Cleaning Validation

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What is a “Cleaning Validation”
Cleaning validation is an activity that is focussed on ensuring that process equipment, test equipment and facilities are suitable for use in manufacturing and can assure the safety and integrity of the output of a process.

Approach to cleaning validation.
Products, raw materials, ingredients (e.g. APIs), can be contaminated by other products or APIs, by cleaning agents, by micro-organisms or by other material (e.g. air-borne particles, dust, lubricants, raw materials, intermediates). In many cases, the same equipment may be used for processing different products. To avoid contamination of product, adequate cleaning procedures are essential. Cleaning procedures must strictly follow carefully established and validated methods of execution.

Normally only cleaning procedures for product contact surfaces of process equipment need to be validated. Consideration should be given to non-contact parts into which product may migrate. For example, seals, flanges, mixing shaft, fans of ovens, heating elements etc..

Cleaning procedures for product changeover in the case of marketed products should be fully validated. Cleaning procedures for products and processes which are very similar, do not need to be individually validated. Generally in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined.

It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation program which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria.

At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.

Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such differences should be considered when designing cleaning procedures as the materials may behave differently.

It is usually not considered acceptable to “test until clean”. This concept involves cleaning, sampling and testing, with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning process, this practice of “test until clean” should not be required. The practice of “test until clean” is not considered to replace the need to validate cleaning procedures.

Products which simulate the physicochemical properties of the substance to be removed may be used instead of the substances themselves, where such substances are either toxic or hazardous.

Cleaning Validation

Regulatory expectations related to cleaning validation:
European and Australian GMP’s (Good Manufacturing Practices).

“Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products”.

“Contamination of a starting material or of a product by another material or product must be avoided……. The significance of this risk varies with the type of contaminant and of product being contaminated. Amongst the most hazardous contaminants are highly sensitizing materials, biological preparations containing living organisms, certain hormones, cytotoxics, and other highly active materials”.

US FDA cGMP’s.

FDA 21 CFR 211.67 (a) “Equipment and 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 beyond the official or other established requirements”

WHO (World Health Organization), “It is of critical importance that particular attention is paid to the validation of analytical test methods, automated systems and cleaning procedures”.

The objective of a cleaning validation is to assure the quality, safety and integrity of product. This is achieved by minimizing the potential for contaminants entering a manufacturing process and minimizing the potential for product contamination.

What are the various cleaning mechanisms widely applied?

Physical removal

Solubility

Wetting

Emulsification

Dispersion

Oxidation

Hydrolysis

Antimicrobial action

Physical Removal.

Cleaning by some mechanical force. the objective is to physically displace any undesired residues. This normally relates to the use of water (possibly pressurized) plus scrubbing. In real life situation, more than one cleaning mechanisms is usually applied.

Solubility.

Solubility involves the dissolution of one chemical (the contaminant) in a liquid solvent. For example, salts may be soluble in water, and certain organic actives may be soluble in acetone or methanol. This is normally one of the primary cleaning mechanisms to be considered during a design phase.

Wetting.

Wetting involves the displacement of one fluid from a solid surface by another fluid. Wetting can be improved by the addition of surfactants. Wetting improves penetration of the cleaning solution into cracks and crevices, which are usually difficult-to clean locations.

Emulsification.

Breaking up an insoluble liquid residue into smaller droplets and then suspending those droplets throughout the water.

Emulsion = Mechanical energy + Surfactants / Polymers.

– Emulsions are thermodynamically unstable (say, 5 to 10 minutes).

– Redeposition of the cleaned residue back onto the equipment surfaces.

– Agitation should be continued till the time to discharge the cleaning solution to the drain.

Dispersion.

Dispersion is similar to emulsification, except that it involves the wetting and de-aggregation of solid particles and then the subsequent suspension of those particles in water. This approach tends to be more important in dry product manufacturing.

Oxidation.

This involves the cleavage of various organic bonds, such as carbon-carbon bonds, by the action of a strong oxidizing agent. Large non-polar molecule into a smaller more polar molecule.

Hydrolysis.

This involves the cleavage of certain bonds in an organic molecule. The resultant hydrolyzed residues must either be water soluble or solubilized at the pH of the cleaning solution.

Antimicrobial action.

Mechanisms that may kill organisms but leave behind nonviable microbial residues.

Questions to be asked when considering a Cleaning Validation.
Several general questions should be addressed when evaluating the cleaning process. For example:

a) At what point does a piece of equipment or system become clean?

b) What does visually clean mean?

c) Does the equipment need to be scrubbed by hand?

d) What is accomplished by hand scrubbing rather than just a solvent wash?

e) How variable are manual cleaning processes from batch to batch and product to product?

f) What is the most appropriate solvent or detergent?

g) Are different cleaning processes required for different products in contact with a piece of equipment?

h) How many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment?

Points to consider
Cleaning validations require approved standard documented operating procedures.

Approved documented protocols must be in place.

Validations will require justified acceptance limits.

Consideration needs to be given to the use of manual verses automatic cleaning procedures.

An ongoing program of monitoring effectiveness will be required.

Use of “worst case” product as a marker for easier other products. For example, smallest batch size, smallest number of maximum daily doses, hardest to clean. Grouping of products. For example grouping based on those products capable of causing the largest possible problems if contaminated, or if they contaminate other products.

Identification of items of equipment that contribute most to cross contamination of the next product.

Identification of “worst case” locations in equipment, for example 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.

Dedicated equipment should be used for products which are difficult to remove (e.g. tarry or gummy residues in the bulk manufacturing), for equipment which is difficult to clean (e.g. bags for fluid bed dryers), or for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit).

Residue detection
The simplest approach may be a visual check, normally suitable for dedicated equipment. Usually included in all protocols and routine monitoring

Chemical testing. Specific methods such as high performance liquid chromatography (HPLC), ion selective electrodes, flame photometry, derivative UV spectroscopy, enzymatic detection and titration

Chemical tests:

a) Non-specific methods that detect the presence of a blend of ingredients such as total organic carbon, pH, and conductivity.

b) Specific methods. The FDA prefers specific methods, but will accept non-specific methods with adequate rationales for their use.

c) Chemical limits can be expressed as a maximum concentration in the next product (ug/ml), amount per surface area (ug/cm2), amount in a swab sample (ug or ug/ml), maximum carryover in a train (mg or g), or concentration in rinse water (ug/ml). There can be a calculated safety based acceptance limit, a lower internal action level, and a lower process control level based on actual manufacturing and measuring experience.

 
Microbial considerations.
a) Endotoxins

b) TAMC – total aerobic microbial count

c) The existence of conditions favourable to reproduction of microorganisms (e.g. moisture, temperature, crevices and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive microbial contamination.

d) The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.

e) In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.

Detergent considerations.
The efficiency of cleaning procedures for the removal of detergent residues should be evaluated. Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected. The possibility of detergent breakdown should be considered when validating cleaning procedures.

The composition of detergents should be known.

If such information is not available, alternative detergents should be selected whose composition can be defined. As a guide, food regulations may be consulted. The manufacturer should ensure that they are notified by the detergent supplier of any critical changes in the formulation of the detergent.

Acceptance criteria
How clean is clean?

What are the bases of defining limits?

What are the impacts of after cleaned residue?

Question:

Does equipment need to be as clean as the best possible available method of residue detection or quantification? No, absolute cleanliness is neither valuable nor feasible. It should be as clean as can reasonably be achieved, to a residue limit that is safe and that causes no product quality concerns.

Criteria applicable to the determination of cleaning validation acceptance criteria. The acceptance criteria should be scientifically justifiable, need to be practically achievable and methodically verifiable.

Acceptance criteria may be based on visual limits, chemical limits, microbiological or endotoxin limits.

Visual clean criteria.
The GMPs require inspection for visual cleanness before manufacture.

Key items to consider for determining visual cleanliness are the angle of view, the distance from equipment surface, the lighting conditions, the viewer’s knowledge. When determining visual cleanliness, the surface must usually be dry.

The types of visual aids utilized in visual inspection will encompass appropriate lighting levels, the use of microscopes, mirrors, fiber-optic scope, UV light…etc..

Chemical residue limits (therapeutically or toxicologically safe criteria):
Therapeutic dose based criteria is most suitable to a drug product (finished product) manufacturing facility.

Toxicological criteria is most suitable for an active drug (API) manufacturing facility

Where cleaning agents are used (other than water), PPM criteria tend to be utilized.

Therapeutic dose based criteria:
Widely based on the assumption that 1/1000 part of therapeutic dose does not have any clinical impact on human (animal) body.

STEP 1:

Determination of MAC (Maximum Allowable Carryover) of Product A (Previous) to Product B (Next)

MAC = [(SRDD (A) × BS (B) × SF)] / LRDD (B)              (unit of mass)

Where,

SRDD = Smallest Recommended Daily Dose (Product A – ACTIVE CONTENT),

BS = batch size (Product B), SF = safety factor and LDD and

LRDD = Largest Recommended Daily Dose (Product B – DRUG PRODUCT)

STEP 2:

Determination of Surface contamination

L1 = MAC / SESA                  (mass / surface area)

Where,

SESA = Shared Equipment Surface Area (for both products)

STEP 3:

Determination of Sampled residue (for swab sample)

L2 = L1 × Swab Area (mass / swab)

SRDD value represents the ACTIVE drug content only. e.g. 5 mg or 10 mg, the dose strength.

LRDD value represents the mass or volume of entire dose. e.g. 250 mg or 20 mL (drug + excipients).

Note: Convert similar items into similar convenient units of measure.

Safety factors:

Approach                                Approach typically applicable to

0.1 to 0.01                               Topical products

0.01 to 0.001                           Oral products

0.001 to 0.0001                       Parenterals, ophthalmic products

0.0001 to 0.00001                   Research, investigational product

Toxicological criteria:
Based on the toxicological information available in Material Safety Data Sheets.

STEP 1:

Determination of NOEL (No Observed Effect Level)

NOEL = LD50 × Empirical factor (unit of mass/kg of body weight)

Where,

LD50 = lethal dose for 50% of animal population in study (mg/kg/day),

Empirical factor = derived from animal model developed by Layton, et.al : 0.001*

* Used by expert panel of WHO (10-3).

STEP 2:

Determination of ADI (Acceptable Daily Intake)

ADI = NOEL × AAW × SF (unit of mass)

Where,

AAW = average adult weight, widely taken as 70 kg,

SF = safety factor (0.01)

Consider average body weight of child where there is any paediatric dose available.

Use LD50 value of mice.

STEP 3:

Determination of MAC (Maximum Allowable Carryover)

MAC = (ADI × BS)  /  LRDD     (any next product)    (unit of mass)

Then use and to derive final swab residue limit.

Then use STEP 2 and STEP 3 previous, to derive final swab residue limit.

10 PPM criteria :
Based on the hypothesis that 10 parts of previous product is therapeutically ineffective if presents in million parts of next product.

STEP 1:

Determination of MAC (Maximum Allowable Carryover)

MAC = (10 × BS) / 1000000       (unit of mass)

Where,

BS = Batch size (smallest available batch size)

Then use STEP 2 and STEP 3 to derive final swab residue limit.

The most stringent acceptance criteria shall be chosen for a cleaning validation study, i.e. the worst case approach. In real life cases, therapeutic or 10 PPM criteria become final acceptance criterion for cleaning validation.

Microbiological criteria.
Microbiological criteria may be based on internal specifications or officially published specifications:

e.g. USP “Microbial Examination of non-sterile products:. Acceptance criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use” :

Administration route        Total aerobic count           Total combined yeasts/molds count
(cfu/g or cfu/mL)               (cfu/g or cfu/mL)
 
Non-aqueous oral                   …..  103                              ……….102
Aqueous oral                           …..  102                              ……….10

Most topicals                           …..  102                              ……….10

e.g. EU GMP, Annex, “Recommended limits for microbiological monitoring of clean areas during operation” :

Grade                                    Contact plates (diam. 55 mm), cfu/plate
A                                             < 1

B                                             5

C                                             25

D                                             50

i.e. recommended limit for microbial contamination in grade D area is : 50/{π × (5.5/2)2}= 2.10 cfu/cm2

Microbiological criteria from internal specifications:  
Will be defined in approved, documented Standard Operating Procedures and must be backed up by justifiable scientific rationale.

Continue at: http://www.presentationeze.com/presentations/product-and-process-validation/product-and-process-validation-full-details/cleaning-validation/

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