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

Susan J. Schniepp

Q: Companies have made a lot of operational changes to accommodate working through the pandemic. What changes do you think will become permanent as a result of the pandemic?

A: There are a number of operational changes that companies have made to 

Editor's Note: This article was published in 

accommodate working through the pandemic. Many of the changes were implemented out of necessity, and some of these changes have the potential to become permanent and normal operating procedures in the future. Patients still need life-saving medicines and companies need to find ways to continue manufacturing safe, effective, and compliant products for these patients despite the challenges presented by the pandemic. Conducting virtual audits, conducting effective virtual training, and enhancing communications with suppliers to ensure an uninterrupted supply chain are among the changes implemented to maintain operations, stay compliant, and continue manufacturing medically necessary products. Each one of these changes have positive and negative aspects that need to be evaluated and debated to determine if they are as effective as the previous processes.

Moving to virtual audits was one of the first changes that was implemented by companies and regulatory authorities. The necessity for virtual audits was to allow companies and regulators to continue to evaluate the compliance stature of manufacturers while respecting stay-at-home and social distancing requirements that prevented in-person site audits.

There are many advantages of performing virtual audits and the key to making a virtual audit successful is preparation and communication. Informational (organizational charts, standard operating procedures, quality manual, etc.) requests should be made prior to the audit, and the requested documents should be reviewed before the commencement of the audit.

Companies can save time and reduce travel expenditures because people will be reviewing documents from home offices. The documentation required for in-person audits will be the same as virtual audits, but rather than making copies for the auditor, the documents can be turned into a PDF file and be sent through a secure system to the requester. Questions regarding the documentation can be addressed through a number of virtual platforms as long as the platform chosen is acceptable to both parties.

Performing a tour of the facility poses unique challenges, and possible solutions need to be vetted between the two parties to determine the most efficient and secure way to share this information. The bottom line is that virtual audits have the potential to be as effective as in-person audits and perhaps may be more time efficient and cost effective.

The same principles applied to conducting virtual audits can also be applied to training. On-line training programs have been used to train remote employees for years. There are a number of technological platforms that can be used to deliver virtual training programs to employees. These platforms allow training material to be pre-recorded and comprehension questions that must be answered correctly in order to continue with the training can be inserted. Remote training allows the employee to
complete the training as their schedule allows.

Another approach is to deliver the training as a webinar using a multiple-person meeting application. You can prepare and distribute the information you will cover in the training, schedule a meeting time, deliver the training, and take questions from the employees during the webinar. If you have multiple manufacturing shifts, you can schedule a training session during each shift to make it easier for second- and third-shift employees to receive the training.

Additionally, virtual training can be enhanced by taking advantage of online training and conference options offered by external organizations. Many external organizations have converted their conferences and training topics to virtual offerings covering a wide variety of topics. Some of these venues are free, and some require a registration fee.

Enhanced communication with suppliers to ensure an uninterrupted supply chain has also become a priority during the pandemic. Many companies are reviewing and enhancing their quality agreements. This is a positive change for the industry as a whole.

The quality agreement should be a living document that is reviewed and revised as often as needed to clarify the responsibilities of the client and the supplier and define how the two parties will communicate with each other. The agreement should clearly identify the roles and responsibilities needed for a successful partnership. Defining the quality relationship between a supplier and a client is complex and requires extensive discussion and attention to detail. The relationship should be open, and communication between the two parties should be as frequent as required to assure that the product being manufactured meets the highest quality standards for the client and for the patients. Bottom line is that quality agreements are important documents that have become front and center for ensuring the supply chain during the pandemic. This is a welcome change that should carry forward in the future.

There are many changes that have the potential to become permanent procedures/operating principles even after the pandemic is under control. Three that should become permanent in the future are the use of virtual audits, the implementation and utilizations of virtual training, and more robust quality agreements that enhance communications between the client and the supplier.

Susan J. Schniepp is distinguished fellow at Regulatory Compliance Associates.


Vol. 32, No. 12
December 2020
Pages: 50, 49

When referring to this article, please cite it as S. Schniepp, "Impact of Pandemic on Permanent Procedures," 

Articles

Virtual audits, virtual training, and more robust quality agreements may become positive impacts on the industry, says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates.


Impact of Pandemic on Permanent Procedures

Q. I am responsible for updating my company’s standard operating procedures (SOPs). My company has been cited several times in audits for not following them, and this situation has worsened since the onset of the pandemic. What advice do you have for me to make sure the SOPs are being followed for now and in the future?

A. You are not alone. Not following SOPs or not having adequate procedures in writing continues to be one of the top observations for the industry in 2019 (1). Companies usually use their SOP to show that they have control over their processes, thereby demonstrating compliance with regulatory expectations. The problem you are having with your SOPs seems to be an ongoing issue not necessarily related to the pandemic. It would seem this situation is exacerbated by the pandemic but not caused by the pandemic. My advice to you would be to take a holistic look at how you create, implement, and modify your SOPs.

There are four simple concepts to keep in mind for having compliant SOPs: Say what you do, do what you say, prove it, improve it. The ‘say what you do’ phrase equates to the written SOP that defines the steps taken to achieve compliance to a regulatory requirement. ‘Do what you say’ equates to following the SOP. ‘Prove it’ means that you need to collect and be able to present data that indicate you have followed the instructions in your SOP and have investigated any incidents where you have deviated from those instructions. Once you have mastered these concepts, you can begin to work on the ‘improve it’ concept by revising and updating your SOPs to reflect current practice and process improvements. These concepts are simple enough to follow, so the being cited by regulators for not following SOPs is disappointing.

Previously in this column, we have discussed the elements of an SOP (2). The problem you are having seems to be related to the SOP content. To address this particular problem, you need to be aware of some of the pitfalls companies encounter when writing SOPs. Writing an SOP with the correct amount of information in it—neither too restrictive nor too ambiguous—is not an easy task. It takes time and effort to create an SOP with the right balance of information (3).

The three most common pitfalls when writing an SOP are providing too much information, providing too little information, and providing unneeded specific information.

Providing too much information in an SOP results in a restrictive process that generates deviations. An example of too much information in an SOP would be listing the serial number for a piece of equipment. Should the piece of equipment need to be changed for any reason, the result is a deviation and an SOP that can’t be followed.

When listing equipment requirements in an SOP, you should describe the piece of equipment but not necessarily to the serial number. It would be best to provide a list of the equipment needed with a general description of its function and capability.

When an SOP provides too little information, it results in an out-of-control process that generates deviations. When there is lack of clarity, it allows for interpretation by the operator. There is the potential for each individual executing the process to interpret the instructions in their own unique way resulting in deviations that need to be investigated and the potential for the regulatory citation of insufficient SOPs. An example of providing too little information might be not specifying the specific order reagents need to be added to generate a reaction. If it is critical to add the reagents in a certain order, that information needs to be specified in the SOP.

SOPs that provide unneeded specific information are also problematic. An example of unneeded specific information might be how dates are recorded in a document. A company needs to be consistent in the way the date is recorded regarding the order of the day, month, and year but can be flexible regarding whether this information is separated by hyphens or slashes. There is no difference between DD/MM/YY and DD-MM-YY. Specifying hyphens versus slashes sets you up for insignificant deviations that wastes time and resources.

Other potential pitfalls to avoid are providing ambiguous information, restricting access to SOPs, allowing access to obsolete SOPs, having unnecessary SOPs describing operations that you don’t perform, and not providing clear instructions for recording data, which could lead to data integrity issues.

Writing an effective SOP and keeping it current is not an easy task.It requires time, effort, and cooperation with the users to achieve the correct balance that allows the process to be easily followed, specifies the correct data to be recorded, reflects the current operations, and can be improved as the process improves through continual improvement. Taking a critical look at the level and detail provided in your SOPs and right sizing the information contained to accurately reflect your operations will help in eliminating an audit observation of not following SOPs or having insufficient SOPs, and these steps may help improve your compliance position.

www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/inspection-observations

, accessed Sept. 14, 2020.
2. S. Schniepp, 

 41 (12) 2017.
3. S. Schniepp, B. Matye, and J. Moldenhauer, 

SOPs Clear and Simple for Healthcare Manufacturers

Susan J. Schniepp is Distinguished Fellow at Regulatory Compliance Associates, LLC.


Volume 44, Number 10
October 2020
Pages: 74, 73

When referring to this article, please cite it as S. Schniepp, "Writing Effective SOPs," 

The amount of detail included in SOPs may help a company stay compliant, says Susan J. Schniepp, Distinguished Fellow at Regulatory Compliance Associates, LLC.

Writing Effective SOPs

Q. I am in charge of training activities for my company. Company policy requires all employees receive annual good manufacturing practice (GMP) training. Since many employees are working from home during the pandemic, I am struggling with how to deliver effective training, and I want to rewrite the policy to eliminate this requirement. Is annual GMP training a regulatory requirement, and can I eliminate this requirement and still be compliant with the regulations?

A. It is important to maintain training for employees even during highly challenging circumstances. In the United States, the regulatory expectation for training is defined in 21 

) 211.25, which states, “Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice [CGMP] (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee’s functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them” (1).

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

has similar requirements specified in Volume 4, Part 1, Chapter 2, which states, “The manufacturer should provide training for all the personnel whose duties take them into production and storage areas or into control laboratories (including the technical, maintenance, and cleaning personnel), and for other personnel whose activities could affect the quality of the product.” The guideline also states, “Besides the basic training on the theory and practice of the quality management system and Good Manufacturing Practice, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed” (2). The regulatory expectation is that companies continue to provide “a high level of assurance that manufacturers comply with CGMP and that products meet specifications,” even during exceptional times (3).

To ensure that training requirements are adhered to and your compliance posture is not jeopardized, I recommend you start by triaging your employees. Those employees in critical roles should be your first priority to receive the necessary training in a timely manner. Employees in less critical roles could receive the training at a later time or maybe receive a truncated version of the training. Remember to document your decision in a well thought out and justified rationale.

The next hurdle to overcome is to determine the most effective way to deliver the training without wasting critical resources. This can be accomplished in a variety of ways. On-line training programs have been used to train remote employees for years. These programs have the capability of allowing the instructor to tape the information and embed questions into the presentation that must be answered before that trainee can continue. This is a great way to train people and measure the effectiveness of that training. It also allows the employee to complete the training as their schedule allows. If you decide to utilize this approach, you need to be sure to set a date for completion of the training and monitor the results of responses so you can follow up on employees that may need some additional explanation or understanding of the concepts included in the training. Another approach would be to deliver the training as a webinar using a multiple person meeting app. You can prepare and distribute the information you will cover in the training, schedule a meeting time, deliver the training, and take questions from the employees during the webinar. If you have multiple manufacturing shifts, you can schedule a training session during each shift to make it easier for second- and third-shift employees to receive the training.

Another approach is to research virtual training and conference options offered by external organizations. Many trade organizations have converted their conferences and training topics to virtual offerings covering a wide variety of topics. Many of these organizations offer the option of listening in real time or to taped recordings. Some of these venues are free, and some require a registration fee. The sessions are usually 90 minutes in length, and many offer an opportunity to ask the speakers questions through a chatroom feature. If you are unable to listen to the webinar live, you may have the option to purchase a recording of it and listen to it at your convenience. The recorded option offered with these webinars can be valuable for training employees who work on the second and third shifts. The companies offering these webinars advertise them well in advance of the event and often send out multiple reminders. The advertising for the webinars highlights who will be speaking, their qualifications, what they will cover in the training, and what you will learn as a participant. In addition, they will also make recommendations on who should attend so you can determine if this is appropriate training for your employees. In some cases, the webinar may offer continuing education credits for attending. This information should be printed out and used to demonstrate the appropriateness of the training.

Finally, you might consider using some employees who are not working remotely to lead some small-group internal training during their shift, employing a train-the-trainer concept. This satellite training can be led by a qualified, trusted, and trained employee representative that has the knowledge and expertise determined by their experience and job performance as determined by you. As with all other training, these discussions should be documented in your training system as well as the rationale for the selection of the designated trainer.

The bottom line is even though people are working remotely, and in-person training may not be feasible, there are still opportunities to ensure employees receive the required training to meet your company’s training expectations. You should sign up to receive emails from companies and organizations that offer online training, review them to determine if they are applicable to your operations, determine who should attend from your company, and make sure you document their attendance for their training record.

 Title 21, Part 211.25, (Government Printing Office, Washington, DC) 145.

EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use

, Chapter 4, Part 1, Chapter 2: Personnel, August 16, 2013.

Draft Guidance for Industry: Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products


Volume 44, Number 8
August 2020
Pages: 58, 56

When referring to this article, please cite it as S. Schniepp, "Training During a Pandemic," 

When in-person training may not be feasible, there are still opportunities to ensure employees receive the required training, says Susan J. Schniepp, distinguished fellow, Regulatory Compliance Associates.

Training During a Pandemic

Q. I am in the quality department and am responsible for investigations, and I have been working from home due to the COVID-19 pandemic. The investigation standard operating procedure (SOP) requires me to perform face-to-face interviews with people and to complete the investigation within 90 days. Working remotely to conduct the interviews is taking much longer, and I am afraid I’ll miss my deadlines. Could I eliminate the interview requirement until I am able to return to the facility?

	A. I certainly understand the challenges of trying to conduct remote face-to-face interviews and the need to try and streamline processes during times of crisis, but now is not the time to take unnecessary, undocumented shortcuts with any of your procedures. My recommendation is that you step back from your frustration with the situation. Focus on the elements you need to conduct a thorough investigation and look at finding alternative means to fulfill the SOP requirements as defined in your contingency plan. If you do not have a contingency plan in place, you should immediately develop one and include appropriate risk-based information. The European Medicines Agency has a guidance on the format for a risk management plan that might help you get started on this activity (1).

	To determine how you might make your operations more efficient during crisis times, I further suggest you review the FDA’s draft guidance titled,

 Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products

 (2). The guidance document states, “This guidance is intended to encourage manufacturers of medically necessary drug products (MNPs) and any components of those products to develop contingency production plans to use during emergencies that result in high absenteeism at production facilities” … “The guidance provides considerations for the development and implementation of a plan for production of MNPs during a crisis, including specific elements that should be included in the plan.” 

	The contingency plan you develop should include information regarding the company’s prevention and risk mitigation processes. The guidance states, “These preventative measures can include steps to prepare personnel such as:

		“Educating employees on topics such as, in the case of a pandemic, personal hygiene (hand washing and coughing and sneezing etiquette), social distancing, and appropriate use of sick leave

		“Encouraging employees to get immunized as appropriate by providing information on local vaccination services or by offering on-site vaccination services, if reasonable

		“Providing information for and encouraging employees to develop family emergency preparedness plans

		“Reviewing CGMP [current good manufacturing practice] regulations regarding appropriate sanitation practices and restriction of ill or sick employees from production areas (see 21 

	The guideline also recommends “that manufacturers, when evaluating activities that might be reduced in frequency, delayed, or substituted by a suitable alternative, first identify and consider activities that are intended by the CGMP regulations to provide controls not connected with the manufacturing of any specific batch. Examples include:

		“Production equipment routine maintenance

		“Utility system performance checks and maintenance (e.g., air temperature, lighting, compressed air)

		“Environmental monitoring of facilities such as cell culture, harvesting, and purification rooms during production

		“Stability testing for certain drug products and components

		“Periodic examinations of data and of reserve samples” (2).

	In addition, the guideline also recommends that, “If the demand for MNPs cannot be met by the measures described above, manufacturers can consider reducing activities that are more directly connected with batch manufacturing or a product accept/reject decision provided that they have a documented rationale or risk assessment to show that the proposed changes will not unacceptably reduce assurance of product quality. Examples include:

		“Not requiring second-person verification of activities for less critical steps (though we recommend a self-check of work)

		“Reducing the number of samples for labor-intensive laboratory testing

		“Forgoing an in-process test to assure adequacy of mix, particularly when making successive batches, where the risk is judged to be low in terms of drug safety and efficacy

		“Delaying completion of deviation investigations of minor events.

		“CDER [the Center for Drug Evaluation and Research] recommends that in taking such measures, firms plan to carefully monitor indicators of product quality to note any unfavorable trends or shifts as a result of the implementation of the Plan. CDER also recommends that firms retain samples for testing at a later date in cases where testing is reduced or omitted because of lack of resources” (2).

	While it is important to act quickly and efficiently during a crisis, the process and product must still be manufactured in accordance with appropriate regulatory requirements. Before you make any drastic changes to SOPs or eliminate process steps you need to read the FDA guidance document, prepare a proper risk assessment, and justify why the removal of the requirement from the SOP does not impact patient safety and product quality. The documentation you provide and the assessments you perform to address some of the extraordinary situations facing you and your colleagues in the effort to produce necessary medical drugs should give you confidence that you have acted appropriately and within the regulations to fulfill patient needs.

Guidance on the Format of the Risk Management Plan (RMP) in the EU–in Integrated Format, 

EMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2 Human Medicines Evaluation (EMA, October 31, 2018).
	2. FDA


	Volume 44, Number 6
	June 2020
	Pages: 62, 60

	When referring to this article, please cite it as S. Schniepp, "

Products must be manufactured in accordance with appropriate regulatory requirements, even during a pandemic, says Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow, Regulatory Compliance Associates.

Following Guidelines During a Crisis

Q. I am preparing my site for an audit and have prepared and trained our employees on the usual topics (training program, standard operating procedures [SOPs], change control, etc.). I am concerned that this traditional approach may not be enough in the current regulatory environment. Can you offer some guidance into other issues I should focus on in preparing for the audit?

	A. This is a great question and shows an insight into the changing regulatory landscape. I think it will be critical in the coming years to focus on addressing certain intangible topics during routing regulatory audits. These topics should be addressed as part of your company’s overall improvement plans and programs.

	I would focus on the following topics as a part of preparing for any routine audit: data integrity, quality culture, aging facilities, investigations/corrective actions and preventive actions (CAPA) and risk management. I am of the opinion that these topics will become routine areas of focus for regulatory inspections regardless of the affiliation of the regulatory authority performing the audit. These topics are not new to the industry. There has been much discussion on their impact on drug shortages. It is my opinion that developing robust programs addressing these issues and incorporating them into everyday routine operations will improve the drug shortage situation, improve a company’s operating performance, and improve the outcome of regulatory inspections for the company.

	FDA has been publishing guidance on these issues over the years, and now as the agency gets ready to finalize the New Inspection Protocols Project (NIPP), it is time to revisit some of these recommendations and implement some of the advice offered. The intent of the NIPP program (1) is to provide inspectional assessments to support tracking and improvement of performance across pharmaceutical manufacturers and products and enhance the production, utility, and consistency of the establishment inspection reports.

	Every company should have a program to address data integrity issues that includes guidance on what data integrity is, how to recognize it, how to prevent violations, consequences for violating the company’s data integrity policy, etc. The program should also address the frequency and effectiveness of employee training on this topic. The program should demonstrate an understanding of regulatory expectations as well as an explanation of how those expectations are incorporated into the data integrity program. The program needs to go beyond the concepts of ALCOA (attributable, legible, contemporaneous, original, accurate) and include the four new attributes in ALCOA+ (complete, consistent, enduring, available) (2, 3).

	The concept of quality culture came about with the introduction of quality metrics. FDA introduced the concept of collecting quality metrics in 2013 (4). Since that time, the industry and regulatory authorities worldwide have embraced the idea that in order to rely on the metrics collected, the company needs to have a culture that supports an open, transparent reporting of “deviations, errors, omissions and aberrant results at all levels of the organization, irrespective of hierarchy” (3). There has been work done by the Parenteral Drug Association and Uni-versity of St. Gallen suggesting the there is a correlation between mature quality attributes and quality culture behaviors. To address the issue of a quality culture during a regulatory inspection, the company should be able to demonstrate their quality system is functional and identifies gaps so the company can implement changes to ensure continuous improvement.

	Aging facilities are of concern because they can lead to drug shortages. It is hard to achieve compliance to current regulatory expectation when manufacturing new and novel products on manufacturing lines that are more than 30 years old and the analytical results rely on outdated methodology (5).  The age of the line usually indicates that the processes being run on those lines are non-automated and require human driven steps. In these situations, it is critical a company demonstrates it has a quality mindset because of the human/product interface. The best way to address this issue in an inspection is to demonstrate that the company has a plan to update its facility over time. The plan should indicate what needs to be updated and a timeline for implementation.

	The need for a robust investigation/CAPA process is clearly defined in global regulations, but it seems the industry still struggles with conducting and documenting root cause when it comes to investigations based on FDA 483 observations (6). The purpose of an investigation is to identify the root cause of a deviation and take appropriate action to correct the issue across the manufacturing/product line. The best way to demonstrate proper control of this process during an investigation is to ensure you have a robust investigation process, which routinely identifies root cause and that once the correction is made, it does not recur (7). The ability to demonstrate this depends on the understanding and training of the people involved in the investigation process and data that shows the problem was addressed and solved (8, 9).

	Every company should have a quality risk management plan (10). A well-written and well-implemented quality risk management plan is an integral and valuable element of an effective quality system. Quality risk management plans are important because they help improve a company’s ability to provide quality product to patients. They are contingency plans with identified actions that help to ensure a continuous supply of product to the market that meets the expectations of being safe, effective, and available. They are dynamic documents that require integration into and data inputs from all departments in order to be successfully implemented at a company (11). Having the plan available for discussion and demonstrating a knowledge of the plan, how it is incorporated into the culture, and making sure it is revised as needed to reflect current practices is critical to having a successful outcome should you be audited on this topic.

	The bottom line is that the regulatory landscape is changing, and it is conceivable that companies will begin to be audited on programs and process that are more subjective than tangible. To be prepared for an audit that touches on the intangibles of a functioning quality management system, companies should begin to formulate programs and systems that address the aforementioned topics.

	1. Office of Pharmaceutical Quality, FDA Pharmaceutical Quality Oversight, One Quality Voice, FDA whitepaper.
	2. S. Schniepp, 

 43 (10) 2019.
	3. World Health Organization, 

Annex 5, Guidance on Good Data and Record Management Practices 

 43 (12) 2019.
	7. S. Schniepp and A. Harrison, 

 40 (2) 2016.
	8. S. Schniepp and A. Harrison, 

 39 (10) 2015.
	9. S. Schniepp and A. Harrison, 


	Vol. 44, No. 4
	April 2020
	Pages: 86,85

	When referring to this article, please cite it as S. Schniepp, "Critical Knowledge for Preparing Audits," 

Addressing data integrity, quality culture, aging facilities, investigations/corrective actions and preventive actions, and risk management is key when conducting audits, says Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow, Regulatory Compliance Associates.

Critical Knowledge for Preparing Audits

Data supporting the quality and safety of product must meet the ALCOA+ elements in order to avoid regulatory citations for data integrity issues.

Pharmaceutical Technology’s March 2020 Regulatory Sourcebook


	eBook: Regulatory Sourcebook, March 2020
	March 2020
	Pages: 10–13

	When referring to this article, please cite it as S. J. Schniepp, “ALCOA+ and Data Integrity," 

Pharmaceutical Technology Regulatory Sourcebook eBook

Data supporting the quality and safety of product must meet the ALCOA+ elements in order to avoid regulatory citations for data integrity issues.
