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. I have heard that the International Council for Harmonization’s (ICH’s) Q9 

(1) is being revised. Do you know what the industry can expect to see with the new version of the document?

	A. You have heard correctly. At the December 2019 PDA Quality Week, attendees learned that ICH Q9 Expert Working Group (EWG) Members will start working on revising the document at the 2020 spring meeting in Vancouver, Canada. The guideline was first published in 2005 and, at the time of publication, it offered an overview of general quality risk management (QRM) principles including an example of a risk management lifecycle approach. In addition, the guideline provided a list of risk tools and quality system areas critical to establishing and maintaining an effective risk management program. As stated on the ICH website, “This Guideline provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality. These aspects include development, manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances, drug (medicinal) products, biological and biotechnological products (including the use of raw materials, solvents, excipients, packaging and labeling materials in drug (medicinal) products, biological and biotechnological products)” (2).

	Over the past 15 years, the industry has tried to implement QRM principles as a part of their quality management systems. The introduction to ICH Q9 states, “Although there are some examples of the use of QRM in the Pharma industry today, they are limited and do not represent the full contributions that risk management has to offer” (1). This statement still holds true today as citations for incomplete corrective action and preventive action (CAPA)/investigations typically ranks in the top five inspectional observations for the pharmaceutical and biopharmaceutical industries. To date, QRM implementation has used simple investigational tools to solve simple problems. In addition, the industry seems to struggle with providing data or metrics to demonstrate that information from investigation results have been used to effect continuous improvement. Speakers at the PDA conference also talked about some of the challenges the industry has faced in trying to implement QRM. These reasons include using QRM to justify actions instead of assessing risk and substituting risk-assessment tools for the QRM process (3). Other problems that seem to prevent effective implementation of QRM is using it to confirm a hypothesis or rationalize non-compliance situations (4).

	Understanding the original purpose of ICH Q9 is crucial in understanding what the industry might see in terms of its revision. Current thinking, as discussed at the PDA conference, is that the EWG will focus on clarifying certain aspects of the document’s concepts in an addendum to the document. Basically, the document itself will probably not be revised but instead will be enhanced by creating a partnering document that will focus more on ‘how to do’ and less on ‘what to do’ with respect to QRM. The ICH Steering Committee approved the Q9 revised concept paper in November 2019, and the EWG is expected to begin working on the revision at the ICH spring meeting. A development integrated addendum according to ICH parlance means only specific sections of the guideline will be targeted for revision but a complete revision is off the table (4).

	It is unclear whether the ICH Q9 revision will become more of a QRM tutorial or whether it will clarify what needs to be achieved in order for a QRM system to be considered robust and effective. To accomplish the vision of making appropriate and acceptable risk-based decisions, QRM needs to be iterative and not a once-and-done exercise within the quality management system. An effective QRM system should implement a risk review program to facilitate continuous improvement efforts.

	At the PDA conference, attendees were given an opportunity to tell EWG representatives what they felt needed to be added or clarified in ICH Q9. They were asked to answer the following question: If you could recommend changes to ICH Q9, 

, what would you recommend? The information will be provided to the EWG representatives for consideration when they begin work enhancing the document and will be posted on the PDA Letter website. Some of the recommendations were as follows:

		Ensure that QRM is recognized by FDA as a required quality system. Currently, the European Medicines Agency (EMA) is more likely to inspect for QRM. There should be consensus regarding more alignment between Europe and the United States on QRM.

		Remove the perception that QRM is not enforced and not part of the quality system.

		Include language that drives a holistic systems approach.

		Provide examples or a case study featuring a QRM tool.

		Expand clarity on the training and documentation needed for applying QRM.

		Clarify difference between risk evaluation and risk control.

		Define roles, particularly decision-maker roles.

		Provide more guidance on risk acceptance.

		Provide additional examples such as how to apply QRM to legacy products.

		Include examples of communication flow.

		Clarify levels of maturity for QRM in enterprise risk management.

		Offer strategies for demonstrating QRM compliance to regulators.

		Recommend how to prioritize compliance versus patient safety concerns.

	Bottom line, ICH Q9 is scheduled to be revised, but the sections to be revised have yet to be identified. There is no timeline available for completion of the revision. Industry has provided feedback to representatives of the EWG on some of their thoughts on what needs to be clarified so that implementation of an effective QRM program can be achieved, and the industry can drive toward continuous improvement realizing what Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, described as, “A maximally efficient, agile, flexible, pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight” (5).

, Step 4 version (2005).
	2. ICH, Quality Guidelines, 


	3. H. Gregg Claycamp, “Quality Risk Management at 15: Are QRM Resilence and Process Maturity on the Horizon,” presentation at 2019 PDA Quality Week (Washington, DC, Dec. 9-10, 2019.
	4. S. Ronninger, “15 Years of ICH Q9: Practical Implementation & Pitfalls,” presentation at 2019 PDA Quality Week (Washington, DC, Dec. 9–10, 2019).
	5. Office of Pharmaceutical Quality, 

FDA Pharmaceutical Quality Oversight, One Quality Voice


	Vol. 44, No. 2
	February 2020
	Pages: 58, 57

	When referring to this article, please cite it as S. Schniepp, "ICH to Revise Quality Risk Management Guideline," 

Articles

ICH will be taking industry comments under consideration when it revises its Q9 guideline in order to clarify QRM requirements, says Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow, Regulatory Compliance Associates.

ICH to Revise Quality Risk Management Guideline

The purpose of a quality risk management plan is to help ensure continued compliance with regulatory requirements, such as good manufacturing practices or good laboratory practices, when events occur during manufacturing that potentially impact patient safety and product quality.

	Learn the four basic elements that should be included in a quality risk management plan.

Pharmaceutical Technology’s December 2019 Regulatory Sourcebook

eBook: Regulatory Sourcebook, December 2019
	December 2019
	Pages: 12–13

	When referring to this article, please cite it as S. Schneipp, “Quality Risk Management Plans Create Effective Quality Systems," 

Pharmaceutical Technology Regulatory Sourcebook eBook

Quality risk management plans provide identified actions to ensure a continuous supply of safe
and effective drug products


Quality Risk Management Plans Create Effective Quality Systems

Q. We have recently contracted with a client to manufacture a pre-filled syringe. Can you tell me what changes I should make to my investigation procedure when investigating deviations and complaints for this type of combination product?

	A. The purpose of performing an investigation into a deviation is to determine why the deviation happened and what impact it has on the product quality. It is important to determine the ‘root cause’ of the deviation. The process used in industry to determine the root cause is the investigation procedure. The investigator should review various quality and manufacturing systems to determine whether they were the cause of the deviation under investigation. Each investigation must address the following elements: root cause, impact to the material or product, the immediate correction taken, the corrective action to prevent re-occurrence for specific product/operation, and the preventive action taken to prevent re-occurrence for all products/operations. The complication with combination products is that the investigation procedure needs to accommodate both the drug and device components of the product.

	One size does not fit all. Simple errors require simple corrections, while serious deviations require broader investigations. The complexity of the investigation is related not only to the seriousness of the investigation but also to the complexity of the factors that could influence the outcome. The best trait to have as an investigator is inquisitiveness. Continuing to ask questions and avoiding assumptions leads to better outcomes. Using other tools, such as fishbone diagrams and determination of most probable number (MPN), are to be encouraged, but they do not take the place of asking questions. The best way to ensure events are not related is to try and relate them, not the other way around. Keep in mind that human error is rarely a true root cause. In addition, you should always verify the facts of the investigation.

	Once you develop an investigational history with the pre-filled syringe, include a historical review in your investigation. This review should determine if the deviation occurred with this or other products, with the specific manufacturing line or other manufacturing lines, and/or with one group of operators or multiple sets of operators. The historical review can help you prioritize the resources and aid in your detailed system review.

	In the situation you described, you can provide a historical review for the drug component part of the pre-filled syringe but you will need to outreach to the syringe supplier and your client to start developing the historical review for the device component until you have a body of knowledge for this component. The best way to obtain necessary information for the investigation of the device component is to establish a communication channel between your company and the supplier of the syringe, with your client’s knowledge and approval. It would be wise to codify what information you would like to have access to through quality agreements with both the syringe supplier and your client.

	The detailed investigation should include a review of equipment and machinery, the manufacturing process, the raw materials used in manufacturing, the specifications, the environment, and finally, the operators. These systems are not the only areas you should look at but are the most probable areas where you will uncover the root cause of the deviation. The raw material or supplier system may need to be updated to accommodate the syringe supplier. Rather than rely on the client’s evaluation and audit of the syringe supplier, it would be beneficial for your company to perform their own audit and assessment and establish a quality agreement. Inform your client that you want to develop your relationship with the syringe supplier to assure their assistance and timely responses for an investigation; make sure you inform your client when you do reach out to the supplier during an investigation. This will help facilitate both your client’s and the syringe supplier’s involvement and open the lines of communication should you require either of their assistance for an investigation.

	Results from the investigation must be documented. The written narrative should clearly explain what happened, when it happened, and who was involved or observed what happened. The narrative documents the solution and rationale for the root cause that was determined through the investigation process. This should also include any action being taken by the syringe supplier should this component be implicated in the investigation.

	The key to any successful investigation is not stopping too soon, and assuming you have the solution prior to completing the investigation. If you follow your investigation procedure, make adjustments to accommodate the new component, and thoroughly document your results, you should have an acceptable investigation regardless of whether you are manufacturing a traditional product or a combination product. 


	Vol. 43, No. 12
	December 2019
	Page: 46

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

Investigating deviations of combination products needs to accommodate both the drug and device components, says Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow, Regulatory Compliance Associates.


Investigating Combination  Product Failures

Q: I am familiar with the term ALCOA as it relates to data integrity, but lately, I have heard people refer to ALCOA+. Can you explain what impact this new acronym has on my company’s data integrity program?

	A: Before we get into the reason for the additions to ALCOA, referred to as ALCOA+, we should review what both of the acronyms mean. The acronym ALCOA requires data be attributable, legible, contemporaneous, original, and accurate. The acronym ALCOA+ adds the concepts that, in addition to ALCOA, data also needs to be complete, consistent, enduring, and available. It is important to understand what each element of ALCOA and ALCOA+ mean in order to apply the concepts appropriately with respect to a company’s records. The following are some general definitions, paraphrased from the Pharmaceutical Inspection Co-operation Scheme (PIC/S) (1), that can be used for understanding the elements of ALCOA and ALCOA+:

		Attributable: The data generated or collected must be traceable back to the individual who generated the information.

		Legible: The data recorded must be readable and permanent.

		Contemporaneous: The results, measurements, etc. must be recorded at the time the work is performed.

		Original: Original or source data are the record, report, notebook etc. where the data point was initially recorded.

		Accurate: The data recorded must be complete, consistent, truthful, and representative of facts.

		Complete: Information that is critical to recreating and understanding an event. This would include any repeat or reanalysis performed on a laboratory test sample.

		Consistent: The data are presented, recorded, dated, or time-stamped in the expected and defined sequence.

		Enduring: The data or information must be maintained, intact, and accessible throughout their defined retention period.

		Available: The data or information must be able to be accessed at any time during the defined retention period.

	Data integrity has always concerned regulatory authorities, but it is important to understand what is prompting the renewed discussion of ALCOA and the introduction of ALCOA+ when discussing data integrity issues. Many of the concepts for ALCOA have been captured in the regulations as far back as 1978. Since that time, the industry has changed dramatically. The generic-drug industry has grown and in the United States alone accounts for more than 80% of the prescriptions written today (2). Coupled with the emergence of biosimilars, virtual companies, contract manufacturing organizations, rapid advances in automation and information technology, and the globalization of the industry have resulted in reinterpretation of the attributes associated with maintaining the integrity of data throughout the product lifecycle, whether those data are generated from electronic, paper-based, or hybrid systems. In addition, there has been an increase in citations internationally by the FDA, European Medicines Agency (EMA), Medicines and Healthcare products Regulatory Agency (MHRA), World Health Organization (WHO), and other health authorities. These changes and increased violations have brought about a resurgence and need to reeducate the industry on the basic principles and concepts regarding the proper control of data used to support the quality and safety of medicines.

	The ALCOA acronym has been used since the 1990s; however, the requirements governing data elements have been in regulations for a much longer period of time. 

chapter 4 states, “Suitable controls should be implemented to ensure the accuracy, integrity, availability, and legibility of documents. Instruction documents should be free from errors and available in writing” (3). The US 

) refers to these elements in various sections of the regulations (4–8). An example for language speaking to the element of attributable is in 21 

 211.194(a)(7), which states, “The initials or signature of the person who performs each test and the date(s) the tests were performed.” Language in 21 

 58.130 (e) addresses the elements of contemporaneous and legible by stating, “All data generated during the conduct of a nonclinical laboratory study, except those that are generated by automated data collection systems, shall be recorded directly, promptly, and legibly in ink. All data entries shall be dated on the date of entry and signed or initialed by the person entering the data.”

	Recent documents issued by WHO (9) and the PIC/S (1) have added to the original ALCOA attributes as indicated above. The PIC/S document actually states, “Some key concepts of GDocPs are summarized by the acronym ALCOA: Attributable, Legible, Contemporaneous, Original, and Accurate. The following attributes can be added to the list: Complete, Consistent, Enduring, and Available. Together, these expectations ensure that events are properly documented and the data can be used to support informed decisions.” WHO refers to ALCOA+ in the title of Appendix 1 to their 2018 document. The last two documents also address the concept of quality culture (10). The impact to your organization is that the quality culture must ensure that data supporting the quality and safety of your product must now meet the ALCOA+ elements in order to avoid regulatory citations for data integrity issues.

Draft Guidance: Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments

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

 11: Electronic Records; Electronic Signatures
	5.  21 

 58: Good Laboratory Practice for Nonclinical Laboratory Studies
	6.  21 

 211: Current Good Manufacturing Practice for Finished Pharmaceuticals
	7.  21 

 212.50: Current Good Manufacturing for Positron Emission Tomography Drugs
	8.  21 

 820: Quality System Regulation
	9.  WHO, 

Annex 5, Guidance on Good Data and Record Management Practices


	Vol. 43, No. 10
	October 2019
	Page: 77

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

Data supporting the quality and safety of product must meet the ALCOA+ elements in order to avoid regulatory citations for data integrity issues, says Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow, Regulatory Compliance Associates.

ALCOA+ and Data Integrity

Q: I am in the quality assurance department at my company. We are a small start-up, and one of my jobs is to develop a quality risk management plan. Can you give me some advice on what I need to consider when putting this plan together?

	A: A well-written and well-implemented quality risk management plan is an integral and valuable element of an effective quality system. During the development and manufacturing of pharmaceutical products, the bottom line is that things can and will go wrong. The purpose of a quality risk management plan is to help ensure continued compliance with regulatory requirements, such as good manufacturing practices or good laboratory practices, when events occur during manufacturing that potentially impact patient safety and product quality.

	International Council for Harmonization (ICH) Q9 states, “Two primary principles of quality risk management are: the evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; and, the level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk” (1).

	In developing your company’s plan, you will need to consider all aspects of the operation that impact the product. Managing your company’s risk with a well-defined plan may help reduce the activities associated with poor quality and inefficiencies associated with the product and the process, such as a reduction in deviations/investigations, scrap or wasted materials, customer complaints, and product yield.

	The concept is to evaluate all aspects of the manufacturing process and identify areas of vulnerability. These vulnerabilities need to be assessed for their impact on the operation and the potential level of risk they pose. A well-written quality risk management plan is an ongoing process requiring rigorous documentation throughout the product lifecycle. It provides a solid rationale for how to improve efficiency and spend resources on the important activities to improve product quality rather than on low-risk activities that have little to no impact.

	There are four basic elements that should be included in a quality risk management plan. The first element is to perform an analysis of the identified risk associated with the operations. For example, if your product is being produced using an older manufacturing line, there is a risk that the line will experience frequent breakdowns.

	The second step is to evaluate the risk in terms of its impact on your ability to supply a quality product. In this case, frequent shut downs can lead to product rejections, yield loss, and potential drug shortages. Once the risk has been identified and the impact evaluated, controls to mitigate the potential situation need to be identified and implemented. Some of the possible mitigation control strategies might include ensuring there are appropriate change parts for the line in inventory or plans to qualify the product production on a new more modern manufacturing line.

	The last key element needed is data input and management. The data evaluated should be able to indicate if and when you need to employ one of your control strategies. In this simple scenario, an increase in down time on the line or a steady decrease in yield could be indicators that the manufacturing line is headed for a catastrophic failure and steps need to be taken to prevent a drug shortage situation.

	The above discussion is only an example of a risk assessment in one area of an operation. Other areas of the process need to be evaluated for potential vulnerabilities and risk. These areas include an evaluation of the reliability of raw material suppliers, stability and compliance of contractual suppliers (e.g., contract manufacturing organizations, contract test organizations), age and reliability of laboratory test equipment, etc. In other words, a solid, well-written and dynamic quality risk management plan will evaluate the overall organization, identify high-risk vulnerabilities, identify strategies for mitigation of the high-risk vulnerabilities, and rely on data to perform continuous monitoring of the vulnerabilities. And, of course, the plan will provide the appropriate documentation and rationale for the decisions.

	Implementing a quality risk management plan in an organization can also be challenging. It needs to be introduced and discussed with all applicable function personnel involved in the operations including, but not limited to, finance, manufacturing, regulatory affairs, purchasing, auditing, and senior management. The plan should be dynamic and should be modified as situations change.

	Let’s say you produce a product and you have a single-source supplier for one of your excipients. You have audited the supplier and have identified some significant gaps in their quality system. You identify this vulnerability in your quality risk management plan and indicate it is a high-risk item because of the lack of compliance of the excipient vendor. One of your mitigation strategies might be to qualify an alternate supplier for the excipient. Once you have qualified that alternate supplier, you need to update your plan to downgrade the risk because you have taken the appropriate steps to mitigate it and eliminate the identified vulnerability.

	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.


	Vol. 43, No. 8
	August 2019
	Pages 50, 49

	When referring to this article, please cite it as S. Schniepp, "Quality Risk Management Plans Create Effective Quality Systems," 

Quality risk management plans provide identified actions to 
ensure a continuous supply of safe and effective drug products, says Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow, Regulatory Compliance Associates.


Q. I’m responsible for quality at a small, virtual startup company, and we contract out all of our activities. I’m working on documentation to contract out our product testing and was wondering what information there is regarding quality agreements and laboratory investigations.

	A. The best place to start is to take a critical look at existing guidance documents and regulations that govern quality agreements and out-of-specification (OOS) investigations.

	The basic philosophy when establishing any quality agreement is to understand that the contract provider and contract giver are partners and their behaviors reflect on each other. The 21 

) 200.10(b) confirms this concept by stating: “The Food and Drug Administration is aware that many manufacturers of pharmaceutical products utilize extramural independent contract facilities, such as testing laboratories, contract packers or labelers, and custom grinders, and regards extramural facilities as an extension of the manufacturer’s own facility” (1).  The next document to review for quality agreements is the FDA guideline titled 

Contract Manufacturing Arrangements for Drugs: Quality Agreements

. Section B, Elements of a Quality Agreement, Part e. Laboratory controls states that a quality agreement should include: “Designation of responsibility for investigating deviations, discrepancies, failures, out-of-specification results, and out-of-trend results in the laboratory, and for sharing reports of such investigations” (2). This confirms that the responsibility for OOS investigations is shared and communication between the contract giver and contract provider is critical. The European Union also addresses the need for a relationship between you and your outsourced laboratory in 

, Chapter 7 (7.15) on Outsourced Activities by stating: “The Contract should describe clearly who undertakes each step of the outsourced activity, e.g. knowledge management, technology transfer, supply chain, subcontracting, quality and purchasing of materials, testing and releasing materials, undertaking production and quality controls (including in-process controls, sampling and analysis)” (3).

	The above regulations establish the need for quality agreements that cover laboratory activities but doesn’t define what needs to be in an OOS procedure. The EU addresses the need to investigate OOSs in their GMPs. 

 Part 1, Section 6.35 states, “Out-of-specification or significant atypical trends should be investigated. Any confirmed out of specification result, or significant negative trend, affecting product batches released on the market should be reported to the relevant competent authorities. The possible impact on batches on the market should be considered in accordance with Chapter 8 of the GMP Guide and in consultation with the relevant competent authorities” (4). Part 2 of the EU GMP guide for APIs states in section 11.15 that: “Any out-of-specification result obtained should be investigated and documented according to a procedure. This procedure should require analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions. Any re-sampling and/or retesting after OOS results should be performed according to a documented procedure” (5).

	The best guidance, however, on conducting OOS investigations is the information provided in FDA’s 

Guidance for Industry, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production

 (6). The responsibilities for the laboratory analyst and supervisor are clearly defined in this guidance and should be reflected in any laboratory OOS procedure. A well-written standard operating procedure (SOP) on OOSs should require investigations to be thorough, timely, unbiased, well documented, and scientifically sound. Often, the procedure will contain a checklist that assists in identifying obvious laboratory errors. The checklist assesses the suitability of analyst qualification and training, use of correct procedure and specification, the calibration and performance of the equipment, correct preparation of test solutions and dilutions, use of proper reagents and standards, calculations, etc. A thorough checklist and analyst documentation are critical in identifying true laboratory error. The SOP should also discuss the sample retesting requirements when a true laboratory error is determined to be the cause of the OOS.

	The most important and critical element for OOS investigations is specifying the timeliness. This should be stipulated in the SOP and, in most cases, the investigation into the OOS, from the laboratory perspective, should be concluded in 24 hours or less. The expectation of when the contract lab will inform you of any OOS obtained should be clearly defined in your quality agreement. The sooner a laboratory error can be ruled out as the cause of the OOS result, the sooner the full-blown manufacturing investigation can be started.

	Taking the time to establish a quality agreement and investigate the details of their OOS procedure is the first step in establishing a good working relationship with your contract test laboratory. This working relationship will become invaluable when an OOS occurs. The final product testing procedure for OOSs isn’t the only one you need to review, however. You should also look at the quality agreement and OOS procedure being used by your manufacturer for in-process test results, assuming they are different entities. The same information required in the final product OOS procedure should be the same for in-process testing.

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

 (FDA, November 2016).
	3. European Commission, 

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

, Chapter 7, Outsourced Activities (EC, January 31, 2013).
	4. EC, 

EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Part 1

, Chapter 6: Quality Control (EC, October 2014).
	5. EC, 

EudraLex, The Rules Governing Medicinal Products in the European Union Volume 4, Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Part II: Basic Requirements for Active Substances used as Starting Materials

Guidance for Industry, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical 


	Vol. 43, No. 6
	June 2019
	Pages 50, 49

	When referring to this article, please cite it as S. Schniepp, "Quality Agreements and Out-of-Specification Investigations," 

A good working relationship between sponsor and contractor will become invaluable when an OOS occurs, says Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow, Regulatory Compliance Associates.