Wednesday, October 31, 2012

Cleaning Validation And Its Importance In Pharmaceutical Industry

Pharmaceutical manufacturers must validate their cleaning process to ensure compliance with cGMP regulations. Minimizing equipment downtime has the potential to impact the efficiency and economics of pharmaceutical production. The main purpose of cleaning validation is to prove the effectiveness and consistency of cleaning in a given pharmaceutical production equipment to prevent cross contamination and adulteration of drug products with other active ingredients like unintended compounds or microbiological contamination, leads to prevent several serious problems and also useful in related studies like packaging component cleaning validation. So it is necessary to validate the cleaning procedures to ensure safety, efficacy, quality of the subsequent batches of drug product and regulatory requirements in Active Pharmaceutical Ingredients (API) product manufacture. The benefits due to cleaning validation are compliance with federal regulations, identification and correction of potential problems, previously unsuspected which could compromise the safety and efficacy of drug products. In this article cleaning, validation and importance are discussed in brief

What Is Cleaning Validation?

Cleaning validation is a requirement in industries such as pharmaceutical manufacturing which adhere to Good Manufacturing Practice (GMP) and Quality Systems Regulations (QSR), and is specific to the cleaning method and cleaner employed.
Simply stated, validation is a documented guarantee that cleaning can be performed reliably and repeatedly to satisfy a predetermined level of cleanliness. Validation is achieved by demonstrating at least three times that the cleaning process removes residues down to acceptable levels. 

Testing for acceptable residues includes:
• Residue identification
• Residue detection method selection
• Sampling method selection
• Setting residue acceptance criteria
• Methods validation and recovery studies
• Writing a procedure and training operators

After establishing three or more times that a process can be repeated reliably to remove residues down to acceptable levels, a program can be implemented to maintain the state of validation where only periodical retesting is required. Changing any part of the cleaning procedure, including the cleaner, mandates revalidation. This entails first cleaning the new cleaners or methods, collecting data, and then cleaning the equipment with the prior validated process before using the equipment. These previously validated steps need to be followed until the new procedure is fully validated.

Generally, process validation is comprised of three parts: Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ) of manufacturing equipment and operations. Cleaning validation can be incorporated in part in to the PQ process. Cleaning validation is done when it’s impractical to verify cleaning on 100% of the production equipment used in high-volume manufacturing operations. Larger-volume manufacturing, such as in the pharmaceutical industry, therefore relies upon validation, which is performed on critical cleaning steps effecting the quality or safety of the final product.

Find more related topic:
A) Different types of contamination's in pharmaceutical industry
B) Identifying Residue and Selecting a Detection Method
C) Cleaning Acceptance Limits for APIs
D) Statistical Evaluation of Cleaning Validation Residue Data

Finding worst case molecule:

Many practitioners evaluate worst-case residues based on the solubility and toxicity of the compound of interest. While this approach may be acceptable when all products manufactured at a site are relatively easily cleaned, such as aqueous parental solutions containing soluble ingredients, it is not adequate for more complex dosage forms. Active ingredients that have the lowest solubility are considered worst-case for the validation of multi product equipment.

Level 0 Risk
Level 1 Risk
Level 2 Risk
Level 3 Risk
Level 4 Risk
Level 5 Risk
Product Difficulty to clean - lab study or subjective
Very easy to clean – water effective
Easy to clean and high mobile in liquid state
Moderately easy to clean – some viscosity issues
Moderately hard to clean – viscous or gelatinous residue
Difficult to clean oily substance, builder or excipient
Very Difficult to clean such as denatured protein, carbopol, titanium dioxide
Toxicity – LD50 (oral rat)
≥ 2500 mg/kg
> 2500 mg/kg and ≤ 1250 mg/kg
>1250 mg/kg and ≤ 500 mg/kg
>500 mg/kg and ≤ 250 mg/kg
>250 mg/kg and ≤ 25 mg/kg
≥ 25 mg/kg
Solubility - g/100mL of water
 Very soluble 100% in water
Freely Soluble 99.9 % in water
Soluble 99% in water
Slightly Soluble >10% but
Very Slightly Soluble < 10% in water
Practically Insoluble < 0.01% in water

Figure 01: Risk categorization table

For more detail : Qualifying Disinfection for Critical Environments and Clean rooms

For further reference see also:
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  1. Very well written.As the latest validation guidance is having terms like verification and testing its good to add ISO documents also in the requirements list.
    The whole article gave a clear path where and how to start.
    I thank the moderator for sharing such a good article.- See more at:

    <a href="
    >equipment validation</a>

  2. After completion of worst case selection, how can we start calculation


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