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

Siegfried Schmitt

	Siegfried Schmitt, Principal Consultant, PAREXEL International, discusses standard operating procedures for the regulatory affairs department.

Q: Our company’s quality unit performs internal audits of all departments that have to comply with healthcare regulations. During a recent internal audit of the regulatory affairs (RA) department, we noted that there were no standard operating procedures (SOPs) in place. The RA department has asked for our help and would like to know which SOPs they will have to create and follow. What advice can you give?


	
	A: The RA department must embed SOPs within a quality management system and create a quality unit responsible for maintaining it. RA departments perform activities that play a critical role in assuring product quality and patient health. Activities include preparing submissions (e.g., new drug applications or variations), label management, and pharmacovigilance. Regulatory authorities typically inspect RA departments because of complaints, recalls, or other non-conformance factors.

	In terms of implementation, many companies will create a central regulatory affairs unit (e.g., RA headquarters) with supporting RA departments distributed across other locations. These are typically referred to as affiliates. The SOPs listed in 

 are typically associated with the RA headquarters, whereby those listed in 

 are typically adopted by the RA affiliates.

	To sum up, controlled and documented processes assure compliance with the regulations, enhance the quality of all deliverables, and ultimately assure patient safety. For that reason, RA departments need to create, adopt, and implement the SOPs that cover their regulated activities. 


	When referring to this article, please cite it as S. Schmitt, “Quality System for a Regulatory Affairs Department," 

Articles

Siegfried Schmitt, Principal Consultant, PAREXEL International, discusses standard operating procedures for the regulatory affairs department.

Quality System for a Regulatory Affairs Department

Q: We are a contract manufacturing organization (CMO), specializing in chemical synthesis of APIs. Since the publication of FDA’s draft guidance,
	

Request for Quality Metrics, Guidance for Industry

 (1), in July 2015, we have been debating how to best capture and report quality metrics in our organization. What do you recommend?

As with all regulations or guidance documents, there can be various approaches to achieving compliance. Quality metrics need to be specific to each business and circumstance. For example, metrics will be different for a site that manufactures a large variety of products in multipurpose equipment in small numbers of batches, compared with a site that produces large volumes of just a couple of products in dedicated process trains.
	
	In addition, it is crucial to ensure that all parties involved understand what will be measured and how to report these metrics. Ideally, metrics should be checked for completeness and correctness before they are presented to be signed. Quality metrics should also be collated, measured, and reported in real-time, not months later in an annual report. Real-time reporting not only saves time and is more efficient, but it reduces error in reporting and allows real-time reaction of the site to metrics, as needed.
	
	The following are a few additional best practices to keep in mind when implementing quality metrics:

		Avoid using quality metrics to drive financial rewards, which can easily lead to behavior that is aimed at benefit maximization rather than improving quality.

		Understand that quality metrics alone do not drive improvements--it requires senior management to provide the required resources for these improvements.

		Achieving 100% perfection is rarely achievable, nor feasible. For example, reducing the number of deviations may be a laudable goal, but trying to have zero deviations is not plausible.

	Measuring quality metrics is not only important because it is becoming a regulatory expectation, but because it is good practice to have in place for the benefit of your company. Therefore, it is important to implement quality metrics, but you must ensure that these are applicable to your unique circumstances and are measurable.

Guidance for Industry: Request for Quality Metrics 


	When referring to this article, please cite it as S. Schmitt, "Reporting Quality Metrics to FDA," 

Siegfried Schmitt, Principal Consultant, PAREXEL International, discusses how to report quality metrics to FDA.

Reporting Quality Metrics to FDA

Q: Our company covers the entire lifecycle for our drugs, from R&D through clinical trials to commercial product. The quality management system covers good clinical practice (GCP) and current good manufacturing practice (cGMP). In a recent client audit, we received an observation: “You do not apply the same level of cGMP to clinical-trial material manufacture as you apply to commercial product.” Is this a new regulatory expectation?

	A: It is not a regulatory expectation to apply the same level of cGMP to investigational new drug (IND) and marketed products. Although it is correct that you need to apply cGMP to all your clinical-trial supplies (referred to as investigational medicinal products [IMP] in the European Union [EU] and IND in the United States) and to commercial operations, the level of CGMP differs. The reasons for this are practical constraints as well as regulatory requirements. Under FDA regulations, the manufacture of most INDs used in Phase I clinical trials is exempt from cGMPs (1) (i.e., 

 is not applicable). For INDs for clinical Phases II and III and for commercial product, cGMP applies (2, 3).

	In the EU, the relevant regulations are in 

(drug product) and Part II (drug substance/API), and IMPs are covered specifically in Annex 13 “Manufacture of Investigational Medicinal Products,” which was last updated in 2010 (4). EudraLex, and any laws and regulations laid down by EU member states, are based on 

, which applies to both IMP and marketed products (5).

	Paragraph 17 in Annex 13 summarizes the differences in cGMP for IMP and marketed product: “Production processes for investigational medicinal products are not expected to be validated to the extent necessary for routine production but premises and equipment are expected to be qualified. For sterile products, the validation of sterilizing processes should be of the same standard as for products authorized for marketing.”

	Though these guidances are useful, they will not necessarily answer all questions. The common adage supported by the majority of regulatory agencies is to apply a scientifically sound risk-based approach to compliance. More information can be found in several publications, including a widely publicized technical report by the Parenteral Drug Association (6).

	The regulators do understand that product and process knowledge will continue to grow during the lifecycle from clinical Phase I to launch and beyond. With increased understanding, companies can and need to apply more controls and move towards a fully validated process. You may wish to discuss the observation with the auditor in light of the regulations and guidance documents mentioned above.

Guidance for Industry: cGMP for Phase 1 Investigational Drugs

Draft Guidance for Industry: INDs for Phase 2 and 3 Studies of Drugs, Including Specified and Therapeutic Biotechnology Derived Products

 Parts 210 and 211.
	4. European Commission, 

EudraLex-Volume 4 Good Manufacturing Practice (GMP) Guidelines

Commission Directive 2003/94/EC on the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use

Technical Report 56 Application of Phase-Appropriate Quality System and CGMP to the Development of Therapeutic Protein Drug Substance 


	When referring to this article, please cite as S. Schmitt, "Phase-Appropriate GMP," 

Siegfried Schmitt, principal consultant, PAREXEL, discusses how the regulatory requirements for CGMPs is the different phases of drug development and manufacture.

Phase-Appropriate GMP

 Our company has been growing and expanding into new markets in recent years. Therefore, we need to revise the contents of our quality system documentation, such as standard operating procedures (SOPs), to reflect the changed circumstances. However, we find it difficult to change SOPs that require approval by more than one department. Do you have any suggestions for improving this process?

  Market expansion provides a good opportunity to review your documentation management process, ensuring timely and efficient revisions of documents, such as SOPs. The best approach for changing SOPs that require approval by more than one department is to restrict the contents of SOPs. Process documentation should be limited to only those steps included within the remit and under the control of just one group or department.

	The modern approach to a pharmaceutical quality system (PQS) recommends ‘identification of the pharmaceutical quality system processes, as well as their sequences, linkages, and interdependencies. Process maps and flow charts can be useful tools to facilitate depicting pharmaceutical quality system processes in a visual manner’ (1). This guideline has been adopted by the European Union, Japan, and the United States, as well as many other countries. These processes--such as change management, material management, or sample management--often involve several departments or groups in an organization (see Figure 1).

	Covering steps 3 and 4 in Figure 1 in one SOP would require the collaboration of departments A and C, plus their respective approvals. While this approach is 

compliant with the applicable regulations, it is discouraged for various reasons, including:

	Proposed changes to the process (e.g., timing) can be different among departments and thus can lead to conflicting situations.

	There is a potential risk that one department will impose upon another how to perform a task. This can potentially lead to a suboptimal or defective process.

	The approval process may differ among the involved parties, leading to frustrating delays and/or complications in achieving timely revisions of the procedures or instructions.

	These concerns point to the importance of restricting the contents of SOPs. In the example above, one would therefore separate the current SOP for steps three and four into separate SOPs--and the process-flow approach needn’t or shouldn’t stop here. Preparing the detailed flow for the activities within the SOP before writing any text will drive a logical and sequential descriptive procedure. All too often, this recommendation is not followed, and the sequence is reversed (i.e., the process flow follows the creation of the SOP’s text). This rarely results in a well-written and easy-to-follow SOP. An additional benefit of the process flow-based approach is that it is also aligned with other quality system approaches, such as International Organization for Standardization (ISO) 9001:2015 Quality Management Systems-Requirements (2).

:
	When referring to this article, please cite it as S.Schmitt, "Managing Market Expansion’s Effect on Procedures," 

Siegfried Schmitt, principal consultant, PAREXEL, discusses how to streamline the document management process during market expansion.

Managing Market Expansion’s Effect on Procedures

	Siegfried Schmitt, principal consultant, PAREXEL, discusses how to ensure archive records can be retrieved.

	Q. We will be replacing some instruments in our laboratory, and the data on the equipment will be archived. We are looking for a low-cost solution, such as cloud-based archives, to accomplish this while remaining compliant. Can you offer any recommendations?

	A. Your approach to archive records that are not required to run the daily business is good business sense. It is also compliant with European regulations, which state: “Data may be archived. This data should be checked for accessibility, readability and integrity. If relevant changes are to be made to the system (e.g., computer equipment or programs), then the ability to retrieve the data should be ensured and tested” (1). The corresponding US regulations can be found in 21 

 (CFR) Part 211.180 (c) and Part 11, which detail essential records and retention periods. You should note that the US requirements of 21 

 Part 11 also apply to archived data and records (2). In general, the US and EU regulations for records are very similar.

	What do these requirements mean for you? Once you have transferred the data to your archive (e.g., a cloud-based archive), you will confirm if the data can be accessed. This exercise must be repeated, as it is necessary to verify that you can actually access the data throughout the data lifecycle, which is typically several years (often in the range of 5–15 years). For this reason, it is essential to maintain the access information somewhere safe for several years.

	Laboratory data may be in some proprietary format depending on the instrument on which they were generated. If this is the case, consider how the data can be read in years to come. It is neither practical nor feasible to maintain software programs that would enable these data to be read. It is highly unlikely that the software will still run on operating systems many years from now, nor will there be many operators who would know how to use the software. A potential solution may be to standardize the data, transferring it into a generic data format.

	A key issue with archived data is maintaining a description or inventory of where the data belongs. Just because a file is named ‘injection 01 29 Oct 2011,’ this does not tell someone years from now that these data belong to the impurity profile for a stability sample for product xyz in month three for an accelerated study. How will you know what the data are, whether they are complete, and who created them and when? This demonstrates that there is no benefit in ‘dumping’ data in an archive--this must be done with the same diligence needed for archiving a paper document.

	It’s also important to consider how long you will need to store the data and what your defined retention periods are. It is well known that paper can be stored for hundreds of years and will still be legible. Experience with electronic archives extends to years, at best decades. This is where you will have to keep in mind the longevity of the electronic archive. Low-cost solutions may be tempting, but is there sufficient assurance that these will still exist at the end of your data lifecycle?

	Your data are valuable, so you will want to be able to access and retrieve them as you please. Therefore, you will need to know where your data are located. Cloud-based archives may be perfectly appropriate for your purpose, but only if you have appropriate controls over their location and access to your data. If the data were in a cloud with lax controls, who might have access to your data? What happens if your archive (e.g., cloud) changes ownership?

	By all means, explore available archiving options, including the cloud, but it is crucial to ensure your data doesn’t become another example of what is often widely labeled as the ‘digital landfill.’

, The Rules Governing Medicinal Products in the European Union, Vol. 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Part 1, Annex 11: Computerised Systems.
	2. FDA, 

Guidance for Industry Part 11, Electronic Records; Electronic Signatures-Scope and Application

 When referring to this article, please cite it as “Good Documentation Practice: Saving Data for the Long Term,” 

Siegfried Schmitt, principal consultant, PAREXEL, discusses how to ensure archive records can be retrieved.

Good Documentation Practice: Saving Data for the Long Term

	Siegfried Schmitt, principal consultant, PAREXEL, discusses how to assure compliance for automated systems.

	Q. We have recently updated our list of computerized systems that require validation, including only systems that store or display data. While all systems on this list have been validated, some were validated more than five years ago. Is this approach compliant with 21 

) Part 11?
	
	A. There is no simple yes or no answer to your question, as we must first look at your list of systems. It is essential to maintain an inventory of all systems in your facility, including those that are automated. Though US regulations do not specifically require it, it is beneficial to include the following information in the inventory list (1):

		What is the intended use of the system?

		Does the system create or store electronic records/electronic signatures?

		Does the system link to the validation documentation?

	The inventory list should have all systems in your facility listed, with a brief rationale of the underlying factors for your decision on each entry--for example, perhaps the building management system in building 101 is only used for the control of the cafeteria and is thus deemed non-GxP relevant. Based on the intended use for each system, one should be able to answer quite easily the second question regarding GxP relevance. All GxP relevant systems must be validated (2).

	It’s also worth noting that the inclusion/exclusion criteria you mentioned for systems that require validation (i.e., must store or display data) may be restrictive. There typically are many automated systems in a facility, such as manufacturing equipment that are critical to process control and product quality, without necessarily storing or displaying data. It is best to expand your criteria to prevent missing any of these systems.

	Whether validation performed prior to 2010 was adequate depends on whether or not you complied with the applicable regulations and continue to do so (2). Thus, the expectation by FDA and other regulatory agencies is that you verify in intervals (e.g., once every three years, following a major upgrade, etc.) the continued compliance status of your computerized system.

 Part 11 on Electronic Records/Electronic Signatures (ER/ES) (3, 4), where you identified a system to store ER/ES, your validation should have covered the ER/ES relevant regulations and guidance documents. Only a review of your validation documentation could determine if you did comply with all the applicable regulations, including Part 11 requirements. This is where your link to the validation documentation is helpful.

	While there are many nuances to determining compliance for certain systems, timeframes, and regulations, your inventory list is essential and the most valuable reference document. It can be used for internal use or for review during audits or inspections, but it must be complete and up to date.

EudraLex, The Rules Governing Medicinal Products in the European Union

, Vol. 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Part 1, Annex 11: Computerised Systems, accessed July 1, 2015.
	2. FDA, 

General Principles of Software Validation; Final Guidance for Industry and FDA Staff

 (FDA, January 11, 2002), accessed July 1, 2015.
	3. FDA, 

 (Government Printing Office, Washington, DC, revised April 1, 2014), accessed July 1, 2015.
	4. FDA,

Guidance for Industry Part 11, Electronic Records; Electronic Signatures--Scope and Application

 (FDA, August, 2003), accessed July 1, 2015.

 When referring to this article, please cite it as "Computerized Systems Validation,” 

Siegfried Schmitt, principal consultant, PAREXEL, discusses how to assure compliance for automated systems.