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

Susan J. Schniepp

	Susan Schniepp, distinguished fellow, and Andrew Harrison, chief regulatory affairs officer and general counsel, both of Regulatory Compliance Associates, discuss performing investigations of biological products.

	Q: I work for a contact manufacturing organization that manufactures traditional and biotech pharmaceutical products, and I am responsible for performing investigations and reporting the results to our clients. It would help me perform my job better if you could tell me the difference between performing investigations for a biological product vs. a traditional pharmaceutical product?

	A: The short answer is there is no process difference when performing deviation investigations for traditional pharmaceutical products vs. biotech products. The differences lie in the complexity of the manufacturing processes and thus the variables that need to be considered regarding what could have impact on the deviation. Chemical process, although sometimes quite complex, often have fewer variables even though many of the categories are the same. For instance, when investigating an unknown impurity in a biological process from a simple oligopeptide fermentation process, the considerations may include fermentation conditions (e.g., time, temperature, oxygen uptake, byproduct production), potential contamination of reactants including master cell banks and fermentation reagents, equipment integrity, and performance. Further considerations for the downstream purification process variables and the effect of a final configuration (e.g., folding) also need to be considered.

	The purpose of performing an investigation into a deviation is to determine why the deviation happened and what its impact was on the product quality. To determine the impact of the deviation on the product quality, it is important to determine the ‘root cause’ of the deviation. The process used in the industry to determine root cause is, of course, the investigation procedure. This procedure, regardless of whether the product you are investigating is biotech or traditional, should require the investigator to review various systems and determine whether they were the cause of the deviation being investigated.

	It is important to remember when performing an investigation to keep in mind a few general rules. Remember, one size does not fit all. Simple errors require simple corrections while serious deviations require broader investigations. The complexity of the investigation is related not only to the seriousness of the investigation but also to the complexity of the factors that could influence the outcome.

	The best tool to have during any investigation is inquisitiveness. Continuing to ask questions and avoid assumptions will lead to a better outcome. Using other tools, such and fishbone diagrams and determination of most probable number (MPN), are to be encouraged but they do not take the place of asking questions. In performing an investigation, it is important for the investigator to widen their perspective and look for ways to relate similar issues. The best way to ensure events are not related is to try and relate them, not the other way around. Keep in mind that human error is rarely a true root cause. There is usually something in the process that causes that human error.

	And finally, always verify the facts of the investigation. It is also important to include a historical review. This review should determine if the deviation occurred with this or other products, with the specific manufacturing line or other manufacturing lines and/or with the operators or other operators. The historical review can help you prioritize the resources and your detailed system review. In addition, some companies make use of tools (fishbone diagram, MPN) to help prioritize resources. These tools, if used correctly, can be helpful in determining root cause but remember, they are just tools and do not take the place of thinking.

	The detailed investigation should include a review of various systems. The systems most often reviewed are equipment and machinery, the manufacturing process, the raw materials used in manufacturing, the specifications, the environment, and finally, the operators. This is not to imply that these systems are the only areas you should look at during the investigation but that these are the most probable areas where you will uncover the root cause of the deviation. Each investigation must address the following elements: root cause, impact to the material or product, the immediate correction taken, the corrective action to prevent re-occurrence for specific product/operation, and the preventive action taken to prevent re-occurrence for all products/operations.

	Once these elements have been investigated, results from the investigation must be documented. The written narrative should clearly explain what happened, when it happened, and who was involved or observed what happened. The narrative documents the solution and rationale for the root cause that was determined through the investigation process.

	The key to any successful investigation is not stopping too soon and assuming you have the solution prior to completing the investigation. Ask questions until you can think of no more questions to ask and be sure to document the answers to your questions.  If you follow your investigation procedure and thoroughly document your results, you should have an acceptable investigation regardless of whether you are manufacturing a traditional product or a biotech product.

 When referring to this article, please cite it as S. Schniepp and A. Harrison, “Investigating Biologics,” 

Articles

Susan Schniepp, distinguished fellow, and Andrew Harrison, chief regulatory affairs officer and general counsel, both of Regulatory Compliance Associates, discuss performing investigations of biological products.

Investigating Biologics

	The long awaited, anxiously anticipated FDA guidance on quality metrics was finally distributed for comment on July 28, 2015. The official title of this guidance for industry is 

Request for Quality Metrics, Guidance for Industry

 (1) and its potential release has been looming on the horizon since 2012.

	The intent of FDA to establish quality metrics first emerged in 2012 when Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA) enhancing FDA’s capability to proactively react to, prevent, and alleviate 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.” 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…” (2).

 Notice (3), 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?”

	After a few years of actively engaging and listening to industry in a variety of venues, this new guideline has finally been released.

	The metrics proposed in the guideline are not new to the pharma industry. Many of them are currently being used by companies to internally measure performance. In some cases, the specified metrics are also reported to the agency via the annual report or are contained in the annual product review. The bio/pharma industry needs to review these metrics and ensure they will provide meaningful data while avoiding unintended consequences.


	The underlying and understated tenet 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. The best way to ensure the data reported has merit is to assess the quality culture of the submitting organization. It is in this area that the new guidance lacks clarity. The guidance leaves the opportunity open to establish quality-culture metrics by stating, “these metrics are not intended to be an all-inclusive set of the quality metrics that FDA could consider useful to assess a product and manufacturer’s state of quality. For example, senior management commitment to quality is an important factor in evaluating the overall health of the PQS [pharmaceutical quality system] and quality culture” (1) and “…the Agency is committed to a dialog with industry to consider benchmarks and standards that could provide acceptable metrics that specifically demonstrate senior management’s commitment to a culture of quality …” (1). This commitment to establishing quality culture metrics is further evidenced by the section in the guideline titled “Optional Metrics Related to Quality Culture and Process Capability/Performance”. In this section, FDA “acknowledges the importance of quality culture to the overall state of quality of the product, process, and commitment to quality” (1).


	FDA proposes three voluntary metrics to try to get at the elusive quality culture. The first optional metric proposed is intended to measure senior management engagement by assessing whether the head of the quality unit and the head of the operations unit have signed the annual product review (APR) or product quality review (PQR). The second optional metric proposed is corrective action and preventive action (CAPA) effectiveness. The measurement for this metric is to indicate the percentage of corrective actions that required retraining of personnel, the assumption being that the root cause of the original deviation (real or due to insufficient analysis) was determined to be insufficient or ineffectual training. The third proposed metric is intended to measure a firm’s process capabilities through a series of three questions. The real question should be if these three optional metrics, taken together, shed any light on the quality culture.

	Management engagement. 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. Assigning the head of quality and the head of operations the task of signing the APR or the PQR does not ensure management engagement nor does it mean that the quality culture is lacking. It is up to an organization to establish the appropriate level of responsibility and signing authority for APR and PQRs. It is up to senior management to provide the people charged with these activities the necessary resources to complete the task in a timely manner with the expectation that they will be held accountable for the contents.

	Retraining personnel. The second optional quality culture metric is specific to CAPA. The proposed metric is to report the percentages of corrective actions involving the retraining of personnel. Without context supporting the retraining of personnel, this metric does not offer insight into the true culture of an organization. It could be argued that any CAPA that results in a reduction or elimination of a recurring deviation would require an element of training personnel. In fact, retraining of personnel on the CAPA issue, how it was solved, and how to implement the necessary change is evidence of management engagement. It should be expected that a majority of CAPAs involve some retraining of personnel.

	Critical quality attributes. The third quality-culture optional metrics involves trying to use critical quality attributes (CQA) as a key indicator of a quality culture. Of the three optional metrics proposed, this one does provide some measurement of the existence of a quality culture. On the surface, the questions just seem to be a regurgitation of information contained in the APR or PQR. Upon closer evaluation, however, it is clear that FDA is trying to measure whether a company drives for continuous improvement through their review and assessment of threshold levels established with CQAs. Companies that have established CQAs and linked them to a requirement to issue a CAPA when they exceed the established threshold levels have demonstrated a commitment to continuous improvement. Continuous improvement programs are, in fact, reliable indicators of the presence of a quality culture.


	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. The problem is that it is difficult to measure something as intangible as culture with cold, hard data. The remaining question is: If taken together, are the three proposed optional metrics indicative of a quality culture? The answer is, maybe.

	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 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, 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.

	Upon observation, 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. 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 employees’ 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. Metrics that could potentially be used to measure a healthy quality culture include a small employee turnover, deviations that identify a root cause other than human error, and pride in the performance of their jobs.


	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.

	There is no set requirement on which 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.

	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.

Request for Quality Metrics Guidance for Industry

, (Rockville, MD, July 2015).
	2. The Food Drug Administration Safety and Innovation Act, Pub. L. 112-144, 126 Stat. 993 (2012).
	3. FDA, “Food and Drug Administration Drug Shortages Task Force and Strategic Plan; Request for Comments” (

:
	When referring to this article, please cite it as A. Harrison and S.Schniepp, "The Metrics of Quality Culture," 

FDA’s proposed guidance for quality metrics raises questions about quantifying the tangibles and intangibles of quality culture.

The Metrics of Quality Culture

	Susan Schniepp, Distinguished Fellow, and Andrew Harrison, Chief Regulatory Affairs Officer and General Counsel, both of Regulatory Compliance Associates, discuss the requirements for a successful corrective action and preventive action (CAPA) system.

Q. I work for a contract manufacturing organization and am responsible for hosting audits and preparing the responses to the observations. I have received multiple comments on my CAPA system from many groups, many with different perspectives. What are the real requirements for a successful CAPA system?

	A. You can take comfort in the fact that you are not alone in this predicament. We consider investigations to be the cornerstone of any CAPA system and based on the data in the FDA database, in Fiscal Year (FY) 2014 25% of the FDA 483 citations issued were for inadequate, incomplete, and undocumented investigations (1). For some reason or another, the industry tends to focus on the immediate correction to the non-conformance, resulting in a failure to investigate and execute the corrective and preventive actions of the CAPA system in an effective and timely manner. Basically, we need to view CAPAs as improvements we make to our processes and procedures to eliminate non-conformances in our products. These improvements are based on the results of the investigations into the non-conformance for root cause. Once the root cause is determined, then a corrective action is identified and implemented into the process. The change is then monitored during a period of time to determine if the proper root cause was identified and if the corrective action was effective (i.e., effectiveness check). In some cases, the root-cause analysis may reveal a potential for an objectionable situation to occur resulting in compromised product. The solutions chosen to avert predicted non-conformance are preventive actions.

	The key to any CAPA system is the initial investigation into the non-conformance to determine the root cause. However, not all investigations are the result of a non-conformance and not all investigations will result in a CAPA. It is important that the investigation be thorough and complete before the CAPA is initiated and implemented.

	The investigation process should make use of root cause analysis tools designed to examine the impact of various process inputs and their effect on the non-conformance. These tools examine the impact of the equipment, process, people, materials, environment, and management on the identified non-conformance. In some cases, depending on the nature of the non-conformance, some areas can be eliminated as having no impact. The rationale for elimination, however, should be documented. As the elimination process progresses, the investigation will naturally and logically hone in on the root cause(s) of the non-conformance. Once this is completed, the actual CAPA can begin.

	If we look at the CAPA system as an expressway, the immediate correction and the investigation are the on ramps, the corrective and preventive actions are the lanes, and the effectiveness checks are the off ramps. The immediate correction and investigation into that occurrence should determine if the non-conformance is a one-time occurrence or if it has happened before. If the non-conformance has happened before, the investigation needs to be conducted to determine the underlying root cause of the non-conformance. Once the root cause has been determined the corrective action and the preventive actions can be implemented and monitored. If the non-conformance does not recur in a specified time frame, the corrective action/preventive action is considered effective and the CAPA can be closed.

	The bottom line is there are many perspectives on what constitutes a good CAPA system, but the reality is the quality and thoroughness of the investigations ultimately drive the effectiveness of the CAPA. When conducting the investigation, it is important not to jump to conclusions on what caused the non-conformance. The investigation should use root-cause analysis tools and should address why potential areas are either eliminated as the root cause or are a potential cause of the non-conformance. If you can conduct a complete investigation, you will ultimately have a robust CAPA program.


	Vol. 39, No. 8â¨
	Page: 78
	Citation: When referring to this article, please cite it as “Defining Crucial CAPA Components,” 

Susan Schniepp, distinguished fellow, and Andrew Harrison, chief regulatory affairs officer and general council, both of Regulatory Compliance Associates, discuss the requirements for a successful corrective action and preventive action (CAPA) system.

Defining Crucial CAPA Components

 “Linking Drug Shortages and Quality Metrics” provided information regarding the link between drug shortages including the enactment of the Food and Drug Administration Safety and Innovation Act, FDA’s efforts to develop a common set of quality metrics for the pharmaceutical industry, the effort of the industry to establish and maintain quality metrics capable of measuring the suitability of pharmaceutical products for the patient, and the capability of the manufacturer to consistently provide these products without delay. At the time the article was published, there was little practical guidance available to the industry that discussed and recommended potential strategies and tools that could be used by manufacturer’s to predict and avoid drug shortages. 

	In December 2014, the Parenteral Drug Association (PDA) published 

), “Risk-Based Approach for Prevention and Management of Drug Shortages,” which provides the bio/pharmaceutical industry with appropriate tools for preventing drug shortages.

	PDA technical reports, authored and peer-reviewed by PDA members, are intended to offer practical guidance on pertinent regulatory and scientific topics that affect the global pharmaceutical industry. Members with expertise in manufacture and quality assurance for sterile biopharmaceutical and pharmaceutical products (the majority type of products subject to drug shortages) authored 

. Although PDA technical reports are not officially recognized guidance, they are often referenced by regulators and regulators may be involved in the writing or approving of the report contents.

 addresses the drug shortage issue from a global perspective and offers relevant, proactive advice applicable to the global pharmaceutical industry. In addition, the paper recognizes several contributing factors potentially responsible for drug shortages: manufacturing issues, quality issues, and supply chain or distribution issues. This is important because 

 recognizes that the issue of a potential drug shortage goes beyond the quality department within an organization.


	The document provides a common language for the industry to use when discussing drug shortages. It is this author’s opinion that it is always important when authoring potential global guidance to establish a common language for the readers. 

 accomplishes this objective by placing a glossary at the beginning of the report and references, when possible, existing definitions from recognized, credible sources. The definition for “harm” for example, is taken verbatim from the International Conference on Harmonization’s (ICH) Q9 guideline, 

. The definition of knowledge management is taken from ICH Q10 

. Using previously established definitions helps the global users of TR68 understand the context and relationship of this document within the regulatory framework of the industry. 

	Once a common language is established, it is easier for a document user to relate to the narrative portion of the document. The narrative of the technical report describes how the issue of drug shortages is global in nature and delineates current global regulatory and legal reporting requirements applicable to manufacturers when facing issues that may result in drug shortages. These issues are not limited to final product manufacturers but may involve suppliers of raw materials crucial for product formulation.

describes how a supply-chain issue, a shortage of acetonitrile in 2008-2009, can prompt a drug shortage. The document discusses how multiple suppliers were unable to provide acetonitrile to the industry because of a series of unforeseen circumstances. This shortage impacted the ability of companies to manufacture APIs that then impacted the manufacture of the final drug product.

	The document is designed to guide bio/pharmaceutical companies in the assessment of the risk of experiencing a drug shortage. 

 uses a risk triage model to collect and assess existing organizational information to determine drug-shortage risk. The model builds on the concepts of management responsibility, supply chain management, quality risk management, knowledge management, regulatory requirements and a company’s compliance history and treats them as integrated interrelated disciplines within an organization.

	The examples included in the document provide templates to combine a company’s information into a comprehensive set of tools that not only measure the potential for a company to experience a drug shortage, but also identify and delineate gaps in organization structure that may exist in quality systems.;

	The document takes the aforementioned concepts and provides a framework for capturing the information in one inclusive document. The completed document can be used as a tool to share within an organization or with clients in determining potential process improvements or necessary resources required to address systemic process gaps.

 can be used in part or in total by raw material and API suppliers, contract manufacturing organizations, and pharmaceutical companies to assess and manage organizational, manufacturing, and quality issues that could contribute to a drug shortage. The document provides tools to predict and hopefully prevent drug shortages in the future.

	The PDA report authors are Emabelle Ramnarine, Genentech; Maik Jornitz, G-CON Inc.; Michael A. Long, Concordia ValSource; Kevin O’Donnell, Health Products Regulatory Authority; Stephan Rönninger, Amgen; Christopher Smalley, Merck Sharp & Dohme; and Anders Vinther, Sanofi Pasteur. The report is available on 


	Susan J. Schniepp is a fellow at Regulatory Compliance Associates, Inc.

PDA’s new technical report provides a template for bio/pharma companies to follow to establish a risk-based approach to prevent drug shortages.

Risk-based Strategies to Prevent Drug Shortages

: When referring to this article, please cite as S. Schniepp, “Tools of the Trade for Preventing Drug Shortages,” 

A new technical report guides bio/pharma companies in establishing a risk-based approach for prevention and management of drug shortages.

Tools of the Trade for Preventing Drug Shortages

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.

Industry players and FDA evaluation possible quality metrics to improve manufacturing efficiencies and avoid drug shortages.