Siegfried Schmitt, PhD, is Vice President Technical at Parexel International, Siegfried.Schmitt@parexel.com.

Siegfried Schmitt

) mentions the role and responsibilities of the quality control unit in 21 

 Parts 210 and 211 (1); however, there is no mention of a ‘quality assurance unit.’ Can you advise on the correct distinction between these two entities?


	
	A. This can indeed be confusing, especially as other regulations and guidance documents refer to a ‘quality assurance system’ (2). Additionally, the European Union current good manufacturing practice (CGMP) regulations require a quality control (QC) unit and mention a quality assurance (QA) unit without being specific about the differences between these two roles (3). In general, only the tasks of the quality control unit are detailed in the regulations. The difference in the respective roles lies in the titles (4): control serves as the activity of managing, while assurance grants freedom from doubt.

	In a pharmaceutical enterprise, it is necessary to measure, test, check, or verify things such as incoming materials, in-process/finished product samples, environmental conditions, etc., which are often part of programs like environmental control or process control. These require the active involvement of the quality control unit, with the support of analytical laboratories or metrology workshops. 

	A pharmaceutical company must establish a pharmaceutical quality system (PQS) (5), which governs all regulated pharmaceutical activities, and is implemented, maintained, and owned by the quality assurance unit. A PQS provides a framework that enables a company to operate in accordance with the regulations and its marketing authorization, therefore enabling compliance. Quality assurance can be viewed as the legislative, with the QC unit being the executive. The below examples describe this difference:

		Standard operating procedures (SOPs): An operating unit within the company writes the SOP using templates and following guidance provided by QA. The QA department’s signature does not normally confirm the technical accuracy and correctness of the contents of the SOP; rather, QA’s signature on the SOP certifies that it has been written using the correct template and followed the process prescribed in the PQS. The analytical laboratory, which is part of QC, prepares the SOP for sample storage. QC’s signature on this SOP certifies the correctness and accuracy of its contents, whereas QA’s signature will only confirm adherence to the PQS.

		Audit trail reviews: These reviews are performed regularly in computerized systems used in a regulated pharmaceutical environment, such as an analytical laboratory. QA should review the audit trail with regards to compliance with the PQS and the regulations; QC should perform the review with regards to the correctness of the analytical work performed.

		Sampling: While QC prepares the sampling procedures and takes samples, QA does not perform sampling. Rather, QA reviews the sampling procedures and observes the sampling in irregular intervals--typically unannounced. QA must, however, assure that all processes are duly described and followed in compliance with the PQS and the regulations. This process of review and observation is also referred to as an internal inspection. 

	In summary, despite some apparent vagueness in regulations, the roles and responsibilities of the QC and QA units can quite easily be deduced from their respective titles, and by carefully reading the regulations.

Art 6 of EU Directives 2003/94/EC and 91/412/EEC

EudraLex Volume 4 Part 1 Chapter 2: Personnel

. 
	4. TheSage English Dictionary and Thesaurus. 
	5. ICH, 


	Vol. 41, No. 9
	September 2017
	Page: 66

	When referring to this article, please cite it as S. Schmitt, "The Role of the Quality Unit," 

Articles

The differences between the quality control and quality assurance units can be found in their names, according to Siegfried Schmitt, principal consultant at PAREXEL.

The Role of the Quality Unit

	Q: Our manufacturing facility is inspected regularly by various agencies. There are differences between these inspections, but one constant is that we always kick off with an opening presentation. Do you have any suggestions how we can make our opening presentations most effective?

	A: This is an astute observation, and it is indeed important to give the opening presentation much thought. In fact, the opening presentation is the only time when a company is in control during an inspection and is the opportunity for the company to present the information that they consider important.

	Let us consider what makes an opening presentation stand out and achieve its objectives. The main objective should be to present the company and facility being inspected in a positive light. Think of the inspectors as customers; ask yourself the following so you may provide the essential information they seek: What do they want to know? Why are they here? 

	The following are some practical suggestions to prepare for the presentation: 
	The presentation should be complete, reviewed, and approved weeks before the inspection. Trying to improve it minutes before the inspectors arrive is never a good idea. Mostly companies use programs such as Microsoft PowerPoint, which works well, so long as presentations do not become overwhelmed by unnecessary transitions or effects. 

	The length of the presentation should not exceed 30 minutes, if possible. It is not uncommon for inspectors to cut presentations short if they think that time is being wasted. One should allocate three minutes per slide, considering time for potential questions to be addressed. While additional slides can be prepared, they should be kept as backup. 

	Technology should be thoroughly checked the day before the inspection to ensure that all is in working order. A back-up copy of the presentation should be ready on a portable device, just in case. 

	The presenter can be the head of quality, the site manager, or the sales manager. The exact title or role of the chosen presenter is less important than their competency and confidence when discussing the contents of the presentation. Far too often, presenters click through a slideshow without portraying passion or genuine interest. Presenters should communicate that they are proud of their plants, quality systems, and place of work. Inspectors will pick up on a lack of enthusiasm and that often impacts inspection results.

	After the inspectors have arrived, the presentation can begin. A color copy of the slides (one slide per page) should be printed and be available for inspectors so that they can take notes and make annotations.

	A presentation’s contents should include a site layout plan, one to two key organizational charts, key operations on site, and inspection history. But what about the quality system? As one inspector put it: ‘usually the level of quality is inversely proportional to the number of times quality is mentioned in the opening presentation.’ 

	In recent years, inspectors’ time is at a premium. It is key that only essential, pertinent facts and figures are included in the slides shown, presenting a company’s commendable aspects, people, and systems. If your presentation follows these suggestions, respecting the time and needs of inspectors, you should see happy inspectors beginning their work, which will ideally lead to a positive inspection.

	When referring to this article, please cite it as S. Schmitt, “Inspections: The Value of the Opening Presentation,” 

The opening presentation gives the company a chance to put their best foot forward, according to Siegfried Schmitt, principal at PAREXEL. 

Inspections: The Value of the Opening Presentation

Q: During a recent inspection by the Chinese regulatory authority, we were informed that our quality system had not met all requirements of Chinese good manufacturing practices (GMP). We export to many countries around the world and regulatory compliance is of the utmost importance. Could you advise on how to mitigate future regulatory risk?


	
	A: It is important to understand the nuances of each regulatory authority and take the appropriate steps to fully abide by each set of standards. Some agencies wish to see their regulations specifically stated in a company’s quality system, whereas others are satisfied with a generic statement (e.g., “we comply with all applicable laws and regulations in the markets we operate in”) about compliance.

	In addition to a generic statement, consider including a list of the regulations (e.g., 21 

 Volume 4 Part II) in your quality manual or similar high-level document. It’s unclear if the inspectors felt your company had not clarified within the quality management system (QMS) which regulations it knowingly complied with. Including a list of regulations will help ensure transparency.

	It is also unclear whether your company assured compliance with all the country’s regulations and provided documented evidence. Inspectors often prefer organizations demonstrate compliance through established processes and documented evidence. All too often, companies list within their standard operating procedures (SOPs) a series of regulations pertinent to the subject of the SOP (e.g., International Council for Harmonization [ICH] Q9 in a risk management SOP). Merely listing a regulation, however, doesn’t demonstrate that you have read, understood, and implemented it into your QMS. You must have a process in which dedicated persons or teams assess regulations for their applicability to your operations, and then implement these into your QMS. Documenting this process provides the necessary proof of compliance.

	In your particular case, employees fluent in the Chinese language should review the regulations, log which regulations they reviewed for documentation purposes, and then implement the new or changed requirements from these regulations within the QMS as necessary. For example, if the cleaning SOP would require an amendment, this amendment should be noted in the change section of the document.

	It is necessary to maintain compliance with current regulations; any regulatory changes must be assessed for their impact on your QMS. This assessment may require a review of all documents in your QMS, unless you maintain a matrix (e.g., in a spreadsheet or relational database) that shows which regulation translates into which documents (e.g., SOPs) within your QMS. Such a correlation matrix has another important benefit: should you plan a change to a system, process, or document, you could easily verify if this is permissible under the regulations impacted by the change.

	It is unlikely that such a matrix is 100% complete, covering all and every regulation from every country you operate in. However, taking a detail-oriented, risk-based approach helps ensure you cover the countries and regulations most critical to your operations. 

	When referring to this article, please cite it as S. Schmitt, "Covering Global Regulations in a Quality System," 

Siegfried Schmitt, PhD, Principal Consultant at PAREXEL, discusses how to mitigate risk in a global regulatory environment.

Covering Global Regulations in a Quality System

	Q: Our quality unit is responsible for hosting audits and inspections for our manufacturing site. We are a contract manufacturer and due to our expanding client base, we are experiencing a growing number of customer audits and regulatory inspections. Can you provide advice for how to best accommodate this increased workload? 

	
	A: First, congratulations on your growing business. In terms of managing this rising number of audits and inspections, we would recommend developing procedures. Formalized processes, in addition to using the right tools, can help make the job more predictable, improve planning, and provide a higher chance of success. You may call this a playbook, or simply “Good Guide to Audits/Inspections.” Being prepared and having a defined process helps reduce uncertainty and drives efficiency.

	It is good practice to start putting together this document by getting input from all parties involved. We recommend starting at the moment an audit or inspection is announced, and then structuring it by phase, such as preparation/planning, hosting, follow up/post event, and close out.

	The guide should include roles, rather than name-specific individuals, when explaining responsibilities involved in the inspection, as this eliminates the need for many updates or changes. For each role, it is beneficial to describe each person’s particular involvement in the inspection (e.g., active or stand by/back up), what and when they are needed, where (e.g., front office or back office “war room”), and any other pertinent information. Note that some roles may only be required occasionally, such as translators.

	This playbook can be in any format suitable for your needs, but often it is in the form of a spreadsheet. A spreadsheet allows activities to easily be added into sequence and the ability to select tasks for individual roles or locations. Furthermore, completed tasks can be ticked off, together with any comments or feedback as required.
	 

	A number of documents and data are typically requested by auditors and inspectors; including, but not limited to:

		Number of out-of-specification (OOS) results

		List of standard operating procedures (SOP)

	
	Having a spreadsheet to refer back to, therefore, is crucial to staying organized and up to date with inspections. Having a running tally readily available in electronic format will greatly reduce the effort with preparations. It can also be beneficial to keep a set of printed copies of all SOPs handy, making these available upon request, which reduces time and effort during the audit or inspection. 

	Ultimately, the key to being prepared for audits and inspections is to follow the old adage: preparation, preparation, preparation. Furthermore, with practice comes experience, and with experience comes perfection. Maintaining procedures and metrics will be helpful for any inspection, especially as you expect to experience more inspections due to a growing client base. 

	When referring to this article, please cite it as S. Schmitt, "Staffing and Preparation for Audits," 

Siegfried Schmitt, PhD, principal consultant, PAREXEL, discusses how to handle audits and inspections during business expansion.

Staffing and Preparation for Audits

Q: We are an established contract manufacturer, and we are preparing for our first inspection by a foreign agency. Although we have many years of experience with our local regulators inspecting us in regular intervals, we are anxious that the foreign inspectors may have different expectations. For example, our employees are very hospitable, but we don’t want this to be seen as offering bribes. Could you provide some guidance and advice?

	A: It is indeed good practice to plan well for inspections, for both the technical and also the administrative part. There are numerous articles written on behavioral dos and don’ts during inspections, but these typically only cover how to answer questions and how to provide evidence. What’s equally important is how you treat the inspector when he comes to your site.

	Making someone’s life more comfortable and providing hospitality are good intentions, but as you point out quite rightly, it is essential not to cross the line into bribery. The following are some practical examples and ways to act during an inspection.

	Foreign inspectors need to travel to your site and most likely will have to stay a number of nights in accommodations nearby. Typically, inspectors will arrange their own travel. Nonetheless, it is simply courteous to offer assistance, such as providing a list of hotels in the vicinity to your site or modes of transportation from the nearest airports. Some inspectors may even ask for more information, such as:
	
	Will there be taxis at the train station?
	Will taxis accept credit cards, and if so, which?
	Where can I find train timetables?
	
	You could offer to pick up the inspector at the airport, train station, hotel, etc., as this may be the most sensible option. Again, the key message here is to merely offer this as a suggestion. Flights might be delayed, ATMs might not work, public transport might not run, taxis might not accept credit cards, etc. An inspector stranded in such circumstances will most likely accept a pick-up by the company.
	Hotels offer varying levels of service, which is well understood. However, good hosts will verify that the rooms reserved are suitable (i.e., are these rooms you would be comfortable staying in? Does the hotel provide basic amenities, such as mirror, hair dryer, bottled water, tea- or coffee-making facilities?). It is always best to verify to ensure a comfortable stay.

	It is also a nice gesture to offer food and drink during an inspection; but be sure to inquire if the inspectors have any allergies first.
	
	Similarly, you should ask inspectors whether the room temperature is to their liking; not everyone enjoys glacial temperatures, even in the height of summer.

	Some inspectors appreciate if they can spend time in prayer and have a quiet room to retreat to. It is nice to be cognizant of this and offer a room they can use.

	The inspectors may wish to spend the evenings, or time before or after the inspection, exploring the area to do some sightseeing or visiting specific events or exhibitions. It is fine to provide tourist information to the inspectors, as long as you do not intend to buy tickets or book tours for them.

	If you follow the gist of the above examples, you will be able to show your great hospitality without being seen as unprofessional or even attempting to bribe. These guidelines work for inspectors from all cultures. Good luck with your inspection.

	When referring to this article, please cite it as S. Schmitt,"The Human Factor in Inspections," 

Siegfried Schmitt, PhD, principal consultant, PAREXEL, discusses how to prepare for an inspection by a foreign regulatory agency.

The Human Factor in Inspections

	Siegfried Schmitt, principal consultant, PAREXEL International, discusses how to find the root cause of the problem.

	Q:Deviations in clinical trials happen, and as such, FDA requires deviations to be investigated and documented. Our company has an established deviation investigation process. What advice can you give to ensure that deviation investigations provide the most optimal corrective actions and preventive actions (CAPA)?

	A:Standard operating procedures (SOPs) for deviation investigations are generally similar from company to company, detailing a logical process flow with execution instructions, and a section on roles and responsibilities. Following a risk-based approach, deviations are classified as minor or major, requiring investigations that differ in resource requirements and detail.

	Finding the root causes of the deviation, rather than merely causal factors, is absolutely essential to follow through with CAPA, a concept that focuses on the root causes of identified problems in an attempt to ultimately prevent their recurrence.

	Root-cause investigations can be performed using a plethora of methodologies (see 

, providing the deviation investigators with all the tools they need. These tools require familiarity with the methodology and regular practice to understand which method(s) will provide the answers you are looking for. It is almost always necessary to apply two or more methodologies in order to find the root causes of a deviation.

Table I: Selected root-cause analysis methodologies.

					Define, measure, analyse, improve, control (DMAIC)

					Failure modes and effects analysis (FMEA)

					Hazard analysis and critical control points (HACCP)

					Statistical process capability analysis

	One factor that can derail the investigation is if too many operators and managers are involved in root-cause investigations. Unless the individuals regularly participate in root-cause investigations, they will not be fully familiar with either process or methodologies. Instead, it is best practice to have core teams of experienced subject matter experts (SMEs) fully support and execute all deviation investigations. This practice delivers consistency, quality, and assurance that the real root causes are found.

	Another factor is that SMEs might be tempted to mistake root causes for causal factors, since the latter would require less investment or resources to fix. This is not good practice-almost always it will be possible to find at least partial solutions that can be implemented.

	To give an example, an operator picked up the wrong tool to fasten a pipe. An investigation revealed the causal factor as ‘human error’ and the actual root causes as ‘tools not clearly and unambiguously labeled’ and ‘insufficient lighting to read the labels.’ Thus, instructing the operator in the procedure would not have resolved the problem. The solutions needed are improved labeling and lighting.

	This example addresses why deviation investigations are so often found to be lacking when reviewed by agency inspectors. These issues can be grouped like this:

		Far too many root causes assigned as ‘human error’

		Inadequate or incorrect use of methodologies

		CAPAs not addressing actual root causes.

		Of course, where human interaction occurs, human error is a possibility. Thus, regulatory agencies expect companies to take measures to either prevent or detect human errors through procedural or technical solutions. If these are applied correctly, the remaining number of deviations that truly are human error will be small (perhaps around the 10% mark).

	The source of the problem with deviation investigations is not the procedure or methodology; it typically is how root-cause analyses are being performed. Improving on that step and following up with logical CAPAs will almost certainly guarantee compliance and satisfied regulatory inspectors.


	Vol. 40, No. 9
	September 2016
	Pages: 98

	When referring to this article, please cite it as S. Schmitt, "Root Cause Analysis: Finding the Root of the Problem," 

Siegfried Schmitt, principal consultant, PAREXEL International, discusses how to find the root cause of the problem.