Manufacturing different products in the same facility is a good way to have an optimum business. When shifting to a new product, you have to remove the previous product traces from the facility to avoid cross-contamination.
Well, cleaning validation is the scientific technique to ensure your previous product traces have been removed to the predetermined levels. In this article, we’ll see what, why, when, and how of this technique.
Cleaning validation guidelines cover a wide range of measurements and specifications to deal with and became just as complex as process validation in recent times. Apart from cleaning validation, we’ll also go through a major classification of available cleaning mechanisms.
What is Cleaning Validation?
Establishing documented, scientific and risk-based evidence that provides a high degree of assurance, a typical cleaning method or procedure will consistently clean the equipment or medical device in compliance with its predetermined specifications and quality attributes taking patient’s safety into consideration. Also to ensure effective development of cleaning processes that’ll take care of the end-user.Definition of Cleaning Validation (General Understanding Taken from Guidelines)
Obviously, cleaning validation is a lesser concern for disposable systems such as single-use fermentors as they don’t get consumed in the next batch.
In recent times, cleaning validation has become a hot topic within the pharma companies due to increased attention and observations made by regulators and market complaints.
Why is Cleaning Validation Needed?
When certain equipment is used to manufacture a product, it leaves behind traces of raw material, cleaning agents, or the product itself. If we want to conduct a product change-over, these traces either contaminate or cross-contaminate the planned product.
To ensure your cleaning process is effective in removing these traces, a cleaning validation program is outlined, executed, and evaluated. Unless the quality unit approves the cleaning validation report, firms should not indulge in the new product campaign.
So priority-wise, we can say cleaning validation is regulatory requirement to ensure and assure:
- Product Safety
- Patient Safety
Integrating the cleaning validation program within QMS and QRM environments for the drug manufacturing operations are carried out by:
- Understanding the risks to the patients
- Impact assessment
- Mitigating those risks
- Assuring finished product safety
The product that is adulterated with the residue of the previous batch of the same product in particular equipment is called Contamination. OR
A new product that is adulterated with the residue of raw materials of the previous product also called Contamination.
A new product that is adulterated with the left behind traces of the previous product in particular equipment is called Cross-Contamination.
Benefits of Performing Cleaning Validation
- Assures patient safety through risk-based studies conducted in the development of the cleaning processes
- Avoids product adulteration
- Helps to achieve a contamination-free product
- Fulfills the regulatory requirements
- Allows you to re-use the same equipment for different products
- Process and cost optimization because of a systematic product change-over
We’ll see further, ways and types of the cleaning processes, how to develop a cleaning validation program, and the expectations of regulatory bodies.
When to Perform Cleaning Validation?
Following situations need a proper cleaning validation study.
- When establishing a fresh commercial process
- When reusing the existing facility for a different product every time
- A major change in raw materials based on impact assessment
- Significant modifications in cleaning procedures
- Introduction of new equipment for the already established process
- Changes in cleaning agent
- Changes that might affect CPPs and CQAs of already approved cleaning validation
Classification of Cleaning
Cleaning processes based on industrial practices can be differentiated into three ways and two types.
3 Ways of Cleaning
There are 3 different ways to clean the equipment, component or accessories. In pharma-related facilities, commonly used cleaning agents are purified water, WFI (Water For Injection), or chemical solvents.
- Cleaning In Place (CIP)
- CIP Skid to Clean the Equipment
- Automated CIP of the Equipment
- Cleaning Out of Place (COP)
- Washers like Tray Washers, Dish Washers, etc.
- Sub-systems of equipment hard to approach in CIP
- Manual Cleaning
- Difficult to clean in COP and hence cleaned using tools such as Cleaning Brushes, Scrubbers, etc.
According to the feasibility:
- Equipment is preferred for an automated cleaning in place i.e. CIP.
- Components or sub-systems being not feasible for CIP are preferred for COP.
- Critical Components or locations of the equipment that are hard to reach during CIP and COP are preferred for Manual Cleaning.
2 Types of Cleaning
As per the common understanding among the pharma professionals, there are two types of cleanings.
- Batch To Batch
- Cleaning of the process equipment in between two batches for ongoing manufacturing campaign of the same product.
- Product to Product
- Cleaning of the process equipment in between the two different products i.e. after finishing the previous product campaign and before initiating a new product campaign
Let’s quickly have a look at different cleaning mechanisms used in pharma or medical devices. Later on, we’ll see the structure of the cleaning program.
Different Cleaning Mechanisms
Residue from equipment can be removed either physically or chemically and chosen based on the consistency and performance-based selection criteria.
- Mechanical or Manual
- Solubilization Using Solvent
Mechanical Cleaning (Manual)
Mechanical cleaning involves the application of scrubbers, brushes, wipes, etc. for removing residue or previous product traces.
Brushing Or Scrubbing
- Detergent solution is prepared with slightly alkaline pH in hot water typically NLT 50°C
- The loose components disassembled from the equipment and dipped in detergent solutions allowing sufficient soaking time.
- A brush, scrubber, or scrapper as suitable is applied on the surface and rinsed under hot or cold water for sufficient time.
|Simple and Flexible||Inconsistent because of manual action|
|Requires exhaustive training||Involves additional man-power|
This involves high-pressure water spray that easily disintegrates the residue from dismantled and dirty components of the equipment.
Moreover, when water alone is insufficient to do this job, a suitable surfactant is considered for further scrubbing or brushing solutions.
Lint-free cloths are commonly used to clean the visible equipment surfaces with the wiping action. Specifications include:
- Wiping directions, patterns, and number of times to repeat the wiping
- Solvent and cleaning agent concentrations
- Quantity of cleaning solution to apply to the wipes
Hydrophobic residue suspended in an aqueous cleaning solution is called Emulsion. This method is typically considered while dealing with insoluble liquid residues and very rarely found applicable in pharmaceutical industries.
However, firms that follow detergent-based washing cycles still may find this method effective. Though considered as a physical cleaning mechanism, it may also fall under Detergents.
Surfactants are introduced in the equipment to form an emulsion. When agitated, breaks down the residue in small droplets and either float or sink based on the density.
Practically speaking, enough variations possible in this method due to the uncertainty of the holding time of the residue.
In this mechanism, a residue is dissolved with a suitable solvent. The common solvent readily available is water which is aqueous in nature.
Non-aqueous solvents are also preferred in specific cases. However, water is non-toxic, cheap, environmental-friendly, does not contribute to chemical degradation, and easy to remove. Hence water is the primary choice.
But, choosing either of them depends on the drug residue solubility characteristics.
This mechanism involves the application of chemical reactions for cleaning purposes and generally includes oxidation and hydrolysis.
Using a strong oxidizing agent, carbon-carbon bonds are broken resulting in smaller molecules that increase the water solubility of the residue.
Hydrolysis mentioned below too has the same impact but on a more specific level. Whereas oxidation is a universal term and hence puts challenges in choosing a specific analytical method to detect unoxidized residue.
Examples of oxidizing agents include Peracetic Acid (CH3CO3H), Hydrogen Peroxide (H2O2), and Sodium Hypochlorite (NaClO), etc.
This method improves the solubility of solvent resulting in hydrolyzed residue with lower molecular weights.
For aqueous solutions, hydrolysis is carried out at elevated temperatures using acids or alkalies. The rate of hydrolysis depends on the nature and quantity of residue and temperature.
It is important to consider the most appropriate analytical method/s to test the efficiency of the cleaning process independently.
This method lowers the surface tension of residue with the help of surfactant addition in water. Wetting results in two actions.
- Residue when wetted reduces its surface tension and improves the rate of dissolution
- Equipment surface when wetted promotes residue disintegration
Dispersion is the same as that of Emulsification. The difference is Emulsification involves the use of liquid particles whereas Dispersion involves the use of solid particles.
Solid particles are wetted and broken down using anionic surfactants and vigorous agitation to form a suspension pool. More importantly, this method is practiced in Oral Solid Dosages (OSD) such as power blending and tablet manufacturing.
Refer Emulsification Above. (Mentioned to show this as a part of Detergents)
In some cases, acids or alkalis are used for proper dissolution yet they require excess removal times to bring them down to neutral pH ranges.
For example, bringing down the pH should be checked at the “drain point” rather than “in-place” to assure complete residue removal from the equipment during cleaning.
These methods can either be used in combination or sequence depending upon the feasibility and nature of residue. It is highly advised that proper study of residue be conducted to decide effective cleaning mechanism.
List of Cleaning Agents
Generally, organic solvents are used in the bulk manufacturing of Active Pharmaceutical Ingredients (APIs).
Reactors with higher working volumes, when cleaned with water alone, may not dissolve the bulk residue stuck to the surface of reactors.
An organic solvent which is used in manufacturing the same drug usually dissolves the API and hence a best suitable choice for cleaning purpose.
However, addressing cost optimization and solvent recovery are crucial aspects while designing the cleaning process. Examples of commonly used solvents: Methanol, Toluene, Acetone, and Ethyl Acetate.
Water used as a stand-alone cleaning agent or in combination with following classifications.
|Commodity Chemicals||Specialty Cleaners|
– Ortho-Phosphoric Acid (H3PO4)
– Nitric Acid (HNO3)
|Surfactants (Based on the charge on polar end)|
– Nonionic (no charge)
– Anionic (+ve)
– Cationic (-ve)
– Amphoteric (+/- based on pH)
– Acetic Acid (CH3COOH)
– Sodium Hydroxide (NaOH)
|Other Cleaners like Chelants, Dispersants, etc.|
You can visit here for a list of cleaning agents. For now, that’s all about cleaning philosophy.
Let’s understand Cleaning Validation. Two things we’ve not seen earlier are critical process parameters and critical quality attributes which play an important role in assuring effective cleaning.
What we’ve understood so far was related to cleaning mechanisms and their commercially available options. Whereas, it is very crucial to define your Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs) for the planned cleaning validation.
Cleaning Validation Program
Critical Process Parameters For Cleaning
- Contact time
- Concentration of the cleaning agent
- Surface Roughness (More the roughness, more the difficult to clean)
- Flow rate
- Proper mixing RPMs
- Dirty Hold Time of Equipment
- Clean Hold Time of Equipment
Critical Quality Attributes For Cleaning
- Product residue
- Cleaning agent residue
- Required concentration of cleaning agent
- Microbial residue
- Number of rinses
- Time of cleaning
Pre-Requisites To Begin Cleaning Validation
Before commencing cleaning validation, following pre-requisites should be met including:
- Cleaning Validation Strategy and Protocol are approved and ready
- Equipment used for most of the products should be identified
- SOP for Equipment Cleaning is established (draft)
- Sampling and Analytical Methods are validated
- A list of CPPs and CQAs is available
- Drug toxicity data is available
- Product contact surface area is calculated
- Training is given to the personnel involved in cleaning validation activity
- Characteristics of drug that contribute to cleaning difficulty are evaluated
Cleaning Validation Process Flowchart
Below flow diagram shows overall strategic activities in cleaning validation.
You may cascade the items as per the suitability of your cleaning process.
A risk-based approach should be preferred to identify the risks associated with:
- Residue of concern
- Priority of selecting sampling locations
- Determining and justifying product/equipment groups
- Defining acceptance criteria
- A sequence of protocol execution
- Product change-over SOPs
Cleaning Validation Protocol and Report
Instead of following any protocol template, it is important to understand its key technical aspects. A protocol should be prepared explaining technical cleaning validation activities that contain:
- Scope and Objective
- Cleaning SOP Draft
- Possible ways of contamination
- Sampling plan and rationale including prioritized sampling locations
- Worst-case conditions
- Selection of analytical method and its validation
- Equipment Dirty and Clean Hold Time Study
- Acceptance criteria
- Technically sound deviation management strategy
- Data monitoring Annexures (if Applicable)
Successful execution of the protocol would be incomplete without a report. So, a report should be prepared to summarize the key achievements of the cleaning validation study including a clear statement of accepted or not accepted.
Selecting a Proper Way of Cleaning
As we’ve seen earlier, there are three ways of cleaning i.e. CIP, COP, and Manual Cleaning. As basic understanding already explained, we’ll see CIP only.
Clean In Place (CIP)
As part of the regulatory expectations, this is the most suitable way of cleaning the equipment. Equipment is cleaned at its existing location with a suitable cleaning agent.
It is recommended to develop and implement an automated cleaning sequence to better control the potential variations. This helps to achieve cleaning consistency and adapt to a similar cleaning pattern.
For Process Vessels and Integrated systems, a static or dynamic spray ball is preferred to ensure complete coverage of 360° including dead spaces near nozzles (one of the major worst-case locations).
A Riboflavin test is conducted to conclude the spray ball is effectively reaching remote spaces of equipment at a defined pressure and flow rate. Riboflavin solution acts as a speck of dirt and can be seen under Ultra-Violet (UV) light.
A typical CIP cycle should generally include the following rinses.
- Pre-rinse with PW or WFI
- Alkali and Acid Wash (if product demands)
- Final Rinse with PW or WFI
A proper air flushing mechanism should also be incorporated to remove the stagnant water from the system which helps in avoiding microbial growth.
Selection of Analytical Methods and Its Validation
Two fundamental types of analytical methods exist.
The selection of these methods requires a science- and risk-based approach. Inappropriate evaluation and selecting any of these methods may invite regulatory controversies.
For example, the FDA clearly states that the companies should determine the specificity of their analytical method. It should not be misinterpreted that FDA expects to use only specific methods. This means the selection of analytical methods requires proper evaluation.
However, EU-GMP states “the analytical method must be specific for the target residue”. These statements may be interpreted in two ways.
- Only specific methods are acceptable OR
- Any of the methods must be specific for that particular target residue even with the non-specific method.
However, the second one interprets more appropriate and that is the reason the European drugmakers generally follow that practice.
Needless to say, there is much depth to it. Hence, proper evaluation of the method selection is very important especially following a scientific and risk-based approach.
Instead of a theoretical explanation, let us quickly draw a table below for easy interpretations.
|Specific Methods||Non-Specific Methods|
|Gives us the exact quantification of the target residue||Relates to the target residue but doesn’t provide its direct measurement or quantification|
|Recommended during cleaning validation||Recommended after cleaning validation OR also complement specific method during cleaning validation|
|Can detect the interference of substances other than residue like cleaning agents||Itself can falsify the measurement of the target residue because of the presence of other substances|
|Examples: HPLC, RP-HPLC with UV, Ion Chromatography||Examples: pH, Conductivity, Visual Detection, and TOC|
To bridge the gap, many pharmaceutical manufacturers follow the general practice i.e. a combination of both methods. Specific methods for primary cleaning validation while non-specific methods for subsequent cleaning verification. But the correct way starts from your science- and risk-based studies.
Another way of choosing these methods is based on the stage of manufacturing.
Initial stages such as bulk drugs or intermediates except toxic APIs may only use non-specific methods that may suffice the requirement. Whereas the formulation or downstream processing may require both.
Analytical Method Validation
Upon successful selection of the analytical method, it is important to validate it for the intended use. All non-pharmacopeial analytical methods require validation.
However, if you want to use any of them even when a pharmacopeial method exists, you’ve to provide a rationale for doing so.
Just to give you clarity, methods described in the monograph of different pharmacopeias are called Pharmacopeial methods, and selecting those methods is evidence-based and need not require a formal method validation.
Anyway, the following characteristics should be covered during the analytical method validation.
- Specificity OR Selectivity
- The ability of the analytical method to accurately measure an analyte and interferences such as cleaning agent.
- Selectivity is checked with blank samples (without an analyte) examined in the anticipated time range of the peak that contains the analyte.
- Accuracy (% Recovery)
- Degree of agreement of the test results produced by the analytical method to the true value. Generally established for a complete specified range of the procedure.
- A known concentration of analyte standard spikes the sample matrix and measure the accuracy using the specified analytical method.
- It is the degree of agreement between the individual test results for the repeatedly applied analytical procedure to multiple samplings.
- It can be calculated by different methods like Statistical, Horwitz equation, etc.
- Limit of Detection
- The lowest concentration at which the instrument detects an analyte but does not necessarily quantify it. The noise to signal ratio should be 1:3.
- Limit of Quantitation
- The lowest concentration at which the instrument both detect and quantify an analyte. The noise to signal ratio should be 1:10.
- The capability of the analytical method to obtain the outcome directly proportional to the concentration of the analyte within a given range.
- 5 concentrations at a minimum are preferred from 50% to 150% across the working range and are injected with a mobile phase to produce a linear relationship.
- It is the concentration range and an interval between the upper and lower limit shown using precision, linearity, and accuracy.
- Stability of Solution
- The time duration of the sample for which it can be stored before the final analysis after extraction.
- Measure to determine the robustness and reliability of the analytical method to deliver linear, accurate, and precise results in all anticipated conditions.
Sampling Methods for Cleaning Validation
According to the FDA guideline, there are 3 types of sampling out of which 2 are generally accepted for cleaning validation.
Direct Surface Sampling (Swab Sampling)
Direct surface sampling (swab sampling) is the most preferred sampling method for hard-to-reach but reasonably accessible areas of the equipment.
A sterile swab made of cotton is attached to a compatible stick just like earbuds.
- The challenge is to use the solvent along with the swab comfortably without interfering with the analytical test. Because swabs may contain certain adhesives that can alter the results.
- These swabs are stored and dipped in a buffer like a phosphate solution or as appropriate to soak the cotton. During sampling, swabs are removed and then applied gently on the equipment surface in one verticle and one horizontal direction without rubbing to and fro.
- Once done for at least 5 to 6 sampling locations, they are put back into the buffer solution and sent to the Quality Unit for evaluating and establishing an acceptable residue content per given surface area as CFU/cm2 or as appropriate.
Though this method is more specific in terms of hard-to-reach areas, it has one major disadvantage i.e. the small surface area for a given sample.
Unlike swab sampling, rinse sampling has the advantage of covering a large surface area of the equipment at a particular instance including the systems that are hard to disassemble frequently.
The required amount of cleaning solvent with the help of a suitable spray ball preferably with 360° coverage used to rinse the equipment. Rinsed samples then collected from the sample points located near the drain lines for physical and microbiological inspection.
One of the major disadvantages of rinse samples is when rinsed, the residue may incompletely solubilize in the rinse solvent like WFI or PW and remain clogged to the equipment surface.
In that case, just checking downstream water for compendial requirements is illogical and hence unacceptable.
Instead, the system should be in place to identify the direct measurement of the residue in the rinse sample such as Infrared sensors or visual inspection, etc.
Indirect Testing or Monitoring Method
Though it is a sampling method or more specifically monitoring method, it is also an indirect measurement that does not specifically provide us exact quantification of the residue.
Hence not acceptable as a stand-alone sampling method during cleaning validation. Instead, it should either be used as complementary to the actual sampling method or should be used after cleaning validation program for routine verification.
It is more specific in cases like bulk drug manufacturing where sampling can be most easily performed through rinsing. The best example of this method is pH, conductivity, and TOC (Total Organic Carbon) measurements.
However, in special cases where other methods fail to detect any presence, this method can be scientifically justified.
Defining Equipment’s Dirty Hold Time and Clean Hold Time
Everything in the world comes with an expiry and cleaning is not an exception to this. Therefore, the timeframe for the cleaning validity and dirty conditions becomes crucial.
- The equipment’s idle time between the end of the last batch and the start of the cleaning process is called Dirty Hold Time.
- The equipment’s idle time between the end of the cleaning process and the start of manufacturing is called Clean Hold Time.
Dirty Hold Time
Dirty hold times are the most crucial aspect of a cleaning validation program as they directly impact the efficiency of the cleaning process.
When equipment left uncleaned for longer durations, the residue attached to the surface may become rigid and dry over a period of time ultimately challenging the cleaning process.
Establishing the dirty hold times for a particular production process depends on the nature of the product, associated processing materials, and their cycle times.
General practice is to conduct 3 consecutive runs of cleaning procedure considering maximum dirty hold time as per the requirement (in most cases around 72 hrs).
These runs should demonstrate the cleaning procedure effective in removing the residue at the considered maximum dirty hold times. Obviously, through bioburden testing.
According to one of the FDA’s 483 observations, cleaning validation and dirty hold times should be established for dedicated as well as non-dedicated equipment. This should also include hard-to-clean equipment for overall confidence in cleaning validation.
Clean Hold Time
Just like dirty hold times, FDA also expects to define clean hold times during the cleaning validation program.
Clean Hold time study generally includes a sampling of clean equipment at a regular interval of around 6-8 hrs. till the equipment completes 24 hrs.
After 24 hrs., sampling is done once per day. Sampling is performed immediately after cleaning and thereafter at specified intervals.
It is better to have a data recording sheet that captures the necessary information. Samples are sent to the lab for bioburden testing (microbiological proliferation).
Example of a monitoring sheet:
|Cleaning Hold Time||Nature of Analysis||Acceptance Criteria|
|0 hrs.||Microbial: CFU/Swab|
|Depends on the application For example,|
Microbial: NMT 10 CFU/Swab
Chemical: NMT 10PPM/Swab
|24 hrs. (Day 1)||————“————||————“————|
|Till the time requirement||————“————||————“————|
Worst-Case Conditions in Cleaning Validation Program
Worst-case conditions for cleaning validation are those when evaluated or measured may result in failure of a cleaning procedure.
Following challenges are considered for establishing the worst-case conditions.
- Drugs with the lowest solubility in their cleaning agent
- Swab locations that are difficult to clean
- The lower therapeutic dose for effective cleaning measurement
- Equipment catering largest number of products
- Drugs with higher toxicity
Acceptance Criteria and Calculations
When it comes to cleaning validation, defining the incomplete acceptance criteria compromises your cleaning efforts.
Two concepts commonly talked about are NOEL and MACO.
Maximum Allowable Carry Over (MACO) tells mathematically, how much of your previous product carry over to the next product.
Whereas, No Observed Effect Level (NOEL) tells the drug quantity that has no observable effect on human health when provided a 50% Lethal Dose.
To better understand this, we’ll break down the acceptance criteria for different scenarios.
NOEL can be calculated as:
Where, LD50 – Lethal Dose at 50% reduction in mg/kg and hence NOEL has an unit of “mg”.
Based on Therapeutic Daily Dose or Safety Criteria
Based on the above calculated NOEL value, MACO can be calculated as
As per this criteria, not more than 0.1% normal therapeutic dose of the previous product shall appear in the maximum daily dose of the next product.
Based on 10 PPM Criteria
As per this, not more than 10 ppm of the previous product shall appear in the next product.
MACO can be calculated as:
Calculating MACO Using Toxicity Data
This approach generally considered during the early stages of drug manufacturing such as Intermediates or APIs. Additionally, this technique is used to calculate MACO for cases that don’t have information regarding the therapeutic dose.
Validating one representative operation to demonstrate its effectiveness on all similar types of operations is called a grouping strategy.
Successful cleaning validation of that representative operation would establish that all the associated grouped operations are also validated.
This strategy helps to minimize the cleaning validation efforts. The FDA does not have a specific policy to consider grouping strategy; however, FDA recommends providing technically sound and scientific rationale for the employed grouping strategy.
Grouping mostly can be of two types.
- Product Grouping
- Equipment Grouping
Product grouping can be performed based on 3 different criteria. Instead of going theoretical here, it would be better to visualize them. Please zoom or open the image in a new tab for better readability.
Unlike Product Grouping, this technique is used to perform cleaning on one representative piece of equipment.
The first and foremost condition of equipment grouping is that all the similar equipment follow the same cleaning procedure.
Additionally, it is not acceptable to group different equipment with the same cleaning mechanism and application e.g. Vacuum Tray Dryer and Roto-Cone Vacuum Dryer. Though the ultimate purpose and cleaning philosophy is the same, the structure and dimensions of the two pieces of equipment are completely different.
Equipment must have a similar design to fall under equipment grouping. And that similar has to be established.
A simple example of equipment grouping is process vessels of different working capacities. Here, “similar design” should indicate different aspects of equipment design such as MOC, Geometry, sub-components, and so on. Simply, one can not group the equipment of Stainless Steel (SS) and Glass Lined Reactors (GLR).
However, a major challenge in the example above is selecting a representative vessel based on worst-case conditions.
How would you define a small capacity vessel as hard to clean than a large-capacity vessel? If it’s justifiable, then no issue. But when there is no way to justify, there is another way.
In such cases, the combination of equipment should be selected for cleaning validation. That is, performing cleaning on the equipment group with one smaller volume vessel and one larger volume vessel. Or else, one can select two pieces of equipment separately for multiple cleaning runs individually.
Both scenarios are assumed to establish an overall degree of assurance for the effectiveness of the cleaning procedure.
Practicality of Using Grouping Strategies
Though the above explanation made available for understanding what grouping is, the cleaning processes should actually be developed focusing more on the risk-based approach through practically conducted scientific studies rather than theoretical principles.
Regulatory Expectations From Cleaning Validation
The professional auditors are trained such that even if they identify any unacceptable practice, they will not provide spoon-feeding. In fact, they don’t have much time to understand your complete cleaning philosophy.
Auditors generally try to understand the sound justifications behind any decisions such as choosing a method of analysis, cleaning agent, cleaning mechanism, etc.
Following are some of the regulatory observations made during their audits, giving more clarity on their expectations.
- The company’s overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval, and documentation of each validation phase, should be documented – EU Guide To Good Manufacturing Practice Part II – Section 12.1 Validation Policy.
- Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use and for its cleaning and maintenance. [21 CFR § 211.63] For example, CP-2 packaging line was modified in a manner that made it difficult for employees to remove the line cover. As a result, the line cover is not removed during line clearance operations and is only removed during preventative maintenance. Per firm personnel, unit dose strips can become caught in this area and are routinely found during maintenance – FDA warning letter 06-NWJ-14 (July 2006)
- 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. This is necessary before any conclusions can be made based on the sample results. A negative result may also be the result of poor sampling techniques – EU Guide To Good Manufacturing Practice Annexure-15, Section 4.10.3.
- Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant – ICH Q7A.
- The specificity of test methods should be documented. For example, instructions for the identification and quantification of peaks when using integrators should be provided, and integrated peaks in the swab samples taken during cleaning validation run eluting close to the retention time of the standard peak should be identified or quantified during the validation exercise – FDA 483 Warning.
- Cleaning validation studies for multiple use equipment were inadequate in that the validation protocol did not identify the cleaning procedure, the total surface area was not considered during the validation study, recovery studies were not done to validate the swab sampling method or filtering of rinse samples, some rinse samples were not analyzed, dates of analyses were inaccurate, and analytical data on rinse samples were not checked by a second person – FDA 483 Warning.
- Pipework systems, valves, and vent filters should be properly designed to facilitate cleaning and sterilization – EU GMP Guide, Annexure 2, Premises and Equipment.
- Tanks, containers, pipework and pumps should be designed and installed so that they may be readily cleaned and if necessary sanitised. In particular, equipment design should include a minimum of dead-legs or sites where residues can accumulate and promote microbial proliferation – PIC/S GMP Guide PE 009-5, Guide to Good Manufacturing Practices For Medicinal Products, Annexure 9, Premises and Equipment.
- Washing and cleaning equipment should be chosen and used in order not to be a source of contamination – PIC/S GMP Guide PE 009-5, Guide to Good Manufacturing Practices For Medicinal Products, Chapter 3/3.37.
- 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 – EU GMP Guide, Annexure 15, Section 4.6.1.
- With regard to transfer lines, they are generally hard piped and easily cleaned and sanitized. In some cases manufacturers have used flexible hoses to transfer product. It is not unusual to see flexible hoses lying on the floor, thus significantly increasing the potential for contamination. Such contamination can occur by operators picking up or handling hoses, and possibly even placing them in transfer or batching tanks after they had been lying on the floor. It is also a good practice to store hoses in a way that allows them to drain rather than be coiled which may allow moisture to collect and be a potential source of microbial contamination. Observe manufacturing areas and operator practices, particularly when flexible hose connection are employed – FDA Guide to Inspections of Oral Solutions and Suspensions 1994.
Considering both cleaning complexity and regulatory importance, defining and measuring your cleaning goals clearly is all that matters especially with sound rationale.
Apart from the cleaning procedures, the selection of the analytical method and its validation carry equal importance. Whenever and wherever possible, every aspect mentioned earlier should be the part of cleaning validation strategy and protocol.
Upon successful completion of cleaning validation activities, firms should consolidate all the observations noted during cleaning validation. A report should be prepared to demonstrate that the predefined goals are met and summarized.
Deviations and NCs should be summarized to show how they’re closed. Investigate your cleaning procedures to determine the potential opportunities for improvement in consistency.
Anyway, the approach should properly document the activities clearly mentioning the pass-fail status of previous cleaning validation.
What challenges do you face during your cleaning validation? Comment below.