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Cleaning method validation in pharmaceutical by FDA

Pharmaceutical products contaminate pharmaceutical products; by a microorganism, cleaning agents, or other materials. in many cases, it may be due to the repeated use of the same equipment for processing. To avoid contamination problems FDA introduced cleaning method validation for pharmaceutical industries.

Pharmaceutical products contaminate pharmaceutical products; by a microorganism, cleaning agents, or other materials. in many cases, it may be due to the repeated use of the same equipment for processing. To avoid contamination problems FDA introduced cleaning method validation for pharmaceutical industries.

FDA design documented and established the expectation that the cleaning process is validated.

The cleaning procedure must be strictly followed, carefully established, and validated method execution. Normally only cleaning systems for product contact surfaces need to be validated; similarly, Consideration should be given to non-contacts parts where a product may be migrated.

Cleaning procedures for product change over in non-dedicated multi-purpose equipment should be fully validated.

SOP describing in detail steps of the cleaning process, including the concentration of the detergents, should be in place for each piece of equipment. Whether or not the CIP (clean in place) system is used to clean processing equipment, microbial aspects of cleaning should be considered. after the cleaning process, equipment may be subjected to sterilization or sanitization procedure whether products may support the microbial growth

Direct surface sampling and rinse sampling procedures are used for samples for cleaning method validation.

Cleaning method validation history:

The food and Drug Administration states that instrumentation to be clean before use is nothing new, hence in 1963 GMP rules (Part 133.4) declared as follows “Equipment shall be maintained in a very clean and orderly manner .” a similar section on instrumentation cleansing (211.67) was enclosed within the 1978 CGMP rules.

Of course, the principle for requiring clean instrumentation is to stop contamination or adulteration of the drug products. Historically, the FDA investigates inadequate cleaning and maintenance of equipment and poor dust control systems. Also, historically speaking, FDA founds contamination of products or the cross-contamination of drug products with potent steroids or hormones.

A number of the product recalled over the past decade because of actual or potential penicillin cross-contamination.

One event that augmented the Food and Drug Administration’s aware of the potential cross-contamination, because of inadequate procedures was followed. resulted in the recall of a finished drug product, Cholestyramine Resin USP in 1988.

The bulk pharmaceutical chemical wants to manufacture the drugs but had contaminated by intermediates small scale. The cross-contamination, in that case, is believed to have been due to the reuse of recovered solvents. The recovered solvents had been contaminated because of a lack of control over the reuse of solvent drums.

Drums that had been wont to store recovered solvents from a chemical production method were later wont to store recovered solvents used for the organic compound producing plan. The company didn’t have controls over these solvent containers, didn’t do adequate testing of container solvents, and did not have validated cleaning procedures.

Some chemical shipments may contaminate bulk pharmaceuticals, resulted in the contamination of the baggage utilized in that facility’s fluid bed dryers with chemical contamination, successively leads to cross-contamination of lots made at that site, where no pesticides were normally produced.

FDA instituted an import alert in 1992 on a foreign bulk pharmaceutical manufacturer that company-made a potent steroid product in addition to a non-steroidal product using common equipment.

This firm was a multi-use bulk pharmaceutical facility. The FDA considered the potential for cross-contamination to be vital and create a serious health risk to the general public.

The firm had only recently started a cleaning validation program at the time of the examination, and it had been thought about inadequate by the Food and Drug Administration. One of the explanations it had been thought-about inadequate was that the firm was only searching for proof of the absence of the previous compound. From TLC tests on the rinse water, the firm had evidence of the presence of residues of reaction byproducts and degradants of the prior process.

Reference: fda.gov/validation-cleaning-processes-793

General requirements for cleaning method validation:

cleaning method validation

General requirements for cleaning method validation:

The FDA expects corporations to have their written procedures (SOP’s) and descriptions of the cleansing processes used for varied items of apparatus. Suppose corporations have one cleansing method for cleansing between different batches of an equivalent product and use a unique way to clean product changes. In that case, we tend to expect the written procedures to address these different scenarios.

Normally only cleaning procedures for product contact surfaces need to be validated. Consideration shall be given to non-contacts parts where there are chances of product migration, e.g., mixing shaft, seals, flanges, fans, and oven heating element. Fluid bed drier (FBD) bags are another example of a difficult-to-wash apparatus and are usually dedicated to a selected product.

When the cleaning process is used only between batches of the same products or lots of the same intermediates in the bulk process, like a single product line, only visible clean criteria should be met. After cleaning, equipment may be subject to sterilization and sanitation, which may support microbial growth.

Cleaning method validation approach:

Cleaning validation can be done for specific products or representatives of product groups.

  • Product-specific cleaning validation: There must be establishing documented evidence for product-specific with the same active principle. Use of the cleaning agent does what it means to do based on a preplanned validation protocol.
  • Cleaning validation of product families or groups of risk. The selecting of similar products and processes concerned range are considered as acceptable. A single validation study of the method can then be carried out, which considers the relevant criteria, called “Grouping,” the following are the “grouping” criteria.
  • The same dosage forms
  • Similar processes
  • Similar formulations
  • The Physiochemical properties of active ingredients, e.g., %solubility and lipophilicity.
  • Similar therapeutic potency
  • Highly toxic products
  • Revalidation (control of change to a validated cleaning method is required.

Criteria for revalidation

  1. in case of equipment, product composition, or cleaning process change.
  2. Periodic revalidation at a defined interval, such as yearly or every two years.

Documentation for cleaning validation:

Validation protocol:

The validation protocol must be ready for cleaning validation before starting the validation activity. The following point must be considered for this protocol.

  • Objective and scope
  • Responsibility
  • Product composition ( active ingredient and main components of detergents used for cleaning) will be tested.
  • Description of the manufacturing method
  • The time interval between production end, starting of cleaning
  • Details cleaning validation procedure
  • Sampling position and areas and diagram with difficult to clean area
  • Sampling procedure
  • Acceptance criteria
  • The analytical method including a limit of detection and a limit of quantitation of those methods.
  • The protocol should be a formality approach by the responsible and authorized person.

The following committee is responsible for validation protocol:

  • Validation Specialist – writes and coordinates the procedure
  • Manufacturing – writes SOPs and provides training to a person involve in the activity.
  • Quality Assurance/Control – approves and implements analytical methods
  • Engineering– communicates changes and equipment data
  • R&D – performs studies on recovery, methods validation, transfer methods, and selects new cleaners.

Validation report:

After completion of cleaning validation, prepare the report, and the conclusion of this report should state if the cleaning process has been validated successfully. validation reports shall consist of:

  • The validation protocol.
  • Tabulated results and acceptance limits.
  • Result of the validation of the analytical method.
  • Any deviation of the manufacturing or cleaning process.
  • The person involved in a validation study, including the name of the person who has sampled the swab.
  • The period during which validation was performed.
  • Summary of the results.
  • The report should be approved.
  • Validation certificates: at the end, validation certificates shall be prepared and signed.

Sampling method for cleaning validation:

The following two types of sampling methods are given below:

  1. Direct surface sampling:
  2. Rinse sampling:

First, direct surface sampling:

  1. Take two pieces of cotton wool of 1 gm each and divides them into two parts equally.
  2. Fix the stencils on the plain equipment surface according to the validation protocol. If sampling is not possible anywhere with stencils, e.g., small parts of the uneven surface, the pieces should be swabbed completely without a stencil.
  3. Dip the swab with the artery clamp into the solvent, press the swabbing unit until it drops free.
sampling procedure for cleaning method validation

Swab the inner area of the stencil with the artery clamp according to or any other validated scheme. Lead the first piece of the surgical cotton wool with smooth pressure with small eight wise moves from one stencil corner to the diagonally opposite corner. Swab with the second piece of cotton wool in the opposite direction. The second stencil has to be sampled in the same manner. The mechanical pressure applied by the chemist while sample should be the same during routine sampling. Put the pieces of cotton wool into a conical flask and close it.

Rinse sampling: large area or part of the equipment that could not be swab should be rinsed sampled or directly extracted by solvents. Tubes, nozzles, pipes, or containers with the surface that are not reasonably accessible for direct surface sampling have to rinse with a solvent. The compound to be sampled should be freely soluble in the solvents. Filter bag of fluidized bed granulation: soak the cleaned filter bags in a solvent and sake for 2 hours. Evaporate 1 liter of rinse sample to dryness by rotary evaporation.

Sampling preparation for cleaning validation:

Swab sample: the sample should be taken according to the following procedure or another validation method. Shake the cotton wool 5-6 times with 200 ml of solvent in total for 30 seconds. Remove the solvent after each shaking step, press out the cotton wool with a spatula and Evaporate the collected extracts until dryness; by rotary evaporation.

Dissolve the residue in the required quantity of solvent and transfer it into the volumetric flask. Filter the solution and determine the amount of the residue according to the method specified in the validation protocol. Keep in mind while the standard used for calculation has a concentration that is similar to the sample.

Rinse sampling: evaporated the collected extracts until dry by rotary evaporation. Dissolve the residue in the required quantity of solvent and transfer it into the volumetric flask.

Filter the solution and determine the amount of residue according to the method specified in the validation protocol. Keep in mind while the standard used for calculation has a concentration that is similar to the sample. Always analyze a blank solution in parallel( solvent handled in the same manner as the swab sample.

Validation of analytical method:

Before the validation of the cleaning method analytical method have to be validated. Active ingredients and detergent shall be soluble in the sampling solvent.

  • Sampling material: cotton wool, polyurethane foam (PUF), or GFC filter, sampling material shall not interfere with the analysis. Recovery from sampling material shall be more than 70%, otherwise modified the solvent or sampling material.
  • Swab material: surgical cotton wool (50% cotton,50% viscose), artery clamp, solvent to stencil made up of polyethylene foil, sampled area of each equipment with plain surface should be 800 cm square (2 stencils of 400 cm square), 50 ml conical flask with stopper, volumetric flask with stopper.
  • A few of the analytical methods for the analysis of cleaning validation sample are:
  1. HPLC
  2. GC
  3. HPTLC
  4. TOC
  5. UV Spectroscopy
  6. pH
  7. conductivity
  8. ELISA

These methods can be used alone or in combination, depending upon the analysis required.

Limits establishments for cleaning validation: The limits selecting depend upon the materials involved and their therapeutic dose.


cleaning method validation

CONCLUSION: Based on the above article cleaning validation is a documented process that is most effective to prove the effectiveness and consistency in the pharmaceutical cleaning of equipment, so it is very important to have an effective cleaning method in place because of regulatory requirements.

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