The objectives of good manufacturing practices (GMP) include the prevention of possible contamination and cross-contamination of pharmaceutical starting materials and products.
These SOP describe the general aspects of cleaning validation, Normally cleaning validation would be applicable for critical cleaning such as cleaning between manufacturing of one product and another, surfaces that come into contact with products, drug products and API at Manufacturing site.
Production Officer / Executive shall be responsible for monitoring cleaning of equipments
QA Officer / Executive shall be responsible for preparation of validation protocol and report.
IPQA Officer shall be responsible for sampling from cleaned equipment as per protocol.
QC Officer shall be responsible for analysis of samples.
Head Productionshall be responsible for checking validation protocol and report.
HeadQuality Controlshall be responsible for checking validation protocol and report.
Head QA shall be responsible for approval of validation protocol and validation report.
Head-QA shall be responsible for the compliance of the SOP.
Health Products and Food Branch Inspectorate ,Guidance Document Cleaning Validation Guidelines GUIDE-0028
World Health Organization ,WHO Technical Report Series, No. 937, 2006
Annex 4 Supplementary guidelines on good manufacturing practices: validation Appendix 3
EU Guideline & VICH Guideline
SOP: Standard Operating Procedure.
QA : Quality Assurance.
QC : Quality Control.
SS : Stainless Steel.
WHO :World Health organization
GMP: Good Manufacturing Practices
API : Active Pharmaceutical Ingredients
ppm : Parts Per Million.
MACO: Maximum Allowable Carry over.
IPQA: In process Quality Assurance.
Cleaning Validation: Cleaning validation is a documented evidence to verify that the procedures used to clean the product residue from equipment and components will consistently & significantly reduce the amount of active ingredient, Excipients and cleaning agent to a concentration within calculated acceptance criteria.
GENERAL INSTRUCTIONS: NA
Cleaning validation protocols and reports
Cleaning validation protocol
Cleaning validation should be described in cleaning validation protocol, which should be formally approved.
In preparing the cleaning validation protocol, the following should be considered
disassembly of system;
— pre cleaning;
— cleaning agent, concentration, solution volume, water quality;
— time and temperature;
— flow rate, pressure and rinsing;
— complexity and design of the equipment;
— training of operators; and
— size of the system.
The cleaning validation protocol should include:
The objectives of the validation process
The Scope of the validation process
The Purpose of the validation process
The people responsible for performing and approving the validation study
The Identification of most sensitive product for contamination on the basis of
maximum daily dose & minimum batch size
Matrix worst case approach table – based on risk analysis
List of equipment with internal surface area of each equipment in sq.cm
Identification of difficult to clean surface of equipment (table & drawing facility) The sampling method used as per product specific requirement
Critical areas, i.e. those hardest to clean, should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place systems. The sampling medium and solvent used should be appropriate to the task.
Swab study shall be performing by following manner
Indirect sampling (Rinse method)
Note: This method allows sampling of a large surface, of areas that are inaccessible or that cannot be routinely disassembled and provides an overall picture. Rinse samples may give sufficient evidence of adequate cleaning where accessibility of equipment parts can preclude direct surface sampling, and may be useful for checking for residues of cleaning agents,
Rinse samples should be used in combination with other sampling methods such as surface sampling.
There should be evidence that samples are accurately recovered. For example, a recovery of > 80% is considered good, > 50% reasonable and < 50% questionable
Analytical methods Validation
The analytical methods should be validated before the cleaning validation is performed. The methods chosen should detect residuals or contaminants specific for the substance(s) being assayed at an appropriate level of cleanliness (sensitivity).
Validation of the analytical method should include as appropriate:
— precision, linearity and selectivity
— limit of detection (LOD);
— limit of quantization (LOQ);
— recovery, by spiking with the analyze
The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminants
Suitable methods that are sensitive and specific should be used where possible and may include ultraviolet (UV) spectroscopy ,Other methods may include (alone or in combination) measurement of total organic carbon (TOC), pH, or conductivity; and Enzyme-linked immunosorbent assay (ELISA
Establishing acceptable limits
Note: uniform distribution of contaminants is not guaranteed.
The acceptance criteria established for contaminant levels in the sample should be practical, achievable and verifiable. The rationale for the residue limits established should be logical, and based on the knowledge of the materials involved
Each situation should be assessed individually. The manner in which limits are established should be carefully considered. In establishing residual limits it may not be adequate to focus only on the principal reactant, because other chemical variations may be more difficult to remove. Where necessary, screening using thin-layer chromatography should be performed in addition to chemical analyses.
There should be no residue from the previous product, from reaction by-products and degradants, or from the cleaning process itself (e.g. Solvents).
The limit-setting be product-specific
Group products into families and choose a worst case product group products into groups according to risk, e.g. very soluble products, products with similar potency, highly toxic, or difficult to detect products;
Use different safety factors for different dosage forms based on physiological response (this method is essential for potent materials).
Limits may be expressed as a concentration in a subsequent product (ppm), limit per surface area (mcg/cm2), or in rinse water as ppm.
The sensitivity of the analytical methods should be defined to enable reasonable limits to be set
The rationale for selecting limits for carry-over of product residues should meet defined criteria. The three most commonly used criteria are:
Visually clean. (No residue should be visible on equipment after cleaning.) Spiking studies should determine the concentration at which most active ingredients are visible. this criterion may not be suitable for high potency, low-dosage drugs
Not more than 10 ppm of one product will appear in another product (basis for heavy metals in starting materials); and not more than 0.1% of the normal therapeutic dose of one product will appear in the maximum daily dose of a subsequent product.
The most stringent of three options should be used.
Revalidation shall be carried out in following situations:
a) Equipment change
b) Cleaning equipment change
c) Change in cleaning agent
d) Change in cleaning procedure
e) During new product introduction
f) Once in three years
Procedure for cleaning validation based on worst case products :
Worst case products on basis of solubility :
Hard to clean product will cover all the easier to clean product also i.e. based on the solubility of products being manufactured, product having least solubility in water can be considered as worst case product.
Worst case product on basis Toxicity data:
Molecule having least LD50 value shall be taken into consideration for cleaning validation
Worst case product on basis of strength:
If the product is manufactured in different strengths, cleaning procedure shall be validated for the highest strength of that particular drug product. If the product contains multi active ingredients, the active ingredient which is less soluble/more in concentration and/or more toxic shall be taken into consideration for cleaning validation.
Worst case on the basis of batch size of next product :
Based on the minimum batch size and maximum surface area of common equipment, product having minimum batch size and maximum surface area can be considered as worst case product.
i) As the batch size of next product comes in the numerator of the formula while calculating acceptance criteria. The product which has minimum batch size should be considered as worst case product, which makes the acceptance criteria more stringent.
ii) As surface area common for both the products is in the denominator of the formula while calculating acceptance criteria. The products which involve maximum no. of equipment should be considered as worst case product which makes the acceptance criteria more stringent.
Worst case based on Maximum daily dose of the product :
The principle for the requirement is that the standard Therapeutic Daily Dose (TDD) of the next product may be contaminated by no more than a certain proportion (1/1000 part i.e. NMT 0.001 dose) of the TDD of the product investigated in the cleaning validation (“worst product”). This method only applies when the therapeutic daily dose is known. Scientific rationale for above statement is that pharmaceuticals are often considered to be non active at 0.1 of their normally prescribed dosage (1/10th) and the facility is solid dosage manufacturing unit.
Worst case on the basis of equipment :
If there are different sizes of the same equipment with same cleaning procedures, cleaning validation for the largest size of that particular equipment is adequate. If there are multiple of a particular equipment with same configuration, material of construction and cleaning procedure, then cleaning validation of one piece of that particular equipment will be adequate
Worst case on basis of 10 PPM criteria:
NMT 10 ppm of previous product shall appear in next product. 10 PPM criteria shall be followed until the identification of the worst case product. Scientific rationale of above statement is based on regulations for food industry which provides for maximum permissible limit of certain levels of hazardous substances.
Waste case on basis of Health Based Data:
The Maximum Allowable Carryover (MACO) should be based upon Permitted Daily Exposure (PDE). In the health based data criteria, the principle of MACO calculation is based on acceptable carry-over of previous product, based upon the PDE, into next product. The molecules having least PDE value shall be taken into consideration for cleaning validation..
Swab Recovery Study and Coupon Recovery Study should be performed.
Record the products which are considered as worst case on the solubility, maximum strength. Therapeutic potency under present product and product which are considered as worst case product based on batch size in Kg and maximum daily dose under product to be considered as next product for calculating acceptance criteria.
Based on the new product introduction and conclusions.
Periodically review the data with respect to new products and new equipment being used for production at the site and observations should be recorded.
This should done to keep a track whether the worst case products is still justified. Based on the above review with respect to new products and new equipment, determine whether validation needs to be carried out or not. A new validation report should be filled in case of change in the worst case product.
Based on the information about batch size, number of dosage units per batch, uncommon equipment, smallest strength manufactured, maximum daily dosage, product contact surface area, solubility of active ingredient in water, chain of equipments used during manufacturing the worst case product can be decided.
Annexure – I : Flow Chart of Cleaning Validation Procedure
Annexure – II : Surface Area Sheet
Annexure –III : Sampling Points
Annexure –IV :Cleaning Validation Protocol
Annexure –V : Cleaning Validation Report