Andrew Harrison is chief regulatory affairs officer and general counsel with Regulatory Compliance Associates.

Andrew Harrison

	Susan Schniepp, distinguished fellow, and Andrew Harrison, chief regulatory affairs officer and general counsel, both of Regulatory Compliance Associates, discuss requirements for successful product technology transfer.

Q: My company is preparing to transfer in a new product to one of our manufacturing facilities. Previous product technology transfers have not always gone smoothly. How can I ensure that this transfer goes well?

 This is a great question and frequently asked. It is important to understand the requirements for a successful technology transfer because its concepts are used when transferring product from a research environment to clinical trial manufacturing, a clinical-trial manufacturer to a commercial-product manufacturer, between company facilities, and/or to a contract manufacturer.
	
	Let’s say that Company A wants to outsource the manufacturing of product to Company B, a contract manufacturer. Company B cannot perform all of the necessary testing associated with the product manufacturing and release, and they need to contract out some of the testing to Company C. In this case, the technology transfer would involve three parties who will need to be included in the technology-transfer process. The questions to answer for a successful product transfer become: who needs to know what to have a successful technology transfer?; how do we maintain open lines of communication between all the involved parties?; and how does this all get managed?
	
	It is important for all parties to be engaged in the technology-transfer process, and because technology transfer can mean different things to different people, one of the first steps in the process should be to establish a common understanding of terms and definitions between all the parties involved. Without a common understanding and/or language, the technical-transfer activity can become confusing, frustrating, and ultimately, unsuccessful.
	
	The Pharmaceutical Research and Manufactures of America’s Quality Technical Committee developed a good definition for technology transfer in 2003. They defined technology transfer as, “The body of knowledge available for a specific product and process, including critical-to-quality product attributes and process parameters, process capability, manufacturing and process control technologies, and quality systems infrastructure” (1). The objective of technology transfer is to impart knowledge that will allow for smooth, continuous manufacturing of the product regardless of its stage in the product lifecycle. This knowledge includes not only what works but also what hasn’t worked.
	
	Once a common understanding is established, the best way to ensure that you have a successful technology transfer is to maintain open lines of communication and develop a timeline that defines when crucial steps in the transfer will be performed. When any of the parties stop communicating or cease to share information, then the technology transfer will fail. It is important for all parties to maintain open communications through the technology-transfer activity. The following six basic concepts should be kept in mind to ensure a smooth technology transfer:

		Robust information exchange. Without a robust and transparent exchange of information the technology-transfer activity has the potential to be frustrating and delayed while people try to find a common understanding and locate necessary information crucial to the success of the activity.

		Planning and project management. By having a good plan and project management tools, the technology transfer is more likely to be completed on time. Establishing realistic deadlines and scheduling the work to meet those deadlines will, again, contribute to a successful technology transfer experience.

		Transfer of analytical assays. It is important to make sure all analytical methods are transferred and that the methods are validated. This helps ensure that the transfer was done correctly and that the site receiving the information can produce the product and analyze it without significant problems arising.

		Small-scale verification at the receiving site. This activity helps keep the project on track. If the small-scale verification can be performed successfully, it is an indicator that the scale-up will go smoothly.

		Pre-GMP engineering runs are desirable. These are not necessary but are desirable because they assure that the equipment being used is functioning properly.

		GMP runs. This is the final step in the process validation and is necessary to confirm that the technology transfer was successful.

	
	Many regulatory authorities reference the concept of technology transfer in their respective regulatory frameworks. Volume 4 of the European Union’s 

Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use

 makes multiple references to technology transfer (2). In section 1.2, it states that GMPs apply to technology-transfer activities. Chapter 4 of the EU guidelines requires “… written policies, procedures, protocols, reports and the associated records of actions taken or conclusions reached, where appropriate, for the following examples … Technology transfer …” Chapter 6 of Volume 4 has a section devoted to the technology transfer of testing methods. The last section of EudraLex Volume 4 that deals with technology transfer is Chapter 7 on Outsourced Activities. This section clearly states that there needs to be written material around technology transfer.
	
	FDA has chosen to address the issue of technology transfer in their guidance titled Contract Manufacturing Arrangements for Drugs: Quality Agreements (3). This guidance states that “A comprehensive Quality Agreement will provide specific terms related to the particular product or products involved” and “the Quality Agreement should include product/component specifications; defined manufacturing operations, including batch numbering processes; responsibilities for expiration/retest dating, storage and shipment, and lot disposition; responsibilities for process validation, including design, qualification, and ongoing verification and monitoring…”
	
	The bottom line is that to have successful technology transfer you need to have a common understanding and language, a way to manage the various steps and information that are crucial to the product, and you need to maintain open communications between all the parties involved in the process.


	1. G. Millili, “Scale-up & Technology Transfer as a Part of Pharmaceutical Quality Systems,” Pharmaceutical Quality System (ICH Q10) Conference, Arlington, VA, Oct. 4-6, 2011.
	2. EC,

 EudraLex, The Rules Governing Medicinal Products in the European Union, 

Volume 4, EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use.
	3. FDA, 

Guidance for Industry, Contract Manufacturing Arrangements for Drugs: Quality Agreements 

 When referring to this article, please cite it as S. Schniepp and A. Harrison, "Requirements for Product Technology Transfer,"

Articles

Susan Schniepp, distinguished fellow, and Andrew Harrison, chief regulatory affairs officer and general counsel, both of Regulatory Compliance Associates, discuss requirements for successful product technology transfer.

Requirements for Product Technology Transfer

Q. I work for a contract manufacturer, and I think we have a fairly robust corrective actions and preventive actions (CAPA) system. Sometimes we close our CAPAs before we have completed our effectiveness check due to the timeline needed to implement and measure the effectiveness of the preventive action. Occasionally, we fail our effectiveness checks, requiring us to reopen our CAPA. This creates a lot of concern during audits. Is there something I can do to prevent this from happening?


	
	A. The key to a robust CAPA system lies in the thoroughness and quality of the investigation. Based on the limited information, it sounds like you are having trouble recognizing the root cause(s) identified during the investigation. The investigation process should make use of root-cause analysis tools designed to examine the impact of the equipment, process, people, materials, environment, and management on the identified non-conformance. The investigation process should review each possible root cause; the investigators should either eliminate it or it should become part of the corrective action. As the elimination process progresses, the investigation will naturally and logically hone in on the root cause(s) of the non-conformance. Any potential root cause that can’t be eliminated needs to be remediated. Most companies make the mistake of stopping too soon and not pursuing all the possible root causes that can’t be eliminated in the investigation stage, which leaves them in the situation you have described.


	It might help if we look at a situation where a probable root cause was identified but not pursued as part of the preventive action. The incident involved the detection of a discolored vial during inspection of lyophilized vials. The vials inspectors discovered several green-hued vials before the packaging phase of the operation. What seemed to be a simple issue isolated to one batch grew and ultimately affected more than 28 batches produced over a two-month period. Several green-hued vials were discovered during inspection of a lyophilized batch of product that was produced on a 20-year-old automated line.

	The inspectors that discoved the vials immediately informed the quality department and an investigation was opened. The lot was put on quality assurance (QA) hold, and the vials were sent out for analysis. Manufacturing on the line was continued while the investigation was being performed. The results of the analysis indicated the green color in the vial was due to the presence of copper. The firm was unable to determine the source of copper in their operation and concluded the copper was most probably due to contamination of the vial at the vial manufacturer and the investigation was closed.

	Seven days after the detection of the first green vials during the manufacturing of a different lyophilized product, the same issue occurred. The original investigation was re-opened and a for-cause audit was performed at the vial manufacturer. The results of the for-cause audit were inconclusive with no definitive source of the copper identified. During the investigation into the vial manufacturer, the company continued to manufacturer other products and implemented a 100% inspection of incoming vials before use.

	Seven days later, a line operator noticed a vial exiting the depyrogenation tunnel that contained a green, gel-like blob in it. The manufacturing run was stopped, and the vial was retrieved and sent for analysis. The green gel was identified as containing copper. The company was still convinced that the contamination was due to poor quality control on the part of the vial manufacturer and continued operations and working with the vial manufacturer to determine the source of the copper.

	To help facilitate the investigation, the firm hired a consultant to go to the glass manufacturer and reaudit their facility. The auditor could not identify the source of the copper at the vial manufacturer and recommended that the company reevaluate their operations for the presence of copper. The company continued to manufacture product but agreed to reevaluate the facility for potential sources of copper.

	This time the facilities and maintenance personnel opened up the line as they would during a routine maintenance shut down. When they opened the depyrogenation tunnel, they discovered the presence of copper on the top of the HEPA filters as well as a coating of green on the side doors to the tunnel. Manufacturing was finally halted on the line until the in-depth evaluation could be performed.

	The root cause of the problem was determined to be a faulty cooling valve in the depyrogenation tunnel, which was identified as a potential root cause but ultimately not pursued because it was at the bottom of the probability list and rated as possible but highly unlikely. The tunnel in question was 20 years old and was bulit with copper piping above the line and the HEPA filters.

	Although the line was routinely maintained and checked, there was no alarm associated with the cooling valves to indicate a failure. The failing valve caused liquid to condense on the copper lines and drip onto the HEPA filters. As more and more liquid collected on the filters. the stress caused the filters to breach, relieving the pressure. This breaching happened on a predictable seven-day cycle. Ultimately, the incident involved the investigation of lots manufactured on the line over a sixth-month period, which was the last time the cooling valve was inspected and determined to be functioning to standards. Once the problem was properly identified, the effective corrective action could be taken; however, by that time, 28 lots of product manufactured for several different clients during the two-month period were rejected because of the presence of green vials intermittantly detected during the inspection process. If the site had conducted a thorough investigation and cleared their equipment, personnel, etc., by pursuing the identified root causes before jumping to the conclusion the vial manufacturer was at fault, they could have stopped manufacturing and corrected the problem before the loss of 28 lots of product.

	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.


	When refering to this article, please cite it as, S. Schniepp and A. Harrison, "Creating Robust CAPA Systems," 

Susan Schniepp, distinguished fellow, and Andrew Harrison, chief regulatory affairs officer and general counsel, both of Regulatory Compliance Associates, discuss how to create a robust CAPA system and how to identify root cause.

Creating Robust CAPA Systems

	Q.I work for a contract manufacturer and am in charge of the standard operating procedures (SOPs). During customer and regulatory audits, we keep being cited for inadequate SOPs. Can you give me some advice on what constitutes a well-written SOP?

	A. You are not alone. In 2014, “inadequate SOPs” was one of the top five most-frequently-cited FDA 483 observations. SOPs are one of the first items auditors review during inspections. SOPs need to reflect your operations and should not be written for regulators. SOPs should be written for your personnel to conduct operations with consistency and quality thus assuring regulatory compliance. Do not write SOPs because you think the regulations require them or for a process, procedure, or operation listed in the regulations that you do not perform. This will continue to lead to audit observations.


	So what are the characteristics of a good SOP? Effective SOPs are tailored to an organization’s design and needs and contain sufficient detail to allow personnel to conduct operations as management wants. If you have an experienced work force, you may need less detail. SOPs take into account who has the authority to make decisions and clearly define accountability (i.e., who per forms what actions). SOPs also provide guidance on what to do when things don’t go right; they delineate decision points and actions to take for each decision. SOPs define the outputs from each process (documentation, product), who owns the process, and identify other stakeholders for the process, which helps determine who requires training on the SOP. The SOPs also specify who needs to ensure the process is working and who initiates changes when needed.

	So what do you need to consider to write a clear, concise SOP with the right amount of information accurately reflecting your established processes? Keep your mind open to different various communication types. SOPs may use various presentation styles as a means of communicating the details of the SOP.


	The following are examples of presentation styles that you may want to consider using when writing your SOPs:

		Playscript (operator does “a” now and “b” next)

		Any combination of the above as long as personnel can follow the instructions.

	Determine the type of style and level of detail that is most effective for your personnel. Also, consider the predominant primary language (it may not be English) and general understanding level of your organization when writing SOPs. Depending on the make-up of the workforce, you may need to consider having dual-language SOPs, which might require translation expertise.


	Certain recommended elements should be included in SOPs. Remember, the format and content of SOPs are not defined by the regulations. Each company must establish the SOP format and content that accurately reflects their operations. The seven basic elements for any SOP are:

		A unique title that corresponds to a unique document number: This combination should be specific enough so that the document referred to can’t be confused with other documents in your document collection. The unique reference number is often an alpha/numeric combination that specifies the functional department that employs the SOP. This unique identifier often includes the version of the SOP for easy reference and to ensure the current version is being used.

		The date that the SOP is considered operational and should be followed by employees: Dictating one date format versus another creates unnecessary/irrelevant deviations. The focus of dates should be their legibility.

		A purpose and a scope that describes why the company has this SOP (what process or procedure is being described) and who in the company needs to adhere to the contents of the SOP: The purpose and scope of an SOP are interrelated. The purpose describes why the SOP is needed, and the scope defines the boundaries of the SOP.

		Roles and responsibilities: The roles and responsibilities should not be a reiteration of the procedure but should describe the parties responsible for ensuring proper execution of the SOP (who may or may not be the individuals performing the step-by-step procedure).

		Change control history of the document: The change control history is important because it establishes the history of the document from initiation to obsoletion. In some cases, it is important for the company to know what sections of an SOP were changed and why they were changed. This valuable information is captured through the change control history and should be included in the change control request.

		Who can sign and vouch for the contents of the document: The SOP is not complete until the official required signatures are applied to the document. The official signatures required for any document may vary from department to department and indicate that the changes to the SOP are: consistent with company policy, ensure the operation continues to be executed in a predictable manner, do not affect the validation status or quality of the product, and that the step-by-step instructions represent the repetitive actions to be performed to ensure the predicated and expected outcome defined by the SOP.

		The step-by-step instructions: The step-by-step instructions represent the repetitive actions to be performed to ensure the predicated and expected outcome defined by the SOP. There is no rule that SOPs need to be written words. If the operation in the SOP can be described easily with a flow diagram, there is no reason not to use this type of informational display. The instructions should not be too long. The longer the SOP is, the poorer the retention of the information. The general rule is SOPs should not exceed 10 pages. If your SOP exceeds 10 pages, you might want to consider breaking it into smaller operations, if possible.

	If you keep these points in mind when writing your SOPs, you should stop receiving the ‘inadequate SOPs’ citation.

 When referring to this article, please cite it as S. Schniepp and A. Harrison, “Crafting Standard Operating Procedures,” 

Susan Schniepp, distinguished fellow, and Andrew Harrison, chief regulatory affairs officer and general counsel, both of Regulatory Compliance Associates, discuss how to write standard operating procedures that hold up to audits.

Crafting Standard Operating Procedures

	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,” 

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.


	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.