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1984 - Samuel Harder Article: ‘Validation of Cleaning procedures’ Concerning the setting of acceptable limits Harder wrote that “Must be practical and achievable by reasonable cleaning procedure… …must be verifiable by analytical methodology existing in the company…. … must be safe and acceptable” 1989 – Doug mendenhall Article: “Cleaning validation” Mendenhall expanded upon the ideas presented by Harder adding ideas, Such as using matrix approach, testing for cleaning agents, placebo batches, and most interestingly pointed out the potential use of visual inspection.And also mendenhall proposed that limits for surface residue levels be calculated based on smallest batch size / Maximum dose combination. Surprisingly these two industry articles laid the foundation from which most cleaning validation acceptance criteria were derived and are origin of many cleaning validation activities.Shortly after these publications a major event began to unfold that shaped the direction of cleaning validation and industry practices. 1989-1992 – The US-FDA Vs Barr Laboratories and the Wolin decision From 1989 to 1992 US-FDA inspected several Barr Laboratories facilities and issued multiple FDA form 483’s with increasing number of observations. The FDA finally sued a Barr Laboratories with district judge Alfred M. Wolin presiding over trail court. The trial ended in Feb 1993 with the decision by judge Wolin injunction against Barr Laboratories.The action on Barr Laboratories case was closely followed by Pharmaceutical Industry and PMA (Pharmaceutical Manufacturer Association) conducted a survey asking many questions on what they were doing in regarding cleaning validation and how companies were setting acceptance limits. In the survey results, PMA listed 44 unique acceptance criteria from the responses which were inconsistent from company to company and in many cases arbitrarily (randomly) selected.Concurrent with Barr Laboratories trial and PMA survey, Foundation or acceptance Limits were further expanded by another publication known in the industry The Fourmen and Mullen Article. 1993 – Fourman and Mullen Article: At the time of Barr Laboratories trial, another company Ely Lilly, was also involved in a number of issues with FDA over cleaning validation specifically on setting of acceptable limits. In 1993 Gary Fourman and Dr. Mike Mullen published an article where they suggested carryover of product residue meet the following criteria. 1. Not more than 0.001 dose of any product will appear in the maximum daily dose of another product. 2. Not more than 10 ppm of a product will appear in another product. 3. No quantity of residue will be visible on the equipment after cleaning procedure are performed. The author even though provided explanation for 0.001 & 10 ppm that is not scientific and no regulatory reference provided. However at that time, this article was land mark in the world of cleaning validation as it was first publication to lay out specific criteria for determining cleaning validation acceptance limits. After effects of Barr Laboratories Decision: During course of trial Judge Wolin observed that GMP regulations were vague and not very detailed- Certainly not detailed enough to expect companies to easily understand what the FDA interpretation and expectations were. Judge Wolin criticized the GMPs for their lack of detail and clarity. The FDA inspectors in the Mid-Atlantic region put together a guide clarifying that what their expectation for cleaning validation. This guide is very detailed and specific. One year later the guide developed by Mid-Atlantic region inspectors was adopted by national centre for use by all FDA inspectors. The guide states that 1.The firm rationale for the residue limits established should be logical based on the manufacturer knowledge of the material involved and be practical, achievable and verifiable. 2.It is important to define the sensitivity of analytical methods in order to set reasonable limits. 3.Clearly stated companies will put thought and analysis in to the selection of their cleaning validation acceptance limits. Simple adoption of the three Fourman and Mullin criteria is not satisfactory without a scientific justification for using these limits. In this guide there is short section with concerns about detergents used in the cleaning process. “If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting to test for residues. A common problem associated with detergent use is its composition. Many detergent suppliers will not provide specific composition, which make it difficult to user to evaluate residues, As with product residues, it is important and it is expected that the manufacturer evaluate the efficiency of cleaning process for the removal of residues”. Moreover FDA make it clear that they expected companies to test for detergent residues not just API residues. Current Cleaning Validation Approach: After Barr Laboratory decision, the concept of cleaning validation was changed year to year in a very drastic way and the number of regulatory agencies guided pharma industries on cleaning validation with detailed guidelines. Current Cleaning Validation Approach: Acceptance Criteria. After Barr Laboratory decision, the concept of cleaning validation was changed year to year in a very drastic way and the number of regulatory agencies guided pharma industries on cleaning validation with detailed guidelines. The subject of cleaning validation has continued to receive a large amount of attention from regulators, companies and customers alike. The integration of cleaning validation with in an effective quality system supported by Quality risk management process enlightens the significance of cleaning validation. Companies must demonstrate during cleaning validation that cleaning procedure routinely employed for a piece of equipment limits potential carryover to an acceptable level. That limit established must be calculated based on sound scientific rational. Cleaning validation should give assurance that the manufacturing operations are performed in such a way that risk to patients related to cleaning validation are understood, assessed for impact are mitigated as necessary. The acceptance criteria for equipment cleaning should be based on visually clean in dry condition and an analytical Limit. Methods for calculating Acceptance criteria: Based on Health based Data MACO should be based on health based data when this data is available. MACO = (PDE/ADE previous X MBS Next) / TDD Next MACO – Maximum Allowable carryover (mg) ADE – Acceptable Daily exposure of previous product (mg/day)
PDE - Permitted daily exposure of previous product (mg/day) MBS – Minimum batch size of next product. TDD – Therapeutic Daily dose for the next product (mg/day) ADE = (NOAEL X BW) / (F1 X F2 X F3 X F4 X F5) NOAEL – No observed adverse effect level BW – Weight of Average adult (ex. 70 Kg) F1 – A factor (Value between 2 and 12) to account extrapolation between species. F1=5 for extrapolation from rats to humans F1=12 for extrapolation from rats to humans F1=2 for extrapolation from rats to humans F1=2.5 for extrapolation from rabbits to humans F1=3 for extrapolation from monkeys to humans F1=10 for extrapolation from other animals to humans F2 – A factor of 10 to account for variability between species F3 – A factor of 10 to account for repeat dose toxicity studies of short term exposure F3 = 1 for studies that last at least one half lifetime (1 year for rodent/rabbits, 7 years for cats, dog and monkeys) F3 = 1 for reproductive studies in which the whole period of organogenesis is covered. F3 = 2 for a 6 month study in rodents or 3-5 study in non-rodents F3 = 5 for 3 month study in rodents or a 2 year study in non-rodents F3 = 10 for studies shorter duration F4 – A factor (1-10) that may be applied in case of sever toxicity F4 = 1 for fetal toxicity associated with maternal toxicity F4 = 5 for fetal toxicity without maternal toxicity F4 = 5 for a teratogenic effect with maternal toxicity F4 = 10 for a teratogenic effect without maternal toxicity F5 – A variable factor that may be applied if no –effect level was established, when LOEL is available. A factor 10 could be used based on severity and toxicity. PDE = (NOAEL X BW) / (UFc X MFX PK) UFc –Composite Uncertainty Factor: combination of factors which reflects the interindividual variability, interspecies differences, sub-chronic-to-chronic extrapolation, LOEL-to-NOEL extrapolation, database completeness.
MF –Modifying Factor: a factor to address uncertainties not covered by the other factors
PK –Pharmacokinetic adjustment Based on Therapeutic daily dose When limited toxicity data is available and the TDD is known MACO should be calculated by following formulae. It is used for final product change over API process A to API process B. MACO = (TDD previous X MBS Next) / (SF X TDD Next) SF – Safety Factor (Generally 1000 used for calculations) Based on LD50 In case where no other data available and only LD50 data is available. Use following formulae. NOEL = (LD50 x BW) /2000 MACO = (NOEL previous X MBS Next) / (SF Next X TDD Next) LD50 – Lethal dose 50 mg/kg animal. The identification of the animal (mouse, rat…etc.) and the way of entry is important. (LD50 is the amount of toxic agent that is sufficient to kill 50% of a population of animals usually with in certain time.) BW – Weight of average adult (ex.70 Kg) SF Next – Safety Factor (For Topical 10-100, for oral products 100 – 1000, for parental 1000 - 10000)
General Limit as Acceptance criteria: If MACO values are unacceptably high or irrelevant carry over figures or toxicological data for intermediates is not known the approach of general limit may be suitable. MACO PPM = MAXCONC X MBS Next MAXCONC = Maximum allowed concentration (kg / kg or ppm) of previous substance in the next batch A general upper limit for maximum concentration of contaminating substance in a subsequent batch is often set to 5 – 500 ppm (100 ppm in APIs is very frequent) of the previous product in to next product depending on the nature of the products produced from the individual company. | 
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