Step by Step How to Do Cleaning Validation

It is essential to prevent and reduce the level of cr ss-contamination in the pharmaceutical industry. Different types of residues need to be considered, including APIs ( Active Pharmaceutical Ingredients) residues, degrad ation products (due to different solubility, toxicity, an d cleanability characteristics in comparison with t he original compound), particulates, endotoxin, environmental d ust, residual rinse water (if product must be dry) as well as potential microbial contaminants (1, 2). In order to reach this goal, cleaning validation study should be carried out to provide a document which proves that process of cle aning has been validated and it can be performed re liably and repeatedly (3). In this article we discuss several aspects of cl eaning validation, such as bracketing, calculation of the acceptance criteria, swab sampling, rinse sampling, documentation. Additionally, some basic requiremen ts to provide necessities for environmental and equipment cleanliness, before commencement of cleaning valid ation study, are taken into account. It is worth mentioni ng that a practical approach is adopted to write th is article. Key-Words: Cleaning validation, Acceptance Criteria , Residue, Swab Sampling, Rinse Sampling Introduction Cleaning Validation Definition: Manufacturing processes have to be designed and carried out in a way that prevent cross-contamination as much as possible. Since most pieces of equipment are being used to manufacture different products, cleaning procedure must be able to remove residues from equipment to an acceptable level . Importance and purpose of cleaning validation: Not only it is required to comply with regulations, but also it is necessary to fulfill customers' requirements. It ensures the safety, identity, strength, and purity of the product which are the basic requirements of cGMP (Current Good Manufacturing Practice). It provides manufacturer with enough confidence that internal control is established properly (5, 6) * Corresponding Author E.mail: ramin3205@gmail.com Tel: 00989122168569 Fax: 00982126212319 It is advisable to perform at least three consecutive and successful applications of the cleaning procedure in order to prove that the method is validated . In case of detecting variable residue, following cleaning (especially an acceptable cleaning), enough attention must be given to effectiveness of the process and operators performance . Equipment cleaning validation maybe performed concurrently with actual production steps during process development and clinical manufacturing. Validation programs should be continued through full scale commercial production (1, . For new chemical entities it is essential to perform a risk assessment analysis before any operation in GMP plants . When cleaning validation is necessary according to guidelines of WHO: Product-contact surfaces (Consideration should be given to non-contact parts into which product may migrate for example, seals, flanges, mixing shaft, fans of ovens, heating elements etc.) Review Article [Asgharian et al., 5(3): March, 2014:3345-3366] CODEN (USA): IJPLCP ISSN: 0976-7126 © Sakun Publishing House (SPH): IJPLS 3346 Cleaning after product changeover (when one pharmaceutical formulation is being changed to another, completely different formulation) Between batches in campaigns (when the same formula is being manufactured over a period of time, and on different days). It seems acceptable that a campaign can last a working week, but anything longer becomes difficult to control and define . Cleaning validation for biological drugs must comply with stricter requirements due to their inherent characteristics (proteins are sticky by nature), parenteral product purity requirements, the complexity of equipment and broad spectrum of materials which need to be cleaned . Prevention of cross contamination in production: Production in segregated areas or using "closed system" of production Providing appropriate air-lock and air treatment system to prevent recirculation or re-entry of untreated or insufficiently treated air Providing comprehensive instructions to discharge clothing used in areas where products with special risk of crosscontamination are processed Using known effective cleaning and decontamination procedures Testing for residues and use of cleaning status labels on equipment (10) Different types of cleaning: Different mechanisms are employed to remove residues from equipment such as mechanical action, dissolution, detergency, saponification, and chemic al reaction. Mechanical action: In this method residues and contaminants are removed through physical actions such as brushing, scrubbing and using pressurized water. Dissolution: It involves using an appropriate solve nt to dissolve residues. Water is usually selected owning to being non-toxic, economical, environment friendly a nd does not leave any residue. However, some residues are only removed by alkaline or acidic solvents. In this case, usage of these cleaning agents is inevitable. Detergency: Detergent acts in four ways as wetting agent, solubilizer, emulsifier, and dispersant in removing the residues and contaminants from equipment. Wetting agents (such as surfactants) decrease the surface tension of cleaning solution, hus they can easily penetrate into the residue. Saponification: This method is based on the breakag e of ester bond in fat residue to form fatty acid and glycerol which are soluble in water. For this purpo se, some alkalis can be used such as NAOH, KOH. Chemical reaction: Oxidation and hydrolysis reactio n chemically breaks the organic residues (6, 11). Cleaning agents: Detergents are not part of the manufacturing proces s. They should be utilized as less as possible and eve n when they are absolutely required to facilitate cle aning, acceptance limits for cleaning agents residues shou ld be defined. The effectiveness of cleaning procedure s for removal of detergent residues should be evaluat ed. Ideally, no (or for ultra-sensitive analytical test methods-very low) amount of residue should be detected. The composition of detergents should be known to manufacturer and they should ensure that they are notified by supplier of any critical chang es in the formulation of the detergent. Detergents should be acceptable to the QA (Quality Assurance)/ QC (Quali ty Control) departments and no superfluous components such as fragrances and dyes should be included in them. Since most products have ingredients with different solubility characteristics, a suitable combination of cleaning agents would be more effective. If a detergent or soap is used for cleaning, consid er and determine the difficulty that may arise at the time of testing for residues. Separate validation of remova l f cleaning agents is not required if the removal of t he cleaning agent is included in the validation of the equipment cleaning from process compounds. It is al so not required for equipment producing only early intermediates or other residues of chemically synthesized APIs (1, 4, 9, 12, 13, 14) . Cleaning agent parameters to be evaluated: i. Easily removable (some detergents leave persistent residues such as cationic detergents, which adhere very strongly to glass and are difficult to remove). ii. The possibility of detergent breakdown should be considered when a cleaning procedure is being validated. Additionally, strong acids and alkalis used during the cleaning process may result in products breakdown which requires to be deemed during cleaning validation. iii. Materials normally used in the process are preferable iv. The design and construction of equipment and surface materials to be cleaned v. Ease of detection Review Article [Asgharian et al., 5(3): March, 2014:3345-3366] CODEN (USA): IJPLCP ISSN: 0976-7126 © Sakun Publishing House (SPH): IJPLS 3347 vi. Solubility properties of the worst case product (not only the API, possibly exist in small quantity, but also all the substances present in the formulation) vii. Environmental consideration viii. Health and safety consideration ix. Knowledge gained through experience x. Manufacturer's recommendation xi. The minimum temperature and volume of cleaning agent and rinse solution xii. Availability, etc. (1, 5, 15, 16, 17) Acceptable amount of cleaning agents: The limit for detergents and cleaning agents, following cleaning, is calculated based on LD 50 value or 10 ppm criteria, whichever is the lowest. LD 50 can represent toxicological properties of cleaning agents, but cleaning agents generally accepted in pharmaceutica ls feature relatively high LD50 which leads to calculation of high acceptable quantities of residues. Therefor e, it is reasonable to select the lowest amount between L D50 and ppm criteria. Another assessment can be carried out in this way that the amount of the residue does not exceed the detection limit of the method of analysi s for the relevant detergent substance. Calculation of cleaning agents residues based on 10 ppm criterion is the same as the calculation of API s residue based on this criterion. Limit calculation for cleaning agent residues: Calculation of the maximum acceptable residue: 4 50 5 10 70 mg LD kg kg ADI SF −     × × ×         = ( ) ( ) [ ] [ ] B g MACO mg ADI mg D g   = ×    ADI = Acceptable Daily Intake SF= Safety Factor which is applied to consider rout of administration B= Batch Size of the subsequent product D= Daily dose of the subsequent product 5×10-4 times LD50 has no measurable pharmacological effects on humans. 70 kg = Average body weight of an adult (18) Personnel: Because a manual procedure is an inherently variabl e method, operators carrying out this method should b e properly trained, monitored, and periodically asses ed. All training carried out should be recorded (1). Suitable working clothing is also important to prevent sprea ding the particles and dust. Since some potentially harm ful organisms can be transferred by personnel and products,