The Basic Facts of Cleaning Validation

Robin Fredric, QA-Validation Department, Novopharm Ltd, Canada. Email: leoroby@yahoo.com

Cleaning validation is primarily applicable to the cleaning of process manufacturing equipment in the pharmaceutical industry. The focus of cleaning validation is those cleaned surfaces that, if inadequately cleaned, could potentially contaminate the product subsequently manufactured in that same equipment. This primarily covers product contact surfaces in the cleaned equipment. Cleaning validation is not performed only to satisfy regulatory authorities. The safety of patients is the primary objective, and product contamination presents serious liability issues for any pharmaceutical manufacturer or contract organization.

The history behind cleaning validation

The unhygienic conditions in Chicago’s meat- packing plants revealed in Upton Sinclair’s novel, “The Jungle”, allowed the government investigators and congress to enact the meat inspection law and the Pure Food and Drugs Act in 1906, the law forbade adulteration, misbranding adulteration, misbranding of foods, drinks, and drugs.
Thirty years later the drug tragedy “elixir of sulfanilamide” which killed over 100 people, greatly dramatized to broaden the existing legislation. On June, 25th 1938 Franklin D. Roosevelt signed the Federal Food, Drug, and Cosmetic Act, it required manufacturers to provide scientific proof of drug safety before it could be marketed.
All these events brought the current regulatory requirements for cleaning validation.

Cleaning:

Cleaning can be defined as removal of residues and contaminants. The residues and contaminants can be the product themselves manufactured in the equipment or residues originating from the cleaning procedure (detergents / sanitizers) or degradation products resulting from the cleaning process itself.

The basic mechanisms involved in removing the residues and contaminants from the equipment are mechanical action, dissolution, detergency and chemical reaction.

1.Mechanical action – It refers to the removal of residues and contaminants through physical actions such as brushing, scrubbing and using pressurized water.

2.Dissolution – It involves dissolving the residues with a suitable solvent. The most common and practical solvent is water being non-toxic, economical, environment friendly and does not leave any residues. Alkaline and acidic solvents are sometimes preferred as it enhances the dissolution of the material, which are difficult to remove.

3.Detergency-Detergent acts in four ways as wetting agent, solubilizer, emulsifier and dispersant in removing the residues and contaminants from the equipment

4.Chemical reaction- Oxidation and hydrolysis reaction chemically breaks the organic residues and contaminant to make them readily removable from the equipment

What is cleaning validation ?

It is documented evidence with a high degree of assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits.

Why cleaning validation ?

To verify the effectiveness of cleaning procedures and to ensure no risks are associated with cross contamination of active ingredients or detergent/sanitizer.

When cleaning validation ?

· Initial qualification of a process/equipment
· Critical change in a cleaning procedure
· Critical change in formulation
· Significant change in equipment
· Change in a cleaning process
· Change in a cleaning agent.

Why we do validation for 3 times ?

Once an FDA was asked why do we do it 3 times?
His answer was - Because if it comes out right once it is an accident, twice coincident, three times validation.

Regulatory requirements:

• FDA has required that the equipment to be cleaned prior to use (GMP regulation-Part 133.4) This is one of the basic GMP requirement and it is indicated in more than one section of 21CFR 211 (FDA, April 1998)
• Section 211.63 relates to the equipment design, size, location, and requires that equipment used in the manufacture, processing, packaging, holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.
• Section 211.65 states that a) the construction of equipment which contact the in-process materials, or drug products shall not be reactive, additive or absorptive so as to alter the safety, identity, strength, quality or purity of the drug product beyond official or other establishment requirements.
b) Any substances required for operation, such as lubricants or coolants, shall not come into contact with components, drug product containers, closures, in-process materials, or drug products so as to alter the safety, identity, strength, quality or purity of the drug product beyond official or other establishment requirements.
• Section 211.67 further requires that the equipment and the utensils shall be cleaned, maintained and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product in form of written procedure including all the parameters during cleaning.
• Section 211.180 and 211.182 relates to the record that should be kept for the maintenance, cleaning, sanitation and inspection of equipment.

The Common elements of Cleaning Validation

· Written cleaning procedures should be established. Attention should be addressed to dedicate certain equipment to specific products, such as fluid bed dryer bags and to residue originating from the cleaning detergent or solvent themselves.

· Procedure on how validation will be performed should be in place.

· Who is responsible for performing and approving the study.

· Acceptance criteria should be set.

· Procedure dealing with the subject of when revalidation study stating issues such as sampling procedure and analytical methods.

· Study should be conducted according to protocol.

· Approved report should state the validity of the cleaning process.

Cleaning procedure

The two common cleaning procedures are,

· Manual cleaning

· Automated cleaning procedures such as CIP (Cleaning In Place

Manual Cleaning Sequence	CIP Cleaning Sequence
Dismantle the parts of equipment to be cleaned	Pre-wash the parts in tap water
Pre-wash the parts with tap water	Wash the pre-washed parts with cleaning solution
Wash the pre-washed parts with cleaning solution	Blow out using compressed air
Rinse the parts in tap water	Rinse the parts with tap water
Rinse now with purified water	Final rinse using purified water
Dry the parts using hot air	Blow out using compressed air
Visual inspection is done to check whether the equipment is clean	Drying using hot and compressed air
Reassemble the parts finally

In all cases cleaning procedure must prove to be effective, consistent and reproducible.

FDA recommends (CIP) should be used to clean process equipment and storage vessels in order to reproduce exactly the same procedure each time (FDA, March 1998).

With manual procedure one must rely on the operator skills and thorough training of the operator is necessary to avoid variability in performance. However in some instances, it may be more practical to use only manual procedures.

Sampling methods for Cleaning Validation

There are three known sampling methods:

1.Swabbing (or direct surface sampling) method

2.Rinse sampling method

3.Placebo method.

Swabbing technique involves the use of a swabbing material, often saturated with solvent, to physically sample the surfaces.

Advantages:

· Dissolves and physically removes sample

· Adaptable to a wide variety of surfaces

· Economical and widely available

· May allow sampling of a defined area

· Applicable to active, microbial, and cleaning agent residues

Limitations:

·An invasive technique that may introduce fibres

·Results may be technique dependent

·Swab material and design may inhibit recovery and specificity of the method

·Evaluation of large, complex and hard to reach areas difficult (e.g., crevices, pipes, valves, large vessels)

·Subject to the vagaries of site selection

Rinse Sampling involves passing a known volume of solution over a large area and analyzing the recovery solution.

Advantages:

·Adaptable to on-line monitoring

· Easy to sample

· Non-intrusive

· Less technique dependent than swabs

· Applicable for actives, cleaning agents and excipients

· Allows sampling of a large surface area

· Allows sampling of unique (e.g., porus) surfaces

Limitations:

· Limited information about actual surface cleanliness in some cases

· May lower test sensitivity

· Residues may not be homogeneously distributed

· Inability to detect location of residues

· Rinse volume is critical to ensure accurate interpretation of results

· Sampling methodology must be defined since rinse sampling method and location can influence results

· May be difficult to accurately define and control the areas sampled, therefore usually used for rinsing an entire piece of equipment, such as a vessel

· Reduced physical sampling of the surface

Placebo sampling can be used to detect residues on equipment through the processing of a placebo batch subsequent to the cleaning process. It is appropriate for active residue, cleaning agent, particulates and microbial testing. Placebos are used primarily to demonstrate the lack of carryover to the next product. The placebo should mimic product attributes. The equipment characteristics also impact the choice of the placebo batch size.

Advantages:

· Placebo contacts the same surfaces as the product

· Applicable for hard-to-reach surfaces

· Requires no additional sampling steps

Limitations:

· Difficult to determine recovery (contaminants may not be evenly distributed in the placebo)

· Lowers analytical specificity and inhibits detectability

· Takes longer and adds expense since equipment must be cleaned after the placebo run

· Placebos must be appropriate for each potential product

· Residues may not be homogenously distributed

· No direct measurement of residues on product contact surfaces

The preferred sampling method and the one considered as the most acceptable be regulatory authorities is the swabbing method.

The Common analytical methods and their basic requirements

Specific and non-specific are the two analytical methods used widely to detect any compound. The choice of using a specific or non specific method can be difficult. If a drug active is highly toxic, a specific method is always recommended.

Chromatographic methods are preferred for cleaning validation studies because of their sensitivity, specificity, and ability to quantify.

Specific method:

It is a method that detects a unique compound in the presence of potential contaminants.

Some examples of specific methods are high performance liquid chromatography (HPLC), Ion chromatography, Atomic absorption, Capillary electrophoresis, and other chromatographic methods.

Non-specific method:

It detects any compound that produces a certain response.

Some examples of non specific methods are Total Organic Carbon (TOC), pH, Titration, and conductivity.

It is always wise to choose the simplest technique that can be used to reach the desired goal.

The basic requirement for the analytical method

The sensitivity of the method shall be appropriate to the calculated contamination limit.

The method shall be practical and rapid, and, as much as possible use instrumentation existing in the company.

The method shall be validated in accordance with ICH, USP, EP requirements.

The analytical development shall include a recovery study to challenge the sampling and testing methods.