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PFIZER CONFIDENTIAL

RE: ANDA 071484 Vincristine Sulfate Injection, USP

Letter of Non-Compliance Response

Hospira Inc., a Pfizer Company (“Pfizer”) is hereby providing this letter in response to the 

Food and Drug Administration (“FDA”) Letter dated December 5, 2019, sent under Section 

506C(f) of the Federal Food, Drug and Cosmetic Act (FD&C Act) concerning notification to

FDA of a meaningful supply interruption of Vincristine Sulfate Injection, USP. During this 

shortage situation that developed very quickly based on a confluence of events, including events 

outside of Pfizer’s control, Pfizer constructively notified the Agency and reacted expeditiously 

to address clinician and patient needs. Pfizer believes it met the requirements of Section 

506C(f) of the FD&C Act. Pfizer now has a sufficient supply of Vincristine in all presentations

available to purchases through the standard distribution chain and is working to build sufficient 

inventory of Vincristine so that supply is on hand to account for un-anticipated interruptions in 

supply.

Introduction

Pfizer is a leading manufacturer of sterile injectable pharmaceutical products with a large 

portfolio of medicines that are used in hospital and similar healthcare settings. Pfizer’s portfolio

of medicines is expansive, with the Sterile Injectable portfolio alone containing approximately

200 molecules and 700 NDCs. Most of these medicines are medically important products and

are manufactured at multiple sites around the world. Many of these medicines are high volume,

low margin products with complex manufacturing processes and regulatory oversight 

constructs. Indeed, the Agency’s October 2019 report, “Drug Shortages: Root Causes and 

Potential Solutions,” captures well the many challenges adversely impacting the viability of the 

US sterile injectable industry which, among other things, have contributed to the untenable

03 January 2020

Captain Valerie Jensen

Associate Director

Drug Shortage Staff

Food and Drug Administration

WO 22, Room 6204

10903 New Hampshire Avenue

Silver Spring, Maryland 20993
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PFIZER CONFIDENTIAL

situation this year where Pfizer became the sole US supplier of generic Vincristine, a product 

first approved by FDA in 1963 and long available in generic form.1 Nevertheless, as this 

response demonstrates, Pfizer is proud of our long-standing commitment to reliably supply

critical life-saving therapies of the highest quality like Vincristine to the patients who need 

them. Indeed, Pfizer’s core mission is to deliver breakthroughs that change patients’ lives.

Pfizer has processes and systems in place to manage risk associated with potential interruptions 

in supply of our medicines, including holding inventory levels and prioritizing the manufacture 

of medically important drug products. Despite our best efforts and given the complexity of the

sterile injectable manufacturing process, supply chain, and related market factors, we do 

experience meaningful interruptions in supply for medicines in our portfolio. In addition to 

dedicating significant efforts and resources to addressing the root cause for those interruptions in 

supply to minimize their duration and impact, Pfizer is committed to timely and open 

communication of those issues to FDA via the Drug Shortages Staff in CDER.

To that end, Pfizer maintains an ongoing program for the identification and reporting of 

meaningful supply interruptions to FDA. Pfizer colleagues responsible for reporting drug 

shortages are in close and continuous communication with those in the manufacturing, supply 

chain and commercial organizations to identify potential interruptions in supply. On a bi-weekly 

basis, Pfizer submits a product availability report to FDA Drug Shortage noting the supply 

status of each of Pfizer’s sterile injectable medicines. The report is sortable, and notes the 

product name, configuration, and NDC, manufacturing plant, supply status (“available”, 

“intermittent stock out”, “depleted”), the reason for the backorder if applicable (“manufacturing 

delay”), estimated next date of delivery, and the estimated date of recovery. Pfizer submits this 

report every two weeks via email directly to FDA Drug Shortage team members.

Pfizer also regularly submits product-specific shortage notifications and follow-up information

to FDA via email, holds quarterly drug shortage update meetings (recently increased to biweekly), and product specific emails and phone calls, as needed. Pfizer’s goal, in addition to 

meeting the requirements of 21 U.S.C. § 356c and 21 CFR 314.81(b)(3)(iii), is timely and 

transparent communication of issues as they arise, providing routine updates to FDA Drug 

Shortage Staff until the supply issue is resolved, and partnering with FDA where possible to 

alleviate supply interruptions and meet patient needs.

 

1

“After reviewing the FDA analysis, published research studies, and stakeholder input, the [FDA] Task 

Force identified three major root causes: Root Cause1: Lack of Incentives to Produce less Profitable Drugs; 

Root Cause 2: Market Does Not Recognize and Reward Manufacturers for Mature Quality Management 

Systems; Root Cause 3: Logistical and Regulatory Challenges Make It Difficult for the Market to Recover After 

a Disruption.” Drug Shortages: Root Causes and Potential Solutions 2019, Executive Summary, Federal Drug 

Shortage Task Force, chaired by the U.S. Food and Drug Administration (FDA) (October 29, 2019), 

http://www.fda.gov/medium/131130/download. 
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PFIZER CONFIDENTIAL

Regulatory Background

NDA and ANDA applicants are required to notify FDA in writing of a permanent 

discontinuance of manufacture or an interruption in manufacturing of a covered drug product2if 

it is likely to lead to a meaningful interruption in supply of that product.

3 The notification must 

be submitted to FDA electronically in a format that FDA can process, review and archive at 

least 6 months prior to the date of a permanent discontinuance or interruption in manufacturing, 

or if not possible because it was not reasonably anticipated, as soon as practicable, but no later 

than 5 business days after the discontinuance or interruption occurs.

4 Notification must include 

the following details:

• The name of the drug subject to the notification, including the NDC;

• The name of the applicant;

• Whether the notification relates to a permanent discontinuance of the drug or an

interruption in manufacturing of the drug;

• A description of the reason for the permanent discontinuance or interruption in 

manufacturing; and

• The estimated duration of the interruption in manufacturing.5

In addition, FDA directs companies to “email drugshortages@fda.hhs.gov to report any 

potential or actual shortage issues.”

6FDA’s website also notes that “[s]hortage notifications and 

updates may be reported to FDA at drugshortages@fda.hhs.gov.7

Beyond the information summarized above, FDA has not published regulations or guidance on 

how or when in the lifecycle of a rapidly evolving supply event it expects to receive drug 

shortage notifications.

Chronology of Vincristine Supply Interruption and Notifications to FDA

 

2 A product is “covered” if it is “life supporting, life sustaining, or intended for use in the prevention or 

treatment of a debilitating disease or condition, including anysuch drug used in emergency medical care or 

during surgery; and [t]he drug product is not a radiopharmaceutical drug product”. 21 CFR 

314.81(b)(3)(iii)(a)(1)-(2).

3

21 CFR 314.81(b)(3)(iii)(a).

4

21 CFR 314.81(b)(3)(iii)(b)(1)-(2).

5

21 CFR 314.81(b)(3)(iii)(c)(1)-(5).

6 U.S. Food and Drug Administration (2019). How to Report a Shortage or Supply Issue. [online] 

Available at: https://www.fda.gov/drugs/drug-shortages/how-report-shortage-or-supply-issue [Accessed17 Dec.

2019].

7 U.S. Food and Drug Administration. (2019). Drug Shortages. [online] Available at: 

https://www.fda.gov/drugs/drug-safety-and-availability/drug-shortages [Accessed 17 Dec. 2019].
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PFIZER CONFIDENTIAL

Vincristine Sulfate Injection, USP (“Vincristine”) is indicated in acute leukemia. Vincristine 

sulfate injection has also been shown to be useful in combination with other oncolytic agents 

in Hodgkin's disease, non–Hodgkin's malignant lymphomas, rhabdomyosarcoma, 

neuroblastoma, and Wilms' tumor. Vincristine is a critical therapy in the treatment of cancer

and is often used in the treatment of childhood cancers. Pfizer is committed to the 

manufacture of this medicine and to reliably supplying it to patients who need it. Pfizer

recognizes the impact on clinicians and patients related to the temporary interruption in supply 

of Vincristine in the fall of 2019. 

The interruption in Pfizer’s supply of Vincristine began in September 2019 and Pfizer began 

providing the market with additional supply in mid-October. While the supply interruption was

ongoing, Pfizer reacted quickly to address the supply interruption by expediting manufacturing

deliveries and allocating8 product to ensure practitioners received needed shipments. Our supply 

continuity team implemented an emergency process with a toll-free call line to help practitioners 

find and obtain product and instituted express direct shipments to ensure patient access to this 

critical medicine. While the interruption was addressed by Pfizer very quickly, Pfizer recognizes 

the impact shortages, particularly for products indicated in the treatment of cancer, have on 

patients, caregivers, and healthcare practitioners. Pfizer will continue to investigate the causes 

for the interruption to help improve operations, reduce the risk of a similar interruptions in the 

future, and further improve reporting of meaningful interruptions in supply. 

In summary, the availability of Vincristine to patients in the US was impacted very suddenly in 

September 2019 following a rapid convergence of several complicated, and in our view, related 

factors (listed in order of occurrence): 

• FDA’s posting on July 5, 2019 on the FDA’s drug shortage website of another 

company’s decision to discontinue supply of Vincristine;

• FDA’s posting on July 23, 2019 of the shortage of Vinblastine Sulfate Injection, USP, 

a medicine that may be used in patient populations that overlap with Vincristine, on 

its drug shortage website;

• A near doubling in demand for Vincristine from the historic units shipped per

month to more than units shipped in August 2019, which we believe included

some hoarding in the market; and,

• A brief delay in release of several oncology medicines, including Vincristine, from our 

manufacturing facility in Melbourne, Australia in September 2019.

Until July of 2019, Vincristine was commercialized in the US market by Pfizer and another 

manufacturer. Pfizer’s market share for Vincristine in the U.S. market averaged 

approximately % in 2018, and increased to approximately % in June of 2019, before the 

other manufacturer ceased supply of Vincristine for the US Market. The supply demand for 

Vincristine then shifted very quickly in August of 2019. Historically, Pfizer shipped

 

8 Allocation includes review of each order as compared to corresponding patient need, and is designed to 

get products to those who need it while limiting the ability of certain buyers to hoard productor buy more than 

is needed.

(b) (4) (b) (4)

(b) (4) (b) (4)
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PFIZER CONFIDENTIAL

approximately units for Vincristine per month. In August of 2019, however, demand for 

the product spiked and more than units were shipped for the month. This spike could not 

have been reasonably anticipated by Pfizer.

At roughly the same time that the other manufacturer of Vincristine left the market, a shortage 

of Vinblastine Sulfate Injection (“Vinblastine”)

9 was posted on FDA’s drug shortages website 

on July 23, 2019. It is our understanding that both Vinblastine and Vincristine are frequently 

used in combination chemotherapy for their respective indications. The common disease 

state where both are used is in Hodgkin’s Lymphoma, and although Vincristine is not a direct 

therapeutic substitute for Vinblastine, we have received feedback that Vincristine was being 

used in certain treatment regimens in place of Vinblastine, due to the shortage of Vinblastine.

It is Pfizer’s view that the more than doubling of demand for Vincristine that occurred in August 

may have been the result of the only other manufacturer of Vincristine posting a notice of 

discontinuation of manufacturing for the product on FDA’s Drug Shortages website on July 5, 

2019 and the Vinblastine shortage occurring at the same time, shifting some demand to 

Vincristine. These developments and considering Pfizer had become the sole supplier for 

Vincristine, caused what Pfizer believes to be hoarding of product by institutions in the US 

market that became concerned about their ability to obtain product in the future. While Pfizer

previously held the majority of market share for Vincristine prior to the other manufacturer’s

discontinuation, market intelligence suggests that health care providers panicked at this

discontinuation notice, prompting an increase in orders for Vincristine in August 2019. This, in 

addition to the shortage of Vinblastine, we believe accounts for why orders spiked from a 

monthly average of units in 2019, to more than units in August. 

Given the stock we had on hand at the time Pfizer believed that there would have been enough 

supply in our inventory to meet demand notwithstanding the manufacturing delay (discussed

below), had this unforeseen more than doubling of demand not occurred. Moreover, Pfizer was 

not aware that it had become the sole supplier for the medicine until the notice of 

discontinuation was posted on FDA’s website. Accordingly, it was not reasonably clear at the 

time, nor could Pfizer have reasonably anticipated these background market factors or the 

impact they would have when manufacturing delays arose in September. Pfizer was fulfilling 

orders, but it was not reasonably clear at this point that there would be a meaningful interruption

in supply.

 

9 Vinblastine is indicated for frequently responsive malignancies: generalized Hodgkin’s disease (Stages III 

and IV, Ann Arbor modification of Rye staging system), lymphocytic lymphoma (nodular and diffuse, poorly and 

well differentiated), histiocytic lymphoma, mycosis fungoides (advancedstages), advanced carcinoma of the testis, 

Kaposi’s sarcoma, Letterer-Siwe disease histiocytosis X); Less frequently responsive malignancies: 

choriocarcinoma resistant to other chemotherapeutic agents, carcinoma ofthe breast, unresponsive to appropriate 

endocrine surgery and hormonal therapy.

(b) (4) (b) (4) (b) (4) (b) (4)
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PFIZER CONFIDENTIAL

On September 5, 2019, Pfizer’s manufacturing facility in Melbourne, Australia

10 opened a 

quality investigation following a quality test on a different product manufactured at the facility

that did not meet specifications. Out of an abundance of caution and to allow a robust quality 

assessment, the Melbourne site placed all oncology medicines, including Vincristine, within the 

site’s control on hold, pausing release of the medicines to the market, and resulting in a 

manufacturing delay. The Melbourne site opened a quality investigation into the OOS result 

on September 5, 2019, and submitted a timely initial Field Alert Report11 to FDA on September 

10, 2019 noting in relevant part, the following: 

“Due to a quality investigation initiated at the Pfizer manufacturing plant, Hospira 

Australia Pty Ltd, located at 1-5, 7-23, 25-39 Lexia Place, Mulgrave, Victoria, 

Australia, all oncology products within the manufacturing site’s control that 

are potentially impacted by this investigation have been placed on site release hold. 

The recommencement of product release is estimated by mid October 2019”12

On September 18, 2019, Pfizer notified FDA’s Drug Shortage Staff via email13 of an open 

investigation at the Melbourne, Australia site that would impact release of oncology products. 

On September 25, 2019, Pfizer submitted to FDA Drug Shortage Staff personnel its bi-weekly 

Sterile Injectable Portfolio Availability Report14, which reflected the supply status for 

Vincristine as of September 23, 2019. As discussed above in the section titled “Introduction”,

Pfizer provides this report to the Drug Shortage Staff to maintain open and transparent 

communication on Pfizer’s large portfolio of critical products. In relevant part, the September 

23 report noted the following:

• Vincristine Sulfate Injection, USP 1 mg/mL Vial (NDC 61703-0309-06) was listed as

“Depleted” with “Next Delivery” and “Estimated Recovery” of September 2019, and

attributed the issue to a manufacturing delay.

• Vincristine Sulfate Injection, USP 2 mg/2 mL (1 mg/mL) Vial (NDC 61703-0309-16) 

was listed in “Limited Supply” with “Next Delivery” and “Estimated Recovery” in 

September 2019 and attributed the issue to a manufacturing delay.

• Vincristine Sulfate Injection, USP 1mg/mL Single Dose Onco-Tain Glass Fliptop 

Novaplus

® (NDC)51703-0309-26 was listed in “limited supply-short dated product”

with the Next Delivery and Estimated Recovery in October 2019 and attributed the 

issue to a manufacturing delay.

• Vincristine Sulfate Injection, USP (Preservative-Free) 2mg/2mL Single Dose Onco-Tain

Fliptop Vial Novaplus

® (NDC61703-0309-25) was listed as “available”. 

 

10 Pfizer manufactures Vincristineand three othersterile injectable oncology med icines at its Melbourne,

Australia facility.

11 Field Alert Reports are required by 21 CFR 314.81(b)(1) for certain potential quality matters.

12 See Attachment 1

13 See Attachment 2

14 See Attachment 3
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PFIZER CONFIDENTIAL

On October 3, 2019, FDA Drug Shortage notified Pfizer that they received an inquiry on supply 

availability of Vincristine. Pfizer communicated that the inventory had since stocked out. 

On October 7, 2019, Pfizer submitted its next routine Sterile Injectable Portfolio Availability 

Report to FDA Drug Shortage via email15. The October 7 report included the following entries 

for Vincristine:

• Vincristine Sulfate Injection, USP 1 mg/mL Vial (NDC 61703-0309-06) was listed as 

“Depleted” with Next Delivery and Estimated Recovery in December 2019. 

• Vincristine Sulfate Injection, USP 2 mg/2 mL (1 mg/mL) Vial (NDC 61703-0309-16) 

was listed as “Depleted” with “Next Delivery” and “Estimated Recovery” in October

2019.

• Vincristine Sulfate Injection, USP (Preservativ-Free) 2mg/2mL (1mg/mL) Single Dose 

ONCO-TAINTM Glass Fliptop Vial Novaplus® (NDC 61703-0309-25) was listed as

“Intermittent Stock Out” with “Next Delivery” and “Estimated Recovery” in December 

2019.

• Vincristine Sulfate Injection, USP 1 mg/mL Single Dose ONCO-TAINTM Glass Fliptop 

Vial Novaplus® (NDC 61703-0309-26) was listed as “Supply Available”. 

In the time between the September 5 pause in product release at the manufacturing site, the 

email sent to FDA on September 18 notifying the Drug Shortage Staff of a product release 

pause at the Melbourne site for oncology products, and the supply reports sent to FDA on 

September 25 and October 7 noting supply status for Vincristine, Pfizer was working diligently 

to both address the underlying manufacturing issue and to understand the potential impact of

this dynamic and quickly evolving supply situation. While the multi-faceted and converging 

factors in the marketplace and within Pfizer are better understood now, they were not clear in 

September when they first emerged. In that uncertainty, Pfizer made reasonable efforts to 

understand the impact on supply and to comply with the spirit of the shortage notification statute 

and regulation by providing information to FDA as it became available, though it may not have 

yet been complete or its impact reasonably clear. 

Additionally, on October 15, 2019, Pfizer provided posting information for the FDA Drug 

Shortages website for Vincristine Sulfate Injection, which was posted on the website by FDA on 

October 16, 2019. By the time Vincristine was posted by FDA as an active drug shortage,

release of product had resumed; deliveries were being expedited to the US. Product was shipped 

to clinicians and available for patients on October 21, 2019.

To address the interruption in supply and mitigate product “hoarding”, Pfizer began

allocating Vincristine and directed its Supply Continuity Team to begin following our 

escalation, approval and fulfillment process in place for customers who request emergency 

and expedited orders, worked closely with hospitals to fulfill, help place, and track orders. 

Customers with questions or a need were instructed to contact our Supply Continuity Team at 

1-844-646-4398.

 

15 See Attachment 4
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PFIZER CONFIDENTIAL

Given the importance of this product to our patients, we also prioritized Vincristine 

manufacturing and increased our production to meet increasing demand. In addition, Pfizer 

has addressed requests from FDA’s Drug Shortage Staff to contact healthcare providers

directly to ensure direct shipment of needed product to practitioners.

Current Supply Status

Pfizer remains committed to the manufacture of this important therapy. Pfizer continues to 

increase production and expedite all deliveries of Vincristine to the US market. Product is also 

available to purchasers through the standard wholesale distribution chain. During the four month 

period from August – November 2019, Pfizer shipped vincristine at a rate of % versus the 

prior 12 month average. In addition to that elevated shipment level, as of December 23rd Pfizer 

has on-hand released inventory at our US distribution centers equivalent to approximately six 

months’ historic average demand (as observed during the Aug 2018 – Jul 2019 period). 

While the shortage has been addressed, Pfizer continues to manage customer orders in response 

to ongoing elevated ordering volumes. During Q1 Pfizer will further increase its vincristine 

inventory coverage so that sufficient supply remains on hand to account for unanticipated 

interruptions in supply or further market demand increases. 

Corrective and Preventive Actions

Pfizer remains committed to addressing drug shortages and to communication with FDA’s Drug 

Shortage Staff. Pfizer is in frequent communication with the Drug Shortage Staff, holds

quarterly calls with FDA, including FDA CDER’s Drug Shortage Staff and Office of 

Compliance Manufacturing Quality, submits bi-weekly Sterile Injectable Portfolio Availability 

Reports with the sortable status of its entire sterile injectable portfolio, and sends ad hoc product 

specific shortage notifications. In addition to the routine communication that already occurs, on

December 1, 2019, Pfizer also began to voluntarily enter new product specific shortage

notifications into the CDER NextGen Portal. Pfizer also recently initiated bi-weekly calls with 

the FDA Drug Shortage Staff, in addition to the quarterly meetings mentioned above to provide 

new shortage information and follow-ups to the Drug Shortage Staff. 

Notwithstanding the communications to FDA on the on September 18, 23 and October 3, 7,

Pfizer recognizes that there are opportunities to further enhance our notification process with 

respect to product specific notifications to enable FDA to evaluate and respond to significant

new shortages rapidly and is conducting an assessment to identify enhancements. While the 

current program provides very frequent communications with FDA, Pfizer will continue to 

maintain and improve close communication between manufacturing sites, supply chain, 

commercial and those responsible for shortage reporting, and to increase the speed and detail of

reporting of meaningful interruptions in supply to FDA.

Anticipated Guidance and Additional Opportunities to Engage

FDA noted in its recent report titled “Drug Shortages: Root Causes and Potential Solutions” that 

it intends to publish new draft guidance by the end of 2019 related to notification requirements 

(b) (4)
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PFIZER CONFIDENTIAL

outlined in 21 U.S.C. § 356c and 21 CFR 314.81(b)(3)(iii). Pfizer welcomes this initiative and 

looks forward to additional guidance from FDA on how to meet the regulatory requirements 

in dynamic supply situations, which will help us to further improve our drug shortage 

reporting program. Pfizer would welcome an opportunity to discuss the challenges 

manufacturers face in understanding and addressing supply interruptions as they arise, 

providing meaningful communications to FDA, and to sharing our learnings and in-market 

experience with policymakers at FDA.

Conclusion

Pfizer understands the importance of Vincristine to patients and is committed to supplying this 

vital therapy to patients in the US. Pfizer remains dedicated to open and timely communication 

with the Drug Shortages Staff on emerging supply interruptions and to compliance with 21 

U.S.C. § 356c and 21 CFR 314.81(b)(3)(iii). To that end, Pfizer has managed a shortage 

notification program that works closely with the Drug Shortages Staff to provide open and 

frequent communications, including regular teleconferences, bi-weekly updates on the status 

of our sterile injectable portfolio, and ad hoc product specific supply notifications. The 

interruption in supply of Vincristine that occurred in September 2019 was in our view the 

result of several background market forces that created a situation where, when a temporary 

delay in release of product from the manufacturing site occurred, Pfizer was not reasonably 

able to anticipate that the delay in release of product would impact supply. While Pfizer 

worked to address the manufacturing issue and understand the potential impact on supply, it 

shared with FDA the information that was readily available and reasonably understood. 

Pfizer reacted expeditiously to address clinician and patient needs, and now has supply of 

Vincristine in all presentations. Pfizer believes it met the requirements of Section 506C(f) of the 

FD&C Act. We recognize there are opportunities to improve our reporting program, 

including, among other things, submission of product-specific shortage notifications. We 

look forward to additional guidance from FDA and to continued partnership with FDA’s Drug 

Shortage Staff.

Should you have any questions regarding this response, please contact me via phone at (224) 

212-4874; or via e-mail at lisa.skeens@pfizer.com.

Sincerely,

Lisa M. Skeens, Ph.D.

Vice President, Global Regulatory Affairs

Hospital Business Unit

Pfizer