Peer Reviewed: Cleaning Validation Residue LimitsHow Clean is Clean?

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Peer Reviewed: Cleaning Validation Residue LimitsHow Clean is Clean?

By Michael Gietl Feb 21, 2013 10:41 am PST

ABSTRACT Cleaning residue limits for cleaning validation must be determined based on scientific and technical principles. Fourman and Mullen established the foundation for what has become the standard industry approach to setting limits for residual actives (1). They proposed that equipment be visually clean, that there be no more than 1/1000th of a daily therapeutic dose of active in the maximum daily dose of the next product (safety limit), and that no more than 10 ppm of active be in the next product (default limit). Regulatory agencies have accepted the above approach. A relatively simple strategy and approach to implement this methodology is proposed. A company may choose to implement a cleaning residue alert limit based on past experience with cleaning performance. Analytical methodology used in the above determinations must be validated and have sufficient sensitivity to accurately determine calculated residue levels consistent with required safety limit, default limit, or alert limit acceptance criteria. Companies must determine their cleaning residue limits based on sound scientific and technical data. INTRODUCTION Residue limits for cleaning, cleaning validation, and numerous associated considerations continue to be a confused, misinterpreted, and generally misunderstood topic of discussion among global validation personnel. Support for this assertion may be found on the US Food and Drug Administration website listing of frequent FDA-483 observations. Cleaning/sanitization/maintenance (Code of Federal Regulations Title 21 Part 211.67) was among the 10 most cited observations for drug inspections each year from 2010 to 2012, accounting for nearly 10% of observations during that timeframe (2). This high frequency of observations belies the plethora of thorough and excellent guidances, presentations, discussions, and other communications on this topic during the past 20 years. The following attempts to clarify basic points. Topics addressed include: How clean is clean? Visually clean and quantitative limits Terminology and definitions Scientific basis for residue limits: key publications and regulatory guidances Application: a simple strategy and approach for implementation. Multiple considerations are addressed. This discussion addresses active drug residues only. QUESTION: HOW CLEAN IS CLEAN?

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Peer Reviewed: Cleaning Validation Residue LimitsHow Clean is Clean?

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The question, How clean is clean? is fundamental. Responses to this question determine how limits are set for residues on product contact surfaces. Answers have qualitative (visual) and quantitative (analytical determination) components. Equipment surfaces must be visually clean (i.e., no residue can be observed by human vision). Equipment surfaces must be cleaned to a defined calculated limit that analytical testing ultimately confirms. For example, no more than 25 g of the residue per cm2 may be detected by a validated analytical method. These relatively simple statements indicate underlying complexity that undoubtedly contributes to general confusion. For example, visually clean determinations assume competent and trained personnel observing surfaces, adequate lighting for observations, thorough and complete observation of surfaces including undersides of equipment, and so on. Analytical determinations assume swab sampling done by trained personnel, most difficult to clean areas sampled, residues proven to be recoverable from surfaces, validated analytical methods, and so on. The aforementioned considerations are beyond the scope of the present discussion but must be generally recognized as having great impact on the cleaning validation process. TERMINOLOGY AND DEFINITIONS Several specific terms are useful for the following discussion: Visually clean: Residue is not able to be seen on equipment Safety Limit: Limit calculated based on intrinsic residue activity or toxicity, surface area of equipment, maximum dose of subsequent product to be manufactured, and a safety factor Default Limit: No more than 10 ppm on residue in subsequent product to be manufactured Uniform contamination: Residue of interest uniformly contaminates subsequent product. For example, residue of interest in mixing tank should uniformly contaminate next product to be manufactured in same mixing tank. Non-uniform contamination: Residue of interest does not uniformly contaminate subsequent product. For example, residue of interest in transfer piping preferentially contaminates first volumes of subsequent product flowing through same transfer piping. SCIENTIFIC BASIS FOR RESIDUE LIMITS The following references are particularly helpful in providing the scientific basis for residue limits. These documents also help explain the terminology and definitions described above. Fourman and Mullen Fourman and Mullen established the foundation for what has become the standard industry approach to setting limits for residual actives. Requirements are: Visually clean No more than 1/1000th of a daily therapeutic dose of active in the maximum daily dose of the next product No more than 10 ppm of active in the next product (1). FDA Guidance In the FDA Guide to Inspections of Cleaning Validations, FDA commented that they do not intend to set specific criteria for manufacturers and lists these limits as examples: 10 ppm, biological activity levels such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as no visible residue. (3). Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) PIC/S, continuing this line of thinking, cites limits based on the most stringent of the following:

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Peer Reviewed: Cleaning Validation Residue LimitsHow Clean is Clean?

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No more than 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product. No more than 10 ppm of any product will appear in another product. No quantity of residue should be visible on the equipment after cleaning procedures are performed. For certain allergenic ingredientsthe limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products (4). The above may also be found in Health Canada Cleaning Validation Guidelines (GUIDE-0028) (5). Each of the above describes safety limits, default limits, and visual cleanliness in their respective documents. Note that although these examples appear in the above guidance documents, it is not tacit approval of these limits for every residue encountered. PRACTICAL APPLICATION The above requirements specified in the guidance documents must be clearly established in the manufacturing plant for cleaning validation. A simple strategy and approach is proposed. The following are discussed: Residue to be measured Residue analytical limitsafety limit and default limit Uniform and non-uniform contamination Expected cleaning performance Analytical method. Residue to Be Measured The first step to implement appropriate residue limits for cleaning is to determine what residue will be measured, the route of administration, and the type of product, such as small molecule, biotech, etc. The residue may be an active pharmaceutical ingredient (API), an excipient, cleaning agent, or other soil. Risk analysis is important in this evaluation. The properties of the residue of interest as well as the properties of the subsequent products to be manufactured and potentially contaminated must be evaluated. For APIs (excluding highly hazardous APIs), the general approach of Fourman and Mullen is preferred. In many cases, this will result in residue levels that are practical, achievable, verifiable, and will not compromise the quality of the next product or the health of the end user. The Fourman and Mullen approach is typically not suitable for highly hazardous compounds. For these types of compounds, International Society of Pharmaceutical Engineers (ISPE) Risk MaPP provides an excellent guide to establishing residue limits. The ISPE document details an approach to all residues, in addition to highly hazardous compounds. The ISPE document approaches limits from a different perspective advocating that limits are established using health based or exposure risks. It recommends approaching limits by evaluating the toxicological risks associated with the active (6). For example, if an active is cytotoxic, the limit is based on the cytotoxic characteristics of the active, not 1/1000th of a daily dose. In situations with certain highly hazardous compounds, one may arrive at limits well beyond the capabilities of current analytical techniques. These cases might warrant the use of disposable or dedicated equipment. Some residues may not fit the above examples. For example, cleaning agents require a slightly different approach. Since cleaning agents dont have a therapeutic dose, one must rely on toxicological information (for example, LD50) for the agent with the appropriate safety factor to determine the allowable daily intake (ADI). The ADI can then be used to calculate the limit for residual cleaning agent. When using this approach, it is recommended that the LD50 animal model and route of administration are taken into account, and appropriate corrections or conversions applied

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Peer Reviewed: Cleaning Validation Residue LimitsHow Clean is Clean?

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when necessary. For example, when cleaning parenteral formulation equipment, if the cleaning agent only has oral LD50 data available, corrections should be made to account for the different routes of administration. Residue Analytical LimitSafety Limit and Default Limit Once the appropriate approach for the analyte of interest is selected, the next step is to determine the limit of residue in the next product to be manufacturedthe safety limit. This approach calculates the limit in the next product utilizing the minimum therapeutic daily dose of the active of the cleaned product, the maximum daily dose of the next product to be manufactured, and an appropriate safety factor. Parenteral Drug Association (PDA) Technical Reports 29 and 49 are excellent resources for sample calculations for a variety of situations (7, 8). This result is then compared to what has become the standard default limit10 ppm. If the calculated safety limit value is greater than 10 ppm, default to 10 ppm. If the calculated safety limit value is less than 10 ppm, use the safety limit value for the residue acceptance criterion. From this result, the values for the maximum allowable carryover (MAC) limit per surface area for swab sampling and limit per rinse sample can be derived. Uniform and Non-Uniform Contamination The Mullen and Foreman approach and calculation described above is appropriate for calculations assuming uniform contamination. In these cases, the residue of interest uniformly contaminates subsequent product manufactured in the same equipment. For example, residue from Product A in a mixing tank should uniformly contaminate Product B manufactured in the same mixing tank. The above considerations and calculations are also suitable for non-uniform contamination calculations. However, additional calculations are also needed to address non-uniform contamination situations. In these cases, the Product A residue preferentially contaminates subsequent product manufactured in the same equipment. These situations occur at the end of a process train such as when solution is filled into vials, capsules are filled on an encapsulation machine, and similar situations. Regulatory agencies recognize that non-uniform contamination is a serious concern in product manufacturing and may even represent the highest risk situation. The PIC/S guidance comments as follows: One cannot ensure that the contaminant will be uniformly distributed throughout the system. It is also an invalid conclusion to make the assumption that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch (4). Expected Cleaning Performance A company may choose to implement another cleaning residue limit based on past experience with cleaning performance. After the cleaning validation has been completed and post-validation cleaning has been successful for a reasonable number of lots, the accumulated actual cleaning data should be analyzed to determine if the residue limit should be reduced. For example, if the cleaning residue limit is 5 ug/cm2, and all historical process data is <1 ug/cm2, a lowered limit may be implemented. A limit of 2 ug/cm2 might be considered. This change may be implemented as an alert limit to cause notification of a change in the cleaning performance. PDA Technical Report 49 discusses this approach (8). A cleaning process might therefore have a safety limit, a default limit that is lower than the safety limit, and a still lower alert limit based on historical data. Analytical Method Analytical methodology used in the above determinations must be validated. Methods must also have sufficient sensitivity to accurately determine residue levels as calculated above. Limits of quantitation (LoQ) and limits of detection (LoD) must be consistent with required safety limit, default limit, or alert limit acceptance criteria. FINAL THOUGHTS

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Peer Reviewed: Cleaning Validation Residue LimitsHow Clean is Clean?

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Setting cleaning validation residue limits can be a daunting task; however, performing some due diligence can ensure limits that are practical, achievable, verifiable, and most importantly, safe. Arbitrary limits are just that arbitraryand can lead to numerous problems including product recalls and regulatory action. Companies should determine their cleaning residue limits based on sound scientific and technical data and be prepared to defend their approach when questions arise. REFERENCES 1. G.L. Fourman & M.V. Mullen, Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations, Pharmaceutical Technology 17 (4), 54-60, 1993. 2. FDA, Inspections Observations, found at: http://www.fda.gov/iceci/EnforcementActions/ucm250720.htm 3. FDA, Guide To Inspections of Validation of Cleaning Processes (Rockville, MD, 1993). 4. PIC/S, Recommendations on Cleaning Validation Document PI 006-1, Pharmaceutical Inspection Cooperation Scheme. Geneva, Switzerland, August 3, 2001. 5. Health Canada, Cleaning Validation Guidelines (GUIDE-0028), Health Canada, January 1, 2008. 6. ISPE, Risk Based Manufacture of Pharmaceutical Products, International Society of Pharmaceutical Engineers, Tampa, FL, 2010. 7. PDA, Technical Report 29 (Revised 2012), Points to Consider for Cleaning Validation, Parenteral Drug Association, Bethesda, MD, 2012. 8. PDA, Technical Report 49, Points to Consider for Biotechnology Cleaning Validation, Parenteral Drug Association, Bethesda, MD, 2010. GXP

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