Cleaning Validation Protocol Format

A cleaning validation protocol format shall be developed for the ‘worst case’ product selected for cleaning validation programme.

Following information (but not limited to) the following included in the cleaning validation protocol.

Numbering of protocol shall done through of respective SOP of Cleaning Validation Protocol Numbering.

Cleaning Validation Protocol Format –

Objective:

A brief description of the purpose of the validation study.

Scope:

This section must include an extent of the cleaning validation protocol.

Responsibilities:

This section includes the different responsibility for completing the cleaning validation programme.

Training:

Provided to all personnel involved in the cleaning validation

Record –Training

Records of training of all personnel involved in the cleaning validation program for understanding and cGMP requirement.

Protocol signature log:

Signature (specimen) of all the person involved in the cleaning validation program mention here for proper identification of person for future reference.

Cleaning Procedure:

Brief description of equipment used for selected product & relevant SOP for equipment cleaning. provide the complete details of cleaning procedure in this part of cleaning validation protocol format.

Sampling Procedure:

Swab samples shall taken after final cleaning of the equipment and once the equipment qualifies the visual inspection test. Sampling procedure should be defined in the protocol.

  • Sampling:
    • Visual Inspection
    • Preparation of swab
    • Dimension of swab sample area.
    • Swab Sampling point

Sampling strategy shall be defined in this part of cleaning validation protocol format.

Documentation

While performing each activity, documentation of the required details shall be done in appropriate attachment of this protocol.

Analytical and microbiological test method:

This section will give references for the adopted analytical and microbiological test method to analyse the samples.

The analytical method must validated for the residue levels, or bio-burden as per the specification given in the protocol. Testing performed by.

All test results must calculated and reported to correspond with the predetermined acceptance criteria.

Validation report

Validation report addressing the cleanliness of each piece of equipment shall generated after compilation of three batch validation.

Acceptance criteria:

The acceptance criteria for the cleaning validation will mentioned in the

specific protocol and will decided based on product matrix.

Deviation:

Any deviation taken during execution of the protocol shall documented in this section.

Justification for the deviation will be authorized by Quality Assurance (QA) Head and Factory Head (Plant Head).

ANALYTICAL METHOD DEVELOPMENT AND VALIDATION

  • The development and validation of analytical procedure for the purpose of analyzing cleaning validation sample requires the selection of appropriate tests.
  • Definition of test :
    • Limit of Quantification:
      • The limit of quantification of an individual analytical procedure is the lowest amount of analyte in a sample, which can be quantitatively determined with suitable precision and accuracy.
      • RSD of area of triplicate injections, Not more than 10.0%
    • Limit of Detection:
      • The limit of detection of an individual analytical procedure is the lowest amount of sample concentration till the peak detects in all of the triplicate injections.
    • Linearity:
      • The linearity of an analytical procedure is its ability (within a given range) to obtain test results, which are directly proportional to the concentration of analyte in the sample at LOQ level.

Correlation coefficient in the range of LOQ to 150% of sample concentration should be less than                                        0.990 and graph shall be visually linear.

  • Instrument Precision and Accuracy and Precision at LOQ Level.
    • This study to check instrument repeatability, method repeatability and accuracy. RSD of area from six replicate injections of standard preparation (at LOQ): Not more than 10%. RSD of % recovery calculated from six replicate sample preparation at LOQ concentration is not more than 10 %.
    • Recovery from placebo at LOQ concentration should be between 80.0 % and 120.0 % .
  • Stability in Analytical solution at room temperature:
    • Analytical solution stability at room temperature shall performed.
    • Stability in analytical solution at room temperature for standard and sample preparation between Initial and specified stability time interval is not more than 10 %.
  • Recovery from spiked swabs:
    • The recovery from spiked swab at LOQ (100%) to different concentration is Not less than 80%.
  • Recovery Study from SS Plate:
    • This study is performed for efficiency checking of swab sampling procedure from the surface by applying the known concentration of standard solution on surface at target and LOQ level. Mean recovery from SS plate is not less than 70.0%. Recovery factor should be considered for evaluation of cleaning validation results.
  • Note : Limits for the carryover of product residues should be based on a toxicological evaluation. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references. Limits should be established for the removal of any cleaning agents used. Acceptance criteria should consider the potential cumulative effect of multiple items of equipment in the process equipment train.

MYTH AND FACTS OF CLEANING VALIDATION.

Myth 1 : “You can’t validate manual cleaning”

Fact :

Automated and manual Cleaning Procedure can be validated.

Actually manual cleaning variability is more as compare to the automated cleaning processes,

Consistency of manual cleaning is depends upon

  • the complete details mentioned in cleaning procedures,
  • trend manpower and
  • adequate cleaning steps.

If cleaning procedure steps are robust, cleaning variability will be minimum. It requires more vigilant to validation maintenance. Design a comprehensive, dependable cleaning validation program.

Myth 2 : During recovery at different spiked level should linear.

Fact : Recovery (in %) are highly variable. It is not reasonable to expect linear response, Swabbing is a manual procedure so variability will be there.

Myth 3 : Any residue is unaccepted.

Fact :

In the current methodology (by TOC or By HPLC)  of evaluation of residue content, there will always be some residue obtained in result.

Detection limits of Analytical procedure actives the lower levels.

If the residue obtained is below the acceptable level, and medically safe and it don’t impact on product quality, same quantity of residue can be accepted.

Myth 4 : For Evaluation of Samples, Always use HPLC instead of TOC.

Fact : 

Perform the Evaluation through validated TOC analyzer

No need to re perform the evaluation with HPLC separately and no need to correlate the result generated by TOC with HPLC.

Method validation of TOC with appropriate standards is sufficient to run the sample on TOC.

No need to perform the test individually, both Analytical procedure by HPLC and by TOC can accepted.

Myth 5 : Always correlate rinse sample results with swab sample results.

Fact :



The rinse samples are different with swab samples, there will be no correlation among the both.

Actually swab focus on small area and rinse focus on larger area, where simulation of surface is not possible for swab sample or difficult to reach areas,

Rinse sample for the same. Swab measures worst case and rinse measures average.

SOP on Cleaning Validation

OBJECTIVE  :

The objectives of good manufacturing practices (GMP) include the prevention of possible contamination and cross-contamination of pharmaceutical starting materials and products.

SCOPE  :

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.

RESPONSIBILITY :

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.

REFERNCES:

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

ABBREVIATIONS :

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.

DEFINITIONS:

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

PROCEDURE :

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

Acceptance Criteria

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

— Reproducibility.

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:

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.

Justification:

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(S):

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

Principles of Cleaning Validation

Principles of Cleaning Validation

  • Cleaning validation should be performed in order to confirm the effectiveness of
    any cleaning procedure for all product contact equipment. Simulating agents may
    be used with appropriate scientific justification. Where similar types of equipment are grouped together, a justification of the specific equipment selected for cleaning validation is expected.
  • A visual check for cleanliness is an important part of the acceptance criteria for cleaning validation. It is not generally acceptable for this criterion alone to be used. Repeated cleaning and retesting until acceptable residue results are obtained is not considered an acceptable approach.
  • It is recognised that a cleaning validation programme may take some time to complete and validation with verification after each batch may be required for some products, e.g. investigational medicinal products. There should be sufficient data from the verification to support a conclusion that the equipment is clean and available for further use.
  • Validation should consider the level of automation in the cleaning process. Where an automatic process is used, the specified normal operating range of the utilities and equipment should be validated.
  • For all cleaning processes an assessment should be performed to determine the variable factors which influence cleaning effectiveness and performance, e.g. operators, the level of detail in procedures such as rinsing times etc. If variable factors have been identified, the worst case situations should be used as the basis for cleaning validation studies.
  • Limits for the carryover of product residues should be based on a toxicological evaluation. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references. Limits should be established for the removal of any cleaning agents used. Acceptance criteria should consider the potential cumulative effect of multiple items of equipment in the process equipment train.
  • Therapeutic macromolecules and peptides are known to degrade and denature when exposed to pH extremes and/or heat, and may become pharmacologically inactive. A toxicological evaluation may therefore not be applicable in these circumstances.
  • If it is not feasible to test for specific product residues, other representative parameters may be selected, e.g. total organic carbon (TOC) and conductivity. The risk presented by microbial and endotoxin contamination should be considered during the development of cleaning validation protocols.
  • The influence of the time between manufacture and cleaning and the time between cleaning and use should be taken into account to define dirty and clean hold times for the cleaning process.
  • Where campaign manufacture is carried out, the impact on the ease of cleaning at the end of the campaign should be considered and the maximum length of a campaign (in time and/or number of batches) should be the basis for cleaning validation exercises.
  • Where a worst case product approach is used as a cleaning validation model, a scientific rationale should be provided for the selection of the worst case product
    and the impact of new products to the site assessed. Criteria for determining the worst case may include solubility, cleanability, toxicity and potency.
  • Cleaning validation protocols should specify or reference the locations to be sampled, the rationale for the selection of these locations and define the acceptance criteria.
  • Sampling should be carried out by swabbing and/or rinsing or by other means depending on the production equipment. The sampling materials and method should not influence the result. Recovery should be shown to be possible from all product contact materials sampled in the equipment with all the sampling methods used.
  • The cleaning procedure should be performed an appropriate number of times based on a risk assessment and meet the acceptance criteria in order to prove that the cleaning method is validated.
  • Where a cleaning process is ineffective or is not appropriate for some equipment, dedicated equipment or other appropriate measures should be used for each product as indicated in chapters 3 and 5 of EudraLex, Volume 4, Part I.
  • Where manual cleaning of equipment is performed, it is especially important that the effectiveness of the manual process should be confirmed at a justified frequency.

Reference :-

Volume 4
EU Guidelines for
Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use
Annex 15: Qualification and Validation