Unapproved Drug Warning Letters

Apr 16, 2009
By: Angie Drakulich
ePT--the Electronic Newsletter of Pharmaceutical Technology



In late March 2009, the US Food and Drug Administration sent Warning Letters to nine companies asking them to stop manufacturing 14 unapproved narcotic drugs. Less than two weeks later, on Apr. 9, 2009, the agency amended those letters when it realized that one particular unapproved opioid (a high concentrate of morphine sulfate oral solution) is desperately needed by patients.

As part of FDA’s unapproved drugs initiative, launched in June 2006, the original Warning Letters went to: Boehringer Ingelheim Roxane (Columbus, OH), Cody Laboratories (Cody, WY), Glenmark Pharmaceuticals (Mahwah, NJ), Lannett Company (Philadelphia, PA), Lehigh Valley Technologies (Allentown, PA), Mallinckrodt Pharmaceuticals Group (St. Louis), Physicians Total Care (Tulsa, OK), Roxane Laboratories (Columbus, OH), and Xanodyne Pharmaceuticals (Newport, KY). The letters asked the companies to stop manufacturing and distributing unapproved products that included high-concentrate morphine sulfate oral solutions and immediate-release tablets containing morphine sulfate, hydromorphone, or oxycodone (oxycodone capsules were not included).

The original FDA press release about the nine Warning Letters stated, “FDA has determined that removal of the unapproved narcotic products will not create a shortage for consumers.” The agency had to backtrack when it received “concerns from patients and healthcare professionals in the palliative care community” that one of the affected opioid products (specifically 20 mg/mL morphine sulfate oral solution) is used to alleviate pain in terminally ill patients. FDA’s Apr. 9 release therefore stated, “The agency has determined that this dosage form is medically necessary, and should remain on the market until an approved alternative becomes available to the patients that need it.”

Companies manufacturing versions of high-concentrate morphine sulfate solution can now continue to do so, but only on an interim basis.

The very next day, Apr. 10, FDA announced permanent injunctions against contract manufacturer Neilgen Pharmaceuticals (Westminster, MD) and its parent company, Advent Pharmaceuticals (East Windsor, NJ), to prevent them from manufacturing and distributing any unapproved, adulterated, or misbranded drugs. An injunction was also filed against two of the companies’ officers, Bharat Patel and Pragna Patel. Neilgen, which operates as Unigen Pharmaceuticals, had been manufacturing unapproved prescription cough and cold products. The companies signed a consent decree to destroy their drug supply and to stop manufacturing and distributing any new drugs without FDA approval.

Read FDA’s guidance document on unapproved drugs.

Read a related blog post on PharmTech Talk.

EMEA Plans on Revising EC GMP Guide to Implement ICH Q10

On 11 March 2009 the European Medicines Agency (EMEA) issued a so-called concept paper. In this paper the authority explains the problems in implementing the ICH Guideline Q10 "Pharmaceutical Quality System" in European legislation und thus proposes a revision of the EC GMP Guide. Following the approval of the ICH Guideline Q10 this transfer is mandatory for the EC.

The EMEA states that requirements regarding a pharmaceutical quality system are already implemented in the EC GMP Guide, and especially in chapter 1. For that reason the authority sees a potential risk for confusion in the regulatory requirements caused by a different terminology in the two documents. In addition to that, in EMEA's view the requirements defined in chapters 1 and 2 of the EC GMP Guide are not up to date any more. A revision is also necessary for the glossary as well as for the chapter 7 "Contract Manufacture and Analysis", as "Outsourcing" was emphasised in the final ICH Q10 version. Further issues to be addressed include:

"Clearer guidance on the handling and investigations of deviations, Corrective and Preventive action and change control.
Emphasising the role of senior management in ensuring that there is an effective Quality Management System to support GMP."
The first draft of the requirements is supposed to be published in July 2009 and is intended for finalisation within a year.

Validation of USP Methods - Incorporation of ISO Terms!

In the first supplement of the USP 32, the revised, general chapter <1225> - Validation of Compendial Methods - was published. This chapter describes the requisite performance characteristics that should be considered to prove the validation of a method in the case of its submission to the Pharmacopoeia.

It is striking that terms coming from ISO standards have also been incorporated, although the wording in pharmaceutical surroundings was until now oriented towards the ICH Guidelines, especially ICH Q2(R1).

This was also the topic of the publication entitled "Making Sense of Trueness, Precision, Accuracy, and Uncertainty" in the Pharmacopoeial Forum of May-June 2008. This article reviews the differences between the terms when used in ICH and ISO. It also states that the terms "trueness" and "uncertainty" do not even exist in the ICH and the USP. The conclusions drawn in this article are as follows: The terms should be clarified in the USP. These clarifications could easily be added to the General Chapters <1010> und <1225>. In the longer term, the USP encourages continued harmonisation of terminology among the involved parties (ISO, ICH, VIM - International Vocabulary of Metrology) and other interested parties.

In the revised chapter <1225> of the first supplement to USP 32, these terms have now been incorporated from ISO 5725-1 and ISO 3534-1.

And the term "reportable value", established from the OOS discussions in recent years, is now also incorporated in this USP chapter.

The requisite performance characteristics to be considered in validation of the types of methods in order to prove their suitability for the USP (accuracy, precision, specificity, detection limit, quantitation limit, linearity, range and ruggedness) remained unchanged.

And when is it necessary to revalidate? Revalidation may become necessary when a revised analytical method is submitted to the USP or when an established, general method is to be used for a new product or for a new starting material.

Validation Findings in FDA Warning Letters 2008

Validation Findings in FDA Warning Letters 2008

The GMP news from 18 February 2009 comprised information on the FDA Warning Letters Report 2008, including the Top 5 deficiencies.

It did not cover deficiencies regarding validation (validation/qualification/calibration) though. This is due to the fact that the findings are listed according to the paragraphs in the 21 CFR 210/211, which does not contain a separate paragraph addressing (process) validation. For that reason the following information does provide an individual validation issues analysis:

In the 22 Warning Letters in the fiscal year 2008 issues regarding validation were criticised 15 times. Top of the list were deficiencies relative to process validation (9 Warning Letters). Five of the letters referred to deficiencies concerning solid dosage forms, 2 concerned semi-solid forms, one addressed radio pharmaceuticals, and one product classification remained unclear.

Two Warning Letters per subject covered issues like inappropriate validation of the sterilisation process, filter validation, "smoke studies" and cleaning validation the authority issued like

Exemplary findings for the issues mentioned above are:

Exclusion of validation batches without providing reasons within a retrospective validation
Missing sampling details in the validation plan
It seems like you did not understand the meaning of a cleaning validation
The cleaning validation master plan does not contain any "scientific rationale" for specific products, sampling locations and acceptance criteria
Swab surfaces are too small
Not all loading patterns were mapped in the validation of the sterilisation process
Inadequate Air Flow Pattern
Further deficiencies concerned issues like

An inadequate calibration of thermocouples
A Media Fill not representing a commercial process
Undocumented removal of filled vials within Media Fills
Conclusion: Although the subject validation is not specifically listed in the 21 CFR 210/211, it still is among the top deficiencies in the Warning Letters issued. Almost 70% of all letters contained one or several findings relative to this subject. 41% were related to process validation.

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Out-of-Specification Results and Failure Investigations in current FDA Warning Letters

Even though the Final FDA Guidance for Industry for Out-of-Specification Results was published quite some time ago, in recent times there have increasingly been FDA warning letters dealing with this theme - improper dealing with OOS results and inadequate investigation of failures.

This is supported by examples of warning letters from 2008 and 2009, extracts of which can be read below.

In March 2008, the FDA wrote in a warning letter:

Investigations into out-of specification (OOS) results for Content Uniformity testing concluded that laboratory error had occurred and required test method changes and validation. However, drug products tested using the same method that caused the OOS results have not been evaluated to determine the lot quality using the newly-modified, valid method.

There is no assurance that any of the test results are accurate and reliable. Conclusions of error investigations are not specific enough to implement adequate corrections.... In addition, they are not always substantiated by sound scientific evidence.... Again, no rationale was provided to support the conclusions.

The test solution that generated the OOS result was discarded without explanation.

The Quality Control Unit allowed the reporting of only the passing results in the final certificate of analysis, thus disregarding the original failing results that could not be invalidated by the investigation. But the procedure stipulates that if the investigation is inconclusive, the original results and the retested results must be individually reported.

In another warning letter written in January 2009, the FDA stated:

Investigations into the failures of batches to meet specifications in response to out-of-specification (OOS) results were incomplete or not documented. In response to OOS results, the batches were remixed and then resampled to obtain passing results without performing adequate investigations into the root cause of your manufacturing problems. Further it was failed to expand investigations to determine if other batches were possibly affected. The OOS review stated only: "The batch was not mixed properly. The batch was remixed." After remixing a passing result was obtained. The OOS investigation was closed and the batch was released without conducting an investigation into the cause of the failure.

In the end the FDA underlined that it is the responsibility of the firm to investigate the cause of the failure of a batch of a drug product to meet its specifications and to include conclusions and follow-up measures to prevent recurrence of such manufacturing problems.

And in a warning letter from February 2009, the following reference was found after a CBER (Center for Biologics Evaluation and Research) inspection:

Your SOP entitled "Procedure for the handling of Out of Specification Results (OOS) " is inadequate, in that it allows for repeat testing of OOS results before notifying Quality Assurance (QA) of nonconformities. Quality Assurance was not notified when a lot failed to meet the licensed final release specifications. These lots were retested without QA investigation and approval. The results of the retesting met the specification, and the lots were released for distribution.

Furthermore a current case from February 2009 concerns the manufacturer of topical application forms. The stability investigations into different lots of different products (ointments and creams) already on the market showed OOS results:


The frequency of discrepancies in stability investigations is significant. There is no evidence that the drug products meet the standard of strength, quality and purity at the time of their use within the expiration period. The necessary field alert reports for stability failures of distributed products were not always reported to the FDA within three working days. When a marketing authorisation holder becomes aware of any such information he is required to report it to the FDA within three working days.

A detailed analysis of all Warning Letters was published just recently. To find more details about the results, please see here. You can order the complete report as "FDA Navigator with Warning Letters Report" here.

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