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 at Regulatory Compliance Associates, discusses the assessment of risk in the processing of intravenous injectable drugs.

Q: I work in the quality group for a manufacturer who makes intravenous (IV) injectable drugs using aseptic processing techniques. Recently, the facility has experienced an increase in the number of viable organisms in our environmental monitoring program. Management has asked me to do a risk-based assessment so we can use our resources effectively. Can you offer some advice on how I should proceed in putting together this assessment?


	
	A: Aseptic processing of IV injectable drugs is certainly one of the riskiest manufacturing operations. Your management is correct to be concerned when there is a reported increase in the number of viable organisms in the environment. It is often difficult to determine where a potential microbial ingress is coming from. This is why so much attention is given to monitoring personnel, equipment, air quality, etc., for microbial organisms and identifying and trending what those organisms are and where they are coming from. A risk-based approach to determine the source of the microbial increase is a good start. It is important to remember aseptic does not mean sterile and the objective in aseptic processing is to keep the product, components, and environment as close to sterile as possible. This is accomplished through proper building, equipment materials, and design; established and validated cleaning procedures; proper training for personnel; and continuous monitoring of the personnel and environment to make sure the sterile core area and the areas supporting it are properly maintained at all times to avoid product contamination that would impact patient safety.

	The first step in developing a risk-based approach for your facility is to break down your operations into the various steps and determine the highest risk posed to those areas. The highest risk areas tend to be those where personnel are intimately involved. Of these areas, one of the most risky is personnel gowning. Proper gowning is crucial to the aseptic operation because, in some cases, such as compounding pharmacies or manual fills for small clinical trial batches, it may be the only barrier between the product and the human. Because we can’t sterilize the human being, we must take care to make sure they understand the proper gowning technique and fastidiously adhere to it so the patient can be assured the product is safe. 
	
	Proper aseptic technique is critical to maintaining the sterile environment where the aseptic product will be filled. In September 2004, FDA finalized their guidance for industry titled 

Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice

	This document placed considerable emphasis on the training and behavior of the personnel involved in the aseptic fill operation. It is important for the company to continually focus on personnel behavior to avoid complacency and potential product risk. As stated in the guideline, “As operator activities increase in an aseptic processing operation, the risk to finished product sterility also increases. To ensure maintenance of product sterility, it is critical for operators involved in aseptic activities to use aseptic technique at all times.” To establish an operator’s skills, the company should have basic training topics covering personal hygiene, proper aseptic technique during operations and gowning activities, proper plating techniques for microbial monitoring, among others. In addition, the company should establish an ongoing training program as a way to maintain and continually improve the operators’ performance. This training should be documented by the quality department through training records, evaluation of the ability of the operator to follow standard operating procedures (SOPs), and monitoring deviations for breaches in aseptic technique during production. The concepts set forth in the FDA guideline are also set forth in the European regulations (2).

	One of the most critical areas for establishing your risk assessment is the subject of proper gowning technique. If the operator can’t follow the proper gowning requirements, the product will be at risk the moment the operator enters into the critical manufacturing area. It is interesting to note that in a recent draft guidance issued for compounding facilities, the failure to properly gown is considered to be an insanitary condition (3). 
	
	Another discipline that should be considered as high risk in the risk assessment is cleaning. The cleaning of the line after manufacturing is personnel dependent and, if done incorrectly, can put the next product manufactured on the line at risk of microbial and/or cross contamination. There are many different disinfectant procedures, and it is important that they be executed effectively. Again, proper training and oversight should help maintain the employee’s skills, therefore avoiding potential product contamination. 

	Bottom-line, when establishing your risk-assessment program, some of the highest risk areas/activities will be those where there is a high level of human involvement. Assessing those areas first as contributing factors to your environmental problem will help you effectively manage your resources. But be advised that whatever the risk-ranking you give to each area/activity involved in your aseptic manufacturing each area must be thoroughly evaluated and vetted because any of the areas could be the potential source of your microbial problem.

Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice

 (CDER, CBER, ORA, September 2004).
	2. European Commission, 

, Volume 4, Annex 1 (November 2008).
	3. FDA, 

Draft Guidance for Industry, Insanitary Conditions at Compounding Facilities

 (CDER Office of Compliance, August 2016).

	When referring to this article, please cite it as S. Schniepp, "Defining Risk Assessment of Aseptic Processes," 

Articles

Susan Schniepp, distinguished fellow at Regulatory Compliance Associates, discusses the assessment of risk in the processing of intravenous injectable drugs.

Defining Risk Assessment of Aseptic Processes

Susan Schniepp, distinguished fellow at Regulatory Compliance Associates, discusses the regulatory requirements for improving manufacturing lines.

	Q: I work for a contract manufacturing organization (CMO) and my management has dedicated capital funds to update some of our manufacturing lines. I need to work with my clients to get approval to make the necessary changes. Many of my clients feel any changes to the manufacturing line would require a prior approval supplement (PAS), which would be a challenge for our company. Do you have any advice regarding a regulatory strategy that I could propose to my clients that would satisfy them and minimize downtime?

	A:  This is a great question and a complicated issue. The pharmaceutical industry has been trying to become more efficient from both manufacturing and regulatory perspectives. The challenge is to improve processes, quality systems, and manufacturing capabilities while operating efficiently and in a manner that ensures safe, effective, and cost-efficient medicines to patients. Many updates to processes and quality systems can be easily and readily implemented with little or no impact on regulatory filings. When a change impacts regulatory filings, it has the potential to disrupt the supply chain if it is not handled appropriately and as efficiently as possible. FDA seems to recognize these situations and has been working to help lessen the regulatory filing burden to companies while not affecting the quality of the products. In the past three years, FDA has issued three important 

	The first step in the process of upgrading your facility is to get the agreement, or at least, an acknowledgment from your clients that they are aware that you intend to upgrade the facility and that it may affect their regulatory filing. The first guideline that helps you facilitate the dialog with your client is the quality agreements guidance issued in May 2013 (1). This guideline states “… FDA recommends that owners and contracted facilities implement written quality agreements as a tool to define communications, delineate responsibilities, and assure the quality, safety, and effectiveness of drug products.” If you have a quality agreement, then you need to check and see whether the contract organization or the client has the responsibility to maintain the facility. If you have relegated this responsibility to your clients and they are hesitant to implement the upgrade, remind them that the quality agreement guideline gives you the authority to maintain your facility (including necessary equipment upgrades) by stating “A quality agreement does not exempt contracted facilities from CGMP requirements related to the operations they perform, regardless of whether such CGMP requirements are specifically discussed in the quality agreement.” Bottom line, both you and your client(s) may have responsibilities outlined in the quality agreement regarding maintaining and upgrading the facility but you, as the CMO, need to adhere to CGMPs and make sure your facility is maintained per 21 Code of Federal Regulations (CFR) 211.58 requirements that “any building used in the manufacture, processing, packaging, or holding of a drug product shall be maintained in a good state of repair.”	 

	The second guideline that helps in updating your facility in a timely manner is the chemistry, manufacturing, and controls (CMC) post-approval manufacturing changes that can be documented in an annual report that was issued in March 2014 (2). This new revision reiterates the concept of like-for-like replacement while expanding some of the facility changes that can be made as an annual report. For instance, the new guidance states, “For equipment used in aseptic manufacturing processes (e.g., new filling line, new lyophilizer), replacement of equipment with that of the same design and operating principle, when there is no change in the approved process methodology or in-process control limits” … and … “In the manufacturing of sterile products, the addition of barriers within a conventional fill area to prevent routine in-process human intervention in an existing filling or compounding area that is qualified and validated by established procedures” are acceptable changes to include in an annual report. Many pharmaceutical professionals would have considered these changes as needing prior approval before being implemented. Be cautious, though; just because these improvements can be managed through the annual report process, you still need to do all the necessary work to ensure the change is appropriate and does not affect product quality.			Comparability protocols			 			There may still be some clients wary of the change even when you notify them of the change and the guidelines that support making the change without going through the PAS process. This is where the third guidance comes into play, and it is the updated guidance on comparability protocols for human drugs and biologics (3). A comparability protocol has the potential to decrease the filing category. For instance, items that would normally be handled as a PAS have the potential to be considered as a changes-being-effected-in-30-days supplement. By employing the use of a comparability protocol you are, in essence, making sure your client understands the change you will be implementing and the data you will be collecting and reviewing to assess that the upgrade was successful and did not affect product quality. The comparability protocol is a nice compromise when you have clients insisting on a PAS and others who are comfortable with the annual reportable strategy. It allows you to file the protocol as a PAS and build the inventory needed in preparation for the anticipated shutdown period.			 			There are no right or wrong answers when recommending filing strategies to a client. Regardless of what the contract manufacturing organization says, the client can always chose an alternative. The best way to convince a client of a filing strategy is to make sure you have a robust quality agreement in place that gives you the responsibility for maintaining your facility. Become familiar with the regulations and use them to justify your recommendation. Finally, use a comparability protocol for proving like-to-like equivalency, and present the recommendation to the client in a documented manner. These steps should help you implement a facility upgrade in a timely manner while reducing your downtime to make the improvement.	

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

Guidance for Industry CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports

Guidance for Industry: Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information 

	When referring to this article, please cite as S. Schniepp, "One Strategy for Updating an Aging Facility," 

Susan Schniepp, Distinguished Fellow at Regulatory Compliance Associates, discusses the regulatory requirements for improving manufacturing lines.

One Strategy for Updating an Aging Facility

Q: I saw where FDA released draft guidance on data integrity. In the guidance, the answer to question 16 says personnel should be trained in detecting data integrity issues as part of a routine current good manufacturing practice (CGMP) training program. Can you give me some advice on how this topic would be addressed in the annual CGMP training?

	 	A: This is a great question. The draft guidance, titled 

, was released April 15, 2016 (1). In the introduction, FDA states, “The purpose of the guidance is to clarify the role of data integrity in current good manufacturing practice …” I don’t think the industry should be surprised by this guidance based on the number of recent warning letters issued with citations referencing questionable data integrity practices (2-4). The guidance itself says “… FDA has increasingly observed CGMP violations involving data integrity during CGMP inspections.” The guidance goes on to say, “This is troubling because ensuring data integrity is an important component of industry’s responsibility to ensure the … quality of drugs, and FDA’s ability to protect the public health.”	 	Specifically question 16 asks, “Should personnel be trained in detecting data integrity as part of a routine CGMP training program?” The answer in the guideline is, of course, yes and cites 21 

) 211.25 and 212.10, which require that employees have the “education, training, and experience, or any combination thereof, to perform their assigned duties.” From an industry perspective, the requirement for data integrity training seems new, but it isn’t. It is normally referred to as good documentation practices (GDP), annual GMP training, and investigations and corrective action and preventive action (CAPA) training. The question is how does one communicate to others that this training regimen relates to proper data handling, which in turn helps eliminate data integrity issues.	 	Annual GMP training is integral to avoiding data integrity problems because it delineates what documents need to be maintained. If the GMPs require a document be preserved, one can assume it is a document that is subject to review and critique during an audit. Focusing on the forms and records required allows one to direct their review efforts on the essential rather than on the superfluous documents that support the safety, efficacy, and quality of the products being manufactured. Once the company’s quality assurance (QA) department has identified these critical documents, the documentation group can then direct their efforts towards appropriately maintaining those documents.	 	

	A critical element in preserving the integrity of the information contained in these records is related to GDP training. GDP training should explain to the employees the necessity of the document in relationship to the quality of the product. GDP training should focus on the importance of the data being recorded, how to correct an error, how to document the reason for the error, explain the timeliness of the signature and date of the person who performed the operation and recorded the necessary information, as well as the role of the verifier’s signature for those steps in the operation that require a witness. GDP training should also include an explanation of the review process and what the operator’s, verifier’s, and reviewer’s signatures means. 	 	The reviewer’s signature should be regarded as complementary to the original operator’s signature. It is there to support that the recording of the data was complete, accurately reflected the function or activity being documented, and that any errors that occurred during the operation were investigated and corrected appropriately. If you are operating with electronic signatures and data collection systems, training should include discussion on the importance of password protection and the reason and rationale for not sharing passwords and accounts so that the integrity of the electronic system is not compromised.	CAPA training	 	Investigation and CAPA training should be taught to staff involved in the recording and reviewing of the documentation. It is important for these individuals to understand how deviations are investigated, if the investigation resulted in a CAPA, and what impact the investigation/CAPA results might have on the product. It should also address how changes made to documentation as a result of the investigations/CAPA have been implemented in the system. Documentation changes made as a result of investigation/CAPA conclusions should prompt retraining on the activity and should encompass any new documentation practices identified.	 	Once the employees are trained in GMP, GDP, and investigations/CAPA training, the QA group should confirm the organization’s understanding of what they were taught through the internal audit review process. This should be viewed as a confirming activity that will strengthen the records, forms, reports, and manufacturing documents that support the product’s manufacturing and release. Issues in documentation procedures identified through the internal audit process should be responded to and tracked in a similar manner, as the company would do for an external audit by a client or a regulatory agency.	 	The information collected during the manufacturing of the product from the receipt of the raw materials, the maintenance of the facility, the testing of the product up to the release of the product, and everything in between is crucial to defending the product once it has been released for patient use. It is crucial that this information be indisputable, whether it is electronic or paper. Bottom line, don’t over react to the guidance by sending your QA staff to criminal investigation training. Instead, utilize the tools you already have in your quality system to reinforce the concept of data integrity throughout your training and audit processes. The best way to combat poor documentation is through the proactive inclusion of data integrity concepts, design, and implementation into your data collection systems whether they are manual or electronic in nature.	 	

Data Integrity and Compliance With CGMP Guidance for Industry

, Draft Guidance (CDER, CBER, CVM, April 2016), www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm495891.pdf	2. FDA, Warning Letter to Chan Yat Hing Medicine Factory, Dec. 15, 2015, www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm481851.htm	3. FDA, Warning Letter to Zhejiang Hisun Pharmaceutical Co., Ltd., Dec. 31, 2015, www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm480035.htm	4. FDA, Warning Letter to Sun Pharmaceuticals Industries Ltd., Dec. 17, 2015, www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm478393.htm. 	 	


	When referring to this article, please cite it as S. Schniepp, "Make Data Integrity Integral to CGMP Training," 

Susan Schniepp, distinguished fellow at Regulatory Compliance Associates, discusses training personnel on data integrity.

Make Data Integrity Integral to CGMP Training

	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,"

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.