regulatory-resources/drug-shortage. Published with permission of PDA. Copyright © Parenteral Drug Association.
|Fig. 1. A risk triage model of patient impact.|
Unfortunately, drug shortages have become more frequent and severe globally since the early 2000s for a variety of reasons . As globalization of the industry increases, the complexity of supply chains grows, global and regional regulatory expectations continue to evolve, and economic and business motivators change. The drivers behind drug shortages in different geographic areas and countries vary, and causes are usually multifactorial. The range of causes includes financial, economic and business concerns; increased or unanticipated market demand; evolving regulatory expectations; manufacturing; quality; good manufacturing practice; capacity; lack of redundancy; and supply chain issues [1, 2]. A high percentage of drug shortages are related to sterile injectable products, especially at specialized facilities such as those preparing toxic (oncolytic) products—and a majority of these shortages in the United States are caused by manufacturing and quality issues [3-6]…
A global problem
The primary objective in the management of drug shortages is preventing harm to patients. In any situation, it is important to maintain continuity of supply such that all patients receive the medicines they need every time they need them in order to manage their medical condition. The risk of potential drug shortages should be considered when making decisions related to supply or manufacture of drug products. This technical report addresses how drug shortages caused by manufacturing and quality issues can be anticipated and avoided using a risk-based approach at a product level.
An example of a shortage that had global impact and needed to be managed by multiple health authorities was “The Great Acetonitrile Shortage” in 2008–2009. Acetonitrile is used as a solvent in many analytical procedures included in submissions for approval of drug products and in chemical reactions for API manufacturing. The two main manufacturers of this solvent are located in the same area in China and were required to stop manufacturing acetonitrile to reduce air pollution for the 2008 Summer Olympics. A few months later in September of 2008, acetonitrile production in Texas was interrupted due to hurricanes in the Gulf of Mexico. These events caused shortages of several active pharmaceutical ingredients (APIs) and drug products. Only a few companies were aware that the product would not be manufactured for a year and therefore built up their inventories of the product in advance. Most regulatory agencies accepted alternative analytical methods on a short-term basis. The US FDA also allowed changes to existing validated test methods within an approved application (New Drug Application [NDA] or Abbreviated New Drug Application [ANDA]) to accommodate using less acetonitrile or an alternative solvent to acetonitrile, and allowed this to be processed as a minor change in the Annual Report for the given drug application, as long as the change met the criteria stated in the US FDA Guidance for Industry, “Changes to an Approved NDA or ANDA” , and Code of Federal Register Title 21CFR314.70(d)(2)(vii) …
The potential causes of drug shortages are complex. The Birgli® report identifies three principal types of causes for drug shortages—economic, business and manufacturing supply chain issues . Although environment and economic policies traditionally focus on addressing reimbursement related topics, it is also very important to control risks to drug availability across the end-to-end product value chain. In this value chain, manufacturing is a key step. Therefore, efforts must be concentrated on uninterrupted manufacturing/distribution, minimizing risks that packaged drugs will be unavailable.
This technical report focuses on addressing shortages caused by manufacturing and quality issues in the end-to-end product value chain.
In the context of a product value or supply chain, a drug shortage starts whenever an API, excipient, API starting material, reagent, solvent, component or even packaging material cannot be made available for the manufacturing process. This can occur due to many reasons, including manufacturing, quality and GMP compliance issues, inadequate manufacturing capacity to meet increased product demand, lack of redundancy, complexity of the supply chain, evolving global regulatory requirements including the complexity associated with implementing them, and dynamic market conditions.
Additional complexity can be added by country or region-specific import testing requirements, which impacts the robustness of the supply chain and restricts companies from recovering fast; this can potentially turn “near misses” into actual drug shortages. Manufacturing and quality issues are often listed as a cause of drug shortages. In this context, shortages might occur as a result of issues related to factors such as supply of direct materials; technical operation of facilities/equipment; unavailability of equipment; new requirements; or GMP or regulatory compliance, identified either by the company itself or by health authorities…
This technical report lays out a practical risk triage model and templates for a Drug Shortage Risk Register, and a Drug Shortage Prevention and Response Plan… Companies can directly leverage the risk triage model and templates provided in this report to establish a Drug Shortage Risk Register for their portfolio of products and build Drug Shortage Prevention and Response Plans for their medically necessary products. This technical report additionally supports and enables marketing authorization holders and manufacturers to meet the requirements in the US of Section 506C of the Federal Food, Drug and Cosmetic Act , and in the EU of Article 13 of the EU GMP Directive 2003/94/EC , to notify relevant health authorities in the event of a drug shortage…
|Fig. 2. Drug shortage prevention and response plan.|
A holistic approach to the prevention and management of drug shortages focused on patient safety is important because there are multiple elements both at a system and a product level that work individually or in combination in the event of a shortage.
At a product level, an end-to-end understanding of the value chain for manufacturing and distribution provides the ability to understand and implement end-to-end controls.
At the system level, appropriate oversight and a robust quality system ensures compliance with applicable laws and regulations. It also should establish mechanisms that provide early warning signals of potential shortages, assess potential causes, drive targeted manufacturing and product quality improvements (including introduction of new technologies and innovation), and enable timely communications with key stakeholders. Other foundational elements should: ensure strong management accountability, foster a sustainable quality culture that enables employees to speak up, reward behaviors that drive joint ownership between operations and quality units for issue resolution, build people skills and capabilities that drive change leadership and excellence in pharmaceutical operations, and establish a governance model that tracks operational and quality performance with the right metrics .
As part of a robust quality system, companies should implement risk management principles  and knowledge management capabilities  to accomplish the following:
- Proactively identify and control risks of interruption in product supply
- Perform clinical/safety risk assessments for their products
- Facilitate risk-based decision-making by companies and health authorities in response to shortages in order to control and reduce harm to patients
In addition to internal risk and knowledge management, it is helpful to have systems that generate reliable and up-to-date knowledge about the marketplace for a company’s products (e.g., trends in demand, usage volumes, market share data). This combined body of information can also be very useful in decision-making about actions needed by both companies and health authorities in order to respond to a shortage. It can help both parties understand the clinical risks of shortage, what advice to communicate to health-care providers, and what measures to take in order to respond quickly to a drug shortage. Information about the supply position for competitor products and alternative therapies is also important for addressing shortage-related issues, though sometimes this information may not always be readily available due to confidentiality considerations. This information can be used, for instance, in the event of a shortage when the supply of an alternative product (where available) can be increased to minimize impact to patients…
Risk triage model
A preventive approach to managing the risk of drug shortages caused by manufacturing quality issues includes a risk assessment method called a “triage.” A triage approach allows a quick and easy assessment of the shortage risks of a product and prioritizes actions for proactive drug shortage management (risk control). Not all products require proactive drug shortage management; only those with the greatest risk to patients require commensurate levels of effort and planning to ensure that supply is adequate and that the “availability” component of the risk calculus is assessed and appropriately managed. The method and tools proposed in this section are intended to help determine whether a proactive Drug Shortage Prevention and Response Plan is required for a product.
…Companies should have robust Quality Risk Management (QRM) and knowledge management systems to both prevent (proactive) and respond (reactive) to drug shortages.
Proactive QRM of drug shortages should involve the following:
- Categorizing each product by criticality based on its indication and patient needs.
Establishing a Drug Shortage Risk Register (single source of information on risks that can result in drug shortages) by proactively identifying and assessing risks (to quality, compliance and supply) that could lead to a shortage, and periodically reviewing this Drug Shortage Risk Register. A Drug Shortage Risk Register should provide the following information that should be updated and reviewed on a regular basis…:
– description of potential drug shortage risks for a product (including source of risk)
– countries/regions that could be affected
– risk level
– risk control actions, owners and due dates status
– key risk leading and lagging indicators that would trigger early and timely responses to potential shortages (including near misses on batch release or ability to meet product demand)
Ensuring timely reduction and management of risks by completing risk control actions defined in the risk control plan, based on criticality. Issues to address in the risk control plan could include:
– inventory and safety stock planning
– demand and supply planning (for all relevant markets) using a sourcing strategy (e.g., dual sourcing)
– capacity planning for manufacturing and distribution (capacity reserve)
– availability of alternate therapies, and
– acceleration of health authority approval of post-approval changes
- Establishing a Drug Shortage Prevention and Response Plan, at least for medically necessary, life supporting or life sustaining products…
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