HOSPIRA – WHEN IS A DRUG RECALL AN ALERT

 FDA RECOMMENDS ALERT TO AVOID DRUG SHORTAGES

In a previous Blog (May 24, 2012) the issue of Warning Letters and how the FDA now on a routine basis is asking their Clients to advise them if the Warning Letter and its consequences will result in shortages was discussed.  In this Blog, the FDA is using “Risk Management” to determine whether overfilled Carpuject pre-filled syringes (Hospira) should be reviewed by the pharmacist and other healthcare providers to visually identify the presence of an overfilled Carpuject pre-filled cartridge to determine whether it is overfilled. 

Several lots have previously been recalled in April (Morphine Sulfate, 04/18/12) and May (Hydromorphone Hydrochloride, 05/14/12) because of this issue.  However, the FDA now believes the health care professional can manage this issue.

The FDA has advised that “subsequent inspection of retained product by Hospira found additional overfilled Carpuject pre-filled cartridges.  The manufacturing problem thought to be responsible for this overfilling has resulted in the risk for overfilled Carpuject pre-filled cartridges for as many as 280 lots of 15 different Carpuject pre-filled cartridge products.”

“FDA is advising healthcare providers to follow the instructions provided with the medication and visually inspect and confirm that the Carpuject pre-filled cartridge contains the labeled fill volume before dispensing and again before administering to patients.”

NEW ADDITION TO WARNING LETTERS’ “BOILERPLATE” PARAGRAPHS

CDER RESPONDS TO MANAGEMENT OF LACK OF AVAILABILITY OF FINISHED DRUG PRODUCT OR API

Recently the FDA has added a new standardized paragraph to each of its Warning Letters for both Finished Drug Products and for Active Pharmaceutical Ingredients.  Please review how the FDA desires you to respond.

“If, as a result of receiving this Warning Letter or in general, you are considering making a decision that will result in a decreased number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER’s Drug Shortages Program immediately, as you begin your internal discussions, at drugshortages@fda.hhs.gov in order to ensure that your action(s) does not adversely affect the public health.”

FDA CBER STERILITY TESTING REQUIREMENTS (610.12) AMENDED (06/04/12)

ELIMINATES SPECIFIED STERILITY TEST METHODS, CULTURE MEDIA FORMULAE, AND CULTURE MEDIA TEST REQUIREMENTS — CLARITY OR CONFUSION?

Summary (Effective June 4, 2012)

The Food and Drug Administration (FDA) is amending the sterility test requirements for biological products. This rule provides manufacturers of biological products greater flexibility, as appropriate, and encourages use of the most appropriate and state-of-the-art test methods for assuring the safety of biological products. FDA is taking this action as part of its ongoing efforts to comprehensively review and, as necessary, revise its regulations related to biological products.

Summary of the Final Rule

FDA is adopting as final, without material change, the proposed requirements for sterility testing. Specifically, this final rule:

1. Eliminates specified sterility test methods, culture media formulae (or formulation), and culture media test requirements; Eliminates specified membrane filtration procedure requirements for certain products; Eliminates specified sterility test requirements for most bulk material;
2. Modifies the repeat sterility test requirements, so that repeat tests will occur only once for each lot. These repeat tests are limited to situations when the quality control unit conclusively determines, after conducting an investigation upon detection of viable microbial contamination during the initial test of the lot, that the contamination is the result of laboratory error or faulty materials used in conducting the sterility test;
3. Replaces the storage and maintenance requirements for cultures of test organisms used to determine the “growth-promoting qualities” of culture media with: (1) Validation requirements specifying that any sterility test used is able to consistently detect the presence of viable contaminating microorganisms and (2) verification of “growth-promoting properties” or microorganism-detection capabilities of test and test components;
4. Replaces the sample size or amount requirement with a requirement that the sample be appropriate to the material being tested;
5. Replaces the Interpretation of test results section under § 610.12(c) with a requirement that manufacturers establish, implement, and follow written procedures for sterility testing that describe, at a minimum, the test method used, the method of sampling, and the written specifications for acceptance or rejection of each lot;
6. Simplifies and clarifies the Exceptions section under § 610.12(h);
7. Identifies the Director of CDER as one of the two Center directors authorized to grant an exemption under the exception provision at § 610.12(h)(2). In the proposed rule, the Center for Devices and Radiological Health was erroneously identified in this exception, instead of the Center for Drug Evaluation and Research.
8. Revises the definition of the term “sterility” under § 600.3(q)
9. Eliminates certain exceptions for allergenic products related to sterility testing under § 680.3(c). 

The entire document may be found at:  http://www.gpo.gov/fdsys/pkg/FR-2012-05-03/pdf/2012-10649.pdf  

Burkholderia cepacia: This Decision Is Overdue

FDA Believes Now is the Time to Remove the Bug from Pharmaceutical Manufacturing

The FDA recently published an article wherein they discuss the rationale for removing B. cepacia from the pharmaceutical arena.  They cite a number of reasons why they believe that this bacterium and its variants should no longer be permitted.  These discussions are continued by S. Sutton, Ph.D. in a Letter to the Editor PDA (J Pharm. Sci. Technol March/April 2012 66: 91-95) where he argues that the FDA is perhaps extending this concept too far.  Enclosed are Dr. Sutton’s concluding remarks as well as Raccasi et.al. counterpoint to this Letter to the Editor (PDA J Pharm Sci Technol March/April 2012 66:96-97).  Please view the entire recent research article by Friedman et al., Burkholderia cepacia: This Decision Is Overdue. PDA J. Pharm. Sci. Technol. 2011, 65 (5), 535–543.

Dr. Sutton’s concluding remarks include:

“I looked for a scientific justification of the unwritten policy of viewing B. cepacia (Bcc) as a pathogenic organism whose presence alone justified recall of batches. As has been amply documented, this has been the de facto standard for years. Unfortunately, this proof is lacking. The discussion presented in this article states that B. cepacia is a pathogen because of recalls involving it and that these recalls involving Bcc prove its status as an objectionable organism. This circular argument is not what is to be hoped for in a rational risk analysis.

In conclusion, then, I appreciate the opportunity to read the opinions of FDA scientists whom I admire, but have to point out not only does the article “Burkholderia cepacia: This Decision Is Overdue” employ questionable logic in risk assessment, it does not adequately support the arguments presented with relevant scientific data or case studies. If it is the intent of the agency to move towards requiring all pharmaceutical, OTC, and personal care products be sterile, this intent should be stated clearly to allow for discussion. If it is the intent to protect CF patients and those at risk for pneumonia from B. cepacia, then this should be done by cost-effective procedures in patient care. There are clearly some products that must be free of B. cepacia (inhalants, for example, and perhaps others based on demonstrated risk to the target population), but this article failed to provide convincing evidence or arguments that would lead to the conclusion that B. cepacia complex must be excluded from all product formats, or that we need to establish procedures for “objectionable organisms” in our manufacturing environment.”

S. Sutton, Ph.D. Letter to the Editor: PDA Journal of Pharmaceutical Science and Technology March/April 2012 66: 91-95

In the Author Response, the FDA comments as follows:

“In closing our paper, we concluded, “The evidence for the objectionable nature of this microorganism is substantial and supported by other independent research (2). B. cepacia is a clear and present danger to patient health and safety. The challenge is undeniable; now is the time to remove B. cepacia from our pharmaceutical manufacturing areas and products.” This conclusion would require manufacturers and application holders to establish specifications for products and criteria for manufacturing areas with sensitivity to the end use of product, and would be a concern for most aqueous, non-sterile products. We are not proposing that the environmental presence of B. cepacia is a batch release criterion, but should be cause for investigation and mitigation. We are proposing that aqueous drug products undergo a risk assessment of the presence of B. cepacia in the product, and analysis of its potential sources with the goal of keeping it out of the process stream.

We believe we are in agreement with Dr. Sutton on most of his points and appreciate his directing our attention to areas that may need more clarity. We appreciate the opportunity for these collegial discussions and to clarify our expectations.”

2) Halls, N. Burkholderia (Pseudomonas) cepacia—a brief profile for the pharmaceutical microbiologist. Eur. J. Parent. Pharm. Sci. 2006, 11 (2), 53.

Author Response PDA J Pharm Sci Technol March/April 2012 66:96-97

I encourage each of you to review the initial article as well as Dr. Sutton’s and the FDA’s response and form your own opinion.  Should B. cepacia have the same status of other “specified” microorganisms listed within USP<62> or should that status be reserved for selected monographs as per USP<1111>?  I encourage you to voice your opinions.

 

NUSIL TECHNOLOGY LLC RECEIVES FDA WARNING LETTER (032312)

API MFG CITED FOR OOS AND MICROBIOLOGICAL ISSUES (B. cepacia) — REFERENCES RECENT PDA J. PHARM SCI & TECH

1. Your firm failed to have an adequate out-of-specification (OOS) procedure to conduct thorough and scientifically sound investigations including corrective actions.

For example, the OOS report number (b)(4) for lot (b)(4) of Simethicone Emulsion USP (30%), MED-341, dated September 17, 2010, states that your firm performed two retests as part of the investigation of a microbial test result of> 11,000 CFU/g. You released the lot based on the results of retesting, which were within the specification of (b)(4). You did not justify the invalidation of the original results, nor identify the root cause of the failure. You relied solely on the acceptable retest results to release the lot. Your OOS Report procedure (SOP#(b)(4)), is deficient because it does not require an analysis of the data, assessment as to whether a significant problem exists, identification of root causes, or allocation of the tasks for corrective actions.

In your response, you stated that you have modified your SOP# (b)(4) to include testing of lots before and after a failing result in your procedure. However, your response is inadequate because you failed to provide evidence that your firm will scientifically justify and document retesting of a lot that fails to meet a microbiological specification, and conduct an appropriate investigation.

COMMENT

Not justifying the invalidation of the original test results nor the identification of the root cause of a failure prior to the release of an API (Active Pharmaceutical Ingredient) is a major Quality issue.  All non-conformances require investigation and identification prior to closing a batch record.  Finding >11,000 CFU/gm is at least one to two logs higher than what is deemed acceptable based upon USP<1111> and far from results that would be normally acceptable.  The finding of B. cepacia within the water system which comprises a high percentage of the Simethicone Emulsion USP (30%) strongly suggests that the microorganism may have been within the initial and retested API.  Based upon current USP<62>, B. cepacia is not considered as a “specified” microorganism which is unacceptable in APIs and final product.  However, the FDA has recently published an article (see PDA J Pharm Sci and Tech 2011, 65 535-543) wherein they make their case for B. cepacia becoming a “specified” bacterium.  Please also visit the Letter to the Editor by Scott Sutton, Ph.D. and his response from the FDA.

2. Your firm failed to establish procedures to adequately clean and store equipment and utensils to prevent contamination or carry-over of material that would alter the API beyond the established specifications.

For example, our inspection established that you do not routinely perform equipment cleaning after each manufacturing run. Your cleaning procedure requires you to clean the equipment when it has been more than (b)(4) since you manufactured the last batch in the same equipment, yet your cleaning validation does not contain data to support a (b)(4) ”dirty hold time.” Your firm determined that failure to clean a transfer hose before use was the probable cause of the microbial contamination of the Simethicone Emulsion USP (30%).

In your response, you stated that you performed a study to evaluate the cleaning step for the transfer hose and that you will sanitize the cleaned hoses with a dry heat treatment prior to use for future batches. Your response is inadequate because it does not provide data to support that your cleaning procedure for the transfer hose cleans and sanitizes the hose adequately. Please provide a validation report that includes microbial test data that evaluates whether your cleaning and sanitization procedures for your transfer hoses and other equipment is adequate.

COMMENT

Making conclusions without support data is a common occurrence observed within Warning Letters.  Validation reports provided to the Agency will provide the data that “backs up” a Client’s assumptions.

3. Your firm failed to adequately validate and monitor the treatment process for your purified water system.

For example, your firm uses purified water as a key ingredient in the manufacture of Simethicone Emulsion USP (30%), MED-341. Between September 2009 and January 2011, you have conducted microbiological tests and found recurrent Burkholderia cepacia contamination.
Your firm failed to assure that your water system is suitably designed and operated to produce appropriate water quality. Regarding the latter, your firm has not established and validated appropriate cleaning and sanitizing schedules for your purified water system.

You have hired a water process subject matter expert and taken other steps to strengthen monitoring of the purified water system. Your response is not acceptable because you have not demonstrated that your purified water system is capable of operating in a continuing state of control. Please provide a validation plan for your purified water system and describe any interim actions that your firm will take to ensure that purified water used in manufacture of your drug products meets its action limits.

COMMENT

The hiring of a “water process subject matter expert” is a step forward for the monitoring of a purified water system.  However, the development and execution of a Cleaning and Sanitization Plan as part of a total Validation Plan which ultimately requires intensive sampling and testing over a prolonged period of time  of the Purified Water System is essential to maintaining the water.  In addition, since the use of temperature to minimize the number of microorganisms appears to be an intermittent feature of the process, it can only be surmised that heat may not have been an on-going requirement to assist in control this contamination problem.

4. Your firm has failed to identify and define critical process parameters and the ranges expected that could affect critical quality attributes.

For example, your firm states that the Simethicone Emulsion USP (30% ), MED-341, manufacturing process is designed to prevent objectionable microbiological contamination with the use of pH and temperature controlling steps. However, your validation protocol and report did not identify pH and temperature as critical parameters. Using this manufacturing process, between September 2010 and November 2010, you produced and distributed several Simethicone lots later found to be contaminated with microbiological organisms, particularly Burkholderia cepacia.

We acknowledge your voluntary recall of Simethicone Emulsion USP 30% lots potentially contaminated with Burkholderia cepacia. In your response, you stated you relied on pH and temperature controlling steps to prevent objectionable microbiological contamination of your active pharmaceutical ingredients. Your response failed to provide information and data to support other specific manufacturing (including but not limited to quality of the input ingredients and storage time limitations) operation provisions that are needed to provide assurance that objectionable microbial contamination is prevented by your process design. Furthermore, your manufacturing process has multiple steps after your pH and heating step that would provide vectors for microbial contamination. For more information on Burkholderia cepacia contamination and control please refer to the article Burkholderia cepacia: This Decision Is Overdue, (PDA J Pharm Sci and Tech 2011, 65 535-543) which can be viewed at the following link, http://joumal.pda.org/content/65/5/535.full.pdf+html. Please provide a report in which you fully identify your manufacturing failure modes and critical control points to prevent objectionable microbiological contamination’ and provide documentation to justify significant manufacturing ranges established.

COMMENT

Many manufacturing operations contain multiple steps.  With these operations multiple steps occurred following the pH and heating step that could provide vectors for microbial contamination.  Developing the failure modes and critical control points throughout each unit operation is critical to prevent objectionable microbial contamination and understanding and justifying the manufacturing ranges that should be utilized in developing an Active Pharmaceutical Ingredient (API).

FDA RELEASES “GLOBAL ENGAGEMENT REPORT” (4/23/12)

NEW REPORT PRESENTS FDA’s FOCUS ON GLOBAL COOPERATION FOR PRODUCT SAFETY

The U.S. FDA Commissioner Margaret A. Hamburg, MD released the Agency’s “Global Engagement Report” detailing the many activities and strategies FDA is using to transform from a domestic to a global public health agency.

This report describes the steps the Agency is taking to ensure the imported food, drugs, medical devices, and other regulated products meet the same rigorous standards for safety and quality as those manufactured domestically.

To access the “Global Engagement Report” and learn more about the FDA global work, please visit the Agency’s web page dedicated to its work on globalization: www.fda.gov/global.

TOP POSTINGS FROM THE BLOG OF BARRY A FRIEDMAN, PHD

A RESPONSE TO YOUR QUERIES RE: FREQUENT TOPICS OF INTEREST

Periodically, I am asked what are the most frequent topics which interest the reader. Because the reader has so many varied interests, it is difficult to determine this without retrospectively reviewing the data.  I have summarized below the “top six” topics that have been viewed since the beginning of 2012.  You may wish to look at what others are viewing.   On a Quarterly basis, I will begin to list these for your review/comments.  Thanks for viewing my Postings this year.

1)   FDA Increases Vigilance on Aseptic Processing Facilities

2)   Ben Venue Receives Yet Another Form FDA 483

3)   USP 61/62 Frequently Asked Questions

4)   FDA Issues Warning Letter for Clinical Supply Manufacturing Facilities

5)   Proposed Changes to USP General Chapter 823 March 30, 2011

6)   2012 Upcoming Webinar/Seminars