GMP Case Studies

Priority review and approval of generic anticancer drug alleviate doxil shortage The FDA defines a drug shortage as a situation in which the total supply of all clinically interchangeable versions of an FDA-regulated drug is inadequate to meet the current or projected demand at the patient level. In recent years, drug shortages are increasing at an alarming rate, affecting the medical facilities and compromising the patient care in world-wide. In the last five years, the drug shortages have steadily increased to three times.

For products on the shortage list, the FDAs office of generic drugs is using a priority review system to expedite the review of generic applications to help alleviate shortages.

A Priority Review designation means FDAs goal is to take action on an application within 6 months (compared to 10 months under standard review).

In case of Priority Review FDA directs overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.

Priority Review approach is intended to make therapeutically important drugs available at an earlier time without compromising the standards for the safety and effectiveness of the drugs that become available through this process.

Most of the medications affected by these shortages are critical products like oncology drugs, anesthetics and anti-microbials. Sterile injectables are potentially at a greater risk of shortage, as compared to oral drugs, because of the more complex and specialized process required for manufacturing them and shortage can last for months.

Recently a case of drug shortage Doxil, manufactured by J & Js subsidiary Janssen has happened. Doxils chemical name is doxorubicin hydrochloride was approved in 1995 for the treatment of ovarian cancer. Doxorubicin HCl liposome injection is used to treat patients with ovarian cancer that has progressed or recurred after platinum-based chemotherapy. Doxil in combination with VELCADEﾃつｮ (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy. Doxil or Doxorubicin HCl Liposome Injection is packaged in 20 mg/l0mL and 50 mg/25mL singleuse vials. Doxorubicin hydrochloride liposome injection is administered intravenously by a health care professional.

Doxil fell into short supply after manufacturing problems at an outside contract manufacturer, Ben Venue Laboratories, a unit of German drugmaker Boehringer Ingelheim, suspended operations in November 2011 due to quality control problems.

Janssen blamed its third party contract manufacturer Ben Venue Laboratories for the shortage of drug, but later these problems were compounded when Ben venue issued a temporary suspension of manufacturing and distribution of drug products due to a series of violations in standards.

In February 2012, the FDA allowed for the temporary importation of Lipodox, which is made by Sun and contains the same active ingredient as Doxil. The agency said it intends to continue allowing the importation of Lipodox until Sun has made enough generic Doxil to meet demand. Generic drugs approved by the FDA have

the same high quality and strength as brand-name drugs. The generic manufacturing and packaging sites passed the same quality standards as those of brand-name drugs. Therefore, to deal with the Doxil shortage, FDA has approved India based Sun Pharmas generic version of Doxil, which is protected by orphan drug marketing exclusivity in a multiple myeloma indication till May 2014. This generic Doxorubicin HC1 Liposome injection USR 2 mg/mL is therapeutically equivalent to Doxil Liposome injection, 2 mg/mL of Janssen Research and Development.

Janssen is also working to improve supplies of its own product, with its most recent statement on Doxil saying the company was coordinating with the Food and Drug Administration (FDA) to release additional supply using an alternative manufacturing process.

The statement, which was released on January 7, 2013, explained that although the process was not approved by the FDA, the product had undergone a full internal review by Janssen to ensure it met standards in both quality and safety.

Janssen said it was working with the FDA to gain approval for this manufacturing process for Doxil, which involves collaboration between Ben Venue Laboratories (BVL) and another supplier.

In February end 2013, a federal judge approved a consent decree under which Ben Venue must bring its Bedford, Ohio facility into compliance with regulatory requirements or face fines and other penalties. The FDA said the company had repeatedly violated good manufacturing practices. Recent inspections found that poorly maintained equipment deteriorated to the point that it shed particles into injectable drugs, the FDA said.

Issues in clean room ad aseptic techniques led to recall of all sterile products Green Valley drugs voluntarily recalled all lots of all sterile products, compounded, repackaged, and distributed by the pharmacy due to lack of sterility assurance and concerns associated with the quality control processes. The recall of sterile products is conducted based on the observations of clean room personnel and certain aseptic techniques. Though they have not received any cases of injury or illness associated with the use of their products, still they recalled all products for the sake of patients interest only. Healthcare professionals were advised to stop the use of all their products and were encouraged to report any adverse event or side effect related to the use of their products.

Visible Glass Particle in a vial Bedford laboratories discovered a single visible glass particle in a vial and voluntarily recalled one lot (Lot 1877093, Exp. Date June 2013) of Acetylcysteine solution. Glass particle can cause airway obstruction resulting in symptoms of choking, wheezing, difficulty in breathing, coughing and potentially hemoptysis. All heathcare facilities were advised not to use the products from the lot no. mentioned above and should immediately quarantine any product for return. Patients who have received the product from this lot should return the product to pharmacist. Healthcare professionals and patients are encouraged to report any adverse event or side effect related to the use of their products.

Microbial Contamination in Povidone Iodine Prep Pads H & P industries, Inc., a manufacturer of over-the counter products, voluntarily recalled all lots of Povidone Prep Pads manufactured by them. Analytical testing showed the presence of Elizabethkingia meningoseptica. Povidone prep pads contaminated with Elizabethkingia meningoseptica could lead to life-threatening infections, especially in neonates, surgical patients and immune-suppressed patients. Povidone Iodine Prep Pads are used to prevent infection in minor cuts, scrapes and burns and are labeled as an antiseptic for preparation of the skin prior to surgery. The affected Povidone Iodine Prep Pads can be identified by the names like Cardinal Health, Medical Specialties, VHA, Triad, Triad Plus, North Safety, Total Resources in their packaging.

Conflicting label requirement leads to confusion for heparin injection labeling General Chapter Injections section requires that the strength per total volume should be the primary and prominent expression of strength on the principal display panel of the label, followed in close proximity by strength per mL enclosed by parentheses. However, the labeling requirement in the current heparin monographs states that the label must reflect only strength per mL. The U.S. Food and Drug Administration (FDA) is now notifying health care professionals, caregivers, and patients about a change to the container and carton labels for heparin products as per General Chapter . This label change will require manufacturers of Heparin Lock Flush Solution, USP and Heparin Sodium Injection, USP to clearly state the strength of the entire container of the medication followed by how much of the medication is in 1 milliliter (mL).

Wrong Active Ingredients in Tevas Adderall 30 mg Tablets General Chapter Adderall is a prescription drug classified as a controlled substance, a class of drugs for which special controls are required for dispensing by pharmacists. It is approved to treat attention deficit hyperactivity disorders (ADHD) and narcolepsy. The counterfeit Adderall tablets are round, white and do not have any type of markings, such as letters or numbers whereas, authentic Adderall 30 mg tablets produced by Teva are round, orange/peach, and scored tablets with "dp" embossed on one side and "30" on the other side of the tablet.

Adderall contains four active ingredients, dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate. Instead of these active ingredients, the counterfeit product contained tramadol and acetaminophen, which are ingredients in medicines used to treat acute pain.

FDA is warning consumers and health care professionals about a counterfeit version of Teva Pharmaceutical Industries Adderall 30 milligram tablets that is being purchased on the Internet.