United States: FDA Issues Important Guidance Documents On Drug Risk Management Plans And Out-of-Specification Test Results

In May 2022, the US Food and Drug Administration (FDA), released two important guidance documents: Risk Management Plans to Mitigate the Potential for Drug Shortages Guidance for Industry and Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production. This Advisory summarizes and analyzes these guidance documents and discusses the impact they may have on pharmaceutical companies.

Risk Management Plans to Mitigate the Potential for Drug Shortages Guidance for Industry

Background

On May 19, 2022, FDA published a new draft guidance for industry on implementing Risk Management Plans (RMPs) to proactively predict and prevent supply disruptions that could potentially lead to drug shortages titled “Risk Management Plans to Mitigate the Potential for Drug Shortages Guidance for Industry” (RMP Guidance).¹ This RMP Guidance is FDA's first interpretation of what the statute requires and describes a framework to consider when developing the content of the RMPs.

Through the years, FDA has worked in collaboration with industry to help prevent or mitigate drug supply disruptions and drug shortages, but drug shortages have persisted.² Reasons include issues related to drug quality, disruptions to supply chain manufacturing operations (e.g., caused by the pandemic, a natural disaster or discontinuation of components by suppliers), limitations in forecasting future demand, and market withdrawals of drug products. FDA views RMPs as important mechanisms that stakeholders can use to proactively identify, assess, and mitigate the risks that might lead to a disruption in the supply of drug products, and thus preemptively reduce the financial and resource burden associated with resolving a shortage and problems that may lead to a shortage.

RMPs: Required Products and Stakeholders

The RMP Guidance sheds light on which entities and what products in the manufacturing supply chain for drugs are required to implement an RMP:

• Any prescription drug products that are life-supporting³, life-sustaining⁴, or intended for use in the prevention or treatment of a debilitating disease or condition, including any such drug used in emergency medical care or during surgery or any such drug that is critical to the public health during a public health emergency declared by the Secretary under section 319 of the Public Health Service Act.
• Any Active Pharmaceutical Ingredient (API) included in the prescription drug products described above.
• Any associated medical device used for the preparation or administration for drug products described above.

The required RMP extends to “primary” and “secondary” stakeholders.⁵ Primary stakeholders include the entity that determines which materials and services are necessary to produce a drug product, such as the holder of the new drug application, and/or the entity with understanding of and capability to make changes to the supply chain. Requirements also encompass “secondary” stakeholders, such as finished product manufacturers that are not primary stakeholders (such as contract manufacturers), manufacturers that physically manipulate and/or process the drug product, and API manufacturers. Likewise, inactive ingredient manufacturers, packagers, and distributors are included in the guidance as “other” stakeholders.

Further, the RMP Guidance delineates the different RMP development strategies for primary and secondary stakeholders. Primary stakeholder RMPs should consistently identify, assess, and mitigate the risk of supply chain disruptions and shortages throughout the organization (or within each subsection) as early as possible in the drug product's regulatory lifecycle, and plan for repairs after any such disruption. Primary stakeholders should also share their RMPs with secondary and other stakeholders of the drug product so they may incorporate parts and refine their own mitigation and avoidance strategies.

Secondary stakeholders should interpret those broad risks identified in primary stakeholders' RMPs to fit the context of their role in the drug product's lifecycle, and address any risks unique to their facility, such as environmental controls that could affect production. A non-exhaustive list of risk factors to be considered by both primary and secondary stakeholders is included in Appendix A of the guidance.⁶

RMPs: Recommended Products

FDA states that RMPs for the following drug products and API should implement an RMP because, if subject to a supply disruption and shortage, they would have a potential effect on patient care:

• Drug products intended to treat rare diseases or conditions.
• Drug products that lack appropriate alternatives.
• Medical countermeasures used in the event of a potential public health emergency.
• Sole source products.
• Drug products with only one API manufacturer in the product's supply chain.
• Drug products with only one finished dosage form (FDF) manufacturer in the product's supply chain.
• Drug products that are manufactured in a facility (including packaging facilities and laboratories) with an inspection in the last five years that was classified as official action indicated (OAI) and there is no other manufacturing facility that is qualified in the product's supply chain to conduct that operation.

RMP Framework and Development Strategy

The RMP Guidance relies on ICH Q9, with some modifications, as the framework to develop an effective RMP. Overall, the RMP Guidance indicates that RMPs should contain a broad strategy that establishes overarching approaches to consistently identify, assess, and mitigate risk across the organization or a subsector of the organization, as well as plans to repair the supply chain after a disruption, as appropriate. FDA recommends the primary stakeholder share its RMP with secondary and other stakeholders of the drug product to incorporate broad strategies and work together to address RMP development and implementation.

The RMP Guidance outlines six steps derived from the ICH Q9 Framework to develop RMPs:

1. Initiating an RMP to proactively assess the risks of a drug supply disruption.
2. Risk Assessments to identify the hazards that have the potential to cause drug supply disruptions, evaluate and estimate the risk of each identified hazard, and evaluate the probability of each risk resulting in a drug supply disruption.
3. Risk Control to reduce risks of a disruption in supply to an acceptable level.
4. Risk Review: Review events at least annually, through internal review and revision of an RMP throughout the life cycle of a drug, and include lessons learned and the root cause of new and near-miss supply disruptions.
5. Proactive Risk Communication with organizations within the drug supply chains, and external stakeholders and regulators, about their RMPs.⁷ A stakeholder can leverage an RMP to communicate and quickly share information with the Agency to prevent or mitigate a shortage.
6. Risk Management Tools, either off-the-shelf or customizable to assist in the development and maintenance of an RMP.

The RMP Guidance also lays out risk considerations for specific RMPs that elaborate on the recommended framework for specific situations.⁸

Note that although the RMP Guidance in nonbinding, there is risk in not following FDA's recommendations. FDA has authority under the CARES Act to evaluate RMPs during inspections and failure to comply with the RMP requirement could lead to an FDA Form 483 citation and further compliance action.

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

In May, FDA also updated an important guidance—the 2006 Out-of-Specification (OOS) Test Results for Pharmaceutical Production Guidance (Updated OOS Guidance).⁹ The Updated OOS Guidance is an important document for manufacturers because FDA often relies on this guidance when issuing warning letters for inappropriate investigations of OOS test results.

Background

When there is a deviation or out-of-specification test result, manufacturers are obligated to inquire about its cause as a deviation from either the measurement or manufacturing process, and which batches are affected. This applies to chemistry-based laboratory testing of drugs. The term OOS results includes all test results that fall outside of the specifications or acceptance criteria established in drug applications, drug master files, official compendia, or by the manufacturer, as well as all in-process laboratory tests that are outside of established specifications. If an initial assessment does not indicate any causative errors were made in the analytical method used to arrive at the data, a full-scale OOS investigation should be conducted in accordance with those steps laid out in the OOS guidance. This new guidance leaves that framework largely in place, but makes a few noteworthy clarifications, outlined below.

Areas of Change

The Updated OOS Guidance addresses the use of outlier results in comparing data sets. Instead of being utilized in a purely informational capacity, the guidance acknowledges that outlier results occasionally have value in estimating, along with all other data from a study, the probability that results conflict with established data sets, and could be part of evidence showing an OOS result. ¹⁰ The Updated OOS Guidance also addresses potential sample preparation variability and potential instrument variability on averaging results, as well as the effects of potential batch formulation variability under a new subsection titled “Averaging results from same final sample preparation.” ¹¹ Lastly, a new footnote within the “Field Alert Reports” section recommends consulting ICH guidance for industry Q1E Evaluation of Stability Data (2004), and reference to the more recent 2021 FDA guidance for industry Field Alert Report Submission Questions and Answers.[[N:The newly added footnote reads: As noted in the ICH guidance for industry Q1E Evaluation of Stability Data (2004), “[i]f the assay value of a batch is lower than 100 percent of label claim at the time of batch release, it might fall below the lower acceptance criterion before the end of the proposed shelf life.” Appropriate actions must be taken if testing results indicate that a batch may fall below assay specifications prior to its expiration date (see § 211.137 and 211.165). See  FDA guidance for industry Field Alert Report Submission Questions and Answers (July 2021)."]]

Although unchanged by the updated OOS guidance, it is important to note that Field Alert Reports (FAR) for application products remain a focus of FDA enforcement. Regulations require submitting, within three working days, an initial FAR for information concerning any failure of a distributed batch, unless the OOS result on the distributed batch is found to be invalid within those three days.¹² The information can always be updated in a follow-up FAR as necessary.

Key Takeaways

These two guidance documents play important roles in FDA's oversight of pharmaceutical manufacturing. The RMP Guidance will allow FDA to better evaluate risks to the supply chain, which may cause it to target inspections to those firms that manufacture products that are at a higher risk of supply chain disruption. Given the recent pandemic and continued state of supply chain risk, emphasis on RMPs will most likely be an important area of FDA focus.

Likewise, failure to investigate OOS test results for batch failures have been an ongoing focus of FDA compliance actions. FARs that are not timely filed as the Updated OOS Guidance specifies can result in warning letters and other actions. Although the updated OOS Guidance only makes minor changes, it is vital manufacturers thoroughly comply with the requirement to investigate OOS test results.

Footnotes

1 FDA, Risk Management Plans to Mitigate the Potential for Drug Shortages Guidance for Industry, (May 2022).

2 See the FDA report “Drug Shortages: Root Causes and Potential Solutions” (2019).

3 See 21 CFR 314.81(b)(3)(iii)(f) and 21 CFR 600.82(f).

4 Id.

5 This includes the manufacturers that are subject to this requirement under section 506C(j) of the FD&C Act.

6 See FDA RMP pgs. 16-18.

7 FDA has published a list of questions for manufacturers to consider as they evaluate the situation and prepare to notify FDA, including whether the manufacturer has a proposal for FDA to review to expedite availability of a product. See Guidance for industry Notifying FDA of a Permanent Discontinuance or Interruption in Manufacturing under Section 506C of the FD&C Act (March 2020); see also 80 FR 38915 at 38922 (July 8, 2015).

8 See FDA RMP at Appendix A, pg. 15.

9 FDA, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, (May 2022).

10 See OOS Guidance, at 11-12, changed from "estimating the probability that the OOS result is discordant from a data set, and this information can be used in an auxiliary fashion, along with all other data from the investigation, to evaluate the significance of the result."

11 See OOS Guidance, at 13.

12 See 21 CFR 314.81(b)(1)(ii).

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