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CONTROLS TO MINIMIZE DISRUPTION OF THE

PHARMACEUTICAL SUPPLY CHAIN DURING THE COVID-19
PANDEMIC
Anthony M Cundell, Dennis Edward Guilfoyle, T. R. Kreil, et al.

PDA Journal of Pharmaceutical Science and Technology 2020,

Access the most recent version at doi:10.5731/pdajpst.2020.012021
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CONTROLS TO MINIMIZE DISRUPTION OF THE PHARMACEUTICAL SUPPLY CHAIN

DURING THE COVID-19 PANDEMIC

Cundell
1*, 2 3
T., D. Guilfoyle , T. R. Kreil , and A. Sawant
4

1 Microbiological Consulting, LLC, Scarsdale, NY USA,

2 Johnson & Johnson, New

3
Brunswick, NJ USA, Takeda, Vienna, Austria, and
4Merck & Co. Inc., Kenilworth, NJ USA

The authors are members of the PDA COVID-19 Task Force.

*Corresponding Author: Microbiological Consulting, LLC, Scarsdale, NY. E-mail:

tonycundell@gmail.com

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ABSTRACT: This article reviews currently available scientific literature related to the

epidemiology, infectivity, survival, and susceptibility to disinfectants of Coronaviruses,

in the context of the controls established to meet Good Manufacturing Practice

regulations and guidance, and the public health guidance issued specifically to combat

the Covid-19 pandemic. The possible impact of the COVID-19 pandemic on the

pharmaceutical supply chain is assessed and recommendations are listed for risk

mitigation steps to minimize supply disruption to pharmaceutical drug products. Areas

addressed include a brief history of the COVID-19 viral pandemic, a description of the

virus, the regulatory response to the pandemic, the screening of employees, the

persistence on inanimate surfaces, cleaning and disinfection of manufacturing facilities,

use of GMP-mandated personal protective equipment to counter the spread of the

disease, the role of air changes in viral clearance, approaches to risk assessment and

mitigation. Biological medicinal products have a great record of safety, yet the cell

cultures used for production can be susceptible to viruses, and contamination events

have occurred. Studies on SARS-CoV-1 for its ability to replicate in various mammalian

cell lines used for biopharmaceutical manufacturing suggest SARS-CoV-2 poses low risk

and any contamination would be detected by currently used adventitious virus testing.

The consequences of the potential virus exposure of manufacturing processes, as well

as the effectiveness of mitigation efforts are discussed. The pharmaceutical supply

chain is complex, traversing many geographies and companies that range from large

multinationals to mid and small size operations. This paper recommends practices that

can be adopted by all companies, irrespective of their size, geographic location, or

position in the supply chain.

KEYWORDS: COVID-19 pandemic, SARS-CoV-2 virus, drug shortage, supply chain,

employee screening, risk assessment, risk mitigation.

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INTRODUCTION

During academic training, every microbiologist learns about pandemics and their

impact on society. However, this bookish knowledge, although foundational, does not

prepare one for all the potential contingencies and scenarios that a pandemic can

present. As of writing this article, there is no approved drug to treat COVID-19 infection

and a shortage of testing capabilities to identify the virus in people exhibiting

symptoms of infection and screening for viral antibodies to determine infected

individuals who have recovered and might have immunity and return to the work place.

It should be noted that several Health Authorities have given emergency authorization

for use of certain drugs and antibody tests. Further, due to global increase in demand,

and disruption in transportation, the COVID-19 pandemic has resulted in major

shortage of medicines needed to treat symptoms of the disease, manage pain or to

prevent or control secondary infections. See Food and Drug Administration (FDA) Drug

Shortage website for additional information (1). In addition, the pandemic has created

a shortage of supplies of disinfectants and sanitizers, personal protective equipment

(PPE) such as masks and gowns needed to meet GMP standards and associated

Standard Operating Procedures (SOP).

Over the last 20 years, the world has experienced outbreaks of major novel respiratory

infectious diseases such as SARS (Severe Acute Respiratory Syndrome) outbreak,

(2002), Influenza pandemic H1N1 (2009), and MERS (Middle Eastern Respiratory

Syndrome) outbreak (2012), and now the COVID-19 pandemic (2020). Pandemics can

disrupt pharmaceutical supply in multiple ways at a time when medicines and vaccines

are critically needed to control the pandemic and treat medical conditions in other

patients not related to respiratory illness. Unavailability of raw materials,

manufacturing supplies, shutdown of transportation systems and most importantly

employee absenteeism due to infections, suspected infections, or fear of infections can

disrupt supply. The U.S. FDA published Guidance for Industry - Planning for the Effects of
High Absenteeism to Ensure Availability of Medically Necessary Drug Products (2) in

March 2011, i.e., following the 2009 Influenza N1H1 pandemic. More recently, the

Medicines and Healthcare Regulatory Agency, United Kingdom (MHRA) (3) and World

Health Organization (WHO)(4) have published guidance on flexibilities in response to

the COVID-19 pandemic. Since the last pandemic in 2009, there has been a massive

global increase in the use of social media platforms as a source of information, which

may or may not be accurate and can result in poor decisions that can impact the drug

supply.

This article reviews currently available scientific information related to coronaviruses,

disinfectants from peer-reviewed journals, authenticated sources such as the U.S.

Federal Centers for Disease Control and Prevention (CDC), Food & Drug Administration

(FDA), World Health Organization (WHO), major Health Authorities and national and

international Good Manufacturing Practices standards. Although the article is primarily

directed toward pharmaceutical drug manufacturing, the content should be useful to all

manufacturers of over the counter drug products, consumer health products, cosmetics,

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and medical devices. The question asked is how potential risks can be identified, and

mitigated to protect our manufacturing facilities, employees, drug products, and

customers from this pandemic respiratory virus? It should be noted that the COVID-19

pandemic is fast moving, and a tremendous amount of new scientific knowledge is

being created every day. The authors have endeavored to make recommendations

based on an anticipated progression of the pandemic in general terms, while the effect

of the pandemic locally and internationally may vary. In addition, local laws,

regulations and other requirements will inform each company’s specific response to the

pandemic.

Potential Risks that Can Result in Drug Shortages

The potential risk associated with COVID-19 can be categorized into i) direct risk posed

by the virus to employees and to product and ii) indirect risk to manufacturing and

distribution activities materialized by policies and controls promulgated by local, state

and national governments to control the pandemic (Figure I).

To assess the direct risk posed by COVID-19, it is important to understand the

epidemiology, infectivity, and susceptibility to disinfection.

Epidemiology of the COVID-19 Pandemic and Related Outbreaks

The 2019 novel coronavirus that was identified as the cause of an outbreak of

respiratory illness is now referred to as the COVID-19 pandemic with the infectious

viral agent designated as SARS-CoV-2. It was first detected in Wuhan, China on

December 12, 2019 (5) and reported to the World Health Organization (WHO) China

Country Office on December 31, 2019 (6). By mid-January, COVID -19 spread to

Thailand, Japan, and Korea and then Europe.

As the rapid spread of COVID-SAR-2 in the USA is well documented in published

literature the authors have used the US as the basis for discussion. The first

documented U.S. case was a 34-year old man who travelled to Wuhan, China to visit

family, returned and reported to an urgent care clinic in Snohomish County,

Washington on January 19, 2020 in response to a health alert from the U.S. Center for

Disease Control and Prevention (7). On March 11, 2020, the World Health Organization

declared Coronavirus Disease 2019 (COVID-19) a pandemic (WHO Statement, 2020) as

it had spread to multiple countries with high prevalence of community transfer. On

January 31, 2020, the U.S. Federal Health and Human Service (HHS) issued a declaration

of a public health emergency related to COVID-19 and mobilized the Operating

Divisions of HHS (8). In addition, on March 13, 2020, the President of the United States

declared a national emergency in response to COVID-19 (9).

By the end of March there were 240,000 confirmed U.S. cases, with over 7,000 deaths,

resulting in declaration of a national emergency by the President of the United States,

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with orders for non-essential workers to work from home. By the end of April, there

were over 1 million U.S. confirmed cases and 60,000 deaths. Pharmaceutical employees

involved in production and testing activities are deemed essential globally; Health

Authorities issued requests for pharmaceutical industry to work to avoid drug

shortages.

Description of SARS-CoV-2 Virus

Coronaviruses are lipid-enveloped, single-stranded, positive sense RNA viruses, with 26

to 32 kilobases, belonging to the genus Coronavirus, which include several relatively

benign, seasonal, common cold viruses and three new more virulent coronaviruses:

severe acute respiratory syndrome coronavirus (SARS-CoV), which emerged in the

human population in 2003; Middle-East Respiratory Syndrome coronavirus (MERS-

CoV), which emerged in humans during 2012; and SARS-CoV-2 that emerged in late

2019 and became COVID-19 pandemic in early 2020 (10, 11, 12)

Enveloped viruses like SARS-CoV-2 are highly susceptible to cleaning agents and

disinfectants, above ambient temperature, and usually do not survive on inanimate

surfaces beyond 2 days. This will be discussed in more detail in the section on

persistence of SARS-Cov-2. The individual coronavirus particles are around 0.125

micron in diameter. N95 facemasks are rated capture 95% of particles down to 0.3

micron. This means that viral particles may still potentially get through this protection.

The virus appears to be dispersed as larger droplets or aerosols and the multiple layers

of the facemasks largely mitigates this risk. In contrast, HEPA filters are 99.97%

effective at 0.3 micron and thus are much more efficient than facemasks.

Sources of the SARS-CoV-2 Virus

Zoonotic respiratory viruses initially emerge by animal-to-human and then largely by

human-to-human transmission and to a lesser degree surface to human transmission.

Dense human populations co-existing with dense chicken, duck, and pig populations as

found in the People’s Republic of China, as well of the consumption of wild animals as

food, favors the emergence of novel respiratory viruses (13, 14). There is little or no

evidence that the coronavirus is either a foodborne or waterborne viral pathogen.

Foodborne viral pathogens are responsible for a larger number of illnesses than

bacterial pathogens annually. They may be classified into three main groups of viral

illnesses; viruses that cause gastroenteritis, e.g., norovirus and rotavirus; enterically

transmitted hepatitis viruses, e.g., hepatitis A; enteroviruses, e.g., poliovirus (15).

Notably foodborne viruses are not associated with respiratory infection.

According to a March 2020 WHO Interim Guidance (16), although SARS-CoV-2

persistence in drinking water is possible, there is evidence from surrogate human

coronaviruses that they are not present in surface or ground water sources or are

transmitted through contaminated drinking water. The coronavirus being an

enveloped virus, with a fragile outer membrane does not survive in the environment

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and would be susceptible to filtration and chlorine treatment prior to water

distribution.

Because SARS-CoV-2 may be shed in fecal matter (up to 10% confirmed presence in

diarrhea) with some earlier reports of fecal-to-oral transmission (17, 18), this route of

transmission should not be treated casually, and personnel hygiene emphasized in

manufacturing facilities.

Public health experts have ruled out the possibility of insect to human transmission.

PERSONNEL HEALTH AND SAFETY

The biggest risk to the community at large, and as such to the pharmaceutical supply

chain is human-to-human transmission of the coronavirus. Protecting the health and

safety of employees should be the top priority of companies. The following points

should be considered and as appropriate built into the pandemic response plans

developed by individual companies.

Social Distancing and Work from Home

Certain local, state, and national governments and their health authorities have issued

social distancing guidelines that may include mandatory stay at home order with a

caveat to exclude ‘essential employees,’ i.e., 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 employees need 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 QA batch record reviewer on site but those that have

paper records, or hybrid paper and paperless systems may need to include such

employee in 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.

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Employees working off-site, using communication tools like mobile telephones, email,

and video conferencing, 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 non-essential while

those employees (operators, as well as, managers) directly involved in product

manufacturing, testing, and distribution viewed as essential. However, this distinction is

not clear-cut. For example, it may be possible to delay a supplier audit of

pharmaceutical ingredient used in the manufacture of an essential drug product; annual

GMP training for packaging operators, or even marketed product stability testing.

Determining what are non-essential 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 non-

essential. These plans should be approved 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

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 suffers 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

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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 pre-symptomatic 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. 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 prior to initiating a

mandatory employee-testing program. Companies outside the U.S. must obviously

consider applicable national and local laws.

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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. Employee should not report to work

and seek medical advice immediately if the body temperature is above

100.4°F/38°C. If screening is conducted at plant entrance, trained screener

should use a calibrated hand-held or wall attached no-touch thermometer.

Employees with 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 suspected 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 co-workers 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.

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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, hallway and entrances.

9. Review of the frequency of excluded employees 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

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,

25) to identify infected travelers compared to virus testing might detect less than half of

those infected due to 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 Californian

hospital system indicated that chief symptoms presenting in the emergency department

by 377 adults were 49% shortness of breath, 34% fever and 32% cough (27).

As testing for the SARS-CoV-2 viruses 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) it appears that

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.

FACILITY AND PROCESS MANAGEMENT

Persistence of Coronavirus on Inanimate Surfaces
Human viruses cannot multiply outside the body and will not survive on inanimate

surface for long. The analysis of 22 studies on the persistence of human coronaviruses

other than SARS-CoV-2 virus (Table I) reveals they may persist on metal, glass or plastic

for up to 9 days (Range 2 hours to 9 days) but they are readily inactivated by

disinfectants and sporicides such as 62-71% ethanol, 0.5% hydrogen peroxide or 0.1%

sodium hypochlorite within 1 minute (28).

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The studies summarized in Table 1 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 RT-PCR 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 antiseptics 0.05-0.2%

benzalkonium chloride and 0.02% chlorhexidine digluconate are less effective requiring

a contact time of up to 10 minutes (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 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, i.e. 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 (TCID 50) in the aerosol suspension for

the 3-hour duration of the experiment with a reduction in infectious titer from 10
3.5 to

10
2.7 TCID50 per mL representing a half-life of 1.1 to 1.2 hours. 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 up to 72 hours, its titer was greatly

reduced (From 10
3.7 to 100.6 TCID50 per mL after 72 hours on plastic and from 10
3.7 to
10
0.6 TCID50 after 48 hours on stainless steel). On copper, apparently due to Cu
2+
toxicity, no viable SARS-CoV-2 was measured after 4 hours and on cardboard no viable

SARS-CoV-2 was measured after 8 hours (29). This means, that in the event that

controls established to exclude an infected employee fails, and in the event that

packaged product is exposed to the virus, the plastic container used for primary

packaging and cardboard used for secondary packaging should not carry infectious

coronavirus, due to 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 on 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, 31, 32). The efficacy of pasteurization (63°C

for 30 minutes) was demonstrated with MERS-CoV in camel, goat and cow milk with the

virus titer reduced from 10

5.5 to less than 100.5 TCID50 (33). Clearly, the heat sensitive

SARS-CoV-2 virus will not survive sterilization processes used in sterile product

manufacturing.

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Inactivation of Viruses Due 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 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 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 contains 75 agents, provides useful information on representative commercially

available products, their active ingredients, contact times and antiviral claims (34).

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 prior to use,

a ready for use product, and sterilized 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 Cleanrooms

Warehouses, offices, laboratories, 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

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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 Personnel Protective Equipment

worn by cleanroom operators and the cleaning and disinfection program will make it

unlikely that the coronavirus will persist in cleanrooms 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 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 central air handler, adding

upper-room UVGI units, increasing the outdoor ventilation rates, and avoiding the use

of lower ventilation rate motivated solely by reduced energy consumption.

Small aerosolized particles, <10 micron, generated by talking, coughing or sneezing will

be suspended in the air and transported into the lower respiratory tract during

breathing while larger drops 10-25 micron will fall through the air and accumulate on

horizontal surfaces (39). Aerosols may be transported some distance by sideway

airflows in non-classified rooms, whereas vertical laminar airflow with floor level exit

registers will sweep the air clean in classified cleanrooms. Table III provides

information on the number of air changes/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 shred by employees. Non-classified areas where non-sterile drug products

are manufactured and all packaging and labeling areas will need to be assessed for the

number 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

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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, personal protective equipment (PPE) will become more important.

A decision should be made whether the workplace wearing of facemasks 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 facemasks in entrapping COVID-19 viral particles has

not been fully established. The level of exposure to co-workers, processing equipment,

and pharmaceutical drug products may determine the choice from homemade

facemasks to cone masks, to medical facemasks to N95 grade facemasks (respirators).

The specifications for different grades of facemasks obtained from commercial supply

catalogs may include:

• Certification Standards: Complies with ASTM F2299; ISO 9001.2015, and ISO

2859-3 1994; ISO 5 Compatible

• Bacterial Filtration: >92%, >95%, or >99% @ 1.0 micron particle size retention

• Reduced particle generation: Layers ultrasonically welded to limit particle

shredding

• Effective Pore Size: 1.0, 0.45 or 0.1 micron

• Usage: Disposable, single use or re-usage

• Sterility: Non-sterile or sterile

FDA Regulation of Facemasks as Medical Devices

The FDA regulates facemasks 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, facemasks 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 use 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.

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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 healthcare setting is regulated by 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 NIOSH that meets

filtration efficiency level per 42 CFR 84.181.

The following are devices suitable for use in a clinical setting when medical staff treats

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 non-powered 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 healthcare setting that is worn

by HCP during procedures to protect both the patient and 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 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, facemasks should

be worn when people leave their places of residence, pharmaceutical companies should

require employees reporting to work to be wearing facemasks and should supply non-

medical masks to be worn on company premises until this recommendation is lifted.

These facemasks 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.

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Pharmaceutical companies as high volume users of facemasks may employ strategies to

conserve these devices when they are in short supply. These include allowing

employees to use home-made cloth facemasks to enter their facilities and continue to

wear them in office areas, the removal of facemasks in isolated offices that maintain

strict social distancing should be allowed, and, when strictly necessary, the re-use 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 due to the COVID-19

pandemic. The data submitted by Steris supported up to 10 sterilizations and re-use. It

was noted that cellulose-based facemasks 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 use of PPE in non-GMP areas. Greater 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 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 e.g.

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.

Due to 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 RESPONSES
Regulatory Response to the COVID-19 Outbreak
On Feb 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 reflects 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

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medical products. Among these U.S. federal agencies are the U. S. Food and Drug

Administration, Center for Disease Control and Prevention, Occupational Safety Health

Administration and the National Institution of Health. Their general contribution to the

mitigation and relief of regulatory formalities will be briefly described below. 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 react swiftly to 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 due 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 Emergency

Use Authorization (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: 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 due to COVID-19. This would

eventually include expedited early vaccine trial for the development of a COVID-

19 vaccine (FDA, March 18, 2020)

5. 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. 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)

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8. FDA issues an Emergency Use Authorization (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. 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 a

cutting red tape, redeploying FDA staff and working day and night to review

requests from companies, scientists and doctors who are working towards

therapies. (March 31, 2020)

10. 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 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 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) has 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 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 manufacturer 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

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requirements. The EMA recommended in order 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, etc. Most gratifying was the

responses 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

to perform 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.

OVERALL RISK ASSESSMENT

Risk Analysis Tools
A number of risk analysis tools, including quality risk management, may be used when

assessing risk factors. Tables V1–XI (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, i.e., 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

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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 due to

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 due to 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, 46, 47). On March, 2020, orders for

broad-spectrum antibiotics like azithromycin and antiviral 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 amongst line employees preventing the

manufacture, testing and distribution of drug products and not product contamination.

There are gaps in our knowledge on the epidemiology of the COVID-19 pandemic

around identifying at risk populations and 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

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

non-permissive, i.e. not support viral growth, to this new virus (Kreil, 2020 Pers.

Com.). 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)) found capable of revealing virus presence (Kreil, 2020 Pers. Com.). 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

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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, i.e.,

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 Bio-manufacturing (CAACB)

study for more details on risk mitigation (49).

DISCUSSION
The objective of our discussion will primarily focus on the unique current conditions

and problems associated with the controls to minimize disruption of the

pharmaceutical supply chain and to highlight other factors that we may not have had

the available information to include in this review publication. Future data and

experiences will eventually fill in the gaps of our current understanding and control of

the COVID-19 pandemic.

The 2020 COVID-19 global pandemic meets all the characteristics of “A Black Swan”

that the best-selling author Nassim Nicholas Talab, defined as an event with low

probability, extreme impact, unforeseen, and retrospective predictability (51). Dr.

Talab, a renowned Professor of Risk and Decision Science, proposed the Black Swan

theory to explain highly improbable events, and the bias in decision making introduced

by past experience, and by pockets of knowledge not available to all decision makers.

Low Probability Events

As per WHO, in 2016 Lower Respiratory Infections were the most deadly

communicable disease causing 3 million deaths worldwide and was 4th overall on the

top 10 global causes of death (52). As per CDC, in 2017 Influenza and Pneumonia was

leading cause of communicable disease causing 55, 672 deaths in the U.S. and was the

8th overall on the top 10 causes of death (53). Although scientists understood the

possibility of another novel highly contagious and deadly respiratory virus outbreak,

past experience gained in managing SARS-COV-1, H1N1 Influenza, and MERS outbreaks

i.e. limited spread may have introduced a bias among some scientists, policy makers,

and public at large in accessing probability and underestimating the rapid spread of the

COVID-19 outbreak into a pandemic.

Extreme Impact Events

The medical impact of a pandemic has been well studied by scientists, however the

impact of mitigation strategies such as social distancing, and the impact of a global to

transportation and resulting economic activity was perhaps not well understood and

anticipated. As such, the scientific, medical, business and legal communities had to

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scramble to find quick solutions and remedies to both the direct and indirect

deleterious impact from this pandemic. The essential nature of the pharmaceutical

industry to combat pandemics i.e. higher level of knowledge and awareness, regulatory

requirement to have business continuity plans, regulatory relief, and GMP controls has

resulted in relatively less impact on the manufacturing activities of pharmaceutical

companies as compared to many other manufacturing and service industries.

Unforeseen Events
The complexity of the supply chain, increased demand for personnel protective

equipment, the inability of essential employees to commute to work during stay at

home orders were unforeseen domino effects. When national catastrophes (i.e.,

tornadoes, hurricanes, forest fires) occur in certain regions of a country there are

generally local, state or federal contingency plans in place to mitigate or coordinate the

multi-response to that effected area. Pandemics being relatively rare events, and each

with unique characteristics and speed of spread can result in many unanticipated

challenges.

Retrospective Predictability
As the pandemic progresses it is easy to connect the dots and conclude that the

pandemic was predictable and different decisions were required. The fast spread of a

novel virus requires decision-making on limited information and decisions need to be

re-valuated as new information becomes available. There needs to be a deliberate and

educated infectious disease preparedness and response plan built into business

continuity plans for the next inevitable pandemic.

Limited Viral Characterization and Transmission Factors

One of our knowledge gaps as it relates to this infections virus is our inability to identify

asymptomatic, infected individuals and exclude them from the pharmaceutical

workplace without widespread testing for the virus and its antibodies. This would be

followed by the problem with a lack of follow-up contact investigations. Lastly, a more

definitive assessment of the efficacy of personnel protective equipment especially

facemasks against the SARS-CoV-2 virus is needed.

Current Industry Manufacturing Practices that are Low Risk

In general, due to the reduced ability of the lipid-enveloped virus to survive (but not

proliferate) outside the human body, cleanroom environmental controls, cleaning and

disinfection programs, and the personnel protection equipment employed in the

pharmaceutical industry are adequate to prevent COVID-19 viral contamination of our

sterile products manufactured in GMP-compliant facilities and do not need to be

changed. Our review includes recent information that the COVID virus does not grow in

the conventional manufacturing cell lines used for the proliferation and production of

biologically based pharmaceutical products (Kriel, 2020 Pers. Com.)

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Risk Mitigation Steps that May Need Re-evaluation

Areas that may need a closer risk assessment may be environmental conditions and

controls in non-sterile product manufacturing rooms and all product labeling and

packaging areas. The engineering and operational standards of the HVAC systems

supplying these workspaces should be reviewed and, if necessary, improved.

Parameters that may need to be assessed may include the number of air changes per

hour, cleaning and disinfection programs, and the personnel protective equipment

worn in these areas. Due to the low risk of viral contamination to our GMP-controlled

pharmaceutical equipment and manufacturing rooms, no product testing for the

presence of the COVID-19 virus is recommended. Until better understood, employees

holding staff positions should work from home. Protocols for the eventual integration of

the total work force back to pre-COVID-19 activity needs to be written and reviewed,

which should include medical and legal staff to allow for the gradual and specific viral

monitoring with a cognizant determination for those who are at highest risk to this

virus. The reliability of the medical platform for making these determinations should be

assessed. For example, the benefit of measuring antibody blood titers to the COVID-19

virus may not be a 100% reliable factor for preventing re-infection to this virus. (WHO

reference. April, 25, 2020)

Critical Risk Mitigation Steps that should be Evaluated

Pharmaceutical companies must aggressively screen their employees for COVID-19

infection and remove those infected, in timely manner, from the workplace. These

actions are necessary to avoid absenteeism due to continuing infection or re-infection

of critical employees and the general work staff and a loss of employees to manufacture,

test, and distribute essential drug products. A more definitive list of the risk mitigation

steps recommended by the authors will be presented in the next section.

CONCLUSIONS
The authors, from their point-of-view as microbiologists, have attempted to review the

risks and recommend mitigation steps that pharmaceutical companies, depending on

their circumstances, should consider implementing in their manufacturing facilities.

The PDA has established a COVID-19 task force with broader representation of the

disciplines within our membership that expand on areas over and above this review.

Recommendations
The following risk mitigation steps to minimize the impact of COVID-19 on the

pharmaceutical supply chain based on the risk classification in Figure I are

recommended:

Direct Risks Posed By the COVID-19 Pandemic (Figure I)

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Personal Health and Safety

• To facilitate social distancing employees able to do their job from home should

be allowed to do so while employees directly involved in the manufacture,

testing, packaging and distribution of pharmaceutical product should be

screened for potential COVID-19 infection and if suspected to be infected should

be excluded from the workplace.

• Non-essential visitors should be denied entry to all manufacturing facilities.

• Install additional hand sanitization stations in non-GMP areas.

• Wearing of facemasks by all employees in non-GMP areas should be considered

after careful evaluations of the risks and benefits and would not be governed by

GMP procedures.

• If a safe and efficacious COVID-19 vaccine is available, it should be made widely

available to the manufacturing employees of pharmaceutical companies.

Product Quality

• Meeting GMP requirements related to Personal Protective Equipment and

excluding at risk employees from manufacturing activities will provide adequate

assurance.

• Testing for the presence of Covid-19 in manufacturing facilities and products is

not recommended.

• Pharmaceutical GMPs should be strictly maintained.

• Determine if mammalian cell lines used for biopharmaceutical production are

not susceptible to the COVID-19 virus.

• Pharmaceutical companies are encouraged to actively monitor.

recommendations from the U.S. CDC, FDA, EMA and the WHO and make changes

to their policies and procedure as the COVID-19 pandemic recedes.

GMP Manufacturing

• Environmental controls, the appropriate use of personnel protective equipment,

and cleaning and disinfectant practices, especially in warehouses, non-sterile

manufacturing areas and packaging lines should be reviewed and updated

where necessary.

• Manufacturing and testing schedules can be adjusted and additional shifts added

to facilitate social distancing and to ensure essential drug products are not in

short supply.

Availability of Supplies

• Strategies for conserving facemasks and other personnel protective equipment

should be implemented.

• Enhance collaboration with suppliers educating them of their importance to the

pharmaceutical industry.

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Indirect Risks posed by the COVID-19 Pandemic (Figure I)

Availability of Employees

• Re-purposing employees for critical activities.

• Supply alternative transportation for employees commuting using public

transportation to work.

Transportation Infrastructure

• Distribute finished goods using dedicated transportation in place of common

carriers.

Availability of raw materials, e.g., drug substances, excipients, solvents, processing

supplies, packaging materials.

• Strengthening existing supplier relations.

• Seeking alternative suppliers.

AKNOWLEDGEMENTS
The authors wish to thank T. Cosgrove, Esq., and A. Caruso for their assistance in

writing the article and the members of the PDA COVID-19 Task Force for their review

and helpful comments

DISCLAIMER
The opinions and suggestions made by the authors in this manuscript do not

necessarily reflect the policies and requirements of their affiliated company

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Tables
Table I: Persistence of Coronaviruses on Inanimate Surfaces (28)

Type of Surface Virus Inoculum (Viral Persistence

Titer) (Temperature)

Steel MERS-CoV 10
5 48 h (20°C)

8-24 h (30°C)

HCoV 10
3 5 d (21°C)

Aluminum HCoV 10
3 2-8 h (21°C)

Wood SARS-CoV-1 10
5 4 d (RT)

Paper SARS-CoV-1 10
6 24 h

10
5 3 h

10
4 < 5 min (All at RT)

Glass SARS-CoV-1 10
5 4 d (RT)

HCoV 10
3 5 d (21°C)

Plastic SARS-CoV-1 10
5 ≤ 5 d (22-25°C)

MERS-CoV 10
5 48 h (20 °C)

SARS-CoV-1 10
7 6-9 d (RT)

10
5 4 d (RT)

HCoV 10
7 2-6 d (RT)

Polyvinylchloride HCoV 10
3 5 d (21°C)

Silicon Rubber HCoV 10

3 5 d (21°C)

Surgical Glove HCoV 5 x 10

3 ≤ 5 d (21°C)

(Latex)

Disposable Gown SARS-CoV-1 10

6 2 d

10
5 24 h

10
4 ≤ 8 h (all at RT)

Ceramic HCoV 10
3 5 d (21°C)

Teflon HCoV 10
3 5 d (21°C)

MERS = Middle East Respiratory Syndrome; HCoV = Human Coronavirus; SARS-CoV-1 =

Severe Acute Respiratory Syndrome

Table II: Anti-virus Activity of Representative Commonly-used Disinfectants and

Sporicidal Agents in the Pharmaceutical Industry (34)

Active Product Name Company Contact Formulation Emerging

Ingredient Time Type Anti-viral

(Minutes) Claim

Hydrogen Accel Virox 5 Dilutable Yes

Peroxide (Concentrate) Technology

Phenolic LpH Steris 10 Dilutable Yes

Phenolic Vesphene II se Steris 10 Dilutable Yes

Sodium CloroxPro™ Clorox 5 Dilutable Yes

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Hypochlorite Clorox® Professional

Germicidal Product Co.

Bleach

Isopropyl DECON-AHOL Veltek NA RTU No

alcohol WFI
® Formula Associates

70%

Hydrogen DECON-SPORE Veltek NA RTU No

peroxide and 200

® Plus Associates

peracetic acid

Quaternary Lysol® Reckitt 5 RTU Yes

ammonium; Disinfectant Benckiser

Ethanol Spray LLC

Hydrogen Oxy-1 Wipes Vorox 0.5

Wipes Yes
Peroxide Technology

Ethanol PURELL GOJO 5 Wipes Yes

Professional Industries

Disinfectant

Wipes

Sodium Clorox Clorox 3 Wipes Yes

Hypochlorite Healthcare® Professional

Bleach Products

Germicidal Co.

Wipes

See EPA List N: Products with Emerging Viral Pathogens and Human Coronavirus

Claims (34)

Table III: Air Velocity and Number of Air Changes per Hour in Cleanrooms (39)

Class of Cleanroom Airflow Type Average Velocity (ft./min.) Air Changes/hr.

ISO 8 (Class 100,000) N/M 1-8 5-48

ISO 7 (class 10,000) N/M 10-15 60-90

ISO 6 (Class 1,000) N/M 25-40 150-240

ISO 5 (Class 100) U/N/M 40-80 240-480

N = Non-unidirectional; M = Mixed Airflow; U = Unidirectional. Note: 10 ft./min. equals

3.048 m. /min.

Table IV: Appropriate personnel protective equipment for routine pharmaceutical

manufacturing (40)

Protective Clothing Non-sterile Manufacturing Sterile Manufacturing

Areas Areas

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Plant uniform or plant Yes Yes

uniform with overalls for

high-risk product and
environment
Hair/beard coverings Yes Yes

Safety glasses Yes Yes

Dedicated shoes or shoe Yes Yes

coverings
Gloves Yes (if in direct product Yes

contact)
Face masks Yes (if in direct product Yes

contact)
Enclosed respirators Only if manufacturing high- Only if manufacturing high-
potency, toxic drugs or potency, toxic drugs or
infectious biological agents infectious biological agents
Sterile cleanroom uniforms No Yes, if in critical aseptic

(coveralls), hoods, sleeves, processing area

goggles, face masks, and

gloves

Table V: Capacity of SARS-CoV-2 to Replicate in Primate and Human Cell Lines

Cell Line Cell Line Origin SARS-CoV References

Replication
CHO Chinese Hamster Ovary Incompatible (Kreil, 2020 Pers.

Com.)

HEK293 Human Embryonic Cells Incompatible (Kreil, 2020 Pers.

Com.)

HT1080 Human fibrosarcoma Incompatible (Kreil, 2020 Pers.

Com.)

A549 Human Adeno carcinoma Incompatible 50

Cells

HUH Human Liver Cells Moderate 50

HEK293T Human Embryonic Cells Moderate 50

VERO African Green Monkey Kidney High 50

Cells

Incompatible = No growth, No Cytopathic Effect (CPE); Moderate = Growth but no CPE;

High = Growth and CPE

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Figure Captions
Figure I: Direct and indirect risks that may result in pharmaceutical drug shortages

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APPENDIX
HACCP Approach to Risk Assessment
A comprehensive risk assessment of the different parts of pharmaceutical supply chain

may be found in Tables VI through XI. The four columns in each table address the input

or activity, potential risk identification, assigned risk rating (low, moderate or high),

existing critical process controls and recommended risk mitigations. The risk

assessment model used is based on food-based HACCP principles that may be

unfamiliar to some people working in the pharmaceutical industry (45). These

represent the informed opinions of the authors with an emphasis on the risk

assessment process and an attempt to capture all relevant aspects of the steps in the

supply chain.

Table VI: Risk Assessment – Management of Human Resources during a COVID-19

Pandemic

Activity Risk Identification Risk Risk Mitigation/Critical

Rating Process Controls
Recruitment of Local; Regional; Low to Remote interviews; Limit

new staff National; Moderate domestic and international travel;

International 14-day quarantine prior to

starting work

Training new Lack of information; Moderate GMP compliance; Coronavirus

hires and Issues not to High awareness training;

existing addressed in Symptoms identification

employees corporate policies

and procedures

Deployment of Domestic; Moderate Staff functions conducted from

employees International to High home; Restrictions on non-

essential domestic and

international travel; deferment of

large staff meetings

Management Staff and line Moderate Illness recognition; Monitoring

and Supervision functions to High with thermal sensors; Universal

of Employees wearing of non-medical

facemasks on the job

Employee Employees working Low Flexibility in working hours;

Attendance sick; Loss of human Stress importance of staying

resources; Inability home when ill; Provide sickness

to commute benefits; Add company sponsored

transportation when public

transportation is unavailable

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Table VII: Risk Assessment – Management of Manufacturing Materials during a COVID-

19 Pandemic

Materials Risk Identification Risk Risk Mitigation/Critical Process

Rating Controls
Pharmaceutical Excipients derived Low Supplier awareness of potential

Excipients from plant, animal or COVID-19 risk; Standard duration

mineral origin; of transit and hold times

Excipients of

synthetic or

semisynthetic origin

Drug Substances Drug substance of Low Standard duration of transit and

synthetic or hold times

semisynthetic origin

Packaging Glass vials, stoppers Low Standard duration of transit and

Components and seals (Sterile hold times; automation of

products) component handling; washing,

Plastic container, depyrogenation and sterilization

heat induction seals (Sterile Products)

and caps (Non-sterile

products)

Labeling Labels and package Low Reduce handling during label

Materials inserts identification and reconciliation

Incoming Ground or surface Low Communication with local water

Potable Water water authority

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Table VIII; Risk Assessment – Testing of Incoming pharmaceutical ingredients,

packaging components, intermediates and finished products during a COVID-19

Pandemic

Materials- Risk Identification Risk Risk Mitigation/Critical

Sampling and Rating Process Controls
Testing
Sampling of Human intervention; Moderate Personnel Protective

Incoming Limited Equipment; sampling booths;

Materials environmental labeling sampled containers

controls in

warehouses

Transportation to Transition through the Low Disinfection of the surface of

the testing area facility containers, drums, shrink-

wrap and pallets

Sample testing Personnel handling Low Personnel Protective

Equipment; limited access to

testing area; environmental

controls

Sample Disposal Low Controlled destruction of

disposition samples

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Table IX: Risk Assessment – Management of Plant Utilities during a COVID-19 Pandemic

Materials – Risk Risk Rating Risk Mitigation/Critical

Plant Utilities Identification Process Controls
Pharmaceutical- Incoming potable Low Maintain existing microbial

grade Water water monitoring program

Pharmaceutical- Distribution lines Low Assure sanitary design

grade Plant Air and delivery

nozzles

Compressed None Low Maintain existing microbial

Gases monitoring program

HVAC System Poor temperature, Low to Reduced recirculation in

humidity and air Moderate more critical areas; Higher

exchange, Re- air change rates; High-

circulation and room ultraviolet

lack of segregation germicidal Irradiation

Domestic and None Low None

Clean Steam

Vacuum Discharge Low Review vacuum discharge

Washing Poor design and Low to Access to detergents, hot

Facilities opportunities for Moderate water, and hand sanitizing

cross- agents;

contamination Segregation of clean and

dirty materials

Waste and Poor separation Moderate Backflow elimination;

Sewage Disposal Segregation of clean and

dirty materials

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Table X: Risk Assessment - Representative Non-Sterile Drug Product (Compressed

Tablet) during a COVID-19 Pandemic

Manufacturing Risk Identification Risk Risk Mitigation/Critical

Process Rating Process Controls
Incoming Material Sampling is an Moderate Sampling booths; Personnel

Sampling and invasive process Protective Equipment (PPE)

Testing

Warehousing Limited Low Improved environmental

environmental control

control

Ingredient Weighing Weighing is an Low to Evaluate weighing booths

invasive process Moderate and PPE

Excipient Size Equipment cleaning Low Upgrade COP and CIP

Reduction operations

Blending Equipment cleaning Low Upgrade COP and CIP

operations

Granulation – Dry Equipment cleaning Low Upgrade COP and CIP

Granulation - Wet operations

Compression Equipment cleaning Low Upgrade COP and CIP

operations

Bulk Tablet Storage None Low None

Packaging and Packaging Low to Evaluate HVAC Systems;

Labeling operations are Moderate Automation of component

labor intensive handling; PPE

Finished Goods Poor environmental Low Improved environmental

Warehousing control control

Shipping Lack of chain of Low Dedicated carriers

custody

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Table XI: Risk Assessment - Representative Sterile Drug Products (Liquid-filled

Stoppered Glass Vials) during a COVID-19 Pandemic

Manufacturing Risk Identification Risk Risk Mitigation/Critical

Process Rating Process Controls
Incoming Material Sampling is an Moderate Sampling booths and

Sampling and invasive process in a Personnel Protective

Testing warehouse Equipment (PPE)

Warehousing Limited Low Improved environmental

environmental control (IEC)

control

Ingredient Weighing is a labor Low to Evaluate weighing booths

Weighing intensive process Moderate and PPE

Bulk Solution Solution preparation Low to Use of Restricted Access

Preparation is a potentially Moderate Barrier Systems (RABS) and

invasive process Isolators

Packaging Component loading Low Automation of component

Component and unloading is a handling; Depyrogenation

Preparation potentially invasive and sterilization of vials and

process stoppers

Sterile Filtration Aseptic processing is Low Use of RABS and Isolators

and Aseptic Filling, a potentially invasive

and Sealing process

Visual Inspection Inspection is an Low Handling automation; IEC;

invasive process PPE

Packaging and Packaging is an Low Handling automation;

Labeling invasive process IEC; PPE

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