WHO Publishes Guidelines on the Use of Quality Risk Management

In August 2010, the WHO published a draft guideline on quality risk management (QRM). With its 24 pages divided into 6 chapters, it is a surprisingly detailed document.
In the introduction (Chapter 1), the WHO points out that it formerly considered the HACCP concept, which comes from the food sector, as a suitable risk management tool. Bit regard to the EU GMP Guide, ICH Q8 and the FDA's risk-based approach, the WHO now sees more pharma-specific concerning QRM. The draft guideline now describes the current WHO approach to QRM, which is now also based on ICH Q9. However, the text underlines the fact that risk management modules other than the one described in ICH Q9 can also be applied. Depending on the process in question, the WHO also sees the emphasis on the individual ICH-Q9 steps as quite different. Yet, the guideline requires that all of the elements from the QRM process of ICH Q9 be implemented. Interestingly, within the framework of QRM, the WHO also sees connections to GCP and GLP. An indirect requirement to use QRM also in those fields?
The second chapter describing QRM considerations for regulatory authorities is also highly interesting. Actually, the descriptions are hidden requirements on a QRM by regulatory authorities directed at marketing authorisation holders and manufacturers. 2.2.1 explicitly includes a checklist for inspecting a QRM, and 2.2.2 lays down the inspection of risk-based decisions.
Chapter 3, in turn, includes highly detailed requirements on QRM for pharmaceutical manufacturers. You can find specifications regarding the topic of training and education, on responsibilities detailed instructions for the initiation of a QRM process up to the establishment of corrective actions and the verification of the QRM plan. A separate part of this chapter is dedicated to the application of QRM in product development and during validation/qualification. Especially with regard to process validation, the guideline refers to the FDA draft on this topic. In a consistent way, dependent on the process knowledge through QRM coming from development, the number of validation or "conformance batches" is not fixed either. A deviation from the classical number three for validation runs is explicitly considered to be possible (e. g. in the validation of the manufacture of orphan drugs).
Chapter 4 is titled "Risk Management Tools". With reference to a document by the Product Quality Research Institute (PQRI), a probability-versus-impact matrix is published. This matrix is meant to facilitate the classification into low, medium or high risks. In this context, the QRM team shall define each status in advance. As a helpful tool, a "consequence table" is also published, giving examples for the classification of probabilities and impacts, e. g. what is marginal impact (no impact on the product). A separate table lists risk management tools and the cases in which they can potentially be applied. Here, the PQRI is also referenced as the source.
A glossary (Chapter 5) complements the other 4 chapters. A salient point is the contents' distinct reference to a Q&A paper by the MHRA on the topic of QRM (see our GMP News from 15 September 2010). Some of the passages were taken over verbatim. Like the MHRA paper, the draft requires a "risk register", too.
Conclusion: The draft shows an astonishing high level of detail and is therefore truly worth reading. It can give guidance also in the preparation for questions regarding the QRM within the framework of an official inspection. Likewise, it provides guidance for initiating a QRM. However, only time will tell whether pharmaceutical companies e. g. in emerging countries can also implement QRM so meticulously. But the document may still be changed within the framework of finalisation in order to facilitate its implementation. The document is said to be available on the WHO web page soon.

Source ECA

Johnny Aguilar, Encarna G, Pilar P, Ganadores del Acc. Concurso Real Academía de Farmacia de Catalunya 2008-2009: Premio Dr. Esteve

El trabajo VALIDACIÓN DE LA INNOVADORA METODOLOGÍA SEDEM PARA SU USO COMO HERRAMIENTA DE PREFORMULACIÓN GALÉNICA SEGÚN LOS CRITERIOS DE CALIDAD POR DISEÑO (ICH-Q8) fue ganador del XXXVII Premio “DR. ESTEVE” 2008-2009 Organizado por la Real Academia de Farmacia de Cat- en Barcelona España

Autores: Johnny Aguilar Encarna García, Pilar P.

Este trabajo ha sido desarrollado en el Departamento de Tecnologia Farmacéutica de la Facultad de Farmacia Universidad de Barcelona constituyendo una parte de mi PhD.

Para acceder al summary del trabajo hacer click AQUI

Johnny Aguilar & Elias B. First Prize I-ISPE SPAIN AWARD

Johnny Aguilar & Elias B. First Prize I-ISPE SPAIN AWARD

To access to this article click here

Johnny Aguilar and Elías Benito of Novartis BdV, winners of the I Prize ISPE Spain to the best technical article of pharmaceutical engineering The prize was given during IV the Congress of ISPE Spain, presided over by Sergio Torralbo. “Contribution to the design of a closed system of Wet granulation totally integrated with High Yields with analysis system online”, under this title hides the meticulous explanatory work developed by Johhny Aguilar, MST Manager and Elías Benito, Process Expert de Capsules of the plant of production of Novartis Barberà, that has made them of the I Prize ISPE Spain winning the best technical article of pharmaceutical engineering. “The article tries to contribute from an analysis of previous risk (ICHQ9) a guide of support in the design of lines of granulation that allows to obtain high performances and in addition on proposes the implementation of systems of integrated analyses line”, winners Johnny and Elias comment. The delivery of the prize was realised during IV the Congress of ISPE Spain that was celebrated the past in Madrid 19 of May

The jury of the I Prize ISPE Spain has evaluated the technical quality, the divulging capacity and the innovating component of presented/displayed articles

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.