The Trials and Tribulations of Assuring Ascorbic Acid Injection Availability - The Struggle Is Over

By Ronald M. McGuff, President, McGuff Pharmaceuticals, Inc.

For those of us on the supply side who have lived it… keeping Ascorbic Acid Injection (AAI) available to physicians has been a roller-coaster of events ever since 1998. As an unapproved drug in the U.S., AAI’s availability to physicians has at many times been sporadic and always susceptible to regulatory changes. Even now, the ability of compounding pharmacies and Outsourcing Facilities to provide AAI in the future is in question.

Today, the FDA has a very restrictive policy towards compounding pharmacies and the compounded medications they create. One especially restrictive policy is known as the “Memorandum of Understanding” (MOU) between the States and FDA. When the MOU is implemented by FDA, compounding pharmacies will be restricted from selling more than thirty percent of their total sales outside their state of residence. This may be further reduced to only 5% if a state declines to sign the FDA’s MOU. If you are a physician that resides in a state that does not have a compounding pharmacy that compounds sterile drugs, your ability to obtain sterile compounded drugs may be significantly impacted. The MOU applies to all compounded drugs both sterile and non-sterile. To further complicate supply, compounding pharmacies are required by FDA guidelines to only compound based on their history of receiving prescriptions. When the MOU is implemented, compounding pharmacies may not be able to immediately support out-of-state physicians.

Additionally, when the MOU is implemented, the MOU will make it difficult or impossible for a physician who resides in a State that does not have a compounding pharmacy producing AAI to obtain it. This physician will be completely at the mercy of out-of-state compounding pharmacies that are limited by FDA guidelines to provide AAI.

The MOU is but one of the roller-coaster events that continue to re-shape access to compounded drugs.

A Brief History of Ascorbic Acid Injection’s Tenuous Supply.

Prior to October, 1998 AAI supply was dependable and available to physicians.

In 1998 everything changed. Steris Laboratories, Inc., the only company actively manufacturing AAI, had failed multiple FDA inspections and signed a Consent Decree of Condemnation and Permanent Injunction.[1] The FDA seized large stocks of drugs, including AAI. This Decree eliminated manufactured AAI from the market without any warning to wholesalers or physicians.

This began nineteen years of roller-coaster events that lead to many AAI drug shortages. Reasons for these shortages include regulatory instabilities along with industry non-compliance issues.

Table 1 identifies the most significant roller-coaster supply events of AAI.

Table 1. Major Events That Created and Alleviated Ascorbic Acid Injection Shortages in the U.S.

Date	Event	Affect on Availability of Ascorbic Acid Injection (AAI)	Result
10/1998	Steris Laboratories, the only manufacturer of AAI, signed a Consent Decree of Condemnation and Permanent Injunction that prevented future manufacturing of AAI.	Immediate and critical AAI shortage without warning. Manufacture of all AAI ceased. Manufacturer recalled all AAI produced.	Significant AAI Shortages. There were few compounding pharmacies producing sterile drugs in 1998.
10/1999	Multiple compounding pharmacies begin producing AAI.	Gradual improvement in AAI availability.	AAI is generally available and office use is common.
4/2002	McGuff Pharmaceuticals, Inc. begins AAI manufacturing and distribution.	AAI is sold as a grandfathered commercial drug product. Multiple manufacturers enter market.	AAI is available in quantities needed. AAI is available from manufacturers and a few compounding pharmacies.
6/2006	FDA publishes ‘Guidance for FDA Staff and Industry Marketed Unapproved Drugs – Marketed New Drugs Without Approved NDAs or ANDAs.’[2]	Possible immediate effect of removing AAI as a manufactured drug. No warning required.	FDA warns industry that drugs marketed without approval may be removed from market. AAI does not have NDA or ANDA approval.
12/2010	FDA declares AAI is not a grandfathered drug and is not an approved Drug. Manufactured AAI is recalled by all manufacturers except Mylan. FDA uses its enforcement discretion to allow Mylan to continue to import and sell AAI in U.S. All U.S. manufacturers remove themselves from U.S. market.	Immediate and critical shortage without warning. U.S. AAI manufacturing shut down.	Loss of all manufactured AAI in U.S. except Mylan’s limited production. Compounding pharmacies gradually re-enter market. Mylan, realizing they have FDA enforced monopoly starts raising AAI price.
9/2012	New England Compounding Center meningitis outbreak sickened 753 individuals and resulted in the death of 64 due to fungal infections resulting from contaminated steroid injections.[3]	No immediate effect, AAI availability good.	FDA and State investigations lead to increased regulatory overview of compounding pharmacy.
11/2013	Federal Drug Quality and Security Act adds significant restraints to pharmacy compounding, distribution and requires individual prescriptions to obtain AAI. FDA starts to inspect 503(a) compounding pharmacies.[4]	Gradual loss of AAI availability. Nineteen FDA draft and final guidances on compounding pharmacy published since July 1, 2014 put extraordinary pressure and uncertainty on compounding pharmacies.[5]	As compounding pharmacies leave sterile drug market AAI becomes more difficult to obtain. Complex procedures required for prescription ordering and production.
2/2015	FDA Draft Memorandum of Understanding Addressing Certain Distributions of Compounded Human Drug Products Between the State and the U.S. Food and Drug Administration[6]	No immediate affect but significantly detrimental to inter-state dispensing / distribution when enforced.	Combines the words dispense and distribute to mean distribute. Will limit inter-state shipment of AAI (and all other compounded drugs) to 5 or thirty percent of all drugs compounded per month.
12/2016	FDA Final Guidance, Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act	Additional restrictions on compounding pharmacies, e.g. compounding in anticipation of prescription.	Further complicates a compounding pharmacy’s ability to produce appropriate quantities of AAI.
10/2017	McGuff Pharmaceuticals receives approval of NDA 209112 for Ascor^® (Ascorbic Acid Injection).[7][8]	AAI as an approved drug will be manufactured now and into the future.	Eliminates AAI dependency on compounding pharmacy and Outsourcing Facility law and regulations. Eliminates need for prescriptions that are required for compounding. Eliminates office use restrictions.

The Role of McGuff Pharmaceuticals

In June of 2006 McGuff management realized that AAI supply was in dire jeopardy due to the recently published ‘Guidance for FDA Staff and Industry Marketed Unapproved Drugs – Marketed New Drugs Without Approved NDAs or ANDAs’. In 2006 AAI was not an approved drug. The writing was on the wall, FDA declared their policy on how unapproved drugs (read AAI) would be removed from the market.

McGuff management recognized the FDA may, at any moment, stop the manufacture of AAI. Additionally, management understood the long term regulatory risk of compounding AAI. In July, 2006 Ronald M. McGuff as President of the McGuff Family of Companies directed all companies to immediately initiate a strategic operational and financial strategy to secure AAI from the regulatory upheaval within the compounding pharmacy market. McGuff Pharmaceuticals, Inc. was directed to apply for and receive Orphan Drug Designation and New Drug Approval (NDA) for AAI to assure its unrestricted availability to physicians and patients.

Each roller-coaster event following McGuff’s 2006 decision reassured McGuff’s management that its chosen course was necessary and appropriate to assure long term, unrestricted availability of AAI.

Orphan Drug and NDA approvals are difficult to achieve. This was an eleven year process. McGuff invested heavily into the process; money, human resources, research, test method development, human clinical trials, and significant technical help from outside consultants were employed. Some of the approval milestones of this eleven year effort are listed in Table 2 below.

Table 2. Significant Events of McGuff’s Effort to Assure Ascorbic Acid Injection Availability

Date	Event	Intent	Result
6/2006	FDA publishes Guidance for FDA Staff and Industry Marketed Unapproved Drugs – Marketed New Drugs Without Approved NDAs or ANDAs	Possible immediate effect of removing AAI as a manufactured drug.	“The writing is on the wall”. FDA warns industry that drugs marketed without approval may be removed from market. AAI does not have NDA or ANDA approval.
7/2006	Ronald M. McGuff declares the strategic goal of the McGuff family of companies is to obtain FDA approval of AAI which will assure future unrestricted availability in the U.S.	As a strategic goal McGuff will direct a major share of all future profit to the pursuit of AAI NDA approval.	Inter-organizational expertise are brought together to prioritize the Orphan Drug and NDA projects. Process to obtain NDA approval created and implemented. FDA notified of intent.
8/2007	The FDA Office of Orphan Drug Products Development grants MPI’s orphan-drug request of Ascorbic Acid Injection.[9]	An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease.	Completion of the first major step for McGuff Pharmaceuticals to submit NDA to FDA.
8/2015	McGuff starts a human clinical trial “A Pharmacokinetics Study of Intravenous Ascorbic Acid.”[10]	This is a Phase 1, single-dose study to evaluate the pharmacokinetics of intravenous Ascorbic Acid.	One Secondary Outcome: Measure: Incidence of treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) grouped by body system.
9/2016	FDA Center for Drug Evaluation and Research (CDER) acknowledges the receipt of MPI’s New Drug Application (NDA) for Ascorbic Acid Injection assigning NDA Reference Number 209112.	The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S	10/2016 FDA review team formally decides the NDA application is complete. This is an important milestone towards gaining AAI approval.
3/2017	McGuff Pharmaceuticals undergoes a 7 day pre-approval inspection (PAI) by FDA. A (PAI) is performed to contribute to FDA's assurance that a manufacturing establishment named in a drug application is capable of manufacturing a drug, and that submitted data are accurate and complete. The PAI is one of the last reviews of the drug approval process, which may effect the availability to the consumer.	Audited for: Compliance with Current Good Manufacturing Practices. For conformance with application commitments. Authentic and accurate data. Laboratory testing of product, including evaluations of the adequacy of analytical methodology.	Result of FDA PAI inspection: FDA recommendation for approval of McGuff Pharmaceuticals manufacturing facility.
6/2017	McGuff designs and validates a new stability-indicating assay using advanced analytical methodologies to further quantify Ascorbic Acid. This assay includes the ability to identify dehydroascorbic acid.	Validated laboratory methods approved by FDA as part of the NDA requirements.	Utilization of new highly sensitive stability-indicating assay methods assures greater product quality.
10/2017	McGuff Pharmaceuticals receives approval of NDA 209112 for Ascor^® (Ascorbic Acid Injection).	Ascorbic Acid Injection becomes an FDA approved drug in the U.S.	The approved Ascor^® (Ascorbic Acid Injection) drug will be sold by the manufacturer, wholesalers and pharmacies as any other approved drug.

McGuff Pharmaceutical’s FDA approval of Ascor^® (Ascorbic Acid Injection)[11] provides the regulatory pathway for AAI availability of the manufactured drug no matter what happens to the regulatory restrictions on compounding pharmacies and Outsourcing Facilities. Currently, only 1 of the seventy-one registered Outsourcing Facilities manufactures AAI and only in 1mL and 5mL Glass. [12]

Further, with the FDA approval of Ascor^® (Ascorbic Acid Injection), physicians will no longer need to write patient specific prescriptions or have restrictions on office use. Ascor^® may be ordered in the same manner as any other approved drug.

FDA approval means much more than a consistent supply of AAI. There are other advantages as well. McGuff is currently supporting nine Investigational New Drug (IND) human clinical trials using AAI. The documentation required to receive FDA IND approval will be significantly reduced by the use of Ascor^® (Ascorbic Acid Injection) in the IND clinical trial documentation. This may potentially allow more IND clinical trials to be submitted for FDA review.

All of us at McGuff are proud of our eleven year effort to secure the supply of Ascorbic Acid Injection now and well into the future. We are also very proud of the knowledge, enthusiasm, and persistence our employees displayed while performing this monumental task.

[1] Consent Decree of Condemnation and Permanent Injunction previously entered against Steris Laboratories, Inc.

http://www.secinfo.com/ds4Px.715d.c.htm

[2] Guidance on Marketed Unapproved Drugs; Compliance Policy Guide

https://www.federalregister.gov/documents/2006/06/09/E6-9032/guidance-on-marketed-unapproved-drugs-compliance-policy-guide-availability

[3] Multistate Outbreak of Fungal Meningitis and Other Infections – Case Count

https://www.cdc.gov/hai/outbreaks/meningitis-map-large.html

[4] FDA draft and final guidances on compounding pharmacy were published since July 1, 2014

https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm452240.htm

[5] Drug Quality and Security Act

https://www.gpo.gov/fdsys/pkg/PLAW-113publ54/pdf/PLAW-113publ54.pdf

[6] Draft Memorandum of Understanding

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/UCM434233.pdf