Controls to Minimize Disruption of the Pharmaceutical Supply Chain During the COVID-19 Pandemic

Social Distancing and Work from Home

Certain local, state, and national governments and their health authorities have issued social distancing guidelines that may include a mandatory stay at home order with a caveat to exclude “essential employees,” that is, employees necessary to keep critical services and activities in operation. To our knowledge, all governments combating the pandemic have classified “pharmaceutical employees” as essential workers. As such, pharmaceutical companies generally have the liberty to determine what employees, if any, should work from home and who should report to work. The authors recommend companies develop a comprehensive contingency plan to identify essential activities and the employees needed to execute such activities. Support staff in quality assurance (QA), regulatory affairs, purchasing, human resources, research and development, planning, sales and marketing, and general management largely may work from home. Staff directly employed in manufacturing operations, quality control testing, engineering and maintenance, security, warehousing, and shipping must be on site and potentially expose each other, facilities, and products to viral contamination.

The employees identified as essential will depend on the manufacturing sites ability to conduct GMP activities remotely via a 21 CFR Part 11 compliant information technology (IT) system. For example, sites that have completely electronic batch records may not need to have a QA batch record reviewer on site, but those that have paper records or hybrid paper and paperless systems may need to include such an employee on the list of essential employees.

Furthermore, the determination of which employees are considered essential will depend, in part, on the level of community spread. For example, site auditors may not be considered essential if the virus threat level is high within the local community, but as the threat decreases, auditors may be included in the list of essential employees.

Employees working off-site, using communication tools like mobile telephones, e-mail, and videoconferencing, can conduct many support activities in the pharmaceutical industry. This will significantly reduce the numbers of employees on-site. In terms of the drug product supply chain, such employees may be viewed as nonessential, whereas those employees (operators, as well as managers) directly involved in product manufacturing, testing, and distribution are viewed as essential. However, this distinction is not clear-cut. For example, it may be possible to delay a supplier audit of a pharmaceutical ingredient used in the manufacture of an essntail drug product, annual GMP training for packaging operators, or even marketed product stability testing. Determining what are nonessential activities and what are essential must be approached in a well-considered manner. The authors recommend that companies develop pandemic contingency plans that mandate essential activities and provide justification and timelines for the completion of activities that are delayed as nonessential. These plans should be ap-proved by their quality control unit and may, importantly, be subject to regulatory review.

Identification of Infected Employees

As we believe that the biggest risk to the supply chain is person-to-person viral transmission followed by surface-to-person transmission, the most important risk mitigation will be excluding infected employees, especially those manufacturing, sampling, and testing drug products, from the pharmaceutical workplace to maintain the workforce and not potentially cause product contamination.

GMP regulations, for example 21 CFR 211.28 d states: Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions that may adversely affect the safety or quality of drug products shall be excluded from direct contact with components, drug product containers, closures, in-process materials, and drug products until the condition is corrected or determined by competent medical personnel not to jeopardize the safety or quality of drug products. All personnel shall be instructed to report to supervisory personnel any health conditions that may have an adverse effect on drug products.

As such, pharmaceutical companies are required to have procedures in place and a training program for employees to self-report and supervisors to observe and detect illness.

The major symptoms of COVID-19 infection are dry cough, fever, and difficulty breathing, but asymptomatic sufferers may shed the virus (19). All employees who self-identify as sick must be encouraged to stay home and report their status to their immediate supervisor and seek medical help. Examples of high-risk factors include sick family members and friends, recent foreign and domestic travel, attendance at events with large crowds such as arena concerts and professional sport games, frequenting places of worship, schools, restaurants, social clubs, and bars, dwelling in high-density population cities and towns, and commuting using public transportation.

To maximize the possibility that employees will self-report potential illness, the authors recommend reviewing sick-leave policies for all employees, including temporary and contract workers. We also recommend that companies enhance general awareness about the symptoms of COVID-19 by reinforcing the need for self-reporting and supervisory vigilance.

Screening Pharmaceutical Employees at the Point of Entry to Manufacturing Facilities

Recent epidemiological studies of COVID-19 suggest that infected individuals may remain asymptomatic or presymptomatic for up to 2 weeks (21). Therefore, in addition to reinforcing GMP requirements to self-report illness, companies should consider instituting procedures to screen employees entering manufacturing facilities. Such procedures need to be developed in accordance with government-mandated requirements and employee rights to privacy, avoidance of discrimination, and respect for existing employee contracts and union agreements.

On April 23, 2020, the U.S. Equal Employment Opportunity Commission (EEOC) issued an update to its guidance that now expressly acknowledges that employers may test employees for COVID-19 and conduct temperature-screening measures without violating the provisions of the Americans with Disabilities Act (ADA) or the Rehabilitation Act (20). According to the EEOC, “an employer may choose to administer COVID-19 testing to employees before they enter the workplace to determine if they have the virus.” Further, as stated by the EEOC: Consistent with the ADA standard, employers should ensure that the tests are accurate and reliable. For example, employers may review guidance from the U.S. Food and Drug Administration about what may or may not be considered safe and accurate testing, as well as guidance from CDC or other public health authorities, and check for updates. Employers may wish to consider the incidence of false-positives or false-negatives associated with a particular test. Finally, note that accurate testing only reveals if the virus is currently present; a negative test does not mean the employee will not acquire the virus later.

The EEOC guidance applies only with respect to the two specified federal statutes in the U.S. We recommend that companies in the U.S. also consider the applicability of relevant state and local law and consult legal counsel as needed before initiating a mandatory employee-testing program. Companies outside the U.S. must obviously consider applicable national and local laws.

Also, in the U.S., the federal Occupational Safety and Health Administration (OSHA) recommends that companies develop an Infectious Disease Preparedness and Response Plan (22). The OSHA updated recommendations state the following: If one does not already exist, develop an infectious disease preparedness and response plan that can help guide protective actions against COVID-19. Stay abreast of guidance from federal, state, local, tribal, and/or territorial health agencies, and consider how to incorporate those recommendations and resources into workplace-specific plans. Plans should consider and address the level(s) of risk associated with various worksites and job tasks workers perform at those sites.

How can employees be screened? Depending on the nature of the workforce, and the confidence and trust management has in the workforce, companies should decide whether to institute mandatory testing and/or institute self-screening or screening during entrance into the plant site.

If screening is performed during entrance to your plant sites, the employees' entry should be staggered to maintain social distancing and prevent delays. In addition to any mandatory COVID-19 testing that may be adopted, the authors believe in their expert opinion that the screening may consist of the following activities:

1. Monitor the body temperature of all employees. If self-monitoring is permitted, employees could check their body temperature using a personal clinical thermometer just prior to leaving for work. Employees should not report to work and should seek medical advice immediately if their body temperature is above 100.4°F/38°C. If screening is conducted at the plant entrance, a trained screener should use a calibrated handheld or wall-attached no-touch thermometer. Employees with a body temperature exceeding 100.4°F/38°C should be segregated and not allowed to enter the facility.

2. Conduct brief interviews of potentially SARS-CoV-2-infected employees to identify those with the common symptoms of fever, dry cough, and difficulties breathing.

3. Take a travel and contact history of a suspected infected employee for the past 14 days to determine the potential for contamination of the manufacturing facility and infection of other employees.

4. Segregate any potentially infected employees and encourage them to get medical care through their regular physician or neighborhood medical center. It would be useful to provide employees with healthcare contact information.

5. Obtain a commitment from the employee to report their medical status and results of any testing for the presence of the coronavirus when they update their sick leave status according to company policy.

6. Determine whether the infected employee's coworkers within social distancing need to be quarantined from the workplace.

7. Determine the potential impact on the manufacturing operation as a result of employee absences.

8. When an employee is confirmed positive for the coronavirus, clean and disinfect the locations directly impacted in their workspace and other high-traffic areas like bathrooms, break rooms, hallways, and entrances.

9. Review of the frequency of employee exclusions by a local oversight committee to determine the need for self-quarantine of potentially infected employees, institute additional risk mitigations, and determine the potential impact to the manufacturing schedule.

The recommended screening listed as 1 through 6 will have recognizable limitations. Multiple screening methods will most likely be more effective than a single method. Clinical thermometers may be in short supply during a pandemic. Studies on the use of infrared thermal image scanners in influenza and COVID-19 airport screening (23⇓–25) to identify infected travelers showed that, compared to virus testing, they might detect less than half of those infected because of the viral incubation period and asymptomatic individuals. Screening each day of entrance to the workplace as compared to a departure or arrival screening at an airport will increase its effectiveness. A recent publication on the presenting characteristics of 5700 patients hospitalized with COVID-19 in the New York City area (26) found that only 31% had an elevated temperature, 17% rapid breathing, and 43% rapid heart rate. No information on the incidence of body ache and coughing was provided. This variability in symptoms will make screening more challenging. Based on these findings, companies are cautioned not to place too much reliance on only temperature screening. Another report from a Northern California hospital system indicated that the chief symptoms in 377 adults when presenting in the emergency department were 49% shortness of breath, 34% fever, and 32% cough (27).

As testing for the SARS-CoV-2 virus to detect infected individuals and the antibody to detect individuals who have been infected and recovered becomes widespread, companies should consider offering testing on a voluntary basis as an effective tool for keeping their workforce. Based on a PDA membership survey (In press) apparently most employees would accept this offer of screening. The best method of managing this testing will become apparent as infectious disease experts gain more experience managing the pandemic and the subsequent return to work.

Persistence of Coronavirus on Inanimate Surfaces

Human viruses cannot multiply outside of the body and will not survive on inanimate surfaces for long. An analysis of 22 studies on the persistence of human coronaviruses other than SARS-CoV-2 virus (Table I) reveals that they may persist on metal, glass, or plastic for up to 9 days (range 2 h to 9 days), but they are readily inactivated within 1 min by disinfectants and sporicides such as 62%–71% ethanol, 0.5% hydrogen peroxide, or 0.1% sodium hypochlorite (28).

The studies summarized in Table I have their technical limitations as they used related coronaviruses but not SARS-CoV-2, different types of inoculum preparations, high inoculum levels, different storage conditions, and reverse transcription polymerase chain reaction assays as a measure of survival and not infectious units determined by cell culture methods. However, until additional studies are conducted with the SARS-CoV-2 virus, these will be indicative and will contribute to our analysis.

Other agents used in the pharmaceutical industry, including the antiseptics 0.05%–0.2% benzalkonium chloride and 0.02% chlorhexidine digluconate, are less effective, requiring a contact time of up to 10 min (28). These findings will strictly limit the ability of novel coronaviruses to contaminate the pharmaceutical supply chain.

A more recent March 17, 2020, letter to the New England Journal of Medicine analyzed the aerosol and surface stability of SARS-CoV-2 (COVID-19) and compared this stability to that of SARS-CoV-1, its most closely related coronavirus (29). The authors of the letter reported 10 experimental conditions, conducted in triplicate, involving the two viruses in five environmental conditions, that is aerosols, inoculated plastic, stainless steel, copper, and cardboard. SARS-CoV-2 remained viable as measured by median tissue culture infectious dose for 50% of the cells to be infected (TCID₅₀) in the aerosol suspension for the 3 h duration of the experiment with a reduction in infectious titer from 10^3.5 to 10^2.7 TCID₅₀/mL, representing a half-life of 1.1–1.2 h. In a controlled environment with many air changes per hour, the virus would be readily removed from the air.

The coronavirus was more stable on plastic and stainless steel than on copper and cardboard. Although the virus could be detected for up to 72 h, its titer was greatly reduced (from 10^3.7 to 10^0.6 TCID₅₀/mL after 72 h on plastic and from 10^3.7 to 10^0.6 TCID₅₀/mL after 48 h on stainless steel). On copper, apparently because of Cu²⁺ toxicity, no viable SARS-CoV-2 was measured after 4 h and on cardboard, no viable SARS-CoV-2 was measured after 8 h (29). This means, that in the event that controls established to exclude an infected employee fail, and in the event that packaged product is exposed to the virus, the plastic container used for primary packaging and the cardboard used for secondary packaging should not carry infectious coronavirus because of the amount of time the drug products will be advancing through the supply chain. Therefore, pharmaceutical products are very unlikely to pose any risk of infecting pharmacists dispensing, medical staff administering, and patients taking such products.

The relationship between temperature and relative humidity and the survival of coronaviruses in aerosols and on surfaces has been investigated. Enveloped viruses were found to survive longer at lower temperatures and humidity and may persist longer in refrigerators and cold rooms (30⇓–32). The efficacy of pasteurization (63°C for 30 min) was demonstrated with MERS-CoV in camel, goat, and cow milk with the virus titer reduced from 10^5.5 to <10^0.5 TCID₅₀ (33). Clearly, the heat sensitive SARS-CoV-2 virus will not survive sterilization processes used in sterile product manufacturing.

Inactivation of Viruses Owing to Routine Cleaning and Disinfection

The coronavirus may be physically removed from a surface with a particle-free wipe, inactivated by detergents in cleaning agents, or inactivated by disinfectants and sporicides. In addition to routine cleaning and sanitization programs established to meet GMP requirements designed to protect product, companies should establish cleaning and sanitization of surfaces in non-GMP areas, including hallways, bathrooms, offices, and other common areas, to protect the health and safety of employees during the pandemic. The controls, qualification, and documentation requirements for GMP activities should be well-established and subject to change control and/or planned deviation. Such controls are not required for sanitization programs designed for the non-GMP areas.

The frequency of cleaning and disinfection of an area in a GMP manufacturing facility will depend on the intensity of traffic in the area and the exposure of personnel to drug product manufacturing. This frequency may range from weekly, to daily, to before and after each shift. It should be emphasized that cleaning to remove grime and product residues prior to the application of disinfectants is critical for their best efficacy. Table II, although not exhaustive as the U. S. Environmental Protection Administration (EPA) List N (34) which contains 75 agents, provides useful information on representative commercially available products, their active ingredients, contact times, and antiviral claims.

Cleaning and disinfection are considered critical GMP processing steps especially in sterile product manufacturing subject to process validation (see 2004 FDA Aseptic Processing Guideline). Guidance on the qualification of individual disinfectants and sporicidal agents may be found in USP <1072> Disinfectants and Antiseptics (35). Media reports highlight the shortage of disinfectants and hand sanitizers. Under the current circumstance, it is the expert opinion of the authors that on an interim basis, alternate suppliers may be identified and a like-for-like substitution made, forgoing process validation and a vendor audit to make up for the shortage. Critical elements for making this like-for-like selection of an alternative source of a disinfectant include reputation of the supplier, active ingredient, active ingredient concentration, EPA and other national registration, efficacy claims, whether the disinfectant formulation is diluted before use or a ready-for-use product, and sterilization by gamma irradiation. To alleviate the shortage of hand sanitizers, the FDA has authorized the in-house production of alcohol hand sanitizers (36), but the authors believe that these materials should not be used in the critical ISO 5 aseptic processing areas.

Viral Clearance by HVAC Systems and HEPA Filters in Clean Rooms

Warehouses, offices, laboratories, and manufacturing and packaging areas in a pharmaceutical manufacturing plant will be served by heating, ventilating, and air conditioning (HVAC) systems to maintain targeted temperature, humidity, and numbers of air changes appropriate for each of these areas. In addition, clean rooms and other controlled areas where sterile drug products are manufactured are supplied with high-efficiency particulate air (HEPA)-filtered air to meet specified air cleanliness levels as well as more stringent requirements for temperature, relative humidity, space pressurization, and number of air changes per hour to prevent product contamination.

In general, the level of environmental control, the PPE worn by clean room operators, and the cleaning and disinfection program will make it unlikely that the coronavirus will persist in clean rooms and contaminate sterile drug products (37). This leaves questions around areas served solely by conventional HVAC systems without HEPA filtration.

The 2014 American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE) Position Document (38) highlights that some infectious diseases including those caused by coronaviruses are transmitted through the inhalation of airborne infectious particles, which can be disseminated through buildings by pathways that include ventilation systems. This transmission may be reduced using dilution ventilation, directional airflow, room pressure differentials, source capture ventilation, air filtration, and ultraviolet germicidal irradiation (UVGI), as well as appropriate cleaning and disinfection practices.

The ASHRAE document addresses control strategies (38). In a practical application, a combination of the individual interventions will be more effective than a single intervention in isolation. It is recommended that a heating and air-conditioning engineer be consulted on the implementation of these strategies. Pharmaceutical companies may consider improving particle filtration for the central air handler, adding upper-room UVGI units, increasing the outdoor ventilation rates, and avoiding the use of a lower ventilation rate motivated solely by reduced energy consumption.

Small aerosolized particles, <10 µm, generated by talking, coughing, or sneezing will be suspended in the air and transported into the lower respiratory tract during breathing whereas larger drops, 10–25 µm, will fall through the air and accumulate on horizontal surfaces (39). Aerosols may be transported some distance by sideways airflows in nonclassified rooms, whereas vertical laminar airflow with floor-level exit registers will sweep the air clean in classified clean rooms. Table III provides information on the number of air changes per hour.

We believe that pharmaceutical manufacturing conducted in classified areas (ISO 8 to ISO 5) will provide environmental conditions that will adequately clear viral particles potentially shed by employees. Nonclassified areas where non-sterile drug products are manufactured and all packaging and labeling areas will need to be assessed for the number of air changes (ventilation rate) to facilitate viral clearance and for their cleaning and disinfection practices. Based on this risk assessment, changes may be necessary.

Hand Sanitization

Hand washing and sanitization are an essential component of GMP controls designed to protect product. In addition to these routine controls, additional hand sanitization stations should be established in non-GMP areas to mitigate risk to employees.

Personal Protective Equipment

As COVID-19 infected individuals cannot be absolutely excluded from our manufacturing sites, PPE will become more important. A decision should be made whether the workplace wearing of face masks would be mandatory or limited to those activities in which personnel have direct contact with drug products. Table IV addresses the appropriate PPE to be worn during non-sterile and sterile drug product manufacturing.

The efficacy of different grades of face masks in entrapping COVID-19 viral particles has not been fully established. The level of exposure to coworkers, processing equipment, and pharmaceutical drug products may determine the choice from homemade face masks to cone masks, to medical face masks to N95 grade face masks (respirators).

The specifications for different grades of face masks obtained from commercial supply catalogs may include:

1. Certification Standards: Complies with ASTM F2299; ISO 9001.2015, and ISO 2859-3 1994; ISO 5 Compatible

2. Bacterial Filtration: >92%, >95%, or >99% @ 1.0 µm particle size retention

3. Reduced Particle Generation: Layers ultrasonically welded to limit particle shedding

4. Effective Pore Size: 1.0, 0.45, or 0.1 µm

5. Usage: Disposable, single use, or re-usage

6. Sterility: Non-sterile or sterile

FDA Regulation of Face Masks as Medical Devices

The FDA regulates face masks and respirators when they meet the definition of a device under section 201(h) of the federal Food, Drug, and Cosmetic Act (FD&C Act). Generally, face masks fall within this definition when they are intended for a medical purpose, including for use by health care professionals (41). These classifications are useful in determining which devices should be used in a pharmaceutical manufacturing facility.

The FDA defines these devices that may be suitable for use in a GMP manufacturing facility as follows:

Face Mask—A mask, with or without a face shield, that covers the user's nose and mouth and may or may not meet fluid barrier or filtration efficiency levels.

Surgical Mask—A mask that covers the user's nose and mouth and provides a physical barrier to fluids and particulate materials. The mask meets certain fluid barrier protection standards and Class I or Class II flammability tests.

N95 Respirator—A disposable half-mask filtering face piece respirator (FFR) that covers the user's airway (nose and mouth) and offers protection from particulate materials at an N95 filtration efficiency level per 42 CFR 84.181. Such an N95 FFR used in a health care setting is regulated by the FDA under 21 CFR 878.4040 (FDA product code MSH) and is either a Class II device that is exempt from premarket notification requirements under section 510(k) of the FD&C Act or is a Class II cleared device.

NIOSH Approved N95 Respirator—An N95 respirator, approved by National Institute for Occupational Safety and Health, that meets filtration efficiency level per 42 CFR 84.181.

The following are devices suitable for use in a clinical setting when medical staff treat COVID-19-infected patients but not in pharmaceutical manufacturing:

Face Shield—A face shield is a device used to protect the user's eyes and face from bodily fluids, liquid splashes, or potentially infectious materials. Generally, a face shield is situated at the crown of the head and is constructed with plastic to cover the user's eyes and face.

Filtering Face Piece Respirator—A filtering face piece respirator (FFR) is a device that is a disposable half-face-piece nonpowered air-purifying particulate respirator intended for use to cover the nose and mouth of the wearer to help reduce wearer exposure to pathogenic biological airborne particulates.

Surgical N95 Respirator—A disposable FFR used in a health care setting that is worn by health care personnel (HCP) during procedures to protect both the patient and the HCP from the transfer of microorganisms, body fluids, and particulate material at an N95 filtration efficiency level per 42 CFR 84.181. A surgical N95 respirator is regulated by the FDA under 21 CFR 878.4040 (FDA product code MSH) and is either a Class II device that is exempt from premarket notification requirements under section 510(k) of the FD&C Act or is a Class II cleared device.

Given the CDC recommendation that in addition to social distancing, face masks should be worn when people leave their places of residence, pharmaceutical companies should require employees reporting to work to be wearing face masks and should supply nonmedical masks to be worn on company premises until this recommendation is lifted. These face masks would be replaced at least twice a day and disposed as potential biohazard waste.

In manufacturing areas where pharmaceutical ingredients, packaging components, intermediates, and finished products are exposed to workers, the PPE recommendations found in Table IV would be strictly followed.

Pharmaceutical companies as high-volume users of face masks may employ strategies to conserve these devices when they are in short supply. These include allowing employees to use homemade cloth face masks to enter their facilities and continue to wear them in office areas, allowing the removal of face masks in isolated offices that maintain strict social distancing, and, when strictly necessary, the reuse of surgical masks after decontamination. On April 9, 2020, the FDA issued an Emergency Use Authorization (EUA) for the emergency use of a Steris Corporation vapor-phase hydrogen peroxide sterilization system for decontaminating compatible N95 respirators for reuse by medical personnel to prevent potential exposure to pathogenic airborne particulates when the respirators are in short supply because of the COVID-19 pandemic. The data submitted by Steris supported up to 10 sterilizations and reuse. It was noted that cellulose-based face masks are incompatible with hydrogen peroxide (42).

Vaccines against the SARS-CoV-2 Virus

The availability of safe and effective vaccines would help relax employee screening, social distancing practices, and the use of PPE in non-GMP areas. More than 40 different vaccines are in development globally with at least two now in Phase I human safety trials as of April 22, 2020. Vaccine clinical development is a complex process, which requires large clinical trials and establishing the long-term safety of the vaccine. The history of vaccine development is replete with examples of safety signals emerging post approval as a result of unexpected immunological response post immunization, for example, Rotashield and Dengvaxia. Further, it should be noted that there is no approved vaccine for SARS-COV-1 and for MERS, outbreaks that occurred in 2002 and 2012, respectively. Because of the widespread disease, recruiting large number of subjects for clinical trials is not expected to be a hurdle for COVID-19 vaccines, but this may change as the pandemic recedes. Despite all-out efforts, Dr. Anthony Fauci, Director of the U.S. National Institute of Allergy and Infectious Diseases, predicts that the availability of a vaccine will take a year to a year and a half, at least (43).

Regulatory Response to the COVID-19 Outbreak

On February 11, 2020, when the WHO formalized the name of the current outbreak as COVID-19, the FDA immediately added this official disease on their website. This new FDA Webpage will soon fill up with a wide range of guidance documents and directives in a very short time. This COVID-19 outbreak has generated an unprecedented response from the FDA and other U.S. regulatory agencies to remove many regulatory hurdles that were hindering the Industry response efforts to monitor and treat this pandemic. These dramatic changes from the global compliance norm reflect the seriousness of this viral threat to our medical supply industry along with the safety of those who work in these industries and those who may be patients in need of these pharmaceutical medical products. Among these U.S. federal agencies are the FDA, the CDC, OSHA, and the NIH. Their general contribution to the mitigation and relief of regulatory formalities will be briefly described following. In a February 14, 2020, press release, the FDA announced that “if a potential shortage or disruption of medical products is identified by the FDA, we will use all available tools to react swiftly and mitigate the impact to U.S. patients and health care professionals”. At this time period, the FDA press releases were focused on the impact of medicine and product coming from China owing to the COVID-19 outbreak that was occurring in that area of the world. It is very unlikely at that time that the pharmaceutical industry or regulators knew how significantly the subsequent global pandemic would impact their routine activities. Subsequently, there has been a significant list of FDA initiatives to minimize the shortage of essential medicine within the U. S. because of active pharmaceutical ingredient (API) unavailability for the manufacturing of the finished products (FDA announcement date February 27, 2020). Included in this list are the following guidance documents and directives and their date of issuance:

1. Critical human drug shortages can be mitigated with lengthening the expiration dates. (FDA, February 27, 2020).

2. A new policy for certain laboratories that develop and begin to use validated COVID-19 diagnostics before the FDA has completed review of their EUA request (FDA, February 29, 2020).

3. The FDA and Federal Trade Commission (FTC) issued seven warning letters to companies for selling fraudulent COVID-19 products. The products cited in these warning letters are teas, essential oils, tinctures, and colloidal silver. (FDA, March 9, 2020).

4. Coronavirus (COVID-19) Update: The FDA issues Guidance for Conducting Clinical Trials. The FDA is aware that protocol modifications may be required, and that there may be unavoidable protocol deviations owing to COVID-19. This would eventually include expedited early vaccine trial for the development of a COVID-19 vaccine (FDA, March 18, 2020).

5. The FDA and National Institutes of Health (NIH) have begun a randomized controlled trial for the treatment of COVID-19 patients with the investigational antiviral drug Remdesivir; interleukin-6 receptor inhibitors; as well as the application of convalescent plasma and hyper-immune globulin, antibody-rich blood products that are taken from blood donated by people who recovered from the virus infection (FDA, March 19, 2020).

6. The FDA provides a guidance document entitled “Temporary policy for preparation of certain alcohol-based hand sanitizer products during the public health emergency”. (FDA, March 20, 2020).

7. The FDA provides maximum flexibility to importers seeking to bring PPE into the U.S. with minimal disruptions during the importing process. The agency provided instructions to manufacturers on how to inform the U.S. Customs and Border Protection with specific advisement to expedite regulatory clearance. (FDA, March 24, 2020).

8. The FDA issues an EUA to allow for the emergency use in health care settings of certain ventilators, anesthesia gas machines modified for use as ventilators, and positive pressure breathing devices modified for use as ventilators (FDA, March 27, 2020).

9. The FDA establishes a new program to expedite the development of potentially safe and effective life-saving treatments. The program is known as the Coronavirus Treatment Acceleration Program (CTAP). This public-private approach is cutting red tape, redeploying FDA staff, and working day and night to review requests from companies, scientists, and doctors who are working toward therapies. (March 31, 2020).

10. The FDA issued a new EUA for non-NIOSH-approved respirators made in China, which makes KN95 respirators eligible for authorization if certain criteria are met. (FDA, April 3, 2020).

The authors of this review applaud the FDA in providing a more flexible regulatory response to the pandemic.

However, caution should be mentioned as to the temporary nature of these allowable regulatory shortcuts during this pandemic, and the return to standard practice should be documented to prevent any regulatory citations made by health authority inspections as the urgency of this historic event diminishes over time

European Union Regulatory Expectations during the COVID-19 Pandemic

As with the FDA in the United States, we are seeing a strong regulatory response to the COVID-19 pandemic from other regions of the world (43). For example, the combined organizations of the European Commission (EC), Heads of Medicines Agencies (HMA), and the European Medicines Agency (EMA) have published a Notice to their Stakeholders. The document is entitled “Questions and Answers on Regulatory Expectations for Medicinal Products for Human Use During the COVID-19 Pandemic” (EU Q&A document, April 2020). We will not discuss the entire Q&A in this review article, but we will highlight some key responses that the European Union (EU) expressed in their handling of deviations in manufacturing and importation of finished products and API as they relate to GMP and good documentation practice (GDP) issues during this pandemic.

Among some of the temporary changes include: (1) measures should be put in place to ensure the validity of GMP certificates that support manufacture and importation of medicinal products into the EU should be extended to avoid disruptions in the availability of medicines, with a liberal time extension to sites located inside the EU; (2) with the difficulty to perform on-site GDP inspections, the validity of GDP certificates will be extended until the end of 2021 with no further company action required; (3) remote batch certification and remote audits of API manufacturers have been expanded, even for those EU companies previously disallowed from this process; and (4) in case of imports of investigational medicinal products from outside of the EU, the companies quality department should ensure that the quality of the batch is in accordance with the terms of the clinical trial authorization and meets EU GMP requirements. The EMA recommended to make this assessment remotely; the companies need to review documents including batch records, in-process test reports, validation status of facilities, the results of any analyses performed after importation, stability reports, storage and shipping conditions, and so forth. Most gratifying was the response to the question can quality requirements be waived/adapted for medicines intended to be used for the treatment of COVID-19 patients? The short answer to this question was “No” but with the EMA offer that if manufacturers were having difficulties performing the compliance quality control steps, they were invited to contact the competent authorities and “to present an adapted control scheme based on a risk-based approach”. There was additional information to help navigate the regulatory hurdles posed by the restrictive travel conditions during this pandemic, so a review of the entire document is suggested for those manufacturing and conducting business in the EU geographic areas.

Risk Analysis Tools

A number of risk analysis tools, including quality risk management, may be used when assessing risk factors. Tables S-I to S-VI (see Appendix) show an example of a hazard analysis and critical control points (HACCP) program approach (originating in the food industry), which summarizes the common inputs, identifies the various risks with ratings from low to high, and suggests common risk mitigations or critical process control points. Risk assessment of the specific steps in the supply chain for a representative non-sterile and sterile drug product, that is, activity, risk level, critical control point, and mitigation are provided (44).

Steps analyzed included staff recruitment, procurement of pharmaceutical ingredients and packaging components, facility design and operation, cleaning and disinfection, utilities, manufacturing processes, packaging and labeling, warehousing, shipment, dispensing, and patient usage.

Drug Shortages

A major responsibility of the pharmaceutical industry and regulators is to anticipate and meet the changed demands for drug products driven by patient treatment and disruption to our supply chain. This statement appeared recently on the FDA website https://www.fda.gov/drugs/drug-safety-and-availability/guidance-notifying-fda-permanent-discontinuance-or-interruption-manufacturing-under-section-506c-fdc.

“Due to the COVID-19 pandemic, FDA has been closely monitoring the medical product supply chain with the expectation that it may be impacted by the COVID-19 outbreak, potentially leading to supply disruptions or shortages of drug and biological products in the U.S. The guidance, Notifying FDA of a Permanent Discontinuance or Interruption in Manufacturing Under Section 506C of the FD&C Act, is intended to help applicants and manufacturers provide the agency with timely and informative notifications about changes in the production of certain drugs and biological products. In urging the submission of these notifications, the guidance may assist in our efforts to prevent or mitigate shortages of such products, including under circumstances outside of the COVID-19 public health emergency.”

Many pharmaceutical drug products have the potential to be in short supply because of increased demand to treat hospitalized COVID-19 patients. Shifting production schedules to meet this increasing demand will help but may create backorders for other needed drugs. The disruption to the supply chain because of absenteeism of production and testing personnel, warehousing and shipping of packaging components, pharmaceutical ingredients and finished products, and imposition of national trade barriers to the free distribution of pharmaceuticals are all serious concerns.

Shortages have been reported for drugs that are used to keep patients' airways open, as well as antibiotics, antivirals, and sedatives (45⇓–47). In March 2020, orders for broad-spectrum antibiotics like azithromycin and antivirals like ribavirin have tripled; medicines for sedation and pain management like fentanyl, midazolam, and propofol have increased by 100%, 70%, and 60%, respectively.

Risk Assessment

The authors believe that as SARS-CoV-2 is a communicable human respiratory virus, the largest risk to the supply chain is absenteeism among line employees preventing the manufacture, testing, and distribution of drug products and not product contamination.

There are gaps in our knowledge of the epidemiology of the COVID-19 pandemic around identifying at-risk populations and the role of antibodies in preventing repeat infection that when filled will help manage our workforce (48).

The cell culture-based manufacturing processes of biological medicinal products can, and has in several instances, been infected by viruses (49). The susceptibility of the currently used manufacturing platforms, such as cell lines CHO, HT1080, and HEK 293 for the new SARS-CoV-2 has already been tested though, and the cell lines were found nonpermissive, that is do not support viral growth, to this new virus (Kreil, 2020 Personal Communication). See Table V for a summary of the lack of capacity of the coronavirus to grow in commonly used cell lines.

The detectability of the new SARS-CoV-2 has also been tested, and the cell line panels used in standard in vitro adventitious virus testing as required by regulatory guidance (ICH Q5A (R1)) were found capable of revealing virus presence (Kreil, 2020 Personal Communication). As might have been expected from experience with the earlier SARS-CoV, the Vero cell line was highly susceptible to infection, which was easily visible by development of a cytopathic effect (49).

The three main risks for viral contamination in cell culture for therapeutic production are the cell source, materials used in cell culture, and exposure of the process stream to the operators or environment with viral clearance, that is, inactivation or removal from the product, being most important in reducing the risk of virus contamination of the finished product. The reader is referred to the Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) study for more details on risk mitigation (49).