Review of Drug and Biologics Recalls: 2009 Through 2019

Eastern Michigan University DigitalCommons@EMU

Master's Theses, and Doctoral Dissertations, Master's Theses and Doctoral Dissertations and Graduate Capstone Projects

2020

Review of drug and biologics recalls: 2009 through 2019

Vimala Devi Gollamudi

Follow this and additional works at: https://commons.emich.edu/theses

Part of the Chemicals and Drugs Commons

Recommended Citation Gollamudi, Vimala Devi, "Review of drug and biologics recalls: 2009 through 2019" (2020). Master's Theses and Doctoral Dissertations. 1049. https://commons.emich.edu/theses/1049

This Open Access Thesis is brought to you for free and open access by the Master's Theses, and Doctoral Dissertations, and Graduate Capstone Projects at DigitalCommons@EMU. It has been accepted for inclusion in Master's Theses and Doctoral Dissertations by an authorized administrator of DigitalCommons@EMU. For more information, please contact [email protected]. Review of Drug and Biologics Recalls: 2009 through 2019

Vimala Devi Gollamudi

Thesis

Submitted to the School of Health Sciences

Eastern Michigan University

in partial fulfilment of the requirements for the degree of

MASTER OF SCIENCE

Clinical Research Administration

Thesis Committee:

Irwin Martin, Ph.D., Chair

Jean Rowan, MD, MS.

July 7, 2020

Ypsilanti, Michigan DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 ii

Acknowledgements

I would like to express my gratitude to Dr. Irwin Martin for his continuous support and his guidance throughout the completion of the paper. I would also like to thank my family, friends and colleagues that has been supportive throughout the process.

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 iii

Abstract

This study analyzed drugs and biologics recalls for the period of 2009 and 2019. The data used in the study was generated from Food and Drug Administration records. A total of 466 drugs and 84 biologics were recalled during the 11-year period. The common causes of drug product recalls included contamination, defective products, and mislabeling. Defective product, mislabeling, and defective packaging were observed to be the common causes of recall for biologics. Injectables have the highest percentage of recalls in drug products, and blood and blood products had the highest percentage of recalls in biologics. Controlling the contamination of injectable and also minimizing mislabeling, defective packaging and defective product of blood and blood products could help in providing safer drugs and biologics to the public.

Keywords: biologics, drugs, recalls, Food and Drug Administration

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 iv

Table of Contents

Acknowledgements ...... ii

Abstract ...... iii

List of Tables ...... vii

List of Figures ...... viii

Chapter 1: Introduction ...... 1

Chapter 2: Background ...... 3

Drugs ...... 3

Biologics ...... 3

Current Good Manufacturing Practices (CGMPs) ...... 4

Recalls and Their Regulation Process...... 6

Major Reasons for Drug Product and Biologic Product Recalls ...... 7

Purpose of the Study ...... 8

Research Questions ...... 9

Chapter 3: Research Design and Methodology ...... 10

Drug Recalls Analysis Research Design and Methodology ...... 10

Reason for the recall...... 11

Type of dosage and route of administration...... 13

Cross tabulation...... 15

Biologic Recalls Analysis Research Design and Methodology ...... 15 DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 v

Reasons for recall...... 15

Type of products...... 17

Cross tabulation...... 18

Chapter 4: Results ...... 19

Drug Recalls Analysis Results ...... 19

Biologic Recalls Analysis Results ...... 25

Chapter 5: Discussion ...... 31

Drug Recalls...... 31

Biologics Recalls ...... 34

Limitations ...... 36

Chapter 6: Conclusion...... 38

References ...... 39

APPENDICES ...... 42

Appendix A: Drug Recalls Raw Data ...... 43

Appendix B: Biologic Recalls Raw Data ...... 130

Appendix C: Reasons for Recall Reported in Every Year from 2009 to 2019 ...... 184

Appendix D: Number of Recalls Reported for Each Type of Product in Every Year from

2009 to 2019 ...... 185

Appendix E: Cross Tabulation of Type of Drug Product Vs Reason for Recall ...... 187 DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 vi

Appendix F: Number of Reasons for Biologic Recalls Reported in Every Year from 2009 to

2019...... 189

Appendix G: Number of Recalls Reported for Each Type of Biologic Product in Every Year

from 2009 to 2019...... 190

Appendix H: Cross Tabulation of Type of Biologic Product Vs Reason for Recall ...... 191

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 vii

List of Tables

Table 1. Description of Reasons for Drug Recalls ...... 12

Table 2. Description of Type of Drug Products ...... 14

Table 3. Description of Reasons for Biologic Recalls ...... 16

Table 4. Description of Type of Biologic Products ...... 17

Table 5. Number of Drug Recalls Per Year from 2009 to 2019 ...... 19

Table 6. Number of Recalls Reported for Each Reason for Drug Recall from 2009 to

2019 ...... 20

Table 7. Number of Recalls Reported for Each Type of Drug Product from 2009 to 2019 ... 22

Table 8. Number of Biologics Recalls Per Year from 2009 to 2019 ...... 25

Table 9. Number of Recalls Reported Under Each Reason for Recall of Biologic Products

from 2009 to 2019 ...... 26

Table 10. Type of Biological Product Recalls from 2009 to 2019 ...... 28

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 viii

List of Figures

Figure 1. Reasons for Recall Reported by Year from 2009 to 2019...... 21

Figure 2. Recalls Due to Mislabeling, Contamination,, and Defective Product from 2009

to 2019...... 21

Figure 3. Number of Recalls Reported Under Each Type of Product by Year from 2009

to 2019...... 23

Figure 4. Trend Pattern of Injectables and Solid Orals Recalls Reported from 2009 to

2019...... 24

Figure 5. Cross Tabulation of Type of Product vs Reason for Recall...... 24

Figure 6. Number of Rreasons for Recalls vs Year From 2009 to 2019...... 27

Figure 7. Mislabeling, Defective Packaging and Defective Product Recalls Reported from

2009 to 2019...... 27

Figure 8. Number of Types of Biologics Products Recalled by Year from 2009 to 2019...... 29

Figure 9. Blood & Blood Products and Vaccines Recalls Reported from 2009 to 2019...... 29

Figure 10. Biologic Product Recalled vs Reason for Recall Reported...... 30 DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 1

Chapter 1: Introduction

A recall is a measure in which someone or something was officially summoned back to its origin (American Society for Quality [ASQ], n.d.) Whereas a product recall is an instance in which a product was requested to be returned, exchanged, or replaced when the manufacturer or an appropriate regulatory agency (for e.g., United States Consumer Product

Safety Commission or United States Food and Drug Administration [FDA]) notices defects that are probably harmful or might hinder the products performance (ASQ, n.d.), when a drug product or a biologic product has been known to be defective and can cause potential harmful effects or might exhibit hindered performance, then that drug or biologic product will be subject to recall by the manufacturer or by the FDA (Nagaich & Sadhna, 2015).

The FDA is one of the oldest consumer protection agency. Originally part of U.S

Department of Agriculture as the Division of Chemistry in 1890, it was renamed the Bureau of Chemistry in 1901, and later as United States Food, Drug and Insecticide Administration, until it was finally renamed as U.S. Food and Drug Administration in 1930. In 1940 then the

U.S. FDA was then transferred to the Federal Security Agency, the Department of Health,

Education and Welfare, and then finally the Department of Health and Human Services

(DHHS; FDA, 2018e). The FDA is responsible for ensuring the safety, efficacy, and quality of products such as foods (dietary supplements, bottled water, food additives etc.), drugs

(prescription and over-the-counter), biologics, medical devices, radiation emitting products, cosmetics, veterinary products, and tobacco products (FDA, 2018g). The FDA regulates the manufacturing, marketing, and distribution of its regulated products. It also makes sure that the science-based information about the products it regulates is made available to the public.

The FDA also plays a significant role in responding to the naturally and deliberately DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 2 occurring health threats to the public (FDA, 2018h). The FDA oversees companies’ strategies for the biologic or drug that is being recalled and classifies the recall based on the extent of the harm that the product in question will cause or had already caused (FDA, 2018d). FDA also makes sure that the company initiating the recall has promptly alerted the public about its recall. If the company fails to promptly notify the public, then the FDA may take it upon itself to alert the public (FDA, 2018d).

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 3

Chapter 2: Background

Drugs

A drug is defined as “a substance which is other than food which affects the structure or function of the body” and “a substance intended for use in cure, diagnosis, mitigation, treatment or prevention of a disease” (FDA, 2017). A drug product is defined as “the finished dosage form that contains a drug substance generally, but not necessarily in association with other active or inactive ingredients” (FDA, 2017).

The Center for Drug Evaluation and Research (CDER) is the part of the FDA that regulates over-the-counter and prescription drugs (FDA, 2019). The CDER’s primary goal is to evaluate drugs before they can be made available to the public. It makes sure that the health benefit of the drug outweighs its risk. A team of CDER reviewers, which includes physicians, chemists, statisticians, and pharmacologists, reviews the submitted application and data and recommends if the drug should be allowed into the marketplace. After marketing approval of the drug, CDER again monitors risks that may not have been detected during the pre-clinical studies and clinical trials. If CDER finds any new health risks related to the drug, it immediately notifies both manufacturer as well as the public. It may request a change in the label or even remove the drug from the market entirely. The manufacturer of the drug also constantly evaluates the efficacy and quality of the drug after it was allowed on the market (FDA, 2016).

Biologics

Biologics are complex mixtures that are derived from natural sources, such as humans, animals, or microorganisms. For example, blood and blood components, allergenics, somatic cells, and tissues are produced with the help of various biotechnology methods. DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 4

Biologics are difficult to identify or characterize; therefore, stringent aseptic conditions are to be applied during the initial manufacturing process. Biologics are used to treat a variety of illnesses and conditions that have no current medical treatments and drugs available (FDA,

2018f).

Biologics are regulated by Center for Biologics Evaluation and Research (CBER) which is a center within the Food and Drug Administration (FDA). CBER ensures the safety and effectiveness of the new biological products by reviewing and evaluating the data submitted by the manufacturer and makes sure the product meets the standards for approval.

It also continuously monitors approved biological products for any new information. It provides up to date information to the public, healthcare professionals, media and the manufacturers of the biological products. (FDA, 2018a). Products that are regulated by

Center for Biologics Evaluation and Research (CBER) include allergenics, blood and blood products, cellular and gene therapy products, tissue & tissue products, vaccines, and xenotransplantation (FDA, n.d.).

Current Good Manufacturing Practices (CGMPs)

The FDA began an initiative in 2002 to improve pharmaceutical manufacturing and product quality. This mainly focused on the current good manufacturing practices (CGMPs), which covers human drugs, biological products, and veterinary drugs (FDA, 2016).

These CGMP regulations help ensure the identity, quality, strength, and purity of the product. These standards are the minimum standards that are to be followed by pharmaceutical manufacturers. They were established in such a way that the manufacturer can decide the best way to implement them by using potential good designs, processing methods, and testing procedures. Because of the flexibilities in these regulations, modern DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 5 technologies can be employed to achieve high-quality data, methods, and products. If the

CGMPs are followed, they could help mitigate instances of deviations, contaminations, failures, and errors and therefore assure that products meet quality standards (FDA, 2018c).

A product’s quality and safety cannot be detected by touch, smell, and sight alone.

CGMP compliance requires extensive testing beyond the appearance of the drug or biologic product. A small sample from a batch is taken for testing to evaluate the batch. If the sample fails to meet standards, the whole batch will be deemed unfit to be allowed into the market.

Hence, it is important to manufacture the products adhering to the CGMP regulations. Few examples of CGMPs are equipment that are properly maintained and calibrated, facilities that are in good conditions, employees who are properly trained and qualified and processes that are reliable and reproducible (FDA, 2018c). The FDA inspects pharmaceutical manufacturing facilities, including the active pharmaceutical ingredient (API) manufacturing facilities all over the USA and also the facilities overseas that manufacture the API and drug products for marketing in the US. These inspections are conducted by highly trained FDA staff. The inspections ensure that the companies are compliant with CGMP regulations. If a company or a facility was found not to be following CGMPs, the drug or biological product manufactured by that facility will be deemed adulterated under the law. Not all CGMP violations are deemed to be harmful to the consumers. In those cases, the FDA advises the public to take their physicians advise before consuming such products. When the CGMP violation results in failure to offer any labeled benefit and moreover presents a health risk, then the FDA moves for recall of that particular drug or biologic product. The FDA can also seize product or issue an injunction to prevent manufacturing if many CGMP violations were observed (FDA, 2018c). DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 6

Code of Federal Regulations (CFR) Chapter 21 contains drug-quality-related regulations in several parts. These regulations lead to a common understanding of the processes to be followed by the drug manufacturers. For example, 21CFR Part 211 describes the CGMP regulations for finished product pharmaceuticals (FDA, 2018b).

Recalls and Their Regulation Process

A recall is an effective way to protect the public from a defective or harmful product.

All recalls are voluntary actions taken by the company. Either the company itself find its product defective or harmful and initiates the recall process or the FDA requests the recall process. Recalls are posted in enforcement reports weekly. The FDA also assures that if a company had initiated a recall that it has made sure that its customers were properly notified and all the products in question were removed from the market properly. The FDA may request additional actions if it feels that the company in question put inadequate efforts into the recall process (FDA, 2018d).

FDA, 2020 also issued a guidance document called Product Recall, Including

Removals and Corrections, Guidance for Industry to provide the industries regulated by the

FDA guidance and recommendation regarding the aspects of recalls. It includes a checklist of documents and information required by the FDA to evaluate and monitor the recall process.

This guidance document provides information about recall submission process, public notification, and evaluation of the recall (such as effectiveness, status reports, root cause, corrective actions and preventive actions taken, and termination of the recall). General guidance is also accessible through 21 CFR part 7, subparts A and C (FDA, 2020).

All FDA regulated products are subject to recall. The recalls are classified into three classes: DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 7

 Class I: The product in question can cause serious health problems or death.

 Class II: The product in question can cause a temporary health issue or might lead to

a slightly serious health condition.

 Class III: The product in question does not cause any serious health concerns but are

in violation of FDA labelling or manufacturing regulations. (FDA, 2010).

Major Reasons for Drug Product and Biologic Product Recalls

Hall, Stewart, Chang, and Freeman (2016) examined the characteristics of drug recalls (prescription, over-the-counter, dietary supplements) and biological products over 30 months. About 3,045 recalls from June 20, 2012, to December 31, 2014, met the inclusion criteria for their study. The investigation of this study revealed that the five most common causes for recalls in this 30-month period were mislabeling, contamination, defective product, adverse reaction, and incorrect potency.

Eissa (2019) collected drug recalls data from 2016 to 2018 from the FDA drug recall website. The reasons for recalls were further grouped into composition issues, lack of sterility assurance, microbial contamination, packaging issues, particles, unapproved drugs and miscellaneous. The study used statistical process control (SPC) tools to evaluate and analyze the data. The general trend was observed to be increasing from 2016 to 2018.

Moreover, the study also showed that major contributors to the recalls were microbiological quality issues (which includes both lack of sterility assurance and microbial contamination), composition issues, and packaging issues.

Wang and Gagne (2012) collected the data of all the drug recalls that were reported from 2004 to 2011 from publicly available FDA enforcement reports. A total of 1,734 drug recall entries were made within this time period. The most common reasons for Class I DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 8 recalls were contamination, incorrect dosage, or incorrect dispensing mechanism of the products. The study also revealed that the FDA had 166 emergency Recall alert system announcements pertaining to human drug recalls from 2004 to 2011, 47% of which were

Class I recalls.

In 2015 and 2016, companies such as B. Braun Medical and Baxter International, Inc, were forced to recall some of their products because of improper packaging of the drug product such as leaky containers which are poorly covered containers that allow light and moisture into the product resulting chemical interaction of the drug product with the environmental elements (Chawla, Singh, & Kumar, 2016). These recalls included dextrose injection, sodium chloride injection, clinimix, metronidazole, and sodium chloride injection

(Chawla et al, 2016). Both United States and Europe-based pharmacopeias have established specifications for sterile product glass containers. In Europe, these specifications include the required standards for packaging, repackaging, and dispensing medical products, while the

United States has established guidelines for light-resistant containers and closures for capsules and tablets (Chawla et al, 2016).

The literature suggests that in most instances, issues related to product contamination are the primary reason for product recall, especially injectables sterility assurances.

Purpose of the Study

The majority of the cited literature used small periods of time such as 2.5 years, or 2 years. Observing the general trends of recalls for more than a 10-year time period will give better perspective on the pattern of these drug and biologic recalls. The purpose of this study is to group and narrow the major causes of recalls, and to provide insight on the most DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 9 common reasons of recalls as well as most common type of product that have been recalled during the 11-year period of 2009 to 2019.

Research Questions

1. What were the total number of drugs and biologics Recalls from 2009 to 2019?

2. What were the most frequent or common reasons for recalls in drugs and biologics

from 2009 to 2019?

3. What were the most frequent or common type of drug and biologic products

recalled from 2009 to 2019?

4. What were the most frequent type of drug and biological products that were recalled

from 2009 to 2019?

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 10

Chapter 3: Research Design and Methodology

Drug Recalls Analysis Research Design and Methodology

All drug recall data for the years 2009 to 2017 were obtained from the FDA’s archives, which were available in FDA.gov under the web page “Archive for Recalls, Market

Withdrawals and Safety Alerts.” When “Recall and Safety Alerts Archive” is clicked, it redirects the user to a different web page within FDA.gov that contains links to the recall archives on a yearly basis. These archived recall data were available on a yearly basis and contained date of recall, product name (sometimes it also contained lot numbers and dosage form), name of the distributer, name of the manufacturer, and reason for recall along with a link that redirected the user to the official notification of that particular recall. These archives have data on all the recalled products regulated by the FDA. These data were then downloaded into an Excel file by using an html to Excel converter. From these data, only prescription drugs, over-the-counter drugs, prescription-only dietary supplements, and IV fluids such as saline and Ringers (intended for human use) were manually selected.

Supplements available without prescription and do not advertise any therapeutic value, homeopathic products, and any products that were advertised as alternative medicine were excluded from the analysis.

Recalls from 2018 and 2019 had not yet been archived and were retrieved from

FDA.gov “Recalls, Market Withdrawals, Safety Alerts” web site. Unlike the archives, these recalls were selected through the “Filters” option provided in the web page, and the data were again downloaded in the Excel format by using the Excel option provided in the web page.

All the drug recalls were compared by reason of recall, type of product, and if the recall was manufacturing (CGMP violations) or drug product/substance related. DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 11

Reason for the recall. The first type of analysis was done based on reason of the recall, (i.e., why they were recalled) and then to narrow down the reasons of recalls they were further reclassified into the following categories: Defective Product, Contamination,

Mislabeling, Incorrect Potency, Adverse Reaction, Defective packaging, Other GMP

Violations, and Other. The categories of reasons for recall and the reasons that apply to the particular category were presented in Table 1. Each recall was classified into the categories which best represented the reason for recall.

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 12

Table 1 Description of Reasons for Drug Recalls

Reason Description Defective Product Discoloration, impurities out of specification, new kind of impurities identified that are harmful or may be carcinogenic, uncharacteristic texture or consistency, inaccurate dosage delivery, empty capsules, precipitation or crystallization, presence on visible particle (that are not related to contamination but are due to precipitation of drug substance or the API or excipients were poorly solubilized ). Contamination Lack of sterility assurance, microbial contamination, presence of any particulate matter that appears to be foreign (e.g., glass particles, fungal or bacterial spores), or presence of any unidentified ingredient or presence of a foreign drug product or material.

Mislabeling Label mix up, wrong drug product with wrong labeling, wrong potency was written, wrong expiration date, or anything that was written incorrectly on the label. Incorrect Potency The drug in the formulation was either sub-potent or super-potent. Adverse Any adverse reaction reported that is due to or might Reaction/Events have been due to or in relation with the drug product. Defective packaging Defective packaging of drug product such as loose cardboard, dented containers or leaky vials, etc., which might compromise the stability, sterility, loss of drug product, possibility of tampering. Other GMP violations Other violations of Good Manufacturing Practices. For example, there were reports of lack of quality assurance, or the methods or processes were not validated properly, etc. Improper storage Drug products that weren’t stored as per the specified conditions storage conditions after manufacturing, during shipping, in the pharmacy or the warehouse. Other These are miscellaneous and they are one-time only incidents and are harder to group individually.

After downloading the recall data from the FDA archives, the drug recall data were selected per the criteria. The selected data were then saved to a different Excel file. The recalls were each assigned a sequential number for ease of counting. A column was added to DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 13 the Excel spreadsheet and the reason for recall as per Table 1 were added (Also refer to

Appendix A). The number of recalls that were reported in each year from 2009 to 2019 were calculated, and then the number of recalls that were reported under each category of reason for recall were counted. Finally, the number of recalls reported in each year under each category for each reason for recall (cross tabulation) were calculated. The most frequent reasons for reported recalls were calculated from January 2009 through December 2019.

Type of dosage and route of administration. The second type of analysis was done based on the type of dosage and its route of administration. These are categorized as type of product formulation, for e.g., oral solid, liquid orals, topical, injectables. There were cases where the type of product recalled was ambiguous, such as more than one product or all the products were recalled that were manufactured by the compounding pharmacy, but the archived report did not mention what kind of products were recalled. The recall letter just stated that all the sterile products were recalled, or all the non-sterile products were recalled, or all the products were recalled. In some instances, a few products were recalled, but it was not specified what type of products these were. The reason for recall in those cases was assigned their own category under the type of product classification. The type of products and the dosage forms that falls under each type is provided in Table 2.

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 14

Table 2 Description of Type of Drug Products

Type of Product Description Oral solids Tablets and capsules Liquid orals Oral suspensions Topicals Creams, ointments, topical solutions Transdermal Patches Ophthalmic Eye drops, eye products Otic Ear products; ear drops Injectables Sterile products for intravenous, intramuscular or other injections Inhalational Drug products that are to be taken by inhaling via nose All sterile products Some recalls include recalling all the sterile products by that specific manufacturing establishment or pharmacy. They include all the sterile products like injectables, ophthalmic, etc. All the products This type of recall includes recall of all kind of products that are manufactured in the facility that is in question or the pharmacy in question.

More than one kind of More than one kind of drug product was recalled but not all product the products. (the recall letter did not specify what kind of products). All non-sterile products Recall of all non-sterile products, that were manufactured in the facility in question or the pharmacy in question. All liquid products Recall of all liquid drug products made by the manufacturing facility in question or pharmacy in question. API Recall of specific active pharmaceutical ingredient (API).

To the above collected data for the drug recalls, another column was added to the

Excel spreadsheet and the appropriate type of product name was added to the drug product as

Table 2 (also refer to Appendix A). The number of recalls that were reported under each type of product were calculated and number of recalls reported in each year under each type of product (cross tabulation) were calculated. Trends were examined for the most frequently recalled type of products reported. DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 15

Cross tabulation. In the third type of analysis, the cross tabulation of type of product recalled under each category of reason for recall were also analyzed.

Biologic Recalls Analysis Research Design and Methodology

For biologic recalls, all the products that were regulated by the CBER were taken into consideration except for the devices such as blood allocating software or any systems that were needed for the use of a biologic but is not marketed with that particular biologic. All the recall data for biologics from 2009 to 2017 were obtained from FDA’s waybackarchive.org, accessible through FDA.gov under the web page “Recalls (Biologics).” Clicking the link under Recalls by year redirected the user to FDA’s waybackarchive-it.org. These archives were available based on the year the official recall notification was issued (reported). These data contained the date of notification (considered as the date reported), brand name, product description, reason for recall, and name of the company. These data were then downloaded to an Excel file format using an html to Excel converter. Unlike the drug recalls, the biologic recalls have their own archive hence eliminating the need of filtering out the biologics manually from all the products that were recalled by the FDA. The recalls from 2018 to 2019 were not yet archived in FDA’s waybackarchive-it.org but were directly available through the “Recalls, Market Withdrawals, Safety Alerts” web page in FDA.gov. For the recalls that were reported in 2018 and 2019 the “filters” option that was provided in the webpage was used and the “Biologics” option was selected. The Biologics recalls were analyzed in three ways:

Reasons for recall. The first type of analysis was done based on the reasons the products were recalled. Recalls were then they were grouped into categories, for e.g., DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 16 contaminations, mislabeling, defective product. The categories of reasons for recall and the reasons that come into the particular category are provided in Table 3.

Table 3 Description of Reasons for Biologic Recalls

Reason Description Mislabeling Label contains wrong information such as wrong lot number, wrong expiration date, mismatched product and accessory labels, etc. Defective product Presence of elevated or unidentified or unreported impurities, failed stability, expired product, decreased reactivity, wrong profile, probes and other accessories were defective, gives or might give faulty test results, or any materials used were expired etc. Adverse Reaction There is or there might be a potential safety hazard. Contamination Lack of sterility assurance, Microbial Contamination, presence of any particulate matter that appears to be foreign (ex: glass particles, fungal or bacterial spores etc.,), or presence of any unidentified ingredient or presence of a foreign material. Also includes any accessory that comes with product such as applicators, warmers, media etc., that was contaminated or looked contaminated. Defective packaging Packaging was loose, product may leak out as soon as it was opened, compromised vial integrity, potential leak etc. Improper storage Products were not stored per the specified storage conditions conditions after manufacturing, during shipping, in the clinic or the warehouse. Incorrect potency Sub-potent or super- potent product. Other Miscellaneous, one-time incidents that are harder to group individually.

After downloading the recall data from the FDA archives, the biologics recall data were selected per the inclusion criteria. The selected data were then saved into a different

Excel file. The total number of recalls were calculated by adding serial numbers to each event. A column was added to the spreadsheet and the reason for recall categories were assigned to each recall based on the definitions in Table 3. (Also refer to Appendix B). The DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 17 number of recalls that were reported in each year from 2009 to 2019 were calculated, then the number of recalls that were reported under each category of reason for recall were analyzed, and finally, the number of recalls reported under every category of reason for recall in each year (cross tabulation) were calculated. Trends of the most frequent reasons for recalls reported were examined.

Type of products. The second type of analysis was based on type of products, e.g., blood and blood products, vaccines, allergenic, (the CBER web page in FDA.gov website was used to determine the type of product). The type of products that falls under each type is presented in Table 4.

Table 4 Description of Type of Biologic Products

Type of Biologic Description Allergenics Allergen extracts, allergen patch tests, antigen skin test

Blood and Blood products Blood, blood components, blood screening tests

Cellular and gene therapy Cell-based treatments Tissue and Tissue products Stem cells, bone marrow, tissues, etc.

Vaccines All kind of vaccines and tuberculin tests

To the data collected for the biologic recalls, another column was added to the spreadsheet, and the appropriate type of product name was added to the biologic products

(Table 4; Appendix B). The number of recalls that were reported under each type of product were calculated and number of types of product recalls reported under each year (cross tabulation) were analyzed. Trends were examined for the most frequently recalled type of products reported DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 18

Cross tabulation. The third type of analysis was cross tabulation of type of product recalled under each category of reason for recall. DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 19

Chapter 4: Results

Drug Recalls Analysis Results

A total number of 466 drug product recalls were reported from January 2009 to

December 2019. The number of recalls reported each year is presented in Table 5.

Table 5 Number of Drug Recalls Per Year from 2009 to 2019

Year Number of drug recalls

2009 18 (3.9%)

2010 34 (7.3%)

2011 34 (7.3%)

2012 33 (7.1%)

2013 61 (13.1%)

2014 41 (8.8%)

2015 29 (6.2%)

2016 31 (6.7%)

2017 15 (3.2%)

2018 92 (19.7%)

2019 78 (16.7%)

Total 466 (100%)

After the recalls were categorized into their respective reasons for recall, the number of recalls that fall under each category were calculated. The percent of each reason for recall to the total number of recalls reported was also calculated (Table 6).

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 20

Table 6 Number of Recalls Reported for Each Reason for Drug Recall from 2009 to 2019

Drug recall type Number of drug recalls

Mislabeling 62 (13.3%)

Contamination 263 (56.4%)

Incorrect potency 25 (5.4%)

Defective packaging 10 (2.1%)

Improper storage conditions 2 (0.4%)

Defective product 87 (18.7%)

Adverse reaction 3 (0.6%)

Other Good Manufacturing 10 (2.1%)

Practices violations

Other 4 (0.9%)

Total 466 (100%)

The number of reasons for recall reported was observed in every year from 2009 to

2019 and is presented as a bar chart Figure 1 (also refer Appendix C). DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 21

Reason for Recall (Drug Product) vs Year Mislabeling 100 Contamination Incorrect potency Defective packaging 80 Improper storage conditions Defective product Adverse reaction 60 Other GMP violations

0 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Figure 1. Reasons for recall reported by year from 2009 to 2019. Recalls due to mislabeling, contamination, and defective products were the most frequently recalled (Figure 2; also refer Appendix C).

Reason for Recall (Drug product) vs Year 50 45 46 45 40 35 34 30 27 25 22 20 20 21 21 17 15 15 16 11 10 9 8 7 5 6 6 6 6 5 5 4 3 4 3 4 0 01 1 1 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Mislabeling Contamination Defective product

Figure 2. Recalls due to mislabeling, contamination, and defective product from 2009 to

2019.

The recalls were categorized based on the selection criteria for the type of product.

The number of recalls that fall under each category were calculated. The percent of each type DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 22 of product that was recalled to the total number of recalls reported from 2009 to 2019 is presented in Table 7.

Table 7

Number of Recalls Reported for Each Type of Drug Product from 2009 to 2019

Type of drug recalls Number of drug recalls (%)

Solid oral 121 (26.0%)

Liquid oral 27 (5.8%)

Injectable 226 (48.5%)

Inhalation 10 (2.1%)

Ophthalmic 22 (4.7%)

Otic 1 (0.2%)

More than one product 5 (1.1%)

All the products 9 (1.9%)

Transdermal 5 (1.1%)

Topical 10 (2.1%)

All sterile products 27 (5.8%)

All non-sterile products 1 (0.2%)

API 1 (0.2%)

All liquid products 1 (0.2%)

Total 466 (100%)

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 23

The number of recalls reported for each type of product was calculated for each year from 2009 to 2019 (Figure 3; Also refer Appendix D).

Solid oral Liquid oral Injectable Type of Drug Product Recalled vs Year Inhalation 100 Ophthalmic Otic 90 More than one product 80 All the products Transdermal 70 Topical All sterile products 60 All non-sterile products API 50 All liquid products

0 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Figure 3. Number of recalls reported under each type of product by year from 2009 to 2019. Solid orals and Injectables were most frequently recalled. (Figure 4; also see

Appendix D).

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 24

Type of Drug Products Frequently Recalled vs Year 40 38 38 35 33 34 30 30 25

20 19 20 17 15 16 16 15 13 10 10 10 10 10

5 4 4 4 2 3 0 1 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Solid oral Injectable

Figure 4. Trend pattern of injectables and solid orals recalls reported from 2009 to 2019. The reason for recalls and type of products that were recalled were cross tabulated to observe which type of product was recalled for which different reasons of recall. The cross tabulated data are presented in Figure 5 (also see Appendix E)

250 Type of product vs Reason for recall

200 Mislabeling Contamination Incorrect potency 150 Defective packaging Improper storage conditions Defective product 100 Adverse reaction Other GMP violations Other 50

Figure 5. Cross tabulation of type of product vs reason for recall.

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 25

Biologic Recalls Analysis Results

A total number of 84 biologics recalls were reported from 2009 to 2019 that fit in the inclusion criteria. The number of recalls reported each year from 2009 to 2019 is presented in

Table 8.

Table 8

Number of Biologics Recalls Per Year from 2009 to 2019

Year Biologics Recalls

2009 8 (9%)

2010 21 (25%)

2011 6 (7%)

2012 16 (19%)

2013 11 (13%)

2014 3 (3%)

2015 4 (4%)

2016 6 (7%)

2017 3 (3%)

2018 5 (5%)

2019 1(1%)

Total 84 (100%)

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 26

After the recalls were categorized into their respective reasons for recall, the number of recalls that fall under each category was calculated. The percent of each reason for recall to the total number of recalls reported is presented in Table 9.

Table 9 Number of Recalls Reported Under Each Reason for Recall of Biologic Products from 2009 to 2019

Biologics recall type Number of biologics recalls

Mislabeling 21 (25.0%)

Contamination 5 (6.0%)

Incorrect potency 5 (6.0%)

Defective packaging 12 (14.3%)

Improper storage conditions 1 (1.2%)

Defective product 29 (34.5%)

Adverse reaction 7 (8.3%)

Other 4 (4.8%)

Total 84 (100%)

The number of each reason for recall by year is presented in Figure 6 (also see

Appendix F). DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 27

Reason for Recall vs Year

25 Mislabeling Contamination Incorrect potency 20 Defective packaging Improper storage conditions 15 Defective product Adverse reaction 10 Other

0 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Figure 6. Number of reasons for recalls VS year from 2009 to 2019. Recalls due to mislabeling, defective product and defective packaging were most frequently recalled (see Figure 7; also refer Appendix F).

Frequent Reasons of Recall (biologics) vs Year 7

6 6

5 5

4 4 4 4

3 3 3 3 3 3 3

2 2

1 1 1 1 1 1 1 1

0 0 0 0 0 0 0 0 0 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Mislabeling Defective packaging Defective product

Figure 7. Mislabeling, defective packaging and defective product recalls reported from 2009 to 2019. DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 28

The type of biologic product and the number of recalls that fall under each category were calculated. The Percent of each recall type that was recalled to the total number of recalls reported is presented in Table 10.

Table 10 Type of Biological Product Recalls from 2009 to 2019

Type of biologics product Number of biologics recalls

Allergenics 3 (3.6%)

Blood and blood products 55 (65.5%)

Cellular and gene therapy products 2 (2.4%)

Tissue and tissue products 1 (1.2%)

Vaccine 23 (27.4%)

Total 84 (100%)

The number of recalls of each type of biologic product was observed in each year from 2009 to 2019 and is presented in Figure 8 (also refer Appendix G). DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 29

Biologic Type vs Year Allergenics

25 Blood and blood products Cellular and gene therapy products 20 Tissue and tissue products

15 Vaccine

0 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Figure 8. Number of types of biologics products recalled by year from 2009 to 2019. Blood and blood products and vaccines were most frequently recalled from years

2009 to 2019 (Figure 9; also refer Appendix G).

Frequent Type of Biological Products Recalled vs Year 14 13 13 12

8 8

6 6 6

4 4 4 4 4 3 3 2 2 2 2 1 1 1 1 0 0 0 0 0 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Blood and blood products Vaccine

Figure 9. Blood & blood products and vaccines recalls reported from 2009 to 2019. DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 30

The reason for recalls and type of products that were recalled were cross tabulated to observe which type of product was recalled for which different reasons for recall (Figure 10; also see Appendix H).

Biologic Product Type vs Recall Type

60 Mislabeling 50 Contamination Incorrect potency 40 Defective packaging Improper storage conditions Defective product 30 Adverse reaction Other 20

0 Allergenics Blood and blood Cellular and gene Tissue and tissue Vaccine products therapy products products

Figure 10. Biologic product recalled vs reason for recall reported.

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 31

Chapter 5: Discussion

Eleven years of drug and biologic recalls were examined for trends over time as well as to gain insight into the most common reasons for recall by product type.

Drug Recalls

A total of 466 drug recalls occurred between the 2009 and 2019. The highest percentage of drug recalls were reported in 2018, followed by 2019, at 19.7% (n = 92) and

16.7% (n = 78) respectively. However, 2017 had the lowest percentage of drug recalls at

3.2% (n = 15). The drug recalls percentage was constant at 7.3% (n = 34) in 2010 and 2011.

Product contamination was the leading cause of recalls reported at 56.4% (n = 263).

This was followed by defective product, mislabeling, and incorrect potency at 18.7% (n =

87), 13.3% (n = 62), and 5.4% (n = 25), respectively. Defective packaging and other GMP violations recorded a slightly lower percentage, each at 2.1% (n = 10). The adverse reactions/events had 0.6% (n = 3) drug recalls. Further, improper storage conditions had the lowest percentage drug recall at 0.4% (n = 2). It is clear that most drugs that are recalled from the market were recalled due to product contamination. Also, defective product and mislabeling were important reasons for drug recalls as well whereas, improper storage conditions and adverse reaction/events were found out to be the lowest reason for recall reported among the 466 that has been reported from January 2009 to December 2019.

The highest percentage of recalls by type of product were injectables at 48.5% (n =

226), followed by solid oral at 26% (n = 121). Likewise, liquid oral and sterile products had

5.8% (n = 27) of drug recalls. The higher percentage of injectable recalls remained consistent from 2009 to 2013 but was reduced from 2013 to 2017, before increasing in 2018 and DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 32 slightly reducing in 2019. The recall rates for solid oral drugs remained low from 2009 to

2017; however, it significantly increased in 2018 and 2019.

Mislabeling, contamination, and defective products were found to be the most common reasons for recalls reported from 2009 to 2019. Their trends through 2009 to 2019 were observed. Recalls that were reported due to contamination had shown a significant increase in their incidence in 2013 and 2018, whereas 2009 shows the lowest number of recalls reported due to contamination. After 2013, there has been slight decrease in the recalls reported due to contamination until 2018 where a sharp increase has been observed followed by a slight decrease in 2019. When it comes to mislabeling and defective products, consistent trends have been observed with slight increase and decrease in recalls reported until 2018 through 2019 for defective products and 2018 for mislabeling, which showed a sharp rise in their incidence.

Injectable and solid orals were observed to be the most frequently recalled products.

Injectables have shown a sharp increase in recalls reported in 2013 and 2018. This kind of same trend was also observed in recalls reported due to contamination. The lowest number of recalls reported for this type of product was observed in 2009. However, solid orals show slightest increase and decrease in the number of recalls reported from 2009 to 2016 and started to increase in 2017 and continuing on till 2019.

The cross tabulation of drug type versus reason for recall shows that the leading cause of recalling injectables is contamination followed by defective product and mislabeling. For solid oral, most recalls were defective product, followed by mislabeling, contamination, and incorrect potency. DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 33

From the overall findings of the study, it is observed that product contamination is the leading cause of recalls in many products. Contamination has been the leading cause of injectable products recall. As per Hall, Stewart, Chang, and Freeman (2016) and Eissa (2019) similar studies were conducted using smaller time periods that also confirm that contamination was a major cause of drug recalls, and injectables were more frequently recalled due to contamination. The foreign particles in the injectables are commonly observed from packaging components (vial closures, glass particles from the vials, plastic, polymers, latex, etc.), fibers, dust, and process related factors like metal and filter components from the manufacturing equipment (Tawde, 2015). Presence of foreign particles can lead to harmful and severe health complications that include anaphylactic shock, pulmonary emboli, and can even death (Tawde, 2015). Based on the present study, product contamination still remains to be a major cause of concern despite of various FDA regulations. Hence, the pharmaceutical industry is encouraged to continue to improve their manufacturing processes (including packaging processes) to minimize contamination during manufacturing, transportation, and handling. Defective products and mislabeling have also significantly attributed to the recall of various types of products in this 11-year time period.

Defective products, which include failed stability; presence of out of specification impurities, etc., which leads to degradation; and loss of activity of the active ingredient, can be very harmful to the patient. For example, degradation of nitroglycerin (which is used in the treatment of angina) to 85% can lead to the death of the patient using it due to insufficient activity (Bajaj, Singla, and Sakhuja, 2012). Mislabeling is also a major cause of recall following contamination and defective product. As per FDA (2010) mislabeling is generally construed as a Class-III recall, but can still pose an indirect threat to the health of the patient DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 34 by providing incorrect information about the drug. The general trend of drug recalls in this

11-year time period has been constantly fluctuating and did not exhibit any obvious pattern.

This makes it difficult to forecast any reliable future trends. Even though with the thorough quality control testing and frequent in process controls in place both by the FDA and pharmaceutical industries, the failure to maintain the quality of a drug product is still observed.

Biologics Recalls

A total of 84 biologic recalls occurred between the 2009 and 2019. The highest percentage of biologic recalls were reported in 2010 at 25% (n = 21), followed by 2012 at

19% (n = 16), and 2013 at 13% (n = 11). The lowest number of biologic recalls reported was observed in 2019 at 1% (n = 1).

Defective product was the leading cause of recalls reported at 34.5% (n = 29); followed by mislabeling at 25% (n = 21); defective packaging at 14.3% (n = 12); adverse reaction 8.3% (n = 7); contamination and incorrect potency, both at 6% (n = 5 each).

Improper storage conditions recorded the lowest percentage of biologics reason for recalls reported at 1.2% (n = 1). Comparatively, as in the case of drug recalls, the lowest cause of biologics recalls reported was improper storage conditions.

Blood and blood products were observed to have the highest percentage of recalls reported at 65.5% (n = 55), followed by vaccines at 27.4% (n = 23). Allergenics had 3.6% (n

= 3) while cellular and gene therapy products had 2.4% (n = 2). Tissue and tissue products had the lowest percentage of recalls reported at 1.2% (n = 1).

Mislabeling, defective product, and defective packaging were observed to be the most common reasons for recall reported from 2009 to 2019. Recalls that were reported due to DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 35 mislabeling show an apparent increase in their incidence in 2010 and 2012. It was also observed that there are zero recalls reported due to mislabeling in 2014, 2015, and 2018.

Recalls reported due to defective product show an increase in their incidence in 2010 and

2012, a slight decrease in their incidence was observed in 2013 and 2014, which was again followed by slight increase in 2015, and was plateaued until 2016.A decrease to zero recalls was observed in 2017. Zero recalls were reported due to this reason in the years 2017 and

2019 with a moderate increase in their incidence in the year 2018. For defective packaging the pattern shows a sharp increase in 2010, 2012, and 2013, followed by a decrease in their incidence. Zero number of recalls were observed for this reason in the years 2009, 2011,

2015, 2016, 2018, and 2019.

Blood and blood products and vaccines were observed to be the most frequently recalled biological products from 2009 to 2019. The trend of blood and blood products recalled from 2009 to 2019 shows that there has been a sharp increase in their recalls in the years of 2010 and 2012. The similar pattern can also be observed in recalls reported due to mislabeling and defective product. The lowest number of recalls for this type of product was observed in the years 2015 and 2019. The trend for recalls of vaccines from 2009 to 2019 was observed. It was observed that there was a slight rise in their recalls in 2010 followed by sharp decrease in 2011, which was followed by a gradual increase in 2012 and 2013. There were zero number of recalls reported for this type of product in 2014, 2016, 2018, and 2019.

In 2015 and 2017, two recalls were reported in total for this product.

The cross tabulation of biologic type versus reason for recall shows that the leading cause of recalling blood and blood products and vaccines is defective product and mislabeling followed by defective packaging. The recalls due to product contamination was DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 36 also only observed in blood and blood products and vaccines and recall due to adverse reaction was observed only in blood and blood products and tissue products.

Overall, findings of the study were that blood and blood products and vaccines were most recalled products. The major causes for the recall of these type of products are defective product, mislabeling and defective packaging. Though contamination was not observed to be the major causes of recall for most of the biologics, defective packaging can greatly attribute to product contamination. In addition to contamination, defective packaging can also attribute to the formation of impurities or loss of potency, which ultimately alter the quality of the product (Chawla et al, 2016). Defective products which include reasons like failed stability and giving wrong results can seriously impact the health and course of treatment for the patient. Mislabeling can misguide the user to take wrong dosage or use it for wrong indications resulting in harmful effect on the patients’ health. Just as drug products there are many in-process controls and regulations in place to regulate biologics. In spite of all these regulations, recalls were still observed due to failure to maintain the quality of the product.

As with drug recalls, biologics does not exhibit an obvious trend from 2009 to 2019. This study helped to get a more detailed perspective on the biologic recalls since, there is not much literature available concentrating biologic recalls.

Limitations

 The FDA recall archives have not updated any additional data about the further

details after the recall notice was posted. Whether the recall was considered class-I, II

or III was also not updated in their recall notices. Since it is unknown about the extent

of harm caused by the recalled product, the recalls classes cannot be assigned

manually and are subject to speculation. DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 37

 Many cases of recalls just say that all the sterile products were recalled, or all the

products were recalled, but the details of the type of products that has been recalled

were not available, so this just makes the data a bit ambiguous when classifying by

the type of product recalled.

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 38

Chapter 6: Conclusion

The analysis of drugs and biologics recalls from 2009 to 2019 revealed that the most significant causes of the recalls for drug products are contamination, defective product, or mislabeling. For biologics the most significant causes of recalls are defective product, mislabeling, or defective packaging. Improper storage conditions caused a lower number of recalls for both drugs and biologics. For drug products, injectables had the highest number of recalls. For biologics, blood and blood products and vaccines had higher percentage of recalls reported, while tissues and tissue products recorded the lowest number of recalls. This implies that the major focus should be on controlling issues of contamination (specifically injectables), defective products (specifically solid orals), and mislabeling of drug products to significantly reduce the number of drug product recalls. Defective products, mislabeling, and defective packaging must be the issues of focus (especially blood and blood products and vaccines) to significantly reduce biologic recalls. There was no observable trend in number or type of recall despite FDA’s tightened regulations. Therefore, the drug and biologic manufactures should ensure that their operations and products comply with the CGMP guidelines and other regulations set by FDA in addition with more stringent in-house operating procedures, testing procedures, and updated manufacturing and testing facilities to significantly minimize the recalls. The FDA can also concentrate on reevaluating the regulations concerning contamination, defective product, and mislabeling, and concentrating on the above mentioned major reasons of recall during site inspections would also help minimize recalls.

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 39

References

American Society for Quality.(n.d.) What is a product recall? Retrieved June 29, 2020, from

www.asq.org: https://asq.org/quality-resources/recalls

Bajaj, S., Singla, D., & Sakhuja, N. (2012, March 24). Stability testing of pharmaceutical

products. Journal of Applied Pharmaceutical Science, 2(3), 129-138.

Chawla, V., Singh, M. P., & Kumar, M. (2016, September 15). Rising Incidences of Product

Recall. Universal Journal of Pharmaceutical Research, 1(1), 33-36.

Eissa, M. E. (2019, June). Drug recall monitoring and trend analysis: A multidimensional

study. Global Journal on Quality and Safety in Healthcare, 2(2), 34-39.

Hall, K., Stewart, T., Chang, J., & Freeman, M. K. (2016, February 15). Characteristics of

FDA drug recalls: A 30-month analysis. American Society of Health-System

Pharmacists, 73, 235-240.

Nagaich, U., & Sadhna, D. (2015, March). Drug Recall: An incubus for pharmaceutical

companies and most serious drug recall of history. International Journal of

Pharmaceutical Investigation, 5(1), 13-19.

Tawde, S. A. (2015, January 5). Particulate matter in injectables: Main cause for recalls.

Journal of Pharmacovigilance, 3(1), 1000e128.

US Food and Drug Administration. (n.d.). Vaccines, blood, and biologics. Retrieved June 29.

2020, from https://www.fda.gov/vaccines-blood-biologics

US Food and Drug Administration. (2010). FDA 101: Product reaclls. Retrieved June 29,

2020, from https://www.fda.gov/consumers/consumer-updates/fda-101-product-

recalls DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 40

US Food and Drug Administration. (2016) CDER: The Consumer Watchdog for Safe and

Effective Drugs. Retrieved June 29, 2020, from https://www.fda.gov/drugs/drug-

information-consumers/cder-consumer-watchdog-safe-and-effective-drugs

US Food and Drug administration. (2017). Drugs@FDA glossary of terms. Retrieved June

29, 2020, from https://www.fda.gov/drugs/drug-approvals-and-databases/drugsfda-

glossary-terms#D

US Food and Drug Administration. (2018a). About CBER. Retrieved June 29, 2020, from

https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/about-

cber

US Food and Drug Administration. (2018b). Current good manufacturing practice (CGMP)

regulations. Retrieved June 29, 2020, from

https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-

manufacturing-practice-cgmp-regulations

US Food and Drug Administration. (2018c). Facts about the current food manufacturing

practices. Retrieved June 29, 2020, from https://www.fda.gov/drugs/pharmaceutical-

quality-resources/facts-about-current-good-manufacturing-practices-cgmps

US Food and Drug Administration. (2018d). FDA's role in drug recalls. Retrieved June 29,

2020, from https://www.fda.gov/drugs/drug-recalls/fdas-role-drug-recalls

US Food and Drug Administration. (2018e). History of FDA's internal organization.

Retrieved June 29, 2020, from https://www.fda.gov/about-fda/history-fdas-fight-

consumer-protection-and-public-health/history-fdas-internal-organization DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 41

US Food and Drug Administration. (2018f). What are "biologics"? Questions and answers.

Retrieved June 29, 2020, from https://www.fda.gov/about-fda/center-biologics-

evaluation-and-research-cber/what-are-biologics-questions-and-answers

US Food and Drug Administration. (2018g). What does FDA regulate? Retrieved June 29,

2020, from https://www.fda.gov/about-fda/fda-basics/what-does-fda-regulate

US Food and Drug Administration. (2018h). What we do. Retrieved June 29, 2020, from

https://www.fda.gov/about-fda/what-we-do#mission

US Food and Drug Administration. (2019). Center for Drug Evaluation and Research,

CDER. Retrieved June 29, 2020, from https://www.fda.gov/about-fda/fda-

organization/center-drug-evaluation-and-research-cder

US Food and Drug Administration. (2020). Product recalls, including removals and

corrections. Retrieved June 29, 2020, from https://www.fda.gov/regulatory-

information/search-fda-guidance-documents/product-recalls-including-removals-and-

corrections

Wang, B., & Gagne, J. J. (2012, July 23). The epidemiology of drug recalls in the United

States. The Journal of the American Medical Association, 172(14), 1110-1111.

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 42

APPENDICES

DRUG AND BIOLOGICS RECALLS: 2009 THROUGH 2019 43

Appendix A: Drug Recalls Raw Data