analytical methods validation. 

This document provided the first comprehensive GMPs for APIs. It touched on everything from the necessary quality management to personnel qualifications to the design and construction of the buildings and facilities. Adopted by the EU, MHLW, and FDA, it serves today as the gold standard for API manufacturing requirements. 

ICH Q10 Pharmaceutical Quality System (2008). 

Adopted by the EU, MHLW, and FDA, this harmonized guideline was the first to define the modern quality system and to discuss how it should be integrated into all aspects of the pharmaceutical business. The document recognized that Quality should not be a stagnant policing organization but a vibrant organization concerned with "continual improvement of process performance and product quality throughout the product lifecycle." It openly discussed management responsibility and challenged the industry to consider that management of outsourced activities was a crucial element of a quality system. The impact of this document on the industry is still being discussed at conferences, and companies are implementing many of its requirements. 

ICH Q11 Development and Manufacture of Drug Substances (2012). 

Released in May 2012, this guideline has only been adopted by the EU to date. Q11 describes approaches to developing and understanding the manufacturing process of the drug substance, and offers guidance on what related information should be included in the Common Technical Document (CTD). The impact of Q11 is currently unknown but this author is sure it will follow the tradition of the other ICH documents. 

As outlined herein, there have been rnage several changes in the pharmaceutical industry during the 35 years that 

magazine has been in existence. A broader industry timeline is contained within these anniversary pages as well. Let's hope the next 35 years are as exciting and successful as the past 35.  

How FDA, USP, and ICH have redirected industry practice.