Recovery Factor Studies in Cleaning Validation: A Practical Guide

Cleaning validation plays a vital role in manufacturing as it ensures that all manufacturing equipment is being cleaned according to the set cleaning limits. Cleaning validation depends on how reliable the chosen analytical method would be as well as how effective the sampling technique used is at getting the residues from the surface of the equipment.

One area that is critical to cleaning validation and often ignored is recovery factor studies. From my experience during regulatory inspections, I have seen that a lot of companies have invested a lot of effort in efforts to determine residue limits and to validate capable analytical methods but they do not put much effort into establishing the cleaning efficiency.

With the help of recovery factor studies one can prove scientifically the effectivity of the sampling method (usually swab sampling or rinse sampling), with which residues can be efficiently recovered from the surfaces of the process equipment. These results help the producers to adjust analytical data whenever it is required and gain confidence in the new cleaning validation program.

What is a Recovery Factor?

Recovery factor refers to the proportion of a specific residue amount that can be successfully retrieved from a specified equipment surface by use of an accepted sampling technique or process.

For instance, if an active ingredient weighing 100 µg is deliberately deposited on the surface of a piece of stainless-steel equipment and lab tests subsequently reveal the presence of 85 µg of the same ingredient, the recovery factor is said to be 85%.

Importance of Recovery Factor Studies

Sampling techniques cannot achieve total recovery of residue from every surface. Recovery rates from various products, equipment materials and sampling techniques differ. The benefits of recovery studies include:

• Proving effectiveness of sampling methods
• Validating swab sampling methods
• Confirming effectiveness of rinse sampling
• Gain assurance on analytical results
• Assist in making scientifically sound calculations of residue
• Meet all regulatory requirements

No recovery study means that the concern of residue results being deceptive arises.

Regulatory Requirements

Regulations seldom involve specific requirements on necessary percentage recovery. However, manufacturers are required to provide scientific reasoning behind the choice of sampling method. When it comes to inspections, it is essential to consider:

• Recovery study protocols
• Rationale for surface choice
• Rationale for product selection
• Calculations of recovery
• Statistical analysis
• Validation reports
• Analysts training documentation

Recovery studies should be conducted concurrently with the general cleaning validation process and not as an isolated laboratory activity.

When Should Recovery Factor Studies Be Performed?

Recovery factor studies should be done before starting the process of routine cleaning validation.

The usage of this kind of study arises under some circumstances, among which are the development of new cleaning validation methods; when new products are introduced; when new equipment is installed; surface materials are changed; and sampling methods are changed.

Every alteration in sampling efficacy should result in the evaluation of recovery factor.

Selecting Representative Equipment Surfaces

The choice of surface is crucial to the reliability of the study. Typical pharmaceutical equipment surfaces are made up of:

• 316L stainless steel
• Glass
• PTFE
• Silicone tubing
• Polypropylene
• Polyethylene
• Hastelloy

The intended purpose should be understood and reflected in the choice of surface. If multiple surface materials exist, separate recovery studies may be necessary.

Selecting the Product for Recovery Studies

A product must be selected which has the toughest possible cleaning situation. Some bases of selection may be:

• Having a very low solubility
• Having a very high potency
• Being made of hard-to-clean formulations
• Having a sticky residue left over
• Very high toxicity
• Worst-case validation matrix of cleaning

From my own experience, firms that use scientifically chosen worst-case products can significantly reduce the number of tests involving recovery studies while keeping compliance with regulations and laws.

Choosing the Sampling Method

Swab sampling and rinse sampling are two widely utilized types of sampling methods.

1. Swab Sampling

Swab sampling is defended on the ground that it gives direct measurement of the residue remaining on the surface of equipment. Some advantages of using the swab method are:

• Specificity of sampling location
• High sensitivity
• Appropriate for difficult to clean surfaces
• Enhances residue localization

To note however is that swab recovery is largely dependent on the technique of the operator as well as the characteristics of the surface.

2. Rinse Sampling

Rinse sampling is used to measure the residues that are eliminated by rinsing the system with an agent that will help to dissolve the residues in question. Some areas that need rinse sampling include:

• Large tanks
• Pipe systems
• Closed systems
• Places where it is not possible to use swabbing

Rinse sampling should not be used instead of swab sampling unless it is proven through scientific evidence.

Practical Procedure for a Recovery Factor Study

Using a protocol for a study improves repeatability.

Step 1: Prepare Test Coupons

To prepare the test coupons, make sure the coupons are free from contaminants and made from an appropriate material used during manufacturing. The preferred coupon sizes:

• 25cm²
• 50cm²
• 100cm²

The surface finish must be similar to that of the process equipment.

Step 2: Apply Known Quantity of Residue

The next step is to prepare a standardized amount of the product in question. Apply a fixed measured amount of residue on the coupon. Let it dry under specified conditions.

Step 3: Recover the Residue

Once the residue is dried, perform the recovery of residue using the specific clean validation method. Controlling the following parameters is crucial:

• Type of swab being used
• Swabbing pattern
• Volume of solvent used
• Pressure of sampling
• Number of strokes

Step 4: Analyze the Sample

The first step in sample analysis is to employ the validated analytical procedure on the recovered sample. The common analytical practices are:

• HPLC
• UV Spectrometry
• TOC Analysis
• GC
• ICP (where necessary)

It is important to ensure that the procedure is in place before carrying out the recovery test.

Step 5: Calculate the Recovery Factor

The recovery factor is obtained by the following calculation:
Recovery factor = (Amount recovered / Amount applied) x 100

Considering the following:
Amount applied = 100 mg
Amount recovered = 88 mg
The above calculation shows that the recovery factor in the above case is 88%.

How Recovery Factors are Applied

When we talk of the 8 µg residue detected during testing process, the recovery factor should be applied. The equation would now look like this:

Corrected residue = Actual residue/Recovery Factor
= 8/0.80
= 10 µg
Notice how the use of the recovery factor helps make an actual estimate of the surface contamination more real-life applicable.

Acceptance Criteria

The authorities do not say that there must be a single percentage although there are some guidelines. Most pharmaceutical companies would insist on their own expectations, such as:

• 70% recovery for the swabbing method
• the same recovery for each repeat
• standard deviation should be acceptable
• the variability should be scientifically justified

Thus, it is much more important for auditors to be aware of the consistency of the process.

Factors Affecting Recovery

Some factors affect the percentage recovery. Among them are:

• Surface texture
• Solubility of the material
• What the swab is made of
• What compound is used for sampling
• Duration of drying
• How the operator does their work
• Environmental conditions
• Sensitivity of the analysis

These factors are very important since they help to maintain uniformity in the sampling.

Documentation Requirements

It is imperative to record all recovery testing. Typical records should include:

• An approved protocol
• Coupon preparation records
• Records on the surface being tested
• Records on standard preparation
• Raw analytical information
• Calculations
• Statistical analyses
• Chromatograms (if there are any)
• Final report
• QA approval

The documentation should facilitate the reconstruction of the recovery testing process at the time of the inspection.

Things to Avoid When Conducting Recovery Factor Analysis

There have been a number of common issues associated with the recovery factor approach during GMP audits. Frequent errors are:

• Making use of non-representative surfaces in the equipment
• Use of the simple clean products in place of worst-case products
• Inconsistency in swab sample technique
• Inadequate sampling
• Poor statistic evaluation
• Not validating the analytical technique before use
• Using recovery factors without valid scientific reason
• Insufficient documentation

In my knowledge, the inconsistency of operator technique is among the seemingly insignificant sources of variation in recovery. At the same time the performance can be improved thanks to standardization training and qualification of employees.

Best Practices for Recovery Factor Studies

Organizations that have developed their cleaning validation practices implement the following rules:

• Conduct a careful selection of the most disadvantageous samples
• Include representative materials used in manufacturing
• Establish standard cleaning and testing procedures
• Train operators before performing cleaning validation
• Perform adequate replication of tests
• Apply validated analytical techniques in evaluations
• Carry out statistical evaluation
• Document each step of the validation process
• Report the recovery factor whenever products or equipment are replaced
• Incorporate the recovery studies within cleaning validation program

Recovery factor studies account for a crucial part of the cleaning validation process because they demonstrate how much residues can actually be retrieved from the surfaces to be studied. The absence of the adequate recovery factor would result in invalid cleaning validation document because the actual residue levels would be underestimated which would increase the possibility of cross-contamination and regulatory problems.

In my personal experience, properly planned recovery studies complain me about the cleaning validation process as a whole. First, it is important to get well chosen surfaces, take into account the hardest products for cleaning, organize representative sampling techniques and observe strict documentation.

Regulatory References

1. FDA Guide to Inspections of Validation of Cleaning Processes
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/validation-cleaning-processes-793
2. FDA Process Validation: General Principles and Practices
https://www.fda.gov/media/71021/download
3. EU GMP Guidelines Volume 4, Annex 15: Qualification and Validation
https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en

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