Cleaning validation

Purpose

To lay down the procedure for Cleaning Validation of manufacturing equipment’s. This SOP describes the validation of cleaning procedures for the removal of contaminants associated with the previous products, residues of cleaning agents as well as the control of potential microbial contaminants.

Procedure

Principle

Products can be contaminated by other products, by cleaning agents, by microorganisms or by other material (e.g. air-borne particles, dust, lubricants, raw materials, auxiliaries). In many cases, the same equipment may be used for processing of different products. To avoid contamination of the product, adequate cleaning procedures are essential.

Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing of products.

Objective of the Cleaning Validation is the confirmation of a reliable cleaning procedure so that the analytical monitoring may be omitted or reduced to a minimum in the routine phase.

Guidelines for Cleaning Validation:

It deals with the validation of equipment cleaning procedures used in the pharmaceutical industry to prevent cross-contamination or adulteration of drug products.

Active ingredients: The most obvious area for evaluation in cleaning validation is removal of active ingredients from the equipment. This evaluation can be carried out by a number of methods, but all have in common the need for adequate analytical methodology and the establishment of practical yet meaningful acceptance criteria for residuals.

Cleaning Validation Approach:

• All new as well as existing equipment shall be validated with respect to cleaning.
• Validation test shall be run according to approved protocol detailing methods, condition, procedure test and acceptance criteria.
• Change control systems at the plant should cover cleaning agents so that the need for revalidation can be assessed whenever cleaning agents are changed

General:

• Normally cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts into which product may migrate. For example, seals, flanges, are mixing shaft, heating elements etc.
• Generally, in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined.
• Several questions should be addressed when evaluating the cleaning process. For example:
• At what point does a piece of equipment or system become clean?
• What does visually clean mean?
• Does the equipment need to be scrubbed by hand?
• What is accomplished by hand scrubbing rather than just a solvent wash?
• How variable are manual cleaning processes from batch to batch and product to product?
• What is the most appropriate solvent or detergent?
• Are different cleaning processes required for different products in contact with a piece of equipment?
• How many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment?
• Cleaning procedures for products and processes which are very similar, do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a Validation Programme which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria.
• At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.
• Control of change to validated cleaning procedures is required. Revalidation should be considered under the following circumstances.
• Re-validation in case of changes to equipment, products or process,
• Documentation:
• A Cleaning Validation Protocol is required for laying down the procedure on how the cleaning process will be validated. It should include the following but not limited to:
• The objective of the cleaning validation process.
• Scope of Validation activities
• Responsibility for performing and approving the validation studies.
• Validation Team.
• Cleaning Validation approach-
• Product Matrix
• Selection of Products
• Selection of Equipment’s
• Process Overview
• Pre cleaning validation requirements
• Precaution and Instruction
• Calculation of MACO
• 10 ppm criteria
• Microbial Contamination
• Cleaning Validation Program
• Selection of Cleaning Procedure
• Clean-In- Place (CIP)
• Clean-out-place (COP)
• Manual Cleaning
• Water Quantity
• Selection of Analytical Method
• Analytical Method Validation
• Specificity Potential interferences
• Selection of extraction solvent
• Recovery Study
• Recovery from Spiked plates/ Coupons or different MOC’s
• Recovery correction Factor
• Sampling Plan, type of Sampling and Selection of Sampling Method
• Evaluation of Cleaning Procedures
• Sampling
• Sampling technique for Chemical Analysis
• Sampling technique for Microbial Analysis
• Determination of Sampling Points
• Equipment Hold Time Study
• Testing Procedure
• Acceptance Criteria
• Selection of Worst Case Product Review of Data
• Justification of selection of Worst case
• Solubility
• Calculation of swab Limit
• Revalidation
• Cleaning Validation final report
• The Validation Protocol & reports shall be prepared by QA, reviewed by concerned department and approved by Head QA.
• A final Validation Report should be prepared. The conclusions of this report should state if the cleaning process has been validated successfully. Limitations that apply to the use of the validated method should be defined (for example, the analytical limit at which cleanliness can be determined).
• Records should be kept for cleaning performed in such a way that the following information is readily available:
• The area or piece of equipment cleaned,
• The person who carried out the cleaning,
• When the cleaning was carried out,

Equipment:

• The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems.
• Dedicated equipment should be used for products which are difficult to remove, for equipment which is difficult to clean, or for products with a high safety risk (e.g. products of high potency which may be difficult to detect below an acceptable limit).

Microbiological Aspects:

• The existence of conditions favorable to reproduction of microorganisms (e.g. moisture, temperature, crevices and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive microbial contamination.
• The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.
• In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.

Analytical methods requirements:

• The analytical methods should be validated before the Cleaning Validation Study is carried out.
• The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable.
• The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery.

Calculation for residuals:

Product Residue Contamination

The rationale for selecting limits of carryover of product residue shall be logically based on the materials involved. The limits should be practical, achievable and verifiable. On the basis of following criteria acceptance limits i.e. Maximum Allowable Carry Over (MACO) shall be established:

10 PPM Criteria:

As per this criterion, not more than 10 ppm of any product will appear in another product.

The following equation is used to calculate the limit of product ‘A’ if the next product on the production schedule is product ‘B’.

Maximum Allowable Carry Over (mg per batch) = 0.00001(mg/mg) X BS in mg

Where,

0.00001 mg of product ‘A’ per 1000000mg of the product ‘B’

BS: Batch size of the next product in mg.                       

On the basis of 10 ppm criteria the MACO limit shall be calculated.

After establishing MACO (with minimum value) the swab limits and / or rinse limits shall be established with respect to total product contact surface area and

total rinse volume respectively.

                                                                                        MACO X 100

Swab Limit (drug in mg per 100 cm2 swabbed area) = ----------------------

                                                                                               TS

Where,

100: Sampled swab area (100 cm2)

TS: Total product contact surface area (cm2)                

Visually Clean Criteria

No quantity of residue should be visible on the equipment after cleaning procedure is performed.

Active ingredient in most of the products is visible at the approximately 100 µg per 10 cm sq. of surface area. Below this level the residue is not visible to human eye.

Stringent Acceptance criteria shall be selected as worst case either from 10 ppm criteria. LOQ shall be considered during selection of acceptance criteria.

Calculation of amount of residue present in rinse & swab:

Rinse:

Content / residue of previous product in the rinse is reported in PPM by Quality Control.

It is to be converted in to milligram by multiplying the QC results with quantity of rinse sample in kg.

The resultant value is the residue of previous product in milligram from entire equipment / part of equipment cleaned.

For possible contamination per 10 cm2 in next product, the resultant value is multiplied by 10 and divided by surface area (in cm2) of the equipment / part of equipment cleaned which is common for the two products.

Example:

Residue of previous product (QC results)                        = 4.86 ppm

Quantity of rinse                                                                  = 30 Liter

Content / residue of previous product in mg                  = 4.86 x 30 =145.80 mg

Surface Area                                                                         = 24193.50 cm2

Possible contamination in next product per 10 cm2         

                                   145.80

                        = -------------------- x 10 = 0.06026 mg / 10 cm2

                                 24193.50

Swab:

Content / residue of previous product in the rinse is reported in µg per 10 cm sq by Quality Control.

It is to be converted in to milligram by dividing the residue in µg by 1000. This is the possible contamination in next product in mg per 10 cm2.

Example:

Residue of previous product (QC results)            = 12.42 µg

Possible contamination in next product per 10 cm2

                                    12.42

                        = ----------------------    = 0.01242 mg /10 cm2

                                  1000

% Recovery Factor shall be applied to calculated results to get the actual residue:

                                                             100

Recovery Factor =   ---------------------------------------

                                        % Recovery (From AMV)

Actual residue = Calculated result X Recovery factor

Procedures for cleaning Validation Based on Bracketing & worst case Rating:

• The cleaning processes of multiple product equipment are subject to requirements for cleaning validation. In order to minimize the amount of validation requirement a worst case approach for the validation can be used. Collect the following information before starting cleaning validation.
• Materials needed to be cleaned from the equipment i.e. active ingredient.
• Equipment chain used during manufacturing of a particular product.
• A list of product that are manufactured using above chain of equipment in the facility.
• Data of surface area of each piece of equipment that is in contact of the product, used in the manufacturing of the product(s) at the formulation site with respect to the batch size.
• For each product collect the following details    
• Batch size in Kg.
• Active ingredient
• Smallest batch manufactured
• Solubility in water.
• Product contact surface area of each piece of equipment in the facility.

Worst Case Rating: Decide the worst case product(s) based on the following:

Select the worst case product based on lowest strength (high potency) lowest solubility of its active ingredient in water from the product matrix and followed by difficulty in cleaning.

Select worst case next product based on the highest ratio of batch

Worst Case Rating shall be as follows:

Potency (TD) >Solubility > Difficult to clean

Methods of evaluation: There several reasonable ways to evaluate the effectiveness of cleaning procedures and the choice of one over the others should be based on the unique characteristics of the equipment and product(s) involved.                          

Swab test: After cleaning the equipment, product contact surfaces can be swabbed to evaluate surface cleanliness. Swabs used should be compatible with the active, in that they should not interfere with the assay, should not cause degradation of the compound, and should allow extraction of the compound for analysis. The solvent used for swabbing should provide good solubility for the compound and should likewise not encourage degradation.

Sampling considerations: The area to be sampled should be in its final condition, as it would be when ready to use. In some cases, it is reasonable to swab the entire product contact surface. However, when this is not reasonable, a known surface area should be tested, and the approximate overall surface area which is represented by the swab(s) should be known. The area to be sampled should be selected using judgment about which areas are most difficult to clean. To ensure accuracy of the overall procedure, it can be applied to a surface which has been deliberately contaminated with a known, low level of the active. Obviously, the surface used for this challenge must be made of the same material as the equipment to be tested.

Advantage: Advantage of direct sampling of that areas, hardest to clean and which are reasonable accessible can be evaluated, leading to establishing a level of contamination or residue per given surface area. Additionally, residues that are dried out or are insoluble can be sample by physical removal.

Rinse samples: Sampling and testing rinse samples for residual active ingredient is commonly used method to evaluate cleanliness the solvent used should be selected based on the solubility of the active ingredient or at least provide adequate solubility. If possible, steps should be taken to ensure the uniformity of the residual material in the rinse prior to sampling. It is also critical that the volume of rinse solvent used be controlled. For equipment designed to hold liquids, either the volume of rinse solvent used should be sufficient to ensure contact with all product contact surfaces, or the method of introducing the rinse solvent should ensure adequate contact with all surfaces.

Cleaning Agent: A second important focus of cleaning validation is the removal of cleaning agents. These are known equipment contaminants which are added, ironically, to assist in the cleaning operation itself. In most cases, more than one cleaning agent is approved for use. The removal of each may have to investigate to ensure that no problems will be encountered with their use. For this reason, it is prudent to limit the number of approved cleaning agents to minimum required for effective cleaning in various situations.

Applications of Sampling Methods

Sampling Method     Common applications (processing equipment)

Swab Sample           Holding tank of filling machine, Manufacturing & storage vessels, filter press & Inline homogenizer

Rinse samples          Vessels and tanks (including agitators), filter housings & filling machine

Acceptability limits:

Determination of acceptability limit is a critical factor while preparing cleaning validation protocol.

The calculation of acceptable level for previous product as contaminant is important while determining the acceptability limit for cleaning validation.

The validation protocol must include the list of all products manufactured in the equipment/facility and in which the cleaning validation shall be performed.

Carry-over of product residues should meet defined criteria; the most stringent limit of the following criteria shall be considered for carry-over of product residues:

Visual inspection criteria: No quantity of residue should be visible to naked        eye on the equipment after cleaning procedures are performed (i.e. less than 100 mcg /25 cm2).

10ppm criteria: Not more than 10ppm of active pharmaceutical ingredient of previous product is permitted in next product.

Hold Time Studies

The objective of hold time study is for establishing time limit between equipment cleaning and reuses it to ensure that the equipment remains clean till the next use.

Equipment Holding Studies prior to cleaning

The interval between the end of production and the beginning of the cleaning process shall be established through equipment holding studies prior to cleaning.

It is important to consider the effect that weekends, holidays and delays might have on the cleaning schedule.

To establish the expiry of cleaning in view of microbiology, equipment shall be kept ideally after 72 hours and microbiological swab shall be taken and analyzed at different intervals (initial,24,48,72 hrs.).

Cleaned Equipment Hold Time Studies

Concerns relative to microbial control are lessened in the production of non-sterile products but are still important. Practices which minimize the potential for contamination by ‘objectionable organisms’ are common in the manufacture of non-sterile formulations.

To establish the expiry of cleaning in view of microbiology, equipment shall be kept ideally after cleaning for 7 days and microbiological swab shall be taken and analyzed at different intervals (0 day, 1 day, 2 day, 3 day, 4 day, 5 day, 6 day and 7 day).

This will be considering as worst case and microbial load should remain well within limit.

Revalidation

Re-validation shall be performed in case of any change, (at least the following but not limited to)

Introduction of a new facility, equipment, process or product.

Change in cleaning procedure.

change in MACO limit and potency of product.

Change in cleaning agent used for cleaning.

Major Modification in processing equipment.

New product/ Equipment Evaluation:

When a new product is introduced in the plant an evaluation is made to determine if cleaning validation is required. If the new product carryover limit is above the previously determined carryover limit and the new product is more soluble and less potent than the target component of the previous product, then cleaning validation is generally not required. This will be documented in the cleaning validation plan.

Introduction of any new product in existing product matrix shall be carried out through New Product/Equipment Evaluation Sheet.

Review and update the cleaning validation product matrix before a new product is introduced in production facility.

Review and update the cleaning validation equipment train if any change in existing equipment train, re-validate the cleaning process if required.