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 am a regulatory professional working for a small company with a product in the early stages of development. Can you tell me when I need to submit the extractable/leachable information for my product?

	A: There is a lot of information on what extractables and leachables are but there is little information on when this information should be submitted to the regulatory authorities. The best place to start in answering your question is to define what extractables and leachables (E&L) are and why they are considered important.

	Extractables are defined as chemical compounds that can be pulled from the primary container/closure components into the drug product. Basically, they are generated by the product and the packaging interacting over time, usually in the presence of a solvent under extreme condition of time and temperature.

	Leachables are slightly different and are defined as compounds that leach or migrate into the product from the interaction between the product and the container/closure system.

	The regulatory requirements that justify performing E&L studies are defined by 21 

) 211.94(a), which states “Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements” (1). Regulation 21 

600.11(h) states, “All final containers and closures shall be made of material that will not hasten the deterioration of the product or otherwise render it less suitable for the intended use. All final containers and closures shall be clean and free of surface solids, leachable contaminants, and other materials that will hasten the deterioration of the product or otherwise render it less suitable for the intended use” (2).

	While the regulations in the United States seem to deal with extractable/leachables from the container/closure system, when deciding what to submit in your registration you should also consider your manufacturing equipment as potential sources of extractables and leachables.

	This can include, but is not limited to, filters, tubing, and/or equipment materials of construction as indicated in the European regulations.

Volume 4, Part 1, Chapter 3 addresses the extractable/leachable concept by stating, “Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive, or absorptive to such an extent that it will affect the quality of the product and thus present a hazard” (3). Traditionally, E&L data were gathered and submitted in the late stages of the drug development process. Packaging suppliers were often able to provide an extractable/leachable package for their materials to the pharmaceutical manufacturer in a format that could be submitted directly to the agencies. Lately, regulatory authorities are requesting this type of information for early stage clinical trial material. This change seems to have come about during the past few years. The extractables and leachables profile in clinical trial material has become a growing concern for regulatory authorities, mostly due to advances including unique packaging materials, new and novel formulations, new drug delivery systems, new combination products being introduced, the emergence of biologics and biosimilars, and the increasing use of single-use disposables systems for manufacturing.

	Why we need to submit this information is clear, but when to submit the E&L data depends on the product type, the container and closure system being used, as well as the materials and equipment used in manufacturing. If you are developing a generic with the same active and packaging components as the brand drug, the E&L report can be submitted and be available later in the process.

	If this is a new novel product associated with clinical trials or an old active being reformulated into a new dosage form (e.g., from a tablet to an injection) then you should probably have the E&L report much earlier in the process.

	If you are updating the manufacturing process of an old product to use single-use disposable systems, you should include the E&L information as early in the filing update as possible. If you are developing a new, novel product using unique packaging components and new manufacturing advancements, this information should be evaluated early in the development of the product and be available to regulators as soon as is feasible.

	Bottom line, there is no clear rule or guidance on when you need to submit E&L data. It depends on the type of product, the packaging materials being used, and the process and materials used to manufacture the product. Performing a risk evaluation on your product by asking the above questions can help your company determine when to have the extractable/leachable information available so the approval process is not delayed, and your product can be available for patients as soon as possible.

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

, Volume 4, Good Manufacturing Practice Guidelines, Part 1, Chapter 3 (European Commission, March 1, 2015).

	When referring to this article, please cite it as S. Schniepp, "Submitting Extractables and Leachables Data to Regulators," 

Articles

The type of product, the packaging materials being used, and the process and materials used to manufacture the product will determine when E&L data should be submitted to regulators, says Susan J. Schniepp, executive vice-president, Post-approval Pharmaceuticals and distinguished fellow at Regulatory Compliance Associates.


Submitting Extractables and Leachables Data to Regulators

Q. I head up the quality control laboratory for a contract manufacturer. Business has been increasing and the laboratory operations are strained, so I am considering outsourcing some of the analytical methods. Can you offer some advice on what I need to consider in choosing a contract test laboratory?

	A. When outsourcing any operation, the primary consideration should always be determining the capabilities of the service provider, in this case a contract test laboratory. This assessment depends on a number of factors including what methods for which products are being considered for outsourcing.

	It is crucial to be transparent with your clients, so the first step is to inform them of your intent to outsource some of the analytical methods traditionally performed by your laboratory. They may have experience with outsourcing analytical methods and may be able to offer advice about what to review when choosing a testing facility. They might also have objections to the further outsourcing of their methods, and this concern should be considered when determining which methods are suitable for outsourced testing.

	The next step should be to perform an audit of the facility you are thinking of using for this activity. During the audit, you want to focus on several areas including the support you will receive during the transfer and validation/verification activities for the methods being outsourced. Some of the methods to be transferred may be proprietary and some may be compendial; the detail involved in transferring them will vary. Either way, outsourcing testing for just one product means multiple methods will be involved during the transfer activities, so it is critical that the test laboratory has a process for onboarding new methods in a timely and efficient manner. Attention should also be paid to how the testing facility maintains and calibrates its equipment and the qualifications of the analysts that are responsible for the material testing.

	Particular attention should be paid to how the contract laboratory handles out-of-specification (OOS) investigations. The general rule is that the laboratory that generated that data owns the analytical data, and therefore, they are responsible for performing any OOS investigations. What you need to focus on for an OOS evaluation is to determine if the contractor’s standard operating procedure is in compliance with FDA expectations (1) and what their communication scheme is for notifying clients when an OOS occurs. The laboratory that generated the data is really the only entity that can verify whether the OOS was a result of laboratory error or if the investigation into the result needs to be expanded to manufacturing. It is important that the contract test laboratory has an open and transparent relationship with their client and that the client has an open and transparent relationship with their client. A robust communication scheme and an open and transparent relationship are crucial for quickly determining the direction of the investigation and ultimately the determination of the final product disposition. All parties in the relationship should be willing to discuss and disclose any method issues that arise. Any reluctance in establishing open communication channels with all parties in the relationship should be considered a red flag.

	Once the audit is complete and you have decided on the methods to be outsourced, you need to construct a quality agreement (2,3) with the laboratory. Defining the responsibilities that might come up over the course of the agreement is a critical step in establishing a long-term productive relationship. Some responsibilities that should be discussed include who will monitor the compendia for method changes and maintaining the stability of reference standards, as well as the proper receipt and handing of the testing samples. Another responsibility that needs to be discussed and clearly defined is who is responsible for initiating and approving change controls for method changes. Clearly defining responsibilities upfront will help to eliminate disagreements and testing delays when issues arise.

	Another consideration that needs to be discussed is the handling and maintenance of the documentation that supports the suitability of the methods. Both the test laboratory and the client should have documentation that supports the use of the methods. If the testing being done has been contracted by a CMO on behalf of a client, the client should also have the documentation supporting the method. The documentation to be shared should include, but not limited to, method development reports, validation and technical transfer/protocol reports, change controls, final test results, OOS investigation reports, and documentation that supports the shipping, receipt, and proper handling of the test samples. The sharing of these data is crucial in establishing continuity between the parties in the event of regulatory inspections or inquiries.

	Outsourcing analytical methods is a critical activity that can affect the operations of the contract test laboratory, the contract manufacturer, and the product owner. Assuring the veracity and the validity of the data is key in defining the success of the relationship and depends on open communication channels between all the parties involved. Establishing a robust quality agreement with the unambiguous delineation of responsibilities and an effective communication scheme will make the outsourcing of test methods a successful experience for the parties involved.

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

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

EudraLex Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use

, Chapter 7, Outsourced Activities (EC, Jan. 31, 2013).


	Vol. 42, No. 6
	June 2018
	Pages: 54, 53

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

Open communication channels between all the parties involved is key when outsourcing analytical methods, says Susan Schniepp, distinguished fellow at Regulatory Compliance Associates.

Outsourcing Analytical Methods

Q. I work in the warehouse and am responsible for maintaining the paperwork associated with incoming and outgoing shipments, including the certificates of analysis (CoA). Can you explain what should be on CoAs and how they relate to GMP compliance?

	A. The International Pharmaceutical Excipients Council defines a CoA as “a legal document that certifies the quality of the excipient and demonstrates the batch conforms to defined specifications, has been manufactured under excipient GMP, and is suitable for use in pharmaceuticals” (1). The same definition can also apply to finished product. Basically, it is a document that confirms a product (an API, excipient, or final product) meets defined and expected criteria that render it suitable for use. It is typically issued by the quality assurance department and lists the actual test results performed as compared to the specification range for the various parameters tested. In addition to the test results and specification range, the CoA should also list the batch number or lot number of the material, the manufacturer and their location, the date the material was produced and, if applicable, the expiration date of the particular material associated with the CoA. It should also have the identity and signature of the person who approved the certificate along with the date of approval. The World Health Organization (WHO) has a document on their website titled, “Model Certificate of Analysis”. This document has a comprehensive list of information suitable to be included in a CoA. The model CoA was developed in conjunction with the 

Guidelines on the Implementation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce

	The CoA plays an important role in GMP compliance. The safety of the pharmaceutical supply chain is of concern to regulators, manufacturers, practitioners, and patients. The process of assuring the suitability of suppliers of pharmaceutical ingredients or products typically starts with an audit. Once the audit is completed and the supplier has been approved, the purchasers need to be able to monitor the credibility of their suppliers. CoAs help because they assure the continued quality of the product by providing “a summary of testing results on samples of products or materials together with the evaluation for compliance to a stated specification” (3). The European regulations require that “Authentic Certificates of Analysis should be issued for each batch ….” (4).

	The veracity of the CoA, however, still needs to be confirmed by the purchaser. When a supplier is new, the results of the CoA are usually confirmed for each shipment of the material by performing independent verification of the CoA results. Once a history of reliable and accurate results from the supplier is established, the purchaser will often perform skip lot testing, in which they verify the CoA results on a defined periodic basis, with the exception of the identity test, which should be performed for each shipment of material received (5).

	Not all materials need to have the results of the CoAs retested to assure their accuracy. Some latitude is given for drug product containers and closures. Some of the tests that need to be performed to verify the results on the CoA for containers and closures may not be practical for the purchaser to perform. In this case, the CoA becomes the evidentiary proof that the material was safe for use. The 21 

 states, “Containers and closures shall be tested for conformity with all appropriate written specifications. In lieu of such testing by the manufacturer, a certificate of testing may be accepted from the supplier, provided that at least a visual identification is conducted on such containers/closures by the manufacturer…” (6). The purchaser still needs to establish the reliability of the container/closure suppliers through the audit process, but CoAs can be used to help determine the consistency of the supplier over a period of time by comparing and trending the CoA results. 

	CoAs are important documents for ensuring the safety of the supply chain. They allow users of pharmaceutical ingredients to monitor and trend the reliability of their suppliers over time and they provide information to the practitioner and patient that the product they are prescribing has meet the necessary requirements. The information contained in these documents is important for establishing the suitability of all the materials and their suppliers (API, excipients, components, containers, closures) used to manufacturer a pharmaceutical product. Using the CoA to track all your suppliers’ reliability over time just makes good business sense.

Certificate of Analysis Guide for Pharmaceutical Excipients, International Pharmaceutical Excipients Council 

EudraLex Volume 4, Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use

, Part I, Basic Requirements for Medicinal Products, Chapter 4: Documentation (EC, 2010).

EudraLex Volume 4, Good Manufacturing Practice, Medicinal Products for Human and Veterinarian Use

, Part II: Basic Requirements for Active Substances used as Starting Materials (EC, 2014).

 211.84(d)(2), Testing and approval or rejection of components, drug product containers, and closures. 

 211.84(d)(3), Testing and approval or rejection of components, drug product containers, and closures.

	When referring to this article, please cite it as S. Schniepp, "CoAs Help Secure the Supply Chain" 

Certificates of analysis can be used to monitor the reliability of products and their suppliers, says Susan Schniepp, distinguished fellow at Regulatory Compliance Associates.


CoAs Help Secure the Supply Chain

Q. I work in the quality and regulatory departments of a contract manufacturer. We have clients with products in various stages of development that are using multiple contracts with multiple services providers for various stages of the manufacturing process. I always struggle with knowing which level of current good manufacturing practices (cGMPs) apply to different development stages. Can you provide some guidance on this point?


	
	A. In today’s pharmaceutical environment, it is not uncommon for more than one company to be involved in the development of a product. Virtual companies may use the services of a contract laboratory, a contract manufacturer, a contract research organization (CRO), etc., to develop their products from conception to market approval. Some of these relationships can be complex, so it is important for every organization involved in the drug development process to be familiar with what the applicable GMPs are and at which stage of the development process they apply (1-4).

	Areas to be reviewed to determine the appropriate level of control needed in concert with the phase development stage include: level of validation of test methods, level of detail needed in batch records, level of control needed on incoming materials, and facility and equipment controls. An example is qualifying raw materials. In Phase I/II of the development process, you may only decide to document the source and quality of the material used to produce the product;  when you enter into Phase III you will want to qualify your supplier and establish a quality agreement in addition to the material qualification.

	Although not all GMP requirements apply to products in the early stages of development, the requirements for change control and deviation investigation should be robust and utilized at all stages of product development. The information documented in change control and as part of an investigation helps ensure that process improvements are efficient and do not repeat strategies that were discounted during earlier stages in the development process. It also helps to capture the product and process history needed in the later phases of development for the process validation activities. 

	To determine the impact of the deviation on the product quality, it is important to determine the ‘root cause’ of the deviation. The process used in the industry to determine root cause is, of course, the investigation procedure. This procedure, regardless of whether the product you are investigating is biotech or traditional, or new or old, should require the investigator to review various systems and determine whether they were the cause of the deviation being investigated. This concept is important because of the aforementioned possibility that more than one company is involved in the product development. When more than one company is involved, there is a necessity for technology transfer (5,6). Without a robust and transparent exchange of information, the technology-transfer activity has the potential to be frustrating and delayed while people try to find a common understanding and locate necessary information crucial to the success of the drug development process. It is important to keep in mind that change control and deviations are critical elements for ensuring product quality and patient safety regardless of the stage of development a product is at in the product lifecycle.
	The criticality of an efficient change-control system that can track and ensure proper evaluation and implementation of changes should be obvious at all stages of product development. As a change becomes more complex (e.g., a change that involves multiple products and country registrations), it becomes harder to implement. Complex changes are difficult enough for a single company with multiple sites, but they are even more exaggerated for virtual companies. For the latter, multiple contract service providers are often involved and each one has its own processes and procedures for managing a requested change. 

	The time required to transfer, validate, train, and obtain regulatory approval for multiple products requires enormous coordination. It is important to keep in mind that as the complexity of the change increases, the need for additional resources can also increase. The complexity of the change can impact the strategies for implementation, the tactics needed to effectively implement the change, and the time it takes for a change to be approved. At the same time, drug license holders will need to establish consistency in their regulatory filings without affecting product quality. When dealing with this change, focus on the steps needed to effectively implement the change. Working closely with your CMO/CRO to identify an accurate timeline for completion, including the necessary training required for employees, can help expedite the time it takes to complete the change request. Coordinating these activities with regulatory requirements also will help ensure necessary changes are implemented globally in an efficient and effective manner throughout the product lifecycle.
	Applying the correct level of cGMPs to the product development stage is really a matter of common sense. The earlier the product phase is, the more flexible your requirements. As the product approaches Phase III, the board requirements should mimic commercialization requirements. The concept is the GMPs applied should be appropriate to the stage of development and that ‘full GMPs’ should be in place during the later stages of clinical development where the final safety and efficacy of a product are being established. Keep in mind that regardless of the phase of development and the level of GMPs being applied, the first and foremost thought when releasing product at any stage for human consumption is: are there adequate controls and knowledge to assure patient safety?

INDs for Phase 1 Studies of Drugs & Biotech Products

Draft Guidance:  INDs-Approaches to Complying with CGMP’s for Phase 1 Drugs 

INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing and Controls Information 

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

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


	Vol. 42, No. 2
	February 2018
	Pages: 62,61

	When referring to this article, please cite it as S. Schniepp, "Applying GMPs in Stages of Development," 

Regardless of the phase of development and the level of GMPs being applied, 
there should be adequate controls and knowledge to assure patient safety, according to Susan Schniepp, fellow at Regulatory Compliance Associates.


Applying GMPs in Stages of Development

Q: I recently transferred to the document control department and am working with people on creating and/or revising standard operating procedures (SOPs). My colleagues have very different ideas on how much information should be included in the SOPs. Some want very detailed instructions and others want minimal information. Can you please advise on how detailed SOPs should be to fulfill regulatory expectations?

	A: There is no right or wrong answer regarding how much or how little information should be contained in an SOP. Whether you work in the medical device, pharmaceutical, or bio-technology industry, you are relying on SOPs to help you perform the day-to-day activities associated with your job. The purpose of an SOP is to define the steps, in logical order, needed to perform a repeatable task and achieve a repeatable outcome. SOPs document the steps of key processes to help ensure a consistent, quality output. SOPs are useful tools for operationalizing, optimizing, and communicating important corporate policies, government regulations, and best practices for ensuring consistent, reliable, and safe medications or medical devices to patients.
	SOPs should be written to allow your personnel to conduct operations in a consistent manner that will assure regulatory compliance and product quality. They need to reflect a company’s specific manufacturing or other operations. The more repeatable and consistent an operation or procedure becomes, the less waste there will be in the process. Consistency in work performance will lead to fewer deviations and investigations associated with the process, which translates into less down time and fewer product rejections. This is just good business sense. 

	SOPs should not be written for regulators, but should reflect a company’s operations. Writing SOPs to appease regulators or because you think the regulatory authorities require them will only lead to confusion and regulatory citations. Writing an SOP for a process, procedure, or operation that you do not perform just because it is listed in the regulations is not advised. This concept is particularly important when taking into consideration today’s environment. They are many virtual and small companies that outsource much of their operations. US 21 Code of Federal Regulations (CFR) 200.10 discusses the relationship between a contract provider and a contract giver 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.” Companies that outsource all or some of their operations should rely on their quality agreements and the SOPs of their contract providers to define how they perform the services being outsourced. Contract providers should not write an SOP that defines something they are not doing that they have contracted for another entity to do. 

	Some companies, in particular start-up companies, might be tempted to purchase pre-written 
	SOPs. This activity might be acceptable on the condition that the -purchased SOP is reviewed and the appropriate changes be made to reflect the actual operations of the company who purchased the SOP. Failure to tailor purchased SOPs to the actual specific process will most likely result in a regulatory citation for failure to follow written procedures. 

	Another consideration for an SOP is the format for communicating the information. A company needs to keep an open mind to various SOP formats and communication types. All SOPs, regardless of format, should offer clear step-by-step instructions and may utilize various presentation styles as a means of communicating the details of the SOP. The following examples are presentation styles to be considered when writing SOPs:

		General description: This describes in paragraph form the necessary elements that need to be performed to successfully execute the SOP requirements. 

		Play script: This is a simple step-by-step instructional SOP. Its format is a written set of instructions with a logical sequence flow (operator does a, then b, then c, etc.). It is similar to following a recipe for making a cake. The majority of SOPs utilize this type of format.

		Flow chart: A flow chart SOP translates the elements of the written step-by-step instructions into a sequence of pictures that define what is needed to perform the operation in the defined sequence of steps displayed in the flow chart.

		Pictorial: A pictorial SOP uses only pictures to communicate to the user the appropriate steps in the SOP and the order they are to be performed. This type of SOP can be useful when there are language concerns.

		Combination: A combination SOP uses multiple methods, such as both words and pictures, to communicate to the user the critical information in the SOP and the order in which the steps are to be performed. 

	The final consideration for effective SOPs is training. The traditional read/understood acknowledgement may not be enough to assure that an employee understands the content of the SOP. Companies should consider group trainings and comprehension evaluations for determining the effectiveness of the SOP. Keep in mind, however, that just because an employee does not pass an SOP comprehension test does not necessarily mean the employee doesn’t understand. It could be an indication of a poorly written SOP or ineffective train-ing. Companies should also consider training on SOPs through the use of video recording. This could include presenting video demonstrating proper technique as well as using video recordings as on the job training tools to evaluate proper technique of an individual. The use of video recording could be most helpful for people who need to gown appropriately to enter into an aseptic manufacturing area. 
	Remember there is no set rule dictating the format of the SOP instructions, and it is up to the company to determine what works best for your facility. SOPs should be written to reflect a company’s business practices, allowing them to optimize efficiency and productivity of their operations. It is important to tailor your procedures to the personnel performing your operations whether highly experienced or relatively new to the regulated environment. The training on an SOP is equally as important as the information contained in the SOP, and companies need to consider the most effective way to train personnel on an SOP. The training presented may not be the same for all SOPs. Bottom line, SOPs and the associated training should be easily understood and able to be followed by the employees who rely on them to perform their job responsibilities.  

	When referring to this article, please cite it as S. Schniepp, “What’s in Your SOP?," 

SOPs need to reflect a company’s specific manufacturing or other operations, says Susan Schniepp, distinguished fellow at Regulatory Compliance Associates.

What’s in Your SOP?

Q.: I am a quality assurance professional in a manufacturing plant. I still struggle with the concept of risk-based decision making. Can you provide me some advice on how I can make appropriate risk-based decisions?

	A.: The pharmaceutical industry continues to change rapidly. Over the past 10-15 years, there have been a number of developments that have impacted how companies approach various aspects of their business including the emergence of the generic industry, biosimilars, virtual companies, contract service organizations, compounding pharmacies and 503B outsourcing facilities, mergers and acquisitions, and more sophisticated information technology platforms. The complexity of the industry today makes risk-based decision making seem convoluted at best.

	Risk-based decision making is difficult no matter what position or department you are in at a company or how many years you have been in your position. Most employees are comfortable when the answer seems to be yes or no. It is much harder to make a decision when the answer lies somewhere in-between the yes and no. So, how do we go about making an appropriate risk-based decision? There isn’t any magical formula or calculation to guide you. To make an appropriate risk-based decision, we need to understand the interrelationship of the product, process, and any associated deviations and investigations that occurred during manufacturing. 

	Let’s take a look at a situation that might help clarify the risk-based decision process. You are the vice-president of quality for a manufacturing organization. One of your products for treatment of cancer is on the drug shortage list because the current API supplier has decided they will no longer provide the API. You were trying to secure a new API manufacturer but could not find one that could reliably provide the API that met the expected quality attributes, so the company has decided to cease providing the drug to the market. 

	You have the last three available lots of the API and have manufactured the associated final product lots. The product is aseptically filled and then lyophilized. During the inspection of the second product lot, the quality inspectors inform you that they have detected a defect and the lot has failed its second acceptable quality limit (AQL) for the defect. The defect detected is defined as product between the vial and the stopper and it displays as a white dot the size of the head of a pin. The standard operating procedure (SOP) defines this defect as ‘cosmetic’. The inspectors also inform you that they expect the product lot will fail the third AQL inspection and that the product will need to be rejected per standard operating procedure requirements. They also inform you that the product has passed all other quality attributes including those determined by chemical analysis and that there were no deviations associated with the manufacturing. You ask your inspectors to halt the inspection for this particular defect while you look into the matter. The question you need to ask is: what further information do I need in order to be sure I make an appropriate decision? 
	The easy decision is to perform the third AQL inspection, fail the lot if it doesn’t pass, and document the reason for the failure. The harder decision is to make a risk-based decision to release the lot. Let’s take a look at some additional information available to help you make your decision. The first thing to determine is the medical indication for the product. In this case, the product is a cancer treatment drug. The second piece of information to determine is if the cosmetic defect has any impact on the potency of the product. In this case, through laboratory analysis, it is determined that the potency or stability of the product is not affected by this particular defect. Based on this information, you document a material review of the situation and recommend ceasing inspection of the cosmetic defect and releasing the product. 

	What information made you comfortable in making this decision? Because this is a life-saving drug that is in short supply, you realize that doctors will potentially need all of this product to be able to safely transition patients to an equivalent treatment because it could take more than one treatment cycle for the doctors to find an appropriate drug substitution. You were also able to determine through chemical analysis the potency was unaffected by the defect and would not pose a threat to patient safety. You will still need to investigate the defect and try and determine its root cause, but based on the data available you should be confident that the product is safe for the patient. If there is any magic formula to risk-based decision making, it is to keep patient safety in mind and focus on whether the product meets its defined quality attributes. If you keep these points in mind you should be able to make reasonable, documentable, and defendable risk-based decisions. 

Volume 41, Number 10
	October 2017
	Pages: 106

	When referring to this article, please cite it as S. Schniepp, “Making Decisions Based on Risk," 

Focusing on whether the product meets its defined quality attributes should help one make reasonable, documentable, and defendable risk-based decisions, according to Susan Schniepp, distinguished fellow at Regulatory Compliance Associates.
