By Tiffany Baker, Christopher Smalley, and Stephen Langille, ValSource, Inc.
Medically necessary drug products are broadly defined as those which diagnose, treat, or prevent a serious disease or medical condition for which there is no other adequate and available substitute or alternate therapies.1, 2 In times of crisis due to epidemics, natural disasters, or other extenuating circumstances, high absenteeism may force companies to continue manufacturing these critical products with reduced staff. A structured approach to problem solving using quality risk management (QRM) techniques can aid in the development and implementation of action plans and knowledge transfer programs to ensure the production of safe and effective drug products in times of staff shortages related to the COVID-19 pandemic.
This is the second of three articles from ValSource authors on some of the challenges of making decisions in difficult times. In the other two articles, we explore how to combat stress with QRM and how military thinking can improve pharma decision making under stressful conditions.
Ensuring Quality And Continued Supply Through Quality Risk Management
The COVID-19 pandemic presents a unique set of challenges to pharmaceutical manufacturers worldwide. High absentee rates may result from employees becoming infected with COVID-19, quarantine due to exposure to COVID-19 infected individuals, family obligations (e.g., child or elder care), or travel restrictions and public transportation disruptions due to local or national quarantine policies.3 Companies are struggling to sort through the high volume of tasks routinely performed in order to focus on those critical to what is most important – protecting patients. The reality is that some of these tasks will have to, temporarily, be reduced or stopped entirely in order to focus resources on ensuring the availability of medically necessary drug products. The FDA’s Center for Drug Evaluation and Research (CDER) published a guidance in 2011 with recommendations for companies forced to plan for the effects of large-scale events resulting in high absenteeism. CDER recommends that each manufacturer conduct a prospective risk assessment for situations where scaled back operations are being considered to ensure that the risk related to reduced activities is assessed, appropriate risk control measures are identified, the measures are approved by the relevant decision makers, and they are included in the development of emergency and/or continuity plans.1
This is, in fact, exactly what QRM was designed to help us do. The primary principles of QRM are uniquely positioned to shift focus in any assessment to what is most critical – namely risk scenarios that impact patient safety and product quality. The first principle, “The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient,” speaks directly to identifying and understanding exactly what will impact our patients and supporting those decisions with sound scientific data. The second principle, “The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk,”4 speaks to the gravity of the assessments required in the event of the COVID-19 pandemic or other events significant enough to lead to widespread high absenteeism. The reduction of routine activities designed under normal operating conditions to ensure an adequate level of control is not a decision to be made lightly and should in nearly all cases be accompanied by a risk assessment to document the decision-making process.
Routine operations and processes can be assessed using tools mentioned in ICH Q9 (or through custom approaches) to determine exactly what is critical to control in the event of a severe resource shortage. Manufacturers should conduct risk assessments to identify potential risks to product safety and quality due to shortages and implement appropriate risk mitigation measures to assure that manufacturers can comply with current good manufacturing practices (CGMPs) and that products meet specifications.1 CDER recommends that unacceptable risks identified through these assessments be captured and tracked in a specific emergency plan risk register and be reviewed at regular intervals throughout the duration of the emergency. Any temporary manufacturing changes due to absenteeism that could affect product quality should be reviewed and approved by the quality unit.
Examples of situations where risk assessments or risk-based approaches can be leveraged during periods of high absenteeism to ensure resources are being focused on product quality and patient safety include:
- Assessment of the manufacturing operation to determine where second person verification of less-critical manufacturing steps could temporarily be reduced.
- Assessment of environmental monitoring or critical utility sampling plans to reduce the frequency of less-critical samples and focus testing efforts on samples indicative of the product experience conditions (critical control points).
- Assessment of tasks performed by external vendors to determine if calibration or preventive maintenance due dates can be extended for less-critical equipment. Reducing external staff on-site can be a proactive way to reduce the likelihood of transmission of COVID-19 in the workplace.
- Assessment of quality system processes to determine if due date extensions are warranted for less-critical items (i.e., minor deviations or preventive actions for minor events) to allow a reduced workforce to carry on critical operations.
- Assessment of in-process testing to determine if a reduction of assays that are not indicative of a loss of control of product critical quality attributes may be possible.
The FDA suggests that companies carefully monitor quality indicators to detect any adverse trends resulting from the activation of the emergency plan. In the event that an adverse trend is identified, the newly discovered risk should be immediately escalated, assessed, and mitigated. Retain samples should be maintained if staff shortages result in the reduction or elimination of some testing.1
Both the EMA and FDA have regulations related to notification responsibilities of companies during drug shortage situations5, 6 and each has published guidance on the topic. 7, 8 The use of risk management principles allows informed decisions to be made related to proactive management and prevention of drug shortages and the timely notification of health authorities before shortages become severe.2
Emergency And Continuity Plans
The use of QRM to determine a path forward in an environment of high absenteeism and reduced resources will result in a series of risk assessments and action plans appropriate and unique to your organization. However, there are some commonalities in risk and action planning that should be included in the response to high absentee rates. Emergency and continuity plans describe how an organization will continue to function to deliver key services and products in times of crisis. Since each drug product and manufacturing operation is unique, plans should address the specific operational needs of a given organization. Pandemics often consist of two or three waves lasting months to years, and absentee rates may fluctuate over the course of the pandemic.3 Flexible short-, medium-, and long-term plans can help manage some of the uncertainty associated with potential staffing shortages that may arise due to the COVID-19 pandemic.
The overall business continuity plan should address issues such as chain of command, emergency contact information, accounting, and business commitments (contractual and legal obligations). Companies should also conduct a risk assessment to identify which products are considered medically necessary drugs based upon the product’s indication, availability of alternate therapies, and probability of shortage.2 Manufacturing priority should be given to the most critical products, such as those for which the company is the sole source (or supplies a significant market share) and products necessary for the maintenance of conditions such as cancer, diabetes, asthma, and high blood pressure. This prioritization should consider individual manufacturing facilities, contractors, and the entire manufacturing operation. Planning should address the number of essential and specialized personnel required to be on-site for CGMP compliant processes, ways in which cross-training of available personnel could be used to expand the pool of available and qualified specialists, and the impact of potential shortages of raw materials, personal protective equipment (e.g., gloves, masks, gowns), or cleaning/disinfection supplies necessary to maintain environmental control of the manufacturing facility.
Emergency plans should specifically address how operational continuity will be addressed during situations that could prevent a significant portion of the population from reporting for duty. Even if an emergency plan has been activated, manufacturers may not be able to meet all statutory and regulatory requirements for medically necessary products. The CDER has stated that it is prepared to exercise enforcement discretion, as appropriate, in order to meet national public health needs. However, the FDA requests that it be notified of both the activation of any emergency plan and the suspension of the emergency plan as part of a return to normal operations.1
Knowledge Management When Experienced Employees Are Absent
Despite the best risk assessment and planning efforts, the COVID-19 pandemic may result in a significant portion of the workforce failing to report for duty. It is not just the loss of the hands to do the work but also the loss of the skill and knowledge needed to continue the successful production of medically necessary products that will be challenging. Managing the absence of critical personnel with years of manufacturing, testing, and product knowledge is just as important as planning for the mass absenteeism that could result from a pandemic.
Before the 20th century, human knowledge doubled every century. By the 1950s, it doubled every 25 years. Today, it is doubling about every 13 months. But what is knowledge, and how is it important to our processes and operations? Knowledge can be divided into two categories: explicit knowledge and tacit knowledge. Explicit knowledge is what is recorded, documented, or available on the internet and in files. It is knowledge that should be well known and understood, such as what a red traffic light means. Tacit knowledge, on the other hand, is unique to each individual. Everyone has tacit knowledge, but in different areas. Tacit knowledge is knowledge that each of us holds that may be unique to our experiences and, therefore, is not known by others. Tacit knowledge, by definition, is not documented. When an employee leaves an organization, unless some action is taken, his or her tacit knowledge is lost to the organization.
Let’s take a moment to describe where tacit knowledge is in the continuum of data and wisdom, starting with data. Data is a fact, a number, an item, or an entry, such as 121 degrees C. Information is the context of data taken together to form a picture in our minds, such as 121 degrees C at 15 psi in an autoclave. Knowledge is information that has been integrated with understanding, so 121 degrees C at 15 psi in an autoclave for 1 minute produces an Fo of 1, which is a measurement of lethality. Wisdom is knowledge that has been integrated with experience and learning such that the knowledge can be beneficially used. For our example, adding the knowledge of the effects of superheated air, steam penetration, and material mass can help us determine whether that Fo of 1 accurately represents the conditions on the material surface.
At times, we do not do an adequate job of moving from data to information, information to knowledge, and knowledge to wisdom. Pharma and biopharma companies measure and store mountains of data. We have the computing power to add context to much of that data, but sometimes we simply don’t make the effort to move along the continuum. For example, a company that performs an operation to coat tablets with a natural product (shellac) offers an employee buyout as part of a workforce reduction. Later, the company couldn’t make coated tablets that met the disintegration/dissolution specification. Perhaps the older, experienced worker didn’t share their tacit knowledge earlier over concerns for their job security, because the importance of sharing the tacit knowledge wasn’t obvious, or due to the belief that the tacit knowledge was explicit or common knowledge. In any case, the wisdom necessary for correctly coating the tablets was lost. How might this paradigm be changed?
There are several pathways to make the change, but one to consider is apprenticeship. The person with the tacit knowledge may be a senior production operator or an executive with several successful projects to their credit. At times, the person with tacit knowledge knows that they have a deeper understanding borne of experience but is reluctant to share it. Providing them with an apprentice ensures continuity and guarantees that significant knowledge is not dependent on one individual. How long might such an apprenticeship last? It depends on how technical the knowledge is, as well as the baseline knowledge held by the apprentice. The apprentice should not be a “blank slate” straight out of school but, rather, someone who is well grounded in the subject so they can integrate the knowledge as it is imparted. A period of three months should be considered, but up to six months might be appropriate in some circumstances. However, circumstances such as retirements or pandemics will certainly limit the time available for knowledge transfer.
Another approach would be to ask the person with the tacit knowledge to produce and execute a lesson plan on the topic. This works best for roles similar to production operator and other nonexecutive roles. Giving the person with tacit knowledge the task of not only authoring a lesson plan but also delivering the lesson will frequently result in the person with the tacit knowledge appreciating the acknowledgment and attention. The goal of the lesson plan should be defined and structured to ensure that the tacit knowledge is conveyed to the student.
Tacit knowledge is lost to organizations much more often than is realized. It could account for repeated errors, deviations, and increased process losses. Companies should work to capture and keep tacit knowledge in the organization just as they would proprietary information, because many times that is exactly what it is.
The COVID-19 pandemic will eventually end, and manufacturing processes will slowly return to normal. However, the need for contingency planning to ensure the supply of medically necessary drug products in the wake of high absenteeism due to local or global crises will remain. An effective absentee management strategy will use QRM to focus on activities with the highest impact to patient safety and product quality, continuity and emergency plans to maintain operations in order to deliver the most critical drug products, and knowledge management practices to ensure the transfer of tacit knowledge from senior employees to more junior staff members. These actions will help ensure the supply of essential medications, aid in communicating with regulatory authorities, and facilitate the return to normalcy once the crisis is over.
- Guidance for Industry - Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products. U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER). March 2011.
- Parenteral Drug Association Technical Report 68: Risk-Based Approach for Prevention and Management of Drug Shortages. 2014.
- Flu and Infectious Disease Outbreaks – Business Continuity Plan. Canadian Centre for Occupational Health and Safety. March 2020.
- International Conference on Harmonization (ICH) Harmonised Tripartite Guideline. Quality Risk Management Q9. 9 November 2005.
- Federal Food, Drug, and Cosmetic Act Chapter V: Drugs and Devices Section 506C [21 U.S.C. 356c]: Discontinuance or Interruption in the Production of Life-Saving Drugs; U.S. Food and Drug Administration: 1997, www.fda.gov/regulatoryinformation/legislation/federalfooddrug andcosmeticactfdcact/fdcactchaptervdrugsanddevices/default.htm (accessed Oct 5, 2014).
- EudraLex, COMMISSION DIRECTNE 2003 / 94/ EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use. European Commission: 2003. europa.eu/legislation_ summaries/ internal_market/ single_market_for_ goods I 1231 ll_en.htm (accessed Oct. 5, 2014). pharmaceutical_and_cosmetic_products /
- Guidance on detection and notification of shortages of medicinal products for Marketing Authorisation Holders (MAHs) in the Union (EEA). European Medicines Agency. July 2019.
- https://www.fda.gov/drugs/drug-shortages/how-report-shortage-or-supply-issue. Accessed 16-March-2020.
About The Authors:
Tiffany Baker is a QRM and microbiology consultant with Concordia ValSource, Inc. She specializes in development and implementation of innovative approaches to QRM, QRM program design, creating a risk-focused culture, and developing risk-based approaches to support contamination control strategies. Baker is an active member of the PDA, a faculty member for PDA’s Training Research Institute, and an instructor for PDA courses on quality risk management foundations and practical application of QRM tools. Additionally, she was a member of the core team who co-authored the ISPE Baseline Guide Volume 5 - Commissioning and Qualification, incorporating QRM into the process. She can be reached at firstname.lastname@example.org.
Chris Smalley, Ph.D., is a consultant for ValSource, Inc. focused primarily on compounding pharmacies. His expertise includes single-use systems and aseptic operations. Previously, he was director of Quality Operations for Wyeth Pharmaceuticals for 12 years, responsible for setting validation standards and validation activities globally. His research experience includes responsibility for Quality in the U.S. operations of the Sanofi Research Division, and earlier he worked for Johnson & Johnson as a plant manager. Smalley has been a member of the PDA Board of Directors and the PDA Science Advisory Board. Currently he is a member of the ISPE Disposables Community of Practice.
Stephen Langille, Ph.D., is a senior microbiology consultant at ValSource, Inc. He specializes in microbiological and particulate matter contamination control. He holds a B.S. degree in biology from the University of Massachusetts and a Ph.D. in microbiology from the University of Maryland. He spent 19 years with the FDA as a microbiology reviewer, branch chief, and director of the Division of Microbiology Assessment in the Center for Drug Evaluation and Research. He can be reached at email@example.com.