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

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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 armacologically 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.

Author(s):

Pei Yang, et al

Journal:

Pharmaceutical Technology, Jan 2, 2005

Dealing with Unknown Peaks

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A common question in training seminars is “How do I deal with unknown peaks in HPLC analysis?” My first answer is a facetious one: “Try TOC; there are no unknown peaks in TOC!” However, TOC is not without its problems. To directly answer the question about unknown peaks in HPLC analysis, the first attempt should be to clarify the question. By unknown peaks, we are talking about unknown peaks in the HPLC samples taken in the cleaning validation protocol itself.

The first attempt should be a preventive one. That is accomplished by trying to identify in the HPLC analytical development all possible “unknown” substances.

Author(s):

Destin A. LeBlanc, Cleaning Validation Technologies Technical Consulting Services

Journal:

Cleaning Memo for FEBRUARY 2005

Cleaning Validation for Packaging Equipment

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Sometimes I am asked about cleaning validation for packaging equipment, and the thought behind the question appears to be that this is not a critical cleaning process and therefore doesn’t require cleaning validation. While it is true that effective cleaning of some packaging equipment may be much easier to achieve, it is not necessarily true that the effectiveness of such cleaning is non-critical.

Before I discuss the topic, let’s make sure of some definitions. By packaging equipment I am referring to primary packaging equipment, usually of a finished drug product. That includes such examples as liquids being filled into vials and then capped, and tablets being filled into bottles and then capped.

Author(s):

Destin A. LeBlanc,Cleaning Validation Technologies Technical Consulting Services

Journal:

Cleaning Memo for MARCH 2005

Cleaning Validation for Packaging Equipment:

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This is a continuation of last month’s Cleaning Memo. In that Cleaning Memo I discussed the criticality of cleaning for primary packaging equipment.

That this is important is evident from the fact that the principle involved (non-uniform contamination of the next batch) is mentioned in the FDA cleaning validation guidance. This month I will focus on issues related to limits and worst-case challenges. As discussed last month, one issue that makes primary packaging equipment critical is that it is possible that residues on some or all surfaces of the primary packaging equipment may preferentially transfer to a small portion (such as the first portion) of the next product packaged. It would be prudent to set limits based on this worst-case assumption (that transfer of residues can preferentially occur into a small portion of the next batch).

Author(s):

Destin A. LeBlanc Cleaning Validation Technologies Technical Consulting Services

Journal:

Cleaning Memo for APRIL 2005.

Using Visible Residue Limits for Introducing New Compounds into a Pharmaceutical Research Facility

Introducing new compounds into a pharmaceutical manufacturing facility can pose ongoing challenges to a facility’s cleaning validation program. Some discussions have described how a cleaning validation program can be conducted (1–2). Several programs have used a worst-case approach to validating a cleaning program (3–8).Approaches for determining the worstcase soil have included evaluating which residue was the last to rinse from the manufacturing vessel (3), using a product grouping strategy (4–6), assessing the relative toxicological properties of the formulation components (7), and relying on the practical cleaning experience of the formulators and equipment cleaners (8). Once a worst-case soil has been validated, however, introducing a new compound requires determining whether this compound is a new worst case.

Author(s):

Richard J. Forsyth and Vincent Van Nostrand,

Journal:

Pharmaceutical Technology, Apr 2, 2005

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

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.

Author(s):

Pei Yang, Kim Burson,Debra Feder, and Fraser Macdonald,

Journal:

Pharmaceutical Technology JANUARY 2005

Using Ion Mobility Spectrometry for Cleaning Verification in Pharmaceutical Manufacturing

Validation of cleaning processes has long played a critical role in pharmaceutical manufacturing. FDA requires that firms provide written documentation detailing the cleaning processes used for various pieces of equipment as well as how the cleaning processes are validated. Validation requires the development of a cleaning verification method with the typical detection limits of either
10 ppm or biological activity levels of 1/1000 of the normal therapeutic dose. Two methods of sampling the surface of equipment after cleaning are direct-surface and rinse sampling. The advantages of the direct-surface method are that it can reach hard-to-clean areas and it allows insoluble residues to be sampled. However, rinse sampling can evaluate a larger surface area as well as areas that are not accessible with a swab.

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Author(s):

Reno Debono, Stephen Stefanou,Matt Davis, Gaurav Walia

Journal:

Pharmaceutical Technology APRIL 2002

Disposable Filtration Lightens Cleaning and Validation Load, Pharmaceutical Makers See Multiple Adva

The latest components in sterile filtration technology are not made to last. In fact, pharmaceutical manufacturers are throwing them out after every batch filtered. Tossed out with them, however, are the expense and time of cleaning, cleaning validation, and maintenance as well as the concerns of crosscontamination associated with multipurpose production lines.

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Author(s):

Maribel Rios,

Journal:

Pharmaceutical Technology SEPTEMBER 2003

Cleaning Verification Case Studies

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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Author(s):

David DeLucia,

Journal:

ISPE , January 1997

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

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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).

Author(s):

Pei Yang, Kim Burson,Debra Feder, Fraser Macdonald

Journal:

Pharmaceutical Technology, Jan 2, 2005

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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Cleaning Validation Acceptance Criterion – Case Study

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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Endotoxin Issues in Cleaning Validation

Destin A. LeBlanc,Cleaning Validation Technologies, Technical Consulting Services The questions that will be addressed in the Cleaning Memo include:“When should I measure endotoxin in a cleaning validation protocol?”“How should I sample for endotoxin?”“What acceptance criterion should I establish for endotoxin?”



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Monitoring a Validated Cleaning Process

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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).

Author(s):

Destin A. LeBlanc

Journal:

Cleaning Validation Technologies, Technical Consulting Services

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

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.
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.

Author(s):

Richard J. Forsyth , Vincent Van Nostrand

Journal:

Pharmaceutical Technology, Oct 2, 2005

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

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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.

Author(s):

Kevin J. Kolodsick , Holly Phillips , Jennifer Feng , Matthew Molski , Carol A. Kingsmill

Journal:

Pharmaceutical Technology, Feb 2, 2006

What is Disinfectant Validation?

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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."

Author(s):

José E. Martinez

Journal:

Pharmaceutical Technology, Mar 2, 2006

Risk-Based Cleaning Validation in Biopharmaceutical API Manufacturing

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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.

Author(s):

Hamid Mollah, Ph.D , Edward K. White

Journal:

BioPharm International, November 2005

Testing a New Chromatography Column for Cleaning Effectiveness

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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.

Author(s):

Chris Antoniou , Hillary Carter

Journal:

BioPharm International, January 2006

Equipment Cleaning Validation Within a Multi-Product Manufacturing Facility

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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:

Author(s):

José A. Morales Sánchez

Journal:

BioPharm International, February 2006

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

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Before formal cleaning validation programs were instituted, visual inspection was the primary means of determining equipment cleanliness. The use of visual inspection is still typically a component of a cleaning validation program and for routine inspections of cleaning effectiveness, but the use of visual inspection as a sole criterion for equipment cleanliness has not been successfully implemented as a valid approach for cleaning validation.

A validated cleaning program based on quantitative visual inspections in conjunction with swab testing is possible. Acceptable visible-residue limits (VRLs) can be established in conjunction with and compared with swab results. Assuming the swab results demonstrated a validated cleaning procedure, if the results are in agreement, then the VRLs may be used going forward. A similar argument has been successfully used to defend the use of rinse sampling established in conjunction with swab results.

Author(s):

Richard J. Forsyth , Jeffrey Hartman , Vincent Van Nostrand

Journal:

Pharmaceutical Technology, Sep 2, 2006

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

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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

Journal:

Pharmaceutical Technology, Nov 2, 2006