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Implementing a compliant cleaning program in the dietary supplement industry: use of Total Organic Carbon methodology to verify equipment cleanliness provides a rapid, efficient and scientifically justified approach to a company's cleaning program.

SINCE FDA ANNOUNCED ITS intention to consider the implementation of Good Manufacturing Practices (GMPs) to the manufacturing, packaging, testing and distribution of dietary supplements (1), the final content and design of the regulations remains unclear. Per the 1994 Dietary Supplement Health and Education Act (DSHEA), dietary supplement GMP regulations will be modeled after the 21 CFR Part 110 GMPs governing human food. Currently, these GMP regulations require the manufacturer to justify programs that ensure the mitigation and control of contamination risks (2).

[ILLUSTRATION OMITTED]

Regardless of the final regulatory format, the prevention of product contamination is an essential component of any GMP program and is necessary to ensure the safety of products used in human or veterinary applications. A major source of contamination risk is in the form of carryover of compounds and cleaning agent residues from the previous manufactured product or cleaning process. The probability for contamination is heightened when multiple compounds or product types are manufactured in the same processing equipment (multi-use equipment). Carryover contamination from previously manufactured products or cleaning agents into the next manufactured product is a legitimate risk for dietary supplement manufacturers; therefore, control and documentation of cleaning processes and cleaning efficacy will become an industry expectation. A guidance document that may be useful for dietary supplement manufacturers to establish a compliant cleaning program is the International Conference on Harmonization (ICH) Q7A, "GMP Guide for Active Pharmaceutical Ingredients." Section 12.7 of Q7A details the concepts that should be considered to ensure mitigation and control of contamination risks.

Master Cleaning Plan

The first step in mitigating and controlling cross contamination is to have a complete understanding of the nature and use of the compounds that are being manufactured. Various manufacturing processes within a multi-product facility may require different cleaning procedures or may require different stringency in cleaning requirements. For example, when a company campaigns multiple lots of a single product, the cleaning procedure may only require a purified water rinse between lots and a visual inspection to verify cleanliness. However, when a different product type is introduced into the facility, the cleaning procedures will typically be more robust and verification of cleanliness may require analytical testing in addition to visual inspection. The justification of a company's cleaning program that includes the application of cleaning procedures and specifications should be identified in a Master Cleaning Plan. The Master Cleaning Plan allows a company to specify the general conditions where various stringency levels of cleaning and verification may be applied (3).

GMP-regulated industries must also have approved procedures in place that define how to execute and document all cleaning processes (including parameters such as temperature, hold times, cleaning agent concentration, etc.). These procedures, along with effective training, will ensure that cleaning and verification activities are consistently performed.

Carryover Limits

When verifying the effectiveness of a cleaning process, the acceptable level of carryover of product or cleaning process (e.g., cleaning agents and solvents) residues are typically established as a function of therapeutic dosage (minimum daily dose of the active ingredient required to treat the patient), toxicity or analytical detection of the compound along with the batch size and daily dose of the next manufactured product (4,5). Additional factors are applied to the carryover limit to account for a degree of safety and robustness to the cleaning program. Actual safety factors are determined based on the risk of potential contamination, and are appropriately set in the dietary supplement industry at 1:100 for innocuous residues to 1:10000 for higher risk residues (toxic, allergenic). The product contact surface area of multi-use equipment is used to determine the maximum residue carryover assuming that residues are uniformly distributed and that all remaining residues after cleaning will disassociate into the next product. After total product contact surface area of manufacturing equipment is determined, the carryover limits for post-cleaning samples can be simply calculated.

Sample Methods

To determine if the equipment meets the established carryover acceptance criteria, swab or rinse samples are obtained from product contact surfaces after cleaning. Swab sampling is also referred to as direct sampling and has been cited by the FDA as the most desirable method for obtaining surface samples for detection of potential residues (6). The selection of swab locations is a critical component of a cleaning program, and must include locations that are representative of all the different functional parts. Swab sites are to be selected that are representative of the hardest to clean locations (e.g., tank baffles, inlets and outlets, nozzles, corners, edges, etc.) and the hardest to clean surface finishes. Justification of swab locations should be documented and used for consistent sampling. Rinse samples are only utilized when selected equipment surfaces are not accessible or they cannot be readily disassembled for direct sampling. Rinse samples will involve grab samples of the final rinse material from the cleaning activity.

The capability and efficiency of the swab or rinse sampling method to recover target residues from equipment surfaces should be evaluated by completing a sample recovery study for each residue and product contact surface material. Sample recovery studies involve spiking multiple concentrations of the specified residue on coupons representative of the same material of construction of the equipment product contact surfaces. These spiking samples are allowed to dry on the coupons, followed by sampling with the specified swab or rinse procedure. Sample recoveries greater than 50% are typically considered acceptable and should be used as a factor in the final carryover limit calculations (7). While swabbing techniques are specified in a procedure and all samplers trained on the procedure to reduce variation in residue recovery, each sampler should perform recovery studies to allow an evaluation of performance variation. The recovery results from each sampler are evaluated based on percent recovery of each residue concentration and compared to predetermined acceptance criteria. Only samplers that meet established criteria should be permitted to sample production equipment. The swabbing procedure, including the type of swabs, vials, extraction solution(s) and Personal Protective Equipment (PPE) should be documented in an approved procedure. All future personnel involved with residue sampling of equipment should be qualified using the approved procedure.

Detection Method Selection

Once sample locations and methods are identified, dirty equipment is sampled and evaluated for residual product and cleaning agents. The selection of an appropriate analytical method to detect residues is also essential for a successful cleaning program. Analytical methods that are specific to the detection of target residues (e.g., HPLC, ELISA, etc.) or non-specific assays that detect groups of compounds (e.g., TOC, UV/Vis, Conductivity, etc.) may be used. Analytical methods used to determine residues in a sample must be validated using the principles provided in ICH Q2(R1) guidance (8) or U.S. Pharmacopeia <1225> (9). Method validation should include, when possible, accuracy, precision, linearity over the targeted range, limit of detection, limit of quantitation, and residue stability.

Total Organic Carbon (TOC) is a non-specific assay that has proved to be a rapid, effective and sensitive analytical method used to quantify carbon-based residues and can be consistently validated to the ICH and USP criteria (10). TOC is a method that measures the carbon contribution of a variety of compounds, including the target residue. Because it is a nonspecific method, a TOC value from a cleaning sample is expressed as if all the detected carbon was due to contribution from the target residue. If the amount of TOC calculated from this method is below the acceptance criterion, then it is justifiable to state that the target residue is below the acceptance criterion.

Total Organic Carbon Method Validation

The basic method validation plan for a TOC cleaning method initially involves a calculation of the theoretical TOC concentration in a compound. This can be obtained from chemical reference manuals or a Material Safety Data Sheet (MSDS). For example: Glucosamine HCL (C6H13N05 HCL) has an identified formula weight of 215.63. The contributed weight from Carbon is 72 (Carbon weight = 12 x 6 Carbon per molecule); therefore, the percent TOC in the compound is 33.39% (72/215.63x100).

Once the theoretical TOC concentration of the compound has been determined, the parameters of accuracy, precision and linearity can be evaluated.

* Accuracy can be defined as the closeness of the test results obtained by the method to the theoretical or true value.

* Precision can be defined as the degree of agreement among individual test results obtained from multiple analyses of the same sample.

* Linearity of a method can be defined as the ability to produce test results that are proportional to the concentration of the target compound within a defined range.

An evaluation of these parameters is accomplished by preparing an aqueous dilution series of the compound. Generally, a concentration gradient of 50 ppm (maximum capability of TOC Analyzer) to 0.125 ppm with 7-10 dilution sets (ICH Q2(R1) guidance recommends 5 concentrations at a minimum8). Each dilution set should be analyzed minimally in triplicate using the TOC methodology.

Typical acceptance criteria for these validation parameters are summarized in the table below.
Parameter  Acceptance Criteria

Accuracy   [+ or -] 20% of the Theoretical Concentration
Precision  [less than or equal to] 20% Relative Standard Deviation (RSD)
           calculated from multiple replicates of the same sample
Linearity  A Correlation Coefficient of
           [greater than or equal to] 0.9800 over the range of the
           dilution series


An important factor in the development and validation of the methodology is the determination of two additional parameters:

* Limit of Detection (LOD) -- defined as the lowest amount of the target material in a sample that can be detected, but not necessarily quantitated.

* Limit of Quantitation (LOQ) -- defined as the lowest amount of the target material in a sample that can be determined with acceptable precision and accuracy.

The LOQ must be sufficiently sensitive to the target compound in order to detect potential carry-over residues6. To ensure the capability of the testing method to detect residue levels around the carryover specifications, the LOQ should be at least 50% of the carryover limit. For example, if the carryover limit for the compound is 10 ppm, then the LOQ must be at least 5 ppm. Per the ICH Q2(R1) guidance, the calculation for the LOD and LOQ of a method can be determined from the Standard Deviation (SD) of replicate blank samples. To calculate the LOD, the SD is multiplied by a factor of 3. To calculate the LOQ, the SD is multiplied by a factor of 10.

The final phase of a method validation is to determine the stability of the compound residues on cleaning sample swabs. The stability time frame of the residues captured on swabs must be established to account for the time between sampling and analysis, especially when swab samples must be shipped to an outside contract laboratory for analysis. Product residues should remain > 80% of the time zero residue concentration in order to provide adequate time for shipping and analysis of the samples.

While the use of TOC methodology to evaluate equipment cleanliness may appear to be complex and stringent when applied to nutritional supplement manufacturing, it is important to recognize the significance of minimizing the risk of cross contamination. Regardless of the products manufactured or cleaning methods used, the following concepts are necessary to consistently provide evidence of cleaning verification:

* Cleaning plan that details and justifies cleaning verification application and methods.

* Procedures and training that provide consistent cleaning and verification.

* Scientifically justified residue limits.

* Appropriate sampling procedures that effectively remove surface residues.

* Validated analytical methodology that detect and quantify specified residues.

* Documented evidence that the previous concepts have been achieved.

Meeting the challenges of these potential GMPs and industry expectations may require an initial investment, but the benefits of compliance, process consistency and meeting customer/industry expectations will provide a positive return on the investment.

REFERENCES

1. FDA. 1997. Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Dietary Supplements; Proposed Rule. Federal Register 62:5699-5709.

2. FDA. 21 CFR 110: Current Good Manufacturing Practice in Manufacturing, Packing or Holding Human Food. I April 2003 (revised).

3. LeBlanc, Destin A. "Validated Cleaning technologies for Pharmaceutical Processing." CRC Press, LLC, 2000, pp 235-237.

4. LeBlanc, Destin A. "Establishing Scientifically Justified Acceptance Criteria for Cleaning Validation of Finished Drug Products." Pharmaceutical Technology. 1998;22;136.

5. Brunkow, R., et al. "Cleaning and Cleaning Validation: A Biotechnology Perspective." PDA, 1996, pp 129-142.

6. FDA. "Guide to Inspections Validation of Cleaning Processes," July, 1993.

7. Yang, Pei. "Method Development of Swab Sampling for Cleaning Validation of a Residual Active Pharmaceutical Ingredient." Pharmaceutical Technology. 2005;29;84.

8. ICH Harmonized Tripartite Guideline. "Validation of Analytical Procedures: Text and Methodology," November, 2005.

9. United States Pharmacopeia, 30th rev. "Validation of Compendial Procedures," May, 2007.

10. Wallace, B, et al. "Implementing Total Organic Carbon Analysis for Cleaning Validation." Pharmaceutical Technology Aseptic Processing supplement 2004; pp 40-43.

By Benjamin Frey, David Koczan, and Kenneth Shrout

Aperio Scientific--A ProPharma Group Company

Benjamin Frey (ben.frey@aperioscientific.com) is director of quality assurance, David Koczan (dave.koczan@aperioscientific.com) is laboratory director, and Kenneth Shrout (kenneth.shrout@aperioscientific.com) is quality control analyst for Aperio Scientific, a microbiological and analytical testing laboratory specializing in cleaning validation support (www.aperioscientific.com).
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Title Annotation:MANUFACTURING SUPPLEMENT: CLEANING VALIDATION
Author:Frey, Benjamin; Koczan, David; Shrout, Kenneth
Publication:Nutraceuticals World
Geographic Code:1USA
Date:Mar 1, 2007
Words:2195
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