Pharmaceutical Validation: February 2008

Sunday, February 24, 2008

Calibration of Lyophilization Pressure Gauges

Gary Osborn and Steve Hansen
Pharmaceutical Technology JUNE 2002 ISO 9000 and FDA requirements mandate that any measurement be traceable to national standards. Calibration of equipment is necessary to ensure traceability, performance, and reliability.This article explains the proper method for the in situ, on-site, or off-site calibration of lyophilizer pressure gauges and offers some important guidelines to ensure the accuracy of a capacitance manometer.For full article Click Here

Development of an In Situ Spectroscopic Method for Cleaning Validation

Narinder K. Mehta, Javier Goenaga-Polo, Samuel P. Hernandez-Rivera, David Hernandez, Peter J. Melling, and Mary A. Thomson, Remspec Corporation
BioPharm International, May 2002 A fiber-optic, mid-IR spectroscopy probe combined with a grazing-angle reflectance sampling head can be used as a solvent-free in situ method for validating cleanliness with substantial improvement in accuracy.

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Implementing Total Organic Carbon Analysis for Cleaning Validation

Pharmaceutical Technology, May 1, 2004
Total organic carbon (TOC) analysis is a fast and effective analytical technique for cleaning validation. Understanding the various types of TOC technologies is essential for choosing the best solution.

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Pharmaceutical Cleaning Validation Method References

Alconox A cleaning validation involves testing for acceptable residues on pharmaceutical manufacturing or medical device surfaces. The validation involves residue identification, residue detection method selection, sampling method selection, setting residue acceptance criteria, methods validation and recovery studies, and finally writing a procedure and training operators. This procedure is used to document acceptable residues 3 or more times and then a rational monitoring program to maintain a validated state is put in place. If you are changing any part of your procedure or cleaner, first clean the new way, collect data and then clean the old way before using any equipment while you are in the process of validating the new procedure.

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Total Organic Carbon Analysis for Cleaning Validation in Pharmaceutical Manufact

Karen A. Clark, Product Manager, Anatel Corporation
ISPE, October 2000 In the pharmaceutical industry, Good Manufacturing Practices (GMPs) require that the cleaning of drug manufacturing equipment be validated.1 Many different validation techniques can demonstrate that the manufacturing equipment is cleaned and essentially free from residual active drug substances and all cleaning agents.Common analytical techniques in the validation process include HPLC, spectrophotometry (UV/Vis), and TOC. HPLC and UV/Vis are classified as specific methods that identify and measure appropriate active and substances. TOC is classified as a non-specific method and is ideal for detecting all carbon-containing compounds including active species, excipients, and cleaning agent(s). 2,3,4,5.

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Defining Three “Consecutive” Runs

Destin A. LeBlanc,Cleaning Validation Technologies,Technical Consulting ServicesCleaning Memo for MARCH 2004 Another question I commonly get is “What constitutes three consecutive runs for cleaning validation protocol purposes?” The basic approach to answering this question is to use the same principles one uses for process validation. If I am validating a blending process in a certain manufacturing vessel, do the three validation runs have to be one after the other, with no intervening product being processed? Or, in between the three manufacturing processes for the validation, am I allowed to blend other products? Most people would agree that the latter is appropriate for process validation.

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Cleaning Verification Case Studies

David DeLucia,
ISPE , January 1997 Creative BioMolecules operates a cGMP plant with 1000L mammalian cell and 1000 L bacterial fermentation capacity. The plant is used for contract manufacturing as well as for CBM’s proprietary products. These case studies will review five campaigns of five products over the last three years. In each case, the goal was to demonstrate that the equipment was properly cleaned and ready for the next campaign.

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Cleaning validation in active pharmaceutical plants – guidance, 2000

APIC Guide to Cleaning Validation in API plants This Guideline has been produced by the Active Pharmaceutical Ingredients Committee(APIC) Working group.Different organizations will be influenced by their companies and the markets that theyserve in the approaches that they take and the policies that they have with respect tothe subject.It is also valuable to bear in mind that this is an area that is changing rapidly and whatwas considered as being acceptable 2-5 years ago is now not adequate. Therefore,companies should be aware of the need to continuously update themselves on currentregulatory requirements.

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College of American Pathologists (CAP) Residue Detection Method

Detergent Residue Testing using a pH Meter, pH Indicator, or Test Kit The following test procedures are suitable for detecting detergent residues resulting from improper rinsing and can be used to meet laboratory accreditation guidelines and questionnaires such as the College of American Pathologist program of State water lab accreditation programs.

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Saturday, February 23, 2008

Monitoring a Validated Cleaning Process

Destin A. LeBlanc
Cleaning Validation Technologies, Technical Consulting Services In discussing monitoring for cleaning validation, it is important to carefully define what one means by “monitoring”. As used here, the term “monitoring” refers to the routine measurements taken on the cleaning process that serve as indicators of whether the process is in a state of control (or considered from the opposite point of view, serve as indicators that the process either is not or may not be in a state of control). The purpose of monitoring is not to have clear evidence that the surfaces are acceptably clean. To do that, one would have to sample the surfaces (much as one would do in a cleaning validation protocol). Monitoring as discussed here refers to monitoring of an already validated cleaning process.

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TOC Issues: Part 1 - Sampling Materials

Destin A. LeBlanc,Cleaning Validation Technologies,Technical Consulting Services Cleaning Memo for APRIL 2004 This Cleaning Memo will address the proper selection of sampling materials used if Total Organic Carbon (TOC) is the sampling method of choice. Particularly since TOC is subject to a multitude of interferences, it is necessary to make sure that the sampling materials provide a consistent TOC value due to those “interfering” materials. Those materials contribute to the TOC “blank”, and are preferably materials which provide a blank with a low, consistent TOC value.

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Method Development of Swab Sampling for Cleaning Validation of a Residual Active

Pei Yang, Kim Burson,Debra Feder, and Fraser Macdonald
Pharmaceutical Technology, Jan 2, 2005 A swab-sampling method was developed for cleaning validation of a residual active pharmaceutical ingredient in samples collected after cleaning the sampling suite. A summary of the strategies and results of the method development is presented. The developed extraction method produced an acceptable level of recovery and precision.Cross contamination with active ingredients is a real concern. The Code of Federal Regulations (CFR) states 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” (1). Cleaning validation is required in the pharmaceutical field to avoid potential clinically significant synergistic interactions between pharmacologically active chemicals (2). Since the issuance of the US Food and Drug Administration’s “Guide to Inspection of Validation of Cleaning Process” in July 1993 (3), cleaning validations have received increasing attention.Validation is required not only for manufacturing sites, but also for the sampling– filling suite in research and development.

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A Roadmap to an Effective Cleaning Program: Validation Considerations

Journal of Validation Technology Once products have been grouped and worst case(s) selected, the next logical question to be answered is "How much product can remain on equipment?". There are many bases for establishing limits for cleaning processes. Some of them are.

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CIP/COP Validation Test Procedure

Jon R. Voss
ISPE, September 1999 In the hopes that sharing a test procedure from our library of ValPro™ procedures will get others to do the same, I submit the following procedure for your use. Let us know what you think! Coverage Test-CIP/COPObjective:The objective of this test is to verify that the sprayballs/wands/bars associated with the system are capable of delivering cleaning solutions to all exposed product contact surface areas. Often spray ball coverage testing is performed as part of the final vessel factory acceptance test. Coverage testing may be performed on-site using the actual equipment that will be used to clean the vessel.

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Cleaning Validation Acceptance Criterion – Case Study

Jon R. Voss, President
ISPE, February 1999 You are fed up, tired of it all. Your boss has been harassing you to develop "a scientifically sound, logical, and rational basis for cleaning acceptance limits." Should be simple enough, right? Yet, every time you ask someone about setting cleaning limits they look at you as if you have three, maybe four heads. Asking a consultant only makes things worse, leaving you more confused when they present you with more theoretical options than you ever imagined possible (but of course offering to help you solve the problem with a team of experts!) You’ve scoured the literature, yet haven’t found anything but theoretical discussions and vague references to the "Mullen and Fourman method." Before kicking the cat or cursing your boss, let’s see what this is really all about.

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Validating and Establishing a Routine Environmental Monitoring Program for Clean Room Environments

Validation Technology In recent years, there has been considerable growth in the demand for more sophisticated Clean Rooms. Many industries are beginning to discover the benefits of Clean Room technology, while other industries are developing their products in such a way that contamination control is becoming more stringent. This is more prevalent for the biotechnology industries where a few kilograms or even grams of product may be worth millions of dollars.Over the last twenty years, the demand for contamination control has increased to such an extent that the present state-of-the-art Clean Rooms are a thousand times cleaner than those designed in the past. Clean Rooms have progressively developed, and the stage has been reached where it is now possible to design a Clean Room to fulfill almost any environmental requirement..

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TOC Issues: Part 3 – Blanks for Recovery Studies

Destin A. LeBlanc, Cleaning Validation Technologies,Technical Consulting Services Cleaning Memo for JUNE 2004 This Cleaning Memo will address issues in the proper selection of blanks for TOC in recovery studies. In this situation, the purpose of sampling is to quantitate the organic residues that may be on the coupon (the model surface used for the study), and then compare that value to amount of organic residues spiked onto the coupon surface.

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Cleaning validation in Active Ingredient Manufacturing plants – Policy

Guide to Cleaning Validation in API plants This Guideline has been produced by the Active Pharmaceutical Ingredients Committee(APIC) Working group.Different organizations will be influenced by their companies and the markets that theyserve in the approaches that they take and the policies that they have with respect tothe subject.It is also valuable to bear in mind that this is an area that is changing rapidly and whatwas considered as being acceptable 2-5 years ago is now not adequate. Therefore,companies should be aware of the need to continuously update themselves on currentregulatory requirements.

For full information Click Here

Application of Visible-Residue Limit for Cleaning Validation Richard J. Forsyth and Vincent Van Nost

Richard J. Forsyth , Vincent Van Nostrand

Pharmaceutical Technology, Oct 2, 2005
© Advanstar Communications. All rights reserved.
Pharmaceutical plants must have visually clean equipment to operate according to good manufacturing practices. Formulators must visually inspect manufacturing equipment for cleanliness before formulation work begins (1). Manufacturers establish and perform visible cleanliness and analytical methods to ensure regulatory compliance. An analyst conducts a visual inspection and confirms visible cleanliness before taking swab samples for chemical analysis (2). The formulator of the subsequent batch conducts a visual inspection before manufacturing work begins. A correlation between available analytical data and visible cleanliness of manufacturing equipment over an extended period of time can expand the practice of performing visual inspections in lieu of swab sampling.

Yet, the US Food and Drug Administration's Guide to Inspection of Validation of Cleaning Processes (3) and other literature (4) discount using a visible limit as the sole acceptance criterion for cleanliness. Conversely, Mendenhall concluded that visible cleanliness criteria were more rigid than quantitative calculations and are clearly adequate for determining cleanliness (5). Other recent articles describe the justification and application of a visible-residue limit (VRL) (6, 7).

Many research teams have established quantitative VRL levels. Fourman and Mullen determined a visible limit of ~100 μg per 2 X 2-in. swab area (8) or ~4 μg/cm2 . Jenkins and Vanderwielen observed residues as low as 1.0 μg/cm2 with a light source (9). Forsyth et al. determined <0.4->10-μg/cm2 VRLs for active pharmaceutical ingredients (APIs) and excipients (6).

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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

©Advanstar Communications. All rights reserved.
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
© Advanstar Communications. All rights reserved.

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

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

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

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

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

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

Author(s):

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