BASICS OF CLEANING VALIDATION

Basics of cleaning validation

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 ?

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

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LIST OF PHARACEUTICAL - INSTRUMENTS AND THEIR USES

*List of PHARACEUTICAL -Instrument and Their Use*

  *Absorptiometer*-instrument for measuring solubility of gases in liquids

 *Actinometer*-instrument for measuring incident radiation

 *Aerometer* -instrument for measuring weight or density of gas

 *Florentine Receiver* -Used to separate liquids based on density

 *Sorptometer* -Used to measure total surface area

 *Quantasorb* -Surface area

 *Areometer* -instrument used for measuring specific gravity

 *Hg Pycnometer* -Granule Density

 *He Pycnometer* -True Density

 *Hygrometer* -Moisture content

 *Cytometer* -instrument for counting cells

 *Hygrometer* -instrument for measuring air moisture

 *Leptometer* -instrument for measuring oil viscosity

 *Nephelometer* -instrument for measuring cloudiness

 *Planimeter* -instrument for measuring area

 *Platometer* -instrument for measuring area; planimeter

 *Psychrometer* -Humidity measurement

 *Pycnometer* -instrument for measuring specific gravity or density

 *Qualimeter* -apparatus for measuring penetrating power of X-ray beams

 *Stereometer* -instrument for measuring specific gravity

 *Tensiometer* -instrument for measuring tension

 *Zymometer* -instrument for measuring fermentation

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TEMPERATURE AND HUMIDITY MAPPING IN STORAGE AREA

Temperature and Humidity Validation/Mapping in Storage Area

Learn about the temperature mapping including the location and number of sensors to be placed in the area.

Temperature and humidity are important factors in the stability of the pharmaceutical ingredients. Temperature sensitive materials can degrade at higher temperature therefore it important to validate the storage area for temperature.

In pharmaceuticals refrigerators, incubators, stability chambers, controlled sample rooms and raw material storage areas are need to be validated. These areas are monitored for 24 hours for three consecutive days.

Limits of the temperature and humidity depend upon the material to be stored in the area. These should be defined according to the recommendation of the manufacturer. We can tighten the limits but it should be justified when we use the wider limits.

Measurement of temperature and humidity should be accurate. Error in temperature and humidity should not be more than ±0.2°C and ±3% respectively. Thermocouples or data logger can be used for the monitoring of the area. If any software is used for the collection of data then it must be validated and comply 21 CFR Part 11 guidelines.

Number of sensors used in temperature and humidity mapping is a confusing topic of the pharmaceutical professionals because most of the regulatory guidelines do not say about the number of sensors to be used in mapping. According to USP a suitable number of thermometers of other temperature recording instruments should be used for temperature mapping.

Related: Principle of Hygrometer and Its Use in Pharmaceuticals

But International Society for Pharmaceutical Engineering (ISPE) says to use 9 sensors for the area less than 2 m3 in volume. These sensors should be placed in all corners and one in the center. If volume of area is between 2 m3 to 20 m3, 15 sensors should be used for mapping. Placement of 9 sensors should be done as 9 sensor configuration and addition sensors should be place at the center of the floor, ceiling and four walls. If area is larger than 20 m3, additional sensors should be used by understanding the criticality of the area. Some distance should be maintained between wall and the sensors. All sensors must be calibrated before starting the mapping and should be traceable to NIST.

Mapping should be done twice in year in coldest and hottest days of the year. Hotspot should find after the mapping and routine temperature mapping should be done at this point.

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QUALIFICATION / VALIDATION

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PHARMA PRODUCT LIFE CYCLE (20 Years)

What is AHU (Air Handling unit)?

What is AHU (Air Handling unit)?

An air handler, or air handling unit (often abbreviated to AHU), is a device used to condition and circulate air as part of a heating, ventilating, and air-conditioning (HVAC) system. An air handler is usually a large metal box containing a blower, heating or cooling elements, filter racks or chambers, sound attenuators, and dampers. Air handlers usually connect to a ductwork ventilation system that distributes the conditioned air through the building and returns it to the AHU. Sometimes AHUs discharge (supply) and admit (return) air directly to and from the space served without ductwork.

Small air handlers, for local use, are called terminal units, and may only include an air filter, coil, and blower; these simple terminal units are called blower coils or fan coil units. A larger air handler that conditions 100% outside air, and no recirculated air, is known as a makeup air unit (MAU). An air handler designed for outdoor use, typically on roofs, is known as a packaged unit (PU) or rooftop unit (RTU).

The design, installation, commissioning and qualification of clean rooms heating, ventilation and air conditioning (HVAC) systems is often one of the largest considerations in the design of a new pharmaceutical or biotechnology manufacturing facility. With high running costs (energy associated with the movement, cooling and heating of air) and the potential to impact upon safety and product quality, getting them right
is important for business, safety and good manufacturing practice (GMP) criticality.

The design of the HVAC system will be based upon the clean room suite that it serves, and will be affected by factors such as the number of rooms served, the layout of the rooms, the equipment within the rooms and, most critically from a qualification perspective, the environmental conditions that the rooms must achieve.

The air handling unit helps maintain each room's clean environment by providing an appropriate volume of clean air to each room at the correct temperature and humidity.

The air is filtered by pleated paper filters called high efficiency particulate air (HEPA) filters which, depending upon the classification of the rooms, are located either within the air handling unit or where the air enters each room. Cooling and heating coils are also located within the air handling unit, increasing or decreasing the air temperature to ensure that the room temperatures remain within specification.

Reliable operation of the air handling unit within established limits is critical, not only to prevent product quality from
being compromised by poor air conditioning, but also for the following reasons:

- to prevent cross contamination of products to maintain operator safety,
- where the HVAC is being used for this purpose to maintain product safety,
- where the HVAC is being used for this purpose.

Defining the Requirements

The cost of change during a project, based on the stage of the project.

Whereas other services and utilities can be (relatively) easily moved within a building's framework once the building work has been completed, the HVAC is much more integral with the building's fabric, making retrospective modifications much more time consuming and expensive. Getting the specification and design right first time is very important.

What are the problems?

If the design phase is completed without considering the compliance aspects of the clean rooms, then there is a high likelihood of incurring significant time delays and costs during the validation period, as a result of having to make mechanical changes to the installation or revisiting some of
the commissioning work.

Some typical examples of areas where problems can occur as a result of not designing for compliance are highlighted below, together with suggested actions to try to avoid these problems from occurring.

Operating tolerances. Design, commissioning and validation criteria must be determined for GMP-critical parameters such as air change rates, room differential pressures, temperature and humidity. For example, different tolerances may need to be applied at commissioning and validation to ensure that the facility will operate reliably within the validation acceptance criteria limits.

Air filtration. The level of air filtration will vary depending upon the classification of the clean rooms being served. For example, an ISO Class 5 room (Class 100) will require terminal HEPA filters, whereas an ISO Class 8 environment (Class 100000) may be achieved by using a high-grade (non-HEPA) filter within the air handling unit. To avoid failures during validation integrity testing it is important for the validation and design teams to discuss the in situ test requirements, and to agree upon appropriate grades of air filtration.

What are the criteria for validation?

During AHU validation, following tests shall be carried out

Filter efficiency test,
Air velocity & number of air changes,
Air flow pattern (visualisation),
Differential pressure, temperature and RH,
Static condition area qualification,
Dynamic condition qualification,
Non-viable count,
Microbial monitoring,
Area recovery and power failure study.

Why re-validation need to be performed?

AHU system shall be revalidated periodically as mentioned in the regulatory standards. AHU shall be revalidated in following cases also.

When basic design of AHU is changed,
When clean room volume is changed,
When new equipment is installed,
When a construction is carried out, that calls for reconstruction of AHU system.

PRODUCT RECALL

There are three type and class of recalls 

Class I : defined as a situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences of death; 

Class II : defined as a situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote; 

class III : defined as a situation in which use of or exposure to a violative product is not likely to cause adverse health consequences. 

Communication:  Communication must effectively remove violative product by giving proper notice to recipients of such products. 

Recall effectiveness monitoring:  The FDA monitors recall effectiveness by follow-up inspection or audit checks or makes recommendations if it finds the recall is ineffective

Strategy:  Each recall is different and requires a different strategy to resolve the problem. 

Public Notification:  The firm has the responsibility to notify the public of the recall, and the FDA does so via the weekly  Enforcement Report. Once a recall has been placed in a weekly  Enforcement Report, the FDA decides when it will be removed.

Status Reports:  Recall Status Reports must be provided periodically to update the FDA on the progress of the recall. 

Termination:  Termination of a recall is determined by the FDARegulated product withdrawal:  Regulated product withdrawals result in complete removal of the product from the market and it will not be available in the future. J. 

Recall facts:  Recalls occur because products are adulterated or misbranded.  The problems with products can occur due to manufacturing/testing method deficiencies, contamination, inconsistent potency, labeling or packaging mix-ups, other product specification problems, dissolution, noncompliance with  National Institute on Drug  Abuse (NIDA) monographs, or bioequivalence/abbreviated new drug application (ANDA) discrepancies.

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