Enhancing Drug Development by Applying LC–MS–MS for Cleaning Validation in Manufacturing Equipment

Kevin J. Kolodsick , Holly Phillips , Jennifer Feng , Matthew Molski , Carol A. Kingsmill
Pharmaceutical Technology, Feb 2, 2006

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Currently, liquid chromatograph–ultraviolet spectrometry (LC–UV) is typically applied to cleaning validations because of its familiarity, robustness, ease of use, and regulatory acceptability. For low-dose compounds, equipment requiring low residue limits, and compounds lacking strong chromophores, the enhanced sensitivity and selectivity of liquid chromatography–mass spectrometry–mass spectrometry (LC–MS–MS) facilitates rapid method development for the detection of low levels of residues of active pharmaceutical ingredients (APIs). LC–MS–MS is an acceptable technique for the analysis of API residues for cleaning validation. More importantly, in applications where sensitivity and selectivity are inadequate using traditional modes of detection, LC–MS–MS offers substantial advantages. LC–MS–MS will afford faster development and analysis time, potentially making it the predominant tool of choice.

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What is Disinfectant Validation?

José E. Martinez
Pharmaceutical Technology, Mar 2, 2006
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Although we commonly talk about "disinfectant validation," the US Food and Drug Administration validates only processes (1). Disinfectants themselves are qualified—that is, found to be effective in the context of a given process, just as we qualify the clean steam supply for an autoclave and then validate the steam sterilization process. The approach to disinfection should be similar, so that a working definition for disinfection process validation would be "establishing documented evidence that a disinfection process will consistently remove or inactivate known or possible pathogens from inanimate objects."

The working definition becomes critical as process operators attempt to comply with the current good manufacturing practice (CGMP) requirements of 21 CFR 211.56 (Sanitation) and 21 CFR 211.67 (Equipment cleaning and maintenance). The Sanitation clauses require that "any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a clean and sanitary condition." And, the Cleaning and Maintenance provisions stipulate that "Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements."

Even though the regulators have never formally defined "disinfectant validation," FDA Form 483 observations and Warning Letters frequently cite failures to ensure proper disinfection.

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Risk-Based Cleaning Validation in Biopharmaceutical API Manufacturing

Hamid Mollah, Ph.D , Edward K. White
BioPharm International, November 2005
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Cleaning validation (CV) is driven by regulatory expectations to ensure that residues from one product will not carry over and cross contaminate the next product.1,2 Regulatory scrutiny is more rigorous in a multiproduct facility compared to a single product establishment. Companies are usually cited either for not having a sound cleaning validation or not meeting the protocol acceptance criteria. Because failing a protocol acceptance criteria is considered a substantial regulatory risk, companies are forced to spend money and resources even though there is minimal or no product risk.

It is vital for a successful cleaning validation to have appropriate acceptance criteria. In developing the acceptance criteria, companies may adopt a conservative approach either to prove that they have a sound cleaning validation program or to ensure that field data (results) will reflect the acceptance criteria. The Food and Drug Administration's (FDA) guidance for determining residue limits is that they must be logical (based on understanding of the process), practical, achievable, and verifiable.3 In validation, adequacy of each cleaning procedure requires demonstration that it can reliably and effectively remove or reduce residues to an acceptable level such that residues from the production of one product will not carry over in significant amounts to the next product. Companies today are faced with the challenge of reducing validation costs in an environment that demands increased compliance with current good manufacturing practices (cGMP). FDA's initiative in pharmaceutical cGMPs for the 21st Century is a science and risk-based approach to product quality regulation. The risk- based approach will enhance the ability to focus on identifying and controlling critical factors that effect process and product quality.

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Testing a New Chromatography Column for Cleaning Effectiveness

Chris Antoniou , Hillary Carter
BioPharm International, January 2006
©Advanstar Communications. All rights reserved.

Cleaning validation is a critical consideration in the pharmaceutical industry. Inadequate cleaning can result in contamination of drug products with bacteria, endotoxins, active pharmaceuticals from previous batch runs, and cleaning solution residues. Such contaminants must be reduced to safe levels, both for regulatory approval and to ensure patient safety.

Regulatory agencies worldwide require validation of pharmaceutical cleaning processes. None, however, offer a specific formulation for validation. Cleaning processes vary according to the nature of the drug being produced, the type of equipment being used, and whether equipment is dedicated or multi-use, among other variables. Thus, a one-size-fits-all validation strategy is impossible. A validated pharmaceutical cleaning process must use principles that are scientifically sound and reproducible. It is the pharmaceutical company's responsibility to set acceptance criteria and to explain the scientific basis for those limits to the regulatory authorities.

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Equipment Cleaning Validation Within a Multi-Product Manufacturing Facility

osé A. Morales Sánchez
BioPharm International, February 2006
©Advanstar Communications. All rights reserved.

Currently, there are multiple publications, as well as guidelines from regulatory agencies that make the critical process of equipment cleaning validation easier. These sources provide in-depth information for the validation specialist, making the development and implementation of a robust cleaning validation program possible within any particular facility developing or manufacturing parenteral, biological, or sterile ophthalmic products.

Extremely important, specific, and above all, mandatory, are the requirements established by regulatory agencies such as the US Food and Drug Administration (FDA), the European Medicinal Evaluation Agency (EMEA), Australia's Therapeutic Goods Administration (TGA), etc. For example, the 2004 Code of Federal Regulations (CFR) Title 21, Volume 4, Section 211.67, states:

"Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product beyond the official or other established requirements."

Additionally, Section 211.182 requires that cleaning procedures must be documented appropriately, and that a cleaning and use log should be established.

This article provides the reader with cleaning validation information enhanced by the author's thirteen years of hands-on experience working in equipment cleaning validation.

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Risk-Management Assessment of Visible-Residue Limits in Cleaning Validation

Pharmaceutical Technology, Nov 2, 2006
© Advanstar Communications, Inc. All rights reserved.

The use of visual inspection as a criterion for equipment cleanliness has always been a component of cleaning validation programs. Mendenhall proposed the use of only visual examination to determine equipment cleanliness as long ago as 1989 (1). He concluded that visible cleanliness criteria were more rigid than quantitative calculations and clearly adequate. The US Food and Drug Administration limited the use of visually clean criterion between lots of the same product (2). LeBlanc raised the question of whether a visible limit as the sole acceptance criterion could be justified (3).

Author(s):

Richard J. Forsyth , Julia Roberts , Tara Lukievics , Vincent Van Nostrand

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Correlation of Visible-Residue Limits with Swab Results for Cleaning Validation

Pharmaceutical Technology, Nov 2, 2006
© Advanstar Communications, Inc. All rights reserved.

The use of visual inspection as a criterion for equipment cleanliness has always been a component of cleaning validation programs. Mendenhall proposed the use of only visual examination to determine equipment cleanliness as long ago as 1989 (1). He concluded that visible cleanliness criteria were more rigid than quantitative calculations and clearly adequate. The US Food and Drug Administration limited the use of visually clean criterion between lots of the same product (2). LeBlanc raised the question of whether a visible limit as the sole acceptance criterion could be justified (3).

Author(s):

Richard J. Forsyth , Julia Roberts , Tara Lukievics , Vincent Van Nostrand

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